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Progressive disability in MS explained?
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Neurology
A less expensive, more convenient treatment option for MS?
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
From EAN 2021
Investigational drug reduces brain lesions in highly active MS
new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.
Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.
The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.
The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.
Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.
The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.
The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.
Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.
The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.
The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAN 2021
Some MS treatments may heighten COVID risk
, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.
Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.
The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.
The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.
The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.
Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.
The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.
The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.
To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).
Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).
Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.
, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.
Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.
The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.
The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.
The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.
Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.
The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.
The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.
To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).
Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).
Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.
, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.
Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.
The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.
The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.
The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.
Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.
The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.
The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.
To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).
Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).
Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.
FROM AAN 2021
Evobrutinib may lower nerve damage biomarker levels
(MS), based on how it’s been found to lower levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the American Academy of Neurology’s 2021 annual meeting.
Jens Kuhle, MD, of the department of biomedicine at University Hospital Basel, Switzerland, said the conclusion was based on reductions in blood levels of neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported for a BTK inhibitor investigated for MS,” Dr. Kuhle said. Evobrutinib targets beta cells and myeloid cells, including macrophages and microglia, to disrupt NfL production.
The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily, and 75 mg twice daily. The post hoc analysis included 166 patients across all arms, with 148 being evaluated at week 24.
Dr. Kuhle said the 75-mg twice-daily group exhibited significantly lower blood NfL levels as early as week 12 with lowered levels maintained to week 24, the last time point the study evaluated – specifically reductions of 18.9% (P = .01) and 16.8% (P = .040) compared with placebo, respectively.
However, the 75-mg once daily dose also showed meaningful reductions when compared with placebo: 15.4% (P = .043) and 14.1% (P = .10) at 12 and 24 weeks, respectively, Dr. Kuhle said. “There were no significant differences seen with the 25-mg once-daily group,” he said.
“These results are promising and indicate evobrutinib at an efficacious dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.
In an interview, Dr. Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive way will lead to more effective treatment of the individual MS patient,” he said.
The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate of permanent disability in MS and other neurodegenerative diseases,” Dr. Kuhle said. “It is anticipated that normalization of NfL to levels in same-age healthy controls should be the adequate treatment target for individual patients.”
NfL could be an “easily accessible and modifiable biomarker” for use in clinical trials of relapsing and progressive MS, he said. The researchers plan to use NfL measurements in the extension phase of the trial.
“An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do that.
The analysis adds to the growing body of evidence supporting the use of blood NfL levels to gauge the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS, said Fredrik Piehl, MD, PhD, a professor at Karolinska University Hospital in Stockholm.
“However,” he added, “this is a short-term phase 2 trial lacking an active comparator. Inhibitors of BTK have been suggested to have a dual action, acting both in the periphery on the adaptive immune response, but also ameliorating local brain tissue inflammation.”
Additional studies with longer duration, active comparators and advanced neuroimaging will be needed to validate the effect of BTKs on NfL levels in MS, Dr. Piehl said.
The study was sponsored by EMD Serono Research and Development Institute, a Merck affiliate. Dr. Kuhle has no relevant financial relationships to disclose. Dr. Piehl reported financial relationships with Biogen, Novartis, Sanofi, Merck, Actelion, Alexion, Argenx, Roche/Genentech, Genzyme, UCB and Parexel.
(MS), based on how it’s been found to lower levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the American Academy of Neurology’s 2021 annual meeting.
Jens Kuhle, MD, of the department of biomedicine at University Hospital Basel, Switzerland, said the conclusion was based on reductions in blood levels of neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported for a BTK inhibitor investigated for MS,” Dr. Kuhle said. Evobrutinib targets beta cells and myeloid cells, including macrophages and microglia, to disrupt NfL production.
The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily, and 75 mg twice daily. The post hoc analysis included 166 patients across all arms, with 148 being evaluated at week 24.
Dr. Kuhle said the 75-mg twice-daily group exhibited significantly lower blood NfL levels as early as week 12 with lowered levels maintained to week 24, the last time point the study evaluated – specifically reductions of 18.9% (P = .01) and 16.8% (P = .040) compared with placebo, respectively.
However, the 75-mg once daily dose also showed meaningful reductions when compared with placebo: 15.4% (P = .043) and 14.1% (P = .10) at 12 and 24 weeks, respectively, Dr. Kuhle said. “There were no significant differences seen with the 25-mg once-daily group,” he said.
“These results are promising and indicate evobrutinib at an efficacious dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.
In an interview, Dr. Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive way will lead to more effective treatment of the individual MS patient,” he said.
The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate of permanent disability in MS and other neurodegenerative diseases,” Dr. Kuhle said. “It is anticipated that normalization of NfL to levels in same-age healthy controls should be the adequate treatment target for individual patients.”
NfL could be an “easily accessible and modifiable biomarker” for use in clinical trials of relapsing and progressive MS, he said. The researchers plan to use NfL measurements in the extension phase of the trial.
“An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do that.
The analysis adds to the growing body of evidence supporting the use of blood NfL levels to gauge the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS, said Fredrik Piehl, MD, PhD, a professor at Karolinska University Hospital in Stockholm.
“However,” he added, “this is a short-term phase 2 trial lacking an active comparator. Inhibitors of BTK have been suggested to have a dual action, acting both in the periphery on the adaptive immune response, but also ameliorating local brain tissue inflammation.”
Additional studies with longer duration, active comparators and advanced neuroimaging will be needed to validate the effect of BTKs on NfL levels in MS, Dr. Piehl said.
The study was sponsored by EMD Serono Research and Development Institute, a Merck affiliate. Dr. Kuhle has no relevant financial relationships to disclose. Dr. Piehl reported financial relationships with Biogen, Novartis, Sanofi, Merck, Actelion, Alexion, Argenx, Roche/Genentech, Genzyme, UCB and Parexel.
(MS), based on how it’s been found to lower levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the American Academy of Neurology’s 2021 annual meeting.
Jens Kuhle, MD, of the department of biomedicine at University Hospital Basel, Switzerland, said the conclusion was based on reductions in blood levels of neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported for a BTK inhibitor investigated for MS,” Dr. Kuhle said. Evobrutinib targets beta cells and myeloid cells, including macrophages and microglia, to disrupt NfL production.
The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily, and 75 mg twice daily. The post hoc analysis included 166 patients across all arms, with 148 being evaluated at week 24.
Dr. Kuhle said the 75-mg twice-daily group exhibited significantly lower blood NfL levels as early as week 12 with lowered levels maintained to week 24, the last time point the study evaluated – specifically reductions of 18.9% (P = .01) and 16.8% (P = .040) compared with placebo, respectively.
However, the 75-mg once daily dose also showed meaningful reductions when compared with placebo: 15.4% (P = .043) and 14.1% (P = .10) at 12 and 24 weeks, respectively, Dr. Kuhle said. “There were no significant differences seen with the 25-mg once-daily group,” he said.
“These results are promising and indicate evobrutinib at an efficacious dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.
In an interview, Dr. Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive way will lead to more effective treatment of the individual MS patient,” he said.
The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate of permanent disability in MS and other neurodegenerative diseases,” Dr. Kuhle said. “It is anticipated that normalization of NfL to levels in same-age healthy controls should be the adequate treatment target for individual patients.”
NfL could be an “easily accessible and modifiable biomarker” for use in clinical trials of relapsing and progressive MS, he said. The researchers plan to use NfL measurements in the extension phase of the trial.
“An important next step is the development of reliable and age-adjusted reference values for NfL measurements in blood to move this biomarker further toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do that.
The analysis adds to the growing body of evidence supporting the use of blood NfL levels to gauge the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS, said Fredrik Piehl, MD, PhD, a professor at Karolinska University Hospital in Stockholm.
“However,” he added, “this is a short-term phase 2 trial lacking an active comparator. Inhibitors of BTK have been suggested to have a dual action, acting both in the periphery on the adaptive immune response, but also ameliorating local brain tissue inflammation.”
Additional studies with longer duration, active comparators and advanced neuroimaging will be needed to validate the effect of BTKs on NfL levels in MS, Dr. Piehl said.
The study was sponsored by EMD Serono Research and Development Institute, a Merck affiliate. Dr. Kuhle has no relevant financial relationships to disclose. Dr. Piehl reported financial relationships with Biogen, Novartis, Sanofi, Merck, Actelion, Alexion, Argenx, Roche/Genentech, Genzyme, UCB and Parexel.
FROM AAN 2021
Common MS treatment wears off more quickly in Black patients
new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.
“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.
He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”
Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.
Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
More severe disease in Black patients
Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.
“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.
Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”
The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.
Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
Clinical implications?
Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.
Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).
However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).
Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.
“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”
Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”
He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”
Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”
“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
Real-world data
Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.
“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”
If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”
Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.
“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.
Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.
He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.
“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.
Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.
A version of this article first appeared on Medscape.com.
new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.
“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.
He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”
Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.
Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
More severe disease in Black patients
Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.
“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.
Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”
The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.
Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
Clinical implications?
Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.
Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).
However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).
Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.
“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”
Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”
He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”
Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”
“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
Real-world data
Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.
“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”
If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”
Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.
“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.
Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.
He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.
“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.
Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.
A version of this article first appeared on Medscape.com.
new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.
“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.
He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”
Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.
Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
More severe disease in Black patients
Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.
“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.
Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”
The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.
Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
Clinical implications?
Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.
Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).
However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).
Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.
“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”
Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”
He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”
Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”
“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
Real-world data
Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.
“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”
If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”
Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.
“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.
Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.
He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.
“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.
Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.
A version of this article first appeared on Medscape.com.
FROM AAN 2021
Can supplementary estrogen relieve MS symptoms in menopausal women?
, a neurologist told colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
This kind of research should explore the effects of aging, including in the brain, and “focus on what is preventable – this dramatic and abrupt loss of estrogen in women with MS,” said Rhonda Voskuhl, MD, of the Brain Research Institute at the University of California, Los Angeles.
“This is a call to action. There’s a huge gap that needs to be filled,” she added in an interview. “Not enough attention has been paid to menopause and cognitive issues in MS and even in healthy women.”
Research has found that many women with MS experience a decline in function during menopause, she said. “They’re having a worsening of their preexisting disabilities,” she noted, due to neurodegeneration.
Dr. Voskuhl highlighted a 2016 study, for instance, that found postmenopausal women with MS on hormone replacement therapy reported better physical function and quality of life than did their counterparts after adjustment for covariates. She also pointed to a 2019 study that concluded that “natural menopause seems to be a turning point to a more progressive phase of MS.”
Estrogen appears to play a significant role. “It’s involved in synaptic plasticity,” she said. “That’s why the disabilities are worsening.”
Dr. Voskuhl supports a year-long, randomized and controlled study of estrogen supplementation in 150-200 participants. The goal, she said, is “not just to prevent loss and bad things from happening but also make improvements.”
In healthy patients, she said, outcomes should include cognitive decline in menopause, cognitive domain outcomes, and region-specific biomarkers in the frontal cortex and hippocampus instead of global cognition and global brain volume. In patients with MS, she said, the focus should be on worsening of disability with emphasis on specific disabilities such as walking and region-specific biomarkers for the motor cortex and spinal cord.
“We need to be looking at cortical gray matter, which we know is responsive to estrogen,” Dr. Voskuhl said. She led a 2018 placebo-controlled study that found women with MS who took estrogen supplements appeared to experience localized sparing of progressive gray matter, which the researchers linked to improved results in cognitive testing. The findings, the study authors wrote, suggest “a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.”
What about men? Does hormone loss worsen their MS? Dr. Voskuhl said there seems to be a connection between lower levels of testosterone and more disability in men with MS. But their situation is different. Loss of testosterone in men is gradual and happens over decades instead of over the short period of menopause in women, she said.
Jennifer Graves, MD, a neurologist at the University of California, San Diego, agreed that it’s time for further research into estrogen supplementation in MS. As she noted, “we don’t know the exact biological mechanism that might link perimenopause with developing a more progressive type of MS.”
She added: “An overall decrease in estrogen may be at play but there are other biological changes around menopause. We must also take care in studies to try to separate out what might be due to ovarian aging versus other types of aging processes that might be happening at the same time.”
Dr. Voskuhl disclosed that she is an inventor on university patents for use of estriol and estrogen receptor–beta ligands as treatments. Dr. Graves reports no relevant disclosures.
, a neurologist told colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
This kind of research should explore the effects of aging, including in the brain, and “focus on what is preventable – this dramatic and abrupt loss of estrogen in women with MS,” said Rhonda Voskuhl, MD, of the Brain Research Institute at the University of California, Los Angeles.
“This is a call to action. There’s a huge gap that needs to be filled,” she added in an interview. “Not enough attention has been paid to menopause and cognitive issues in MS and even in healthy women.”
Research has found that many women with MS experience a decline in function during menopause, she said. “They’re having a worsening of their preexisting disabilities,” she noted, due to neurodegeneration.
Dr. Voskuhl highlighted a 2016 study, for instance, that found postmenopausal women with MS on hormone replacement therapy reported better physical function and quality of life than did their counterparts after adjustment for covariates. She also pointed to a 2019 study that concluded that “natural menopause seems to be a turning point to a more progressive phase of MS.”
Estrogen appears to play a significant role. “It’s involved in synaptic plasticity,” she said. “That’s why the disabilities are worsening.”
Dr. Voskuhl supports a year-long, randomized and controlled study of estrogen supplementation in 150-200 participants. The goal, she said, is “not just to prevent loss and bad things from happening but also make improvements.”
In healthy patients, she said, outcomes should include cognitive decline in menopause, cognitive domain outcomes, and region-specific biomarkers in the frontal cortex and hippocampus instead of global cognition and global brain volume. In patients with MS, she said, the focus should be on worsening of disability with emphasis on specific disabilities such as walking and region-specific biomarkers for the motor cortex and spinal cord.
“We need to be looking at cortical gray matter, which we know is responsive to estrogen,” Dr. Voskuhl said. She led a 2018 placebo-controlled study that found women with MS who took estrogen supplements appeared to experience localized sparing of progressive gray matter, which the researchers linked to improved results in cognitive testing. The findings, the study authors wrote, suggest “a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.”
What about men? Does hormone loss worsen their MS? Dr. Voskuhl said there seems to be a connection between lower levels of testosterone and more disability in men with MS. But their situation is different. Loss of testosterone in men is gradual and happens over decades instead of over the short period of menopause in women, she said.
Jennifer Graves, MD, a neurologist at the University of California, San Diego, agreed that it’s time for further research into estrogen supplementation in MS. As she noted, “we don’t know the exact biological mechanism that might link perimenopause with developing a more progressive type of MS.”
She added: “An overall decrease in estrogen may be at play but there are other biological changes around menopause. We must also take care in studies to try to separate out what might be due to ovarian aging versus other types of aging processes that might be happening at the same time.”
Dr. Voskuhl disclosed that she is an inventor on university patents for use of estriol and estrogen receptor–beta ligands as treatments. Dr. Graves reports no relevant disclosures.
, a neurologist told colleagues at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
This kind of research should explore the effects of aging, including in the brain, and “focus on what is preventable – this dramatic and abrupt loss of estrogen in women with MS,” said Rhonda Voskuhl, MD, of the Brain Research Institute at the University of California, Los Angeles.
“This is a call to action. There’s a huge gap that needs to be filled,” she added in an interview. “Not enough attention has been paid to menopause and cognitive issues in MS and even in healthy women.”
Research has found that many women with MS experience a decline in function during menopause, she said. “They’re having a worsening of their preexisting disabilities,” she noted, due to neurodegeneration.
Dr. Voskuhl highlighted a 2016 study, for instance, that found postmenopausal women with MS on hormone replacement therapy reported better physical function and quality of life than did their counterparts after adjustment for covariates. She also pointed to a 2019 study that concluded that “natural menopause seems to be a turning point to a more progressive phase of MS.”
Estrogen appears to play a significant role. “It’s involved in synaptic plasticity,” she said. “That’s why the disabilities are worsening.”
Dr. Voskuhl supports a year-long, randomized and controlled study of estrogen supplementation in 150-200 participants. The goal, she said, is “not just to prevent loss and bad things from happening but also make improvements.”
In healthy patients, she said, outcomes should include cognitive decline in menopause, cognitive domain outcomes, and region-specific biomarkers in the frontal cortex and hippocampus instead of global cognition and global brain volume. In patients with MS, she said, the focus should be on worsening of disability with emphasis on specific disabilities such as walking and region-specific biomarkers for the motor cortex and spinal cord.
“We need to be looking at cortical gray matter, which we know is responsive to estrogen,” Dr. Voskuhl said. She led a 2018 placebo-controlled study that found women with MS who took estrogen supplements appeared to experience localized sparing of progressive gray matter, which the researchers linked to improved results in cognitive testing. The findings, the study authors wrote, suggest “a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.”
What about men? Does hormone loss worsen their MS? Dr. Voskuhl said there seems to be a connection between lower levels of testosterone and more disability in men with MS. But their situation is different. Loss of testosterone in men is gradual and happens over decades instead of over the short period of menopause in women, she said.
Jennifer Graves, MD, a neurologist at the University of California, San Diego, agreed that it’s time for further research into estrogen supplementation in MS. As she noted, “we don’t know the exact biological mechanism that might link perimenopause with developing a more progressive type of MS.”
She added: “An overall decrease in estrogen may be at play but there are other biological changes around menopause. We must also take care in studies to try to separate out what might be due to ovarian aging versus other types of aging processes that might be happening at the same time.”
Dr. Voskuhl disclosed that she is an inventor on university patents for use of estriol and estrogen receptor–beta ligands as treatments. Dr. Graves reports no relevant disclosures.
FROM ACTRIMS FORUM 2021
Neurologic drug prices jump 50% in five years
, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).
“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.
“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.
The study findings were published online March 10 in the journal Neurology.
$26 billion in payments
Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.
To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.
In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.
To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.
The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.
Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.
From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.
However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
Treatment barrier
Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.
When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).
Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”
Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.
“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
‘Unfettered’ price-setting
Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.
Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.
Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.
He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.
Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.
The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.
A version of this article first appeared on Medscape.com.
, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).
“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.
“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.
The study findings were published online March 10 in the journal Neurology.
$26 billion in payments
Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.
To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.
In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.
To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.
The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.
Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.
From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.
However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
Treatment barrier
Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.
When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).
Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”
Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.
“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
‘Unfettered’ price-setting
Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.
Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.
Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.
He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.
Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.
The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.
A version of this article first appeared on Medscape.com.
, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).
“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.
“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.
The study findings were published online March 10 in the journal Neurology.
$26 billion in payments
Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.
To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.
In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.
To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.
The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.
Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.
From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.
However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
Treatment barrier
Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.
When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).
Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”
Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.
“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
‘Unfettered’ price-setting
Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.
Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.
Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.
He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.
Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.
The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Sun exposure linked to reduced pediatric MS risk
, research shows. The use of sunscreen does not appear to affect the risk.
“This is the first study, as far as we are aware, to investigate the effect of sun exposure in pediatric MS,” first author Prince Sebastian, of the ANU Medical School, Australian National University, Canberra, said during a presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“In order to reduce the incidence of MS, parents should be encouraged to allow their children to spend at least 30 minutes outdoors in the sun every day, while using adequate sun protection,” Mr. Sebastian said.
“This is especially important for children with a family history of MS,” he said. As the findings show, “you can use adequate sun protection and still get the benefit of sun exposure in terms of MS risk reduction.”
Low sun exposure, exposure to ultraviolet light, and vitamin D have been well established as modifiable risk factors for MS in adults. However, research is lacking on the effect of these factors upon patients younger than 18 years who have pediatric MS, a less common form of the disease. Pediatric MS constitutes about 5% of all MS cases.
To investigate the issue, Mr. Sebastian and colleagues evaluated data on 332 patients with pediatric MS who were between the ages of 4 and 22 years. The patients were enrolled at 16 MS centers around the United States. They were compared by sex and age with 534 control persons aged 3-22 years who did not have MS.
For the patients with MS, the median disease duration was 7.3 months, and 63% were female. The median age of the patients was 15.9 years.
Compared with those who did not have MS, patients with MS were significantly less likely to have been exposed to cigarette smoke (17.8% vs. 14.2%). They were significantly more likely to be overweight (23.8% vs. 14.2%), and the median anti-VCA level was higher (3.7 vs. 2.2).
Those who were exposed to the sun during the most recent summer for a duration of 30 minutes to 1 hour daily, as determined on the basis of self-report or parent report, had a 2.6-fold reduced risk of having MS, compared with those who spent less than 30 minutes outdoors daily (odds ratio, 0.39; P < .05), after adjusting for age, sex, birth season, the child’s skin color, the mother’s education, smoke exposure, being overweight, and Epstein-Barr virus infection.
Sun exposure for 1-2 hours daily was associated with a 7.4-fold reduced risk for MS, compared with exposure of 30 minutes or less (OR, 0.13; P < .001).
The odds were similar for those with 2-3 hours of sun exposure (OR, 0.21; P < .001) and for those with more than 3 hours of daily exposure (OR, 0.14; P < .001), versus less than 30 minutes.
Mr. Sebastian and his team also assessed the role of summer ambient levels of UV light and whether such exposure conferred a similar degree of protection. The risk for MS was lower among those who were exposed to higher summer ambient UV levels than among those exposed to lower levels (OR, 0.80; P = .046).
He noted, “Based on the results, individuals residing in Florida (28° N) would have 20% lower odds of MS, compared with an individual residing in New York (40° N).”
Interestingly, median rates of the use of sun protection were similar for the participants with MS and those without MS (OR, 0.95), suggesting that the use of sunscreen did not reduce the protective effect of sun exposure.
“We predicted that greater use of protection would limit effective sun exposure and would therefore increase MS risk,” Mr. Sebastian said, “but we don’t see that, and it’s probably because someone who uses sun protection likely gets more sun exposure anyway.”
“Our results suggest that you can use adequate sun protection and still get most of the benefit in terms of MS prevention, which is quite encouraging,” he added.
For those with MS, median serum 25(OH)D levels were higher (27.7 ng/mL vs. 23.7 ng/mL; P < .001), but Mr. Sebastian noted that this difference was likely attributable to the use of vitamin D supplementation after an MS diagnosis. An important limitation of the study was a lack of data on supplementation.
Stronger effect of frequent sun protection
Previous studies have shown a link between sun exposure and MS. A study published in 2018 compared 2,251 patients with MS with 4,028 control persons who did not have MS. The participants were in Canada, Italy, and Norway.
In that study, for most of the patients with MS, the age of onset was older than 18 years. In that study, there was a nearly 50% increased risk among those with the lowest degree of summer sun exposure in comparison with those who had the highest level of exposure (risk ratio, 1.47).
Contrary to the current study, that study did show an effect of the use of sun protection – those with the lowest degree of sun exposure during summer and winter and the highest use of sun protection had the highest risk for MS. They had a 76% increased risk, compared with those who had the highest degree of sun exposure and the least use of sun protection (RR, 1.76).
Sandra Magalhaes, PhD, of the University of New Brunswick, Fredericton, Canada, who was first author on that study, noted that the new study of pediatric MS adds valuable evidence on the issue.
“This study is important, as it adds to the etiological literature on MS implicating relevance of sun exposure,” Dr. Magalhaes said.
“We have a number of studies that have demonstrated an important effect of reduced levels of sun exposure and increased risk of MS. However, these studies focus on adult-onset MS populations; rather, the new study adds to the existing literature, as it also implicates sun exposure in etiology of pediatric-onset MS,” she said.
Notably, their previous work, unlike the current study, showed that, among those who experienced low levels of sun exposure, the risk for MS was higher for those who used sunscreen frequently.
“Overall, in their limited time outdoors, use of sunscreen may further increase risk of MS, which makes sense, since limited time outdoors in less sun, adding sun protection means [exposure to] even less sun.”
The findings of both studies support the bulk of research indicating that sun exposure is beneficial with regard to MS.
“There is a need for promoting balanced safe sun practices to reduce disease burden, especially in countries and cultures where children spend a lot of time indoors,” Dr. Magalhaes said. “Sun exposure has a number of important physiological roles, including vitamin D synthesis but also immune system functioning.”
Mr. Sebastian and Dr. Magalhaes have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, research shows. The use of sunscreen does not appear to affect the risk.
“This is the first study, as far as we are aware, to investigate the effect of sun exposure in pediatric MS,” first author Prince Sebastian, of the ANU Medical School, Australian National University, Canberra, said during a presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“In order to reduce the incidence of MS, parents should be encouraged to allow their children to spend at least 30 minutes outdoors in the sun every day, while using adequate sun protection,” Mr. Sebastian said.
“This is especially important for children with a family history of MS,” he said. As the findings show, “you can use adequate sun protection and still get the benefit of sun exposure in terms of MS risk reduction.”
Low sun exposure, exposure to ultraviolet light, and vitamin D have been well established as modifiable risk factors for MS in adults. However, research is lacking on the effect of these factors upon patients younger than 18 years who have pediatric MS, a less common form of the disease. Pediatric MS constitutes about 5% of all MS cases.
To investigate the issue, Mr. Sebastian and colleagues evaluated data on 332 patients with pediatric MS who were between the ages of 4 and 22 years. The patients were enrolled at 16 MS centers around the United States. They were compared by sex and age with 534 control persons aged 3-22 years who did not have MS.
For the patients with MS, the median disease duration was 7.3 months, and 63% were female. The median age of the patients was 15.9 years.
Compared with those who did not have MS, patients with MS were significantly less likely to have been exposed to cigarette smoke (17.8% vs. 14.2%). They were significantly more likely to be overweight (23.8% vs. 14.2%), and the median anti-VCA level was higher (3.7 vs. 2.2).
Those who were exposed to the sun during the most recent summer for a duration of 30 minutes to 1 hour daily, as determined on the basis of self-report or parent report, had a 2.6-fold reduced risk of having MS, compared with those who spent less than 30 minutes outdoors daily (odds ratio, 0.39; P < .05), after adjusting for age, sex, birth season, the child’s skin color, the mother’s education, smoke exposure, being overweight, and Epstein-Barr virus infection.
Sun exposure for 1-2 hours daily was associated with a 7.4-fold reduced risk for MS, compared with exposure of 30 minutes or less (OR, 0.13; P < .001).
The odds were similar for those with 2-3 hours of sun exposure (OR, 0.21; P < .001) and for those with more than 3 hours of daily exposure (OR, 0.14; P < .001), versus less than 30 minutes.
Mr. Sebastian and his team also assessed the role of summer ambient levels of UV light and whether such exposure conferred a similar degree of protection. The risk for MS was lower among those who were exposed to higher summer ambient UV levels than among those exposed to lower levels (OR, 0.80; P = .046).
He noted, “Based on the results, individuals residing in Florida (28° N) would have 20% lower odds of MS, compared with an individual residing in New York (40° N).”
Interestingly, median rates of the use of sun protection were similar for the participants with MS and those without MS (OR, 0.95), suggesting that the use of sunscreen did not reduce the protective effect of sun exposure.
“We predicted that greater use of protection would limit effective sun exposure and would therefore increase MS risk,” Mr. Sebastian said, “but we don’t see that, and it’s probably because someone who uses sun protection likely gets more sun exposure anyway.”
“Our results suggest that you can use adequate sun protection and still get most of the benefit in terms of MS prevention, which is quite encouraging,” he added.
For those with MS, median serum 25(OH)D levels were higher (27.7 ng/mL vs. 23.7 ng/mL; P < .001), but Mr. Sebastian noted that this difference was likely attributable to the use of vitamin D supplementation after an MS diagnosis. An important limitation of the study was a lack of data on supplementation.
Stronger effect of frequent sun protection
Previous studies have shown a link between sun exposure and MS. A study published in 2018 compared 2,251 patients with MS with 4,028 control persons who did not have MS. The participants were in Canada, Italy, and Norway.
In that study, for most of the patients with MS, the age of onset was older than 18 years. In that study, there was a nearly 50% increased risk among those with the lowest degree of summer sun exposure in comparison with those who had the highest level of exposure (risk ratio, 1.47).
Contrary to the current study, that study did show an effect of the use of sun protection – those with the lowest degree of sun exposure during summer and winter and the highest use of sun protection had the highest risk for MS. They had a 76% increased risk, compared with those who had the highest degree of sun exposure and the least use of sun protection (RR, 1.76).
Sandra Magalhaes, PhD, of the University of New Brunswick, Fredericton, Canada, who was first author on that study, noted that the new study of pediatric MS adds valuable evidence on the issue.
“This study is important, as it adds to the etiological literature on MS implicating relevance of sun exposure,” Dr. Magalhaes said.
“We have a number of studies that have demonstrated an important effect of reduced levels of sun exposure and increased risk of MS. However, these studies focus on adult-onset MS populations; rather, the new study adds to the existing literature, as it also implicates sun exposure in etiology of pediatric-onset MS,” she said.
Notably, their previous work, unlike the current study, showed that, among those who experienced low levels of sun exposure, the risk for MS was higher for those who used sunscreen frequently.
“Overall, in their limited time outdoors, use of sunscreen may further increase risk of MS, which makes sense, since limited time outdoors in less sun, adding sun protection means [exposure to] even less sun.”
The findings of both studies support the bulk of research indicating that sun exposure is beneficial with regard to MS.
“There is a need for promoting balanced safe sun practices to reduce disease burden, especially in countries and cultures where children spend a lot of time indoors,” Dr. Magalhaes said. “Sun exposure has a number of important physiological roles, including vitamin D synthesis but also immune system functioning.”
Mr. Sebastian and Dr. Magalhaes have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, research shows. The use of sunscreen does not appear to affect the risk.
“This is the first study, as far as we are aware, to investigate the effect of sun exposure in pediatric MS,” first author Prince Sebastian, of the ANU Medical School, Australian National University, Canberra, said during a presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“In order to reduce the incidence of MS, parents should be encouraged to allow their children to spend at least 30 minutes outdoors in the sun every day, while using adequate sun protection,” Mr. Sebastian said.
“This is especially important for children with a family history of MS,” he said. As the findings show, “you can use adequate sun protection and still get the benefit of sun exposure in terms of MS risk reduction.”
Low sun exposure, exposure to ultraviolet light, and vitamin D have been well established as modifiable risk factors for MS in adults. However, research is lacking on the effect of these factors upon patients younger than 18 years who have pediatric MS, a less common form of the disease. Pediatric MS constitutes about 5% of all MS cases.
To investigate the issue, Mr. Sebastian and colleagues evaluated data on 332 patients with pediatric MS who were between the ages of 4 and 22 years. The patients were enrolled at 16 MS centers around the United States. They were compared by sex and age with 534 control persons aged 3-22 years who did not have MS.
For the patients with MS, the median disease duration was 7.3 months, and 63% were female. The median age of the patients was 15.9 years.
Compared with those who did not have MS, patients with MS were significantly less likely to have been exposed to cigarette smoke (17.8% vs. 14.2%). They were significantly more likely to be overweight (23.8% vs. 14.2%), and the median anti-VCA level was higher (3.7 vs. 2.2).
Those who were exposed to the sun during the most recent summer for a duration of 30 minutes to 1 hour daily, as determined on the basis of self-report or parent report, had a 2.6-fold reduced risk of having MS, compared with those who spent less than 30 minutes outdoors daily (odds ratio, 0.39; P < .05), after adjusting for age, sex, birth season, the child’s skin color, the mother’s education, smoke exposure, being overweight, and Epstein-Barr virus infection.
Sun exposure for 1-2 hours daily was associated with a 7.4-fold reduced risk for MS, compared with exposure of 30 minutes or less (OR, 0.13; P < .001).
The odds were similar for those with 2-3 hours of sun exposure (OR, 0.21; P < .001) and for those with more than 3 hours of daily exposure (OR, 0.14; P < .001), versus less than 30 minutes.
Mr. Sebastian and his team also assessed the role of summer ambient levels of UV light and whether such exposure conferred a similar degree of protection. The risk for MS was lower among those who were exposed to higher summer ambient UV levels than among those exposed to lower levels (OR, 0.80; P = .046).
He noted, “Based on the results, individuals residing in Florida (28° N) would have 20% lower odds of MS, compared with an individual residing in New York (40° N).”
Interestingly, median rates of the use of sun protection were similar for the participants with MS and those without MS (OR, 0.95), suggesting that the use of sunscreen did not reduce the protective effect of sun exposure.
“We predicted that greater use of protection would limit effective sun exposure and would therefore increase MS risk,” Mr. Sebastian said, “but we don’t see that, and it’s probably because someone who uses sun protection likely gets more sun exposure anyway.”
“Our results suggest that you can use adequate sun protection and still get most of the benefit in terms of MS prevention, which is quite encouraging,” he added.
For those with MS, median serum 25(OH)D levels were higher (27.7 ng/mL vs. 23.7 ng/mL; P < .001), but Mr. Sebastian noted that this difference was likely attributable to the use of vitamin D supplementation after an MS diagnosis. An important limitation of the study was a lack of data on supplementation.
Stronger effect of frequent sun protection
Previous studies have shown a link between sun exposure and MS. A study published in 2018 compared 2,251 patients with MS with 4,028 control persons who did not have MS. The participants were in Canada, Italy, and Norway.
In that study, for most of the patients with MS, the age of onset was older than 18 years. In that study, there was a nearly 50% increased risk among those with the lowest degree of summer sun exposure in comparison with those who had the highest level of exposure (risk ratio, 1.47).
Contrary to the current study, that study did show an effect of the use of sun protection – those with the lowest degree of sun exposure during summer and winter and the highest use of sun protection had the highest risk for MS. They had a 76% increased risk, compared with those who had the highest degree of sun exposure and the least use of sun protection (RR, 1.76).
Sandra Magalhaes, PhD, of the University of New Brunswick, Fredericton, Canada, who was first author on that study, noted that the new study of pediatric MS adds valuable evidence on the issue.
“This study is important, as it adds to the etiological literature on MS implicating relevance of sun exposure,” Dr. Magalhaes said.
“We have a number of studies that have demonstrated an important effect of reduced levels of sun exposure and increased risk of MS. However, these studies focus on adult-onset MS populations; rather, the new study adds to the existing literature, as it also implicates sun exposure in etiology of pediatric-onset MS,” she said.
Notably, their previous work, unlike the current study, showed that, among those who experienced low levels of sun exposure, the risk for MS was higher for those who used sunscreen frequently.
“Overall, in their limited time outdoors, use of sunscreen may further increase risk of MS, which makes sense, since limited time outdoors in less sun, adding sun protection means [exposure to] even less sun.”
The findings of both studies support the bulk of research indicating that sun exposure is beneficial with regard to MS.
“There is a need for promoting balanced safe sun practices to reduce disease burden, especially in countries and cultures where children spend a lot of time indoors,” Dr. Magalhaes said. “Sun exposure has a number of important physiological roles, including vitamin D synthesis but also immune system functioning.”
Mr. Sebastian and Dr. Magalhaes have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS FORUM 2021
Erythropoietin falls short of neuroprotection in optic neuritis
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg (Germany), in presenting the results at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
The TONE trial
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Dr. Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Dr. Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1,000 mg/day).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
Reduced conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the department of neurology at the University Hospital Dusseldorf (Germany), and a coauthor on the study, said.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Dr. Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Dr. Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days – that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial nevertheless important
Commenting on the study, E. Anne Yeh, MD, of the division of neurology at the Hospital for Sick Children, Toronto, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she said.
In addition, improved metrics for gauging outcomes are needed to better determine the true effects, she added.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind – negative or positive – are valuable in improving understanding, Dr. Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Dr. Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Dr. Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Dr. Lagreze, Dr. Albrecht, and Dr. Yeh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg (Germany), in presenting the results at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
The TONE trial
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Dr. Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Dr. Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1,000 mg/day).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
Reduced conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the department of neurology at the University Hospital Dusseldorf (Germany), and a coauthor on the study, said.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Dr. Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Dr. Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days – that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial nevertheless important
Commenting on the study, E. Anne Yeh, MD, of the division of neurology at the Hospital for Sick Children, Toronto, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she said.
In addition, improved metrics for gauging outcomes are needed to better determine the true effects, she added.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind – negative or positive – are valuable in improving understanding, Dr. Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Dr. Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Dr. Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Dr. Lagreze, Dr. Albrecht, and Dr. Yeh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis as a clinically isolated syndrome,” said first author Wolf A. Lagreze, MD, of the University of Freiburg (Germany), in presenting the results at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
There are currently no treatments that provide neuroprotection for patients with optic neuritis, which can result in the degeneration of retinal ganglion cells, the axons of which form the optic nerve.
Although methylprednisolone, the standard treatment, can be of benefit, it has no effect in preventing neurodegeneration or subsequent vision impairment.
Importantly, optic neuritis, which can be a first sign of multiple sclerosis (MS), is considered an ideal model for an acute inflammatory attack on the nervous system and resulting neurodegeneration. Therefore, any treatment that provides neuroprotection for patients with optic neuritis could have potentially exciting broader implications.
The TONE trial
Preclinical studies have shown that EPO provides a small, potential degree of neuroprotection. To further evaluate EPO in this setting, Dr. Lagreze and colleagues conducted the TONE trial (Treatment of Optic Neuritis With Erythropoietin) in Germany between 2014 and 2017, in which they enrolled 108 patients with optic neuritis.
Inclusion criteria were having only unilateral optic neuritis as a clinically isolated syndrome that presented within 10 days of the first symptoms and having moderate to severe loss of visual acuity.
Persons with known MS were excluded; however, patients who were diagnosed with MS at the beginning of the study during the workup evaluation were included. Hence, about 20% of patients did have newly diagnosed MS, Dr. Lagreze noted.
The participants were randomly assigned in double-blind 1:1 ratio to receive treatment with either 33,000 IU EPO or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1,000 mg/day).
The final analysis included 52 patients who received EPO and 51 patients who received placebo. There were no significant differences between the groups in the first primary outcome of retinal nerve fiber layer atrophy, assessed with optic coherence tomography at week 26 (P = .76).
Likewise, no significant difference between groups was observed in the second primary outcome of low-contrast visual acuity at week 26, assessed using the 2.5% Sloan chart score of the affected eye (P = .38).
In addition, there were no significant differences between the groups in the rates of optic neuritis relapse.
In terms of safety measures, one patient in the EPO group developed sinus venous thrombosis, which was treated with anticoagulants and resolved without complications.
Reduced conversion to MS?
Interestingly, after 6 months, significantly fewer patients in the EPO arm (36%) had converted from clinically isolated syndrome to MS, compared with 57% in the placebo arm (P = .032). The difference became apparent as early as week 4.
Although those findings suggest that EPO provided some neuroprotection, there are notable caveats, Philippe Albrecht, MD, of the department of neurology at the University Hospital Dusseldorf (Germany), and a coauthor on the study, said.
“The significant separation of EPO and placebo group regarding MS conversion was observed very early on in the course and did not change thereafter,” Dr. Albrecht noted.
“One would expect a true disease-modifying effect of EPO on MS conversion to take longer to develop, and this early separation may very well have been due to an imbalance in the treatment groups, [for example] regarding MRI imaging findings such as gadolinium enhancement at baseline,” he said.
Dr. Lagreze said that it was a surprise to see no benefit from the drug, and a closer look at certain subgroups may still be worthwhile. Factors that could have a bearing on results include a shorter time interval for inclusion, having no concomitant use of steroids, and longer duration of treatment with EPO.
“If I could do the study again, I would do the treatment for longer than 3 days – that was based on experiences in previous EPO trials,” he said. “I would also love to do the trial without the concomitant methylprednisolone, but that is not possible from an ethical point of view.”
Trial nevertheless important
Commenting on the study, E. Anne Yeh, MD, of the division of neurology at the Hospital for Sick Children, Toronto, agreed that a challenge in evaluating therapies for optic neuritis is the potential for confounding from existing therapies that patients need to take.
“This agent could not be evaluated alone for its protective effect in comparison to no treatment at all,” she said.
In addition, improved metrics for gauging outcomes are needed to better determine the true effects, she added.
“The development of newer vision-related outcome metrics is important for future studies, and many are hard at work on both structural and functional metrics that may help us to understand the benefits of any protective therapies in a more nuanced manner than we are currently able to,” she said.
However, results of any kind – negative or positive – are valuable in improving understanding, Dr. Yeh underscored.
“Negative results can be disappointing in any trial, especially one in which alternative therapeutic pathways are being sought,” Dr. Yeh said. “I want to emphasize, however, that the fact that we are even considering and completing trials in this area is important.”
Dr. Yeh noted that she is currently involved in a trial that is evaluating the diabetes drug metformin for its remyelinating potential. “We hope to have some pilot data on MS in a few years,” she said.
Dr. Lagreze, Dr. Albrecht, and Dr. Yeh have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACTRIMS FORUM 2021