Pharmacology

Myopia affects roughly one-third of the population worldwide - a figure that is projected to reach 50% by 2050. Low-dose atropine, which helps curb the condition, currently is available in the United States only through compounding pharmacies. The products contain preservatives – raising questions about potential toxicities to the eye – and may not be of pharmaceutical grade. In a new study published in JAMA Ophthalmology, a preservative-free eyedrop containing 0.01% atropine led to significant improvements in several markers of myopia in children who received the experimental therapy.

Methodology

• The CHAMP study was a double-masked, placebo-controlled, randomized, phase 3 trial conducted between Nov. 20, 2017, and Aug. 22, 2022, that involved children at 26 sites in North America and 5 centers in Europe.
• Children received either 0.01% or 0.02% atropine drops once per day.
• Patients were aged 3-16 years. They demonstrated a spherical equivalent refractive error (SER) of −0.50 diopter (D) to −6.00 D astigmatism no worse than −1.50 D.
• Of these patients, 573 were included in a safety analysis, and 489 were included in a modified intention-to-treat analysis.

Takeaways

• After 36 months, the 0.01% dose of atropine was associated with a significantly lower responder proportion (odds ratio, 4.54) and slower progression of SER and axial elongation.
• The effect of the 0.02% dose on responder proportion and SER progression was not statistically significant, but the treatment was associated with slower axial elongation.
• The researchers observed no serious ocular adverse events and few serious nonocular events, none of which was determined to be associated with the treatment.

In practice: According to the researchers, “from a risk/benefit perspective, the efficacy and safety observed suggests that low-dose atropine may provide a treatment option for children aged 3-17 years with myopia progression, which may lead to less frequent or delayed change in glasses, progression to less severe correction, and potentially reduce long-term sequelae, which could lead to vision loss later in life, such as myopic maculopathy.”

Study details: The CHAMP study was led by Karla Zadnik, OD, PhD, of Ohio State University, Columbus, and was funded by Vylulma.

Limitations: The researchers said the trial was potentially limited by the fact that patients switched from the study drug to confounding treatments. In addition, patients at the low and high age ranges were not well represented.

Disclosures: Dr. Zadnik received consultant fees from Vyluma during the study.

A version of this article first appeared on Medscape.com.

Myopia affects roughly one-third of the population worldwide - a figure that is projected to reach 50% by 2050. Low-dose atropine, which helps curb the condition, currently is available in the United States only through compounding pharmacies. The products contain preservatives – raising questions about potential toxicities to the eye – and may not be of pharmaceutical grade. In a new study published in JAMA Ophthalmology, a preservative-free eyedrop containing 0.01% atropine led to significant improvements in several markers of myopia in children who received the experimental therapy.

Methodology

• The CHAMP study was a double-masked, placebo-controlled, randomized, phase 3 trial conducted between Nov. 20, 2017, and Aug. 22, 2022, that involved children at 26 sites in North America and 5 centers in Europe.
• Children received either 0.01% or 0.02% atropine drops once per day.
• Patients were aged 3-16 years. They demonstrated a spherical equivalent refractive error (SER) of −0.50 diopter (D) to −6.00 D astigmatism no worse than −1.50 D.
• Of these patients, 573 were included in a safety analysis, and 489 were included in a modified intention-to-treat analysis.

Takeaways

• After 36 months, the 0.01% dose of atropine was associated with a significantly lower responder proportion (odds ratio, 4.54) and slower progression of SER and axial elongation.
• The effect of the 0.02% dose on responder proportion and SER progression was not statistically significant, but the treatment was associated with slower axial elongation.
• The researchers observed no serious ocular adverse events and few serious nonocular events, none of which was determined to be associated with the treatment.

In practice: According to the researchers, “from a risk/benefit perspective, the efficacy and safety observed suggests that low-dose atropine may provide a treatment option for children aged 3-17 years with myopia progression, which may lead to less frequent or delayed change in glasses, progression to less severe correction, and potentially reduce long-term sequelae, which could lead to vision loss later in life, such as myopic maculopathy.”

Study details: The CHAMP study was led by Karla Zadnik, OD, PhD, of Ohio State University, Columbus, and was funded by Vylulma.

Limitations: The researchers said the trial was potentially limited by the fact that patients switched from the study drug to confounding treatments. In addition, patients at the low and high age ranges were not well represented.

Disclosures: Dr. Zadnik received consultant fees from Vyluma during the study.

A version of this article first appeared on Medscape.com.

Myopia affects roughly one-third of the population worldwide - a figure that is projected to reach 50% by 2050. Low-dose atropine, which helps curb the condition, currently is available in the United States only through compounding pharmacies. The products contain preservatives – raising questions about potential toxicities to the eye – and may not be of pharmaceutical grade. In a new study published in JAMA Ophthalmology, a preservative-free eyedrop containing 0.01% atropine led to significant improvements in several markers of myopia in children who received the experimental therapy.

Methodology

• The CHAMP study was a double-masked, placebo-controlled, randomized, phase 3 trial conducted between Nov. 20, 2017, and Aug. 22, 2022, that involved children at 26 sites in North America and 5 centers in Europe.
• Children received either 0.01% or 0.02% atropine drops once per day.
• Patients were aged 3-16 years. They demonstrated a spherical equivalent refractive error (SER) of −0.50 diopter (D) to −6.00 D astigmatism no worse than −1.50 D.
• Of these patients, 573 were included in a safety analysis, and 489 were included in a modified intention-to-treat analysis.

Takeaways

• After 36 months, the 0.01% dose of atropine was associated with a significantly lower responder proportion (odds ratio, 4.54) and slower progression of SER and axial elongation.
• The effect of the 0.02% dose on responder proportion and SER progression was not statistically significant, but the treatment was associated with slower axial elongation.
• The researchers observed no serious ocular adverse events and few serious nonocular events, none of which was determined to be associated with the treatment.

In practice: According to the researchers, “from a risk/benefit perspective, the efficacy and safety observed suggests that low-dose atropine may provide a treatment option for children aged 3-17 years with myopia progression, which may lead to less frequent or delayed change in glasses, progression to less severe correction, and potentially reduce long-term sequelae, which could lead to vision loss later in life, such as myopic maculopathy.”

Study details: The CHAMP study was led by Karla Zadnik, OD, PhD, of Ohio State University, Columbus, and was funded by Vylulma.

Limitations: The researchers said the trial was potentially limited by the fact that patients switched from the study drug to confounding treatments. In addition, patients at the low and high age ranges were not well represented.

Disclosures: Dr. Zadnik received consultant fees from Vyluma during the study.

A version of this article first appeared on Medscape.com.

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

A version of this article first appeared on Medscape.com.

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

A version of this article first appeared on Medscape.com.

The prophylactic use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke did not reduce the risk of poor functional outcome in the PRECIOUS trial.

“The results of PRECIOUS do not support preventive use of antiemetic, antipyretic, or antibiotic drugs in older patients with acute stroke,” senior study author Bart van der Worp, MD, professor of acute neurology at University Medical Center, Utrecht, the Netherlands, concluded.

“This trial was all about prevention,” trial co-investigator, Philip Bath, MD, professor of stroke medicine at the University of Nottingham (England), said in an interview.

“It was trying to improve outcomes by preventing infection, fever, and aspiration pneumonia, but the message from these results is that while we should be on the lookout for these complications and treat them early when they occur, we don’t need to give these medications on a prophylactic basis.”

The PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) trial was presented at the annual European Stroke Organisation Conference, held in Munich.

Dr. Van der Worp explained that infections, fever, and aspiration pneumonia frequently occur following stroke, particularly in older patients, and these poststroke complications are associated with an increased risk of death and poor functional outcome.

“We assessed whether a pharmacological strategy to reduce the risk of infections and fever improves outcomes of elderly patients with moderately severe or severe stroke,” he said.

Previous studies looking at this approach have been performed in broad populations of stroke patients who had a relatively low risk of poststroke complications, thereby reducing the potential for benefit from these interventions. 

The current PRECIOUS trial was therefore conducted in a more selective elderly population with more severe strokes, a group believed to be at higher risk of infection and fever.  

The trial included patients aged 66 years or older with moderately severe to severe ischemic stroke (National Institutes of Health Stroke Scale score ≥ 6) or intracerebral hemorrhage.

They were randomized in a 3 x 2 factorial design to oral, rectal, or intravenous metoclopramide (10 mg three times a day); intravenous ceftriaxone (2,000 mg once daily); oral, rectal, or intravenous paracetamol (1,000 mg four times daily); or usual care.

Medications were started within 24 hours after symptom onset and continued for 4 days or until complete recovery or discharge from hospital, if earlier.

“We assessed these three simple, safe, and inexpensive therapies – paracetamol to prevent fever; the antiemetic, metoclopramide, to prevent aspiration; and ceftriaxone, which is the preferred antibiotic for post-stroke pneumonia in the Netherlands,” Dr. van der Worp said.

The primary outcome was modified Rankin Scale (mRS) score at 90 days.

The trial was aiming to enroll 3,800 patients from 67 European sites but was stopped after 1,493 patients had been included because of lack of funding. After excluding patients who withdrew consent or were lost to follow-up, 1,471 patients were included in the intention-to-treat analysis.

Results showed no effect on the primary outcome of any of the prophylactic treatments.

“None of the medications had any effect on the functional outcome at 90 days. This was a surprise to me,” Dr. Van der Worp commented. “I had expected that at least one of the medications would have been of benefit.”

A secondary outcome was the diagnosis of pneumonia, which again was not reduced by any of the medications.

“Remarkably, neither ceftriaxone nor metoclopramide had any effect on the risk of developing pneumonia. It was all quite disappointing,” van der Worp said.

There was, however, a reduction in the incidence of urinary tract infections in the ceftriaxone group.

Trying to explain why there was a reduction in urinary tract infections but not pneumonia with the antibiotic, Dr. Van der Worp pointed out that poststroke pneumonia is to a large extent caused by a mechanical process (aspiration), and bacteria may only play a minor role in its development. 

He said he was therefore surprised that metoclopramide, which should prevent the mechanical process of aspiration, did not reduce the development of pneumonia.

He suggested that some patients may have already experienced aspiration before the metoclopramide was started, noting that many patients with acute stroke already have signs of pneumonia on CT scan in the first few hours after symptom onset.

A previous smaller study (MAPS) had shown a lower rate of pneumonia in stroke patients given metoclopramide, but in this study the drug was given for 3 weeks.

Discussing the PRECIOUS trial at the ESOC meeting, Christine Roffe, MD, professor of stroke medicine at Keele (England) University, and senior investigator of the MAPS study, suggested that a longer period of metoclopramide treatment may be needed than the 4 days given in the PRECIOUS study, as the risk of pneumonia persists for longer than just a few days.  

She noted that another trial (MAPS-2) is now underway in the United Kingdom to try and confirm the first MAPS result with longer duration metoclopramide.  

Dr. Van der Worp responded: “Certainly, I think that the MAPS-2 study should be continued. It is investigating a much longer duration of treatment, which may be beneficial, especially in patients with more severe strokes.” 

On the reason for the disappointing results with paracetamol, Dr. Van der Worp elaborated: “We found that only a very few of these older patients developed a fever – only about 5% in the control group. Paracetamol did reduce the risk of fever, but because the proportion of patients who developed fever was so small, this may have been why it didn’t translate into any effect on the functional outcome.” 

Dr. Roffe concluded that PRECIOUS was an important study. “There is also a positive message here. We have all been worried about using too many antibiotics. We need to make sure we use these drugs responsibly. I think this trial has told us there is little point in using antibiotics in a preventative way in these patients.”

She added that although the trial was stopped prematurely, it had produced decisive results.

“Yes, I believe that even if the trial was much larger, we still would not have shown an effect,” Dr. Van der Worp agreed.

A version of this article first appeared on Medscape.com.

An experimental, proprietary cannabinoid-based drug in development for diabetic neuropathy outperformed pregabalin (Lyrica) in a clinical trial, achieving significant reduction in pain severity, new top-line results released by Zelira Therapeutics suggest.

“The implications of these results for patients are incredibly promising,” principal investigator Bryan Doner, DO, medical director of HealthyWays Integrated Wellness Solutions, Gibsonia, Pa., said in a news release.

“Through this rigorously designed study, we have demonstrated that ZLT-L-007 is a safe, effective, and well-tolerated alternative for patients who would typically seek a Lyrica-level of pain relief,” he added.

The observational, nonblinded trial tested the efficacy, safety, and tolerability of ZLT-L-007 against pregabalin in 60 adults with diabetic nerve pain.

The study had three groups with 20 patients each (pregabalin alone, pregabalin plus ZLT-L-007, and ZLT-L-007 alone).

Top-line results show the study met its primary endpoint for change in daily pain severity as measured by the percent change from baseline at 30, 60, and 90 days on the Numerical Rating Scale.

For the pregabalin-only group, there was a reduction in symptom severity at all follow-up points, ranging from 20% to 35% (median percent change from baseline), the company said.

For the ZLT-L-007 only group, there was about a 33% reduction in symptom severity at 30 days, and 71% and 78% reduction, respectively, at 60 and 90 days, suggesting a larger improvement in symptom severity than with pregabalin alone, the company said.

For the pregabalin plus ZLT-L-007 group, there was a moderate 20% reduction in symptom severity at 30 days, but a larger reduction at 60 and 90 days (50% and 72%, respectively), which indicates substantially greater improvement in symptom severity than with pregabalin alone, the company said.

The study also met secondary endpoints, including significant decreases in daily pain severity as measured by the Visual Analog Scale and measurable changes in the short-form McGill Pain Questionnaire and Neuropathic Pain Symptom Inventory.

Dr. Doner noted that the top-line data showed “no serious adverse events, and participants’ blood pressure and other safety vitals remained unaffected throughout. This confirms that ZLT-L-007 is a well-tolerated product that delivers statistically significant pain relief, surpassing the levels achieved by Lyrica.”

The company plans to report additional insights from the full study, as they become available, during fiscal year 2023-2024.

A version of this article first appeared on Medscape.com.

An experimental, proprietary cannabinoid-based drug in development for diabetic neuropathy outperformed pregabalin (Lyrica) in a clinical trial, achieving significant reduction in pain severity, new top-line results released by Zelira Therapeutics suggest.

“The implications of these results for patients are incredibly promising,” principal investigator Bryan Doner, DO, medical director of HealthyWays Integrated Wellness Solutions, Gibsonia, Pa., said in a news release.

“Through this rigorously designed study, we have demonstrated that ZLT-L-007 is a safe, effective, and well-tolerated alternative for patients who would typically seek a Lyrica-level of pain relief,” he added.

The observational, nonblinded trial tested the efficacy, safety, and tolerability of ZLT-L-007 against pregabalin in 60 adults with diabetic nerve pain.

The study had three groups with 20 patients each (pregabalin alone, pregabalin plus ZLT-L-007, and ZLT-L-007 alone).

Top-line results show the study met its primary endpoint for change in daily pain severity as measured by the percent change from baseline at 30, 60, and 90 days on the Numerical Rating Scale.

For the pregabalin-only group, there was a reduction in symptom severity at all follow-up points, ranging from 20% to 35% (median percent change from baseline), the company said.

For the ZLT-L-007 only group, there was about a 33% reduction in symptom severity at 30 days, and 71% and 78% reduction, respectively, at 60 and 90 days, suggesting a larger improvement in symptom severity than with pregabalin alone, the company said.

For the pregabalin plus ZLT-L-007 group, there was a moderate 20% reduction in symptom severity at 30 days, but a larger reduction at 60 and 90 days (50% and 72%, respectively), which indicates substantially greater improvement in symptom severity than with pregabalin alone, the company said.

The study also met secondary endpoints, including significant decreases in daily pain severity as measured by the Visual Analog Scale and measurable changes in the short-form McGill Pain Questionnaire and Neuropathic Pain Symptom Inventory.

Dr. Doner noted that the top-line data showed “no serious adverse events, and participants’ blood pressure and other safety vitals remained unaffected throughout. This confirms that ZLT-L-007 is a well-tolerated product that delivers statistically significant pain relief, surpassing the levels achieved by Lyrica.”

The company plans to report additional insights from the full study, as they become available, during fiscal year 2023-2024.

A version of this article first appeared on Medscape.com.

An experimental, proprietary cannabinoid-based drug in development for diabetic neuropathy outperformed pregabalin (Lyrica) in a clinical trial, achieving significant reduction in pain severity, new top-line results released by Zelira Therapeutics suggest.

“The implications of these results for patients are incredibly promising,” principal investigator Bryan Doner, DO, medical director of HealthyWays Integrated Wellness Solutions, Gibsonia, Pa., said in a news release.

“Through this rigorously designed study, we have demonstrated that ZLT-L-007 is a safe, effective, and well-tolerated alternative for patients who would typically seek a Lyrica-level of pain relief,” he added.

The observational, nonblinded trial tested the efficacy, safety, and tolerability of ZLT-L-007 against pregabalin in 60 adults with diabetic nerve pain.

The study had three groups with 20 patients each (pregabalin alone, pregabalin plus ZLT-L-007, and ZLT-L-007 alone).

Top-line results show the study met its primary endpoint for change in daily pain severity as measured by the percent change from baseline at 30, 60, and 90 days on the Numerical Rating Scale.

For the pregabalin-only group, there was a reduction in symptom severity at all follow-up points, ranging from 20% to 35% (median percent change from baseline), the company said.

For the ZLT-L-007 only group, there was about a 33% reduction in symptom severity at 30 days, and 71% and 78% reduction, respectively, at 60 and 90 days, suggesting a larger improvement in symptom severity than with pregabalin alone, the company said.

For the pregabalin plus ZLT-L-007 group, there was a moderate 20% reduction in symptom severity at 30 days, but a larger reduction at 60 and 90 days (50% and 72%, respectively), which indicates substantially greater improvement in symptom severity than with pregabalin alone, the company said.

The study also met secondary endpoints, including significant decreases in daily pain severity as measured by the Visual Analog Scale and measurable changes in the short-form McGill Pain Questionnaire and Neuropathic Pain Symptom Inventory.

Dr. Doner noted that the top-line data showed “no serious adverse events, and participants’ blood pressure and other safety vitals remained unaffected throughout. This confirms that ZLT-L-007 is a well-tolerated product that delivers statistically significant pain relief, surpassing the levels achieved by Lyrica.”

The company plans to report additional insights from the full study, as they become available, during fiscal year 2023-2024.

A version of this article first appeared on Medscape.com.

Sotagliflozin, a novel agent that inhibits sodium-glucose cotransporter 1 as well as SGLT2, has received marketing approval from the Food and Drug Administration for reducing the risk for cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with heart failure, and also for preventing these same events in patients with type 2 diabetes, chronic kidney disease (CKD), and other cardiovascular disease risk factors.

This puts sotagliflozin in direct competition with two SGLT2 inhibitors, dapagliflozin (Farxiga) and empagliflozin (Jardiance), that already have indications for preventing heart failure hospitalizations in patients with heart failure as well as approvals for type 2 diabetes and preservation of renal function.

Officials at Lexicon Pharmaceuticals, the company that developed and will market sotagliflozin under the trade name Inpefa, said in a press release that they expect U.S. sales of the agent to begin before the end of June 2023. The release also highlighted that the approval broadly covered use in patients with heart failure across the full range of both reduced and preserved left ventricular ejection fractions.

Lexicon officials also said that the company will focus on marketing sotagliflozin for preventing near-term rehospitalizations of patients discharged after an episode of acute heart failure decompensation.

They base this niche target for sotagliflozin on results from the SOLOIST-WHF trial, which randomized 1,222 patients with type 2 diabetes recently hospitalized for worsening heart failure and showed a significant 33% reduction in the rate of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure, compared with control patients during a median 9 months of follow-up. Nearly half of the enrolled patients received their first dose while still hospitalized, while the other half received their first dose a median of 2 days after hospital discharge. The drug appeared safe.
 

Cutting heart failure rehospitalizations in half

An exploratory post hoc analysis of SOLOIST-WHF showed that treatment with sotagliflozin cut the rate of rehospitalizations roughly in half after both 30 and 90 days compared with control patients, according to an abstract presented at the 2022 annual scientific sessions of the AHA that has not yet been published in a peer-reviewed journal.

The only SGLT2 inhibitor tested so far when initiated in patients during hospitalization for heart failure is empagliflozin, in the EMPULSE trial, which randomized 530 patients. EMPULSE also showed that starting an SGLT2 inhibitor in this setting was safe and resulted in significant clinical benefit, the study’s primary endpoint, defined as a composite of death from any cause, number of heart failure events, and time to first heart failure event, or a 5-point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days.

In the DELIVER trial, which tested dapagliflozin in patients with heart failure with preserved ejection fraction, roughly 10% of patients started study treatment during or within 30 days of heart failure hospitalization, and in this subgroup, dapagliflozin appeared as effective as it was in the other 90% of patients who did not start the drug during an acute or subacute phase.

Despite the SOLOIST-WHF evidence for sotagliflozin’s safety and efficacy in this economically important clinical setting, some experts say the drug faces an uphill path as it contends for market share against two solidly established, albeit dramatically underused, SGLT2 inhibitors. (Recent data document that 20% or fewer of U.S. patients eligible for treatment with an SGLT2 inhibitor receive it, such as a review of 49,000 patients hospitalized during 2021-2022 with heart failure with reduced ejection fraction.)

Others foresee a clear role for sotagliflozin, particularly because of additional facets of the drug’s performance in trials that they perceive give it an edge over dapagliflozin and empagliflozin. This includes evidence that sotagliflozin treatment uniquely (within the SGLT2 inhibitor class) cuts the rate of strokes and myocardial infarctions, as well as evidence of its apparent ability to lower hemoglobin A1c levels in patients with type 2 diabetes and with an estimated glomerular filtration rate below 30 mL/min per 1.73 m², a property likely linked to inhibition of SGLT1 in the gut that dampens intestinal glucose absorption.
 

Sotagliflozin uptake ‘will be a challenge’

“It will be a challenge” for sotagliflozin uptake, given the head start that both dapagliflozin and empagliflozin have had as well-documented agents for patients with heart failure, commented Javed Butler, MD, a heart failure clinician and trialist who is president of the Baylor Scott & White Research Institute in Dallas.

Given the position dapagliflozin and empagliflozin currently have in U.S. heart failure management – with the SGLT2 inhibitor class called out in guidelines as foundational for treating patients with heart failure with reduced ejection fraction and likely soon for heart failure with preserved ejection fraction as well – “I can’t imagine [sotagliflozin] will be considered a preferred option,” Dr. Butler said in an interview.

Another expert was even more dismissive of sotagliflozin’s role.

“There is no persuasive evidence that sotagliflozin has any advantages, compared with the SGLT2 inhibitors, for the treatment of heart failure,” said Milton Packer, MD, a heart failure specialist and trialist at Baylor University Medical Center, Dallas. “I do not see why U.S. physicians might pivot from established SGLT2 inhibitors to sotagliflozin,” unless it was priced “at a very meaningful discount to available SGLT2 inhibitors.”

At the time it announced the FDA’s approval, Lexicon did not provide details on how it would price sotagliflozin. Existing retail prices for dapagliflozin and empagliflozin run about $550-$600/month, a price point that has contributed to slow U.S. uptake of the drug class. But experts anticipate a dramatic shake-up of the U.S. market for SGLT2 inhibitors with expected introduction of a generic SGLT2 inhibitor formulation by 2025, a development that could further dampen sotagliflozin’s prospects.

Other experts are more optimistic about the new agent’s uptake, perhaps none more than Deepak L. Bhatt, MD, MPH, who led both pivotal trials that provide the bulk of sotagliflozin’s evidence package.

copyright CYIM

In addition to SOLOIST-WHF, Dr. Bhatt also headed the SCORED trial, with 10,584 patients with type 2 diabetes, CKD, and risks for cardiovascular disease randomized to sotagliflozin or placebo and followed for a median of 16 months. The primary result showed that sotagliflozin treatment cut the combined rate of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure by a significant 26% relative to control patients.
 

A clear MACE benefit

“The data from SOLOIST-WHF and SCORED look at least as good as the data for the SGLT2 inhibitors for heart failure, and what appears to be different are the rates for MI and stroke in SCORED,” said Dr. Bhatt, director of Mount Sinai Heart, New York.

“I believe the rate of major adverse cardiovascular events [MACE] were reduced [in SCORED], and this is different from the SGLT2 inhibitors,” he said in an interview.

In 2022, Dr. Bhatt reported results from a prespecified secondary analysis of SCORED that showed that treatment with sotagliflozin cut the rate of MACE by a significant 21%-26%, compared with placebo. This finding was, in part, driven by the first data to show a substantial benefit from an SGLT inhibitor on stroke rates.

And while SCORED did not report a significant benefit for slowing progression of CKD, subsequent post hoc analyses have suggested this advantage also in as-yet-unpublished findings, Dr. Bhatt added.

But he said he doubted nephrologists will see it as a first-line agent for slowing CKD progression – an indication already held by dapagliflozin, pending for empagliflozin, and also in place for a third SGLT2 inhibitor, canagliflozin (Invokana) – because sotagliflozin lacks clear significant and prespecified evidence for this effect.

Dr. Bhatt also acknowledged the limitation of sotagliflozin compared with the SGLT2 inhibitors as an agent for glucose control, again because of no evidence for this effect from a prospective analysis and no pending indication for type 2 diabetes treatment. But the SCORED data showed a clear A1c benefit, even in patients with severely reduced renal function.
 

Mostly for cardiologists? ‘Compelling’ reductions in MIs and strokes

That may mean sotagliflozin “won’t get much use by endocrinologists nor by primary care physicians,” commented Carol L. Wysham, MD, an endocrinologist with MultiCare in Spokane, Wash.

Sotagliflozin “will be a cardiology drug,” and will “have a hard time” competing with the SGLT2 inhibitors, she predicted.

Dr. Bhatt agreed that sotagliflozin “will be perceived as a drug for cardiologists to prescribe. I don’t see endocrinologists, nephrologists, and primary care physicians reaching for this drug if it has a heart failure label.” But, he added, “my hope is that the company files for additional indications. It deserves an indication for glycemic control.”

The evidence for a heart failure benefit from sotagliflozin is “valid and compelling,” and “having this option is great,” commented Mikhail N. Kosiborod, MD, a cardiologist, vice president of research at Saint Luke’s Health System, and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. But, he added, “it will be a reasonably tall task for sotagliflozin to come from behind and be disruptive in a space where there are already two well-established SGLT2 inhibitors” approved for preventing heart failure hospitalizations, “with a lot of data to back them up,”

The feature that sets sotagliflozin apart from the approved SGLT2 inhibitors is the “really compelling decrease” it produced in rates of MIs and strokes “that we simply do not see with SGLT2 inhibitors,” Dr. Kosiborod said in an interview.

He also cited results from SCORED that suggest “a meaningful reduction in A1c” when indirectly compared with SGLT2 inhibitors, especially in patients with more severe CKD. The lack of a dedicated A1c-lowering trial or an approved type 2 diabetes indication “will not be a problem for cardiologists,” he predicted, but also agreed that it is less likely to be used by primary care physicians in low-risk patients.

“I can see myself prescribing sotagliflozin,” said Dr. Kosiborod, a SCORED coinvestigator, especially for patients with coexisting type 2 diabetes, heart failure, CKD, and atherosclerotic cardiovascular disease. These patients may get “more bang for the buck” because of a reduced risk for MI and stroke, making sotagliflozin “a solid consideration in these patients if the economic factors align.”

Like others, Dr. Kosiborod cited the big impact pricing will have, especially if, as expected, a generic SGLT2 inhibitor soon comes onto the U.S. market. “Access and affordability are very important.”

SOLOIST-WHF and SCORED were sponsored initially by Sanofi and later by Lexicon after Sanofi pulled out of sotagliflozin development. Dr. Butler has been a consultant for Lexicon as well as for AstraZeneca (which markets Farxiga), Boehringer Ingelheim and Lilly (which jointly market Jardiance), and Janssen (which markets Invokana), as well as for numerous other companies. Dr. Packer has been a consultant for AstraZeneca, Boehringer Ingelheim, Lilly, and numerous other companies. Dr. Bhatt was lead investigator for SOLOIST-WHF and SCORED and has been an adviser for Boehringer Ingelheim and Janssen and numerous other companies. Dr. Wysham has been an adviser, speaker, and consultant for AstraZeneca, Boehringer Ingelheim, Lilly, Janssen, Novo Nordisk, and Sanofi, an adviser for Abbott, and a speaker for Insulet. Dr. Kosiborod was a member of the SCORED Steering Committee and has been a consultant for Lexicon, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and numerous other companies.

A version of this article first appeared on Medscape.com.

Sotagliflozin, a novel agent that inhibits sodium-glucose cotransporter 1 as well as SGLT2, has received marketing approval from the Food and Drug Administration for reducing the risk for cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with heart failure, and also for preventing these same events in patients with type 2 diabetes, chronic kidney disease (CKD), and other cardiovascular disease risk factors.

This puts sotagliflozin in direct competition with two SGLT2 inhibitors, dapagliflozin (Farxiga) and empagliflozin (Jardiance), that already have indications for preventing heart failure hospitalizations in patients with heart failure as well as approvals for type 2 diabetes and preservation of renal function.

Officials at Lexicon Pharmaceuticals, the company that developed and will market sotagliflozin under the trade name Inpefa, said in a press release that they expect U.S. sales of the agent to begin before the end of June 2023. The release also highlighted that the approval broadly covered use in patients with heart failure across the full range of both reduced and preserved left ventricular ejection fractions.

Lexicon officials also said that the company will focus on marketing sotagliflozin for preventing near-term rehospitalizations of patients discharged after an episode of acute heart failure decompensation.

They base this niche target for sotagliflozin on results from the SOLOIST-WHF trial, which randomized 1,222 patients with type 2 diabetes recently hospitalized for worsening heart failure and showed a significant 33% reduction in the rate of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure, compared with control patients during a median 9 months of follow-up. Nearly half of the enrolled patients received their first dose while still hospitalized, while the other half received their first dose a median of 2 days after hospital discharge. The drug appeared safe.
 

Cutting heart failure rehospitalizations in half

An exploratory post hoc analysis of SOLOIST-WHF showed that treatment with sotagliflozin cut the rate of rehospitalizations roughly in half after both 30 and 90 days compared with control patients, according to an abstract presented at the 2022 annual scientific sessions of the AHA that has not yet been published in a peer-reviewed journal.

The only SGLT2 inhibitor tested so far when initiated in patients during hospitalization for heart failure is empagliflozin, in the EMPULSE trial, which randomized 530 patients. EMPULSE also showed that starting an SGLT2 inhibitor in this setting was safe and resulted in significant clinical benefit, the study’s primary endpoint, defined as a composite of death from any cause, number of heart failure events, and time to first heart failure event, or a 5-point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days.

In the DELIVER trial, which tested dapagliflozin in patients with heart failure with preserved ejection fraction, roughly 10% of patients started study treatment during or within 30 days of heart failure hospitalization, and in this subgroup, dapagliflozin appeared as effective as it was in the other 90% of patients who did not start the drug during an acute or subacute phase.

Despite the SOLOIST-WHF evidence for sotagliflozin’s safety and efficacy in this economically important clinical setting, some experts say the drug faces an uphill path as it contends for market share against two solidly established, albeit dramatically underused, SGLT2 inhibitors. (Recent data document that 20% or fewer of U.S. patients eligible for treatment with an SGLT2 inhibitor receive it, such as a review of 49,000 patients hospitalized during 2021-2022 with heart failure with reduced ejection fraction.)

Others foresee a clear role for sotagliflozin, particularly because of additional facets of the drug’s performance in trials that they perceive give it an edge over dapagliflozin and empagliflozin. This includes evidence that sotagliflozin treatment uniquely (within the SGLT2 inhibitor class) cuts the rate of strokes and myocardial infarctions, as well as evidence of its apparent ability to lower hemoglobin A1c levels in patients with type 2 diabetes and with an estimated glomerular filtration rate below 30 mL/min per 1.73 m², a property likely linked to inhibition of SGLT1 in the gut that dampens intestinal glucose absorption.
 

Sotagliflozin uptake ‘will be a challenge’

“It will be a challenge” for sotagliflozin uptake, given the head start that both dapagliflozin and empagliflozin have had as well-documented agents for patients with heart failure, commented Javed Butler, MD, a heart failure clinician and trialist who is president of the Baylor Scott & White Research Institute in Dallas.

Given the position dapagliflozin and empagliflozin currently have in U.S. heart failure management – with the SGLT2 inhibitor class called out in guidelines as foundational for treating patients with heart failure with reduced ejection fraction and likely soon for heart failure with preserved ejection fraction as well – “I can’t imagine [sotagliflozin] will be considered a preferred option,” Dr. Butler said in an interview.

Another expert was even more dismissive of sotagliflozin’s role.

“There is no persuasive evidence that sotagliflozin has any advantages, compared with the SGLT2 inhibitors, for the treatment of heart failure,” said Milton Packer, MD, a heart failure specialist and trialist at Baylor University Medical Center, Dallas. “I do not see why U.S. physicians might pivot from established SGLT2 inhibitors to sotagliflozin,” unless it was priced “at a very meaningful discount to available SGLT2 inhibitors.”

At the time it announced the FDA’s approval, Lexicon did not provide details on how it would price sotagliflozin. Existing retail prices for dapagliflozin and empagliflozin run about $550-$600/month, a price point that has contributed to slow U.S. uptake of the drug class. But experts anticipate a dramatic shake-up of the U.S. market for SGLT2 inhibitors with expected introduction of a generic SGLT2 inhibitor formulation by 2025, a development that could further dampen sotagliflozin’s prospects.

Other experts are more optimistic about the new agent’s uptake, perhaps none more than Deepak L. Bhatt, MD, MPH, who led both pivotal trials that provide the bulk of sotagliflozin’s evidence package.

copyright CYIM

In addition to SOLOIST-WHF, Dr. Bhatt also headed the SCORED trial, with 10,584 patients with type 2 diabetes, CKD, and risks for cardiovascular disease randomized to sotagliflozin or placebo and followed for a median of 16 months. The primary result showed that sotagliflozin treatment cut the combined rate of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure by a significant 26% relative to control patients.
 

A clear MACE benefit

“The data from SOLOIST-WHF and SCORED look at least as good as the data for the SGLT2 inhibitors for heart failure, and what appears to be different are the rates for MI and stroke in SCORED,” said Dr. Bhatt, director of Mount Sinai Heart, New York.

“I believe the rate of major adverse cardiovascular events [MACE] were reduced [in SCORED], and this is different from the SGLT2 inhibitors,” he said in an interview.

In 2022, Dr. Bhatt reported results from a prespecified secondary analysis of SCORED that showed that treatment with sotagliflozin cut the rate of MACE by a significant 21%-26%, compared with placebo. This finding was, in part, driven by the first data to show a substantial benefit from an SGLT inhibitor on stroke rates.

And while SCORED did not report a significant benefit for slowing progression of CKD, subsequent post hoc analyses have suggested this advantage also in as-yet-unpublished findings, Dr. Bhatt added.

But he said he doubted nephrologists will see it as a first-line agent for slowing CKD progression – an indication already held by dapagliflozin, pending for empagliflozin, and also in place for a third SGLT2 inhibitor, canagliflozin (Invokana) – because sotagliflozin lacks clear significant and prespecified evidence for this effect.

Dr. Bhatt also acknowledged the limitation of sotagliflozin compared with the SGLT2 inhibitors as an agent for glucose control, again because of no evidence for this effect from a prospective analysis and no pending indication for type 2 diabetes treatment. But the SCORED data showed a clear A1c benefit, even in patients with severely reduced renal function.
 

Mostly for cardiologists? ‘Compelling’ reductions in MIs and strokes

That may mean sotagliflozin “won’t get much use by endocrinologists nor by primary care physicians,” commented Carol L. Wysham, MD, an endocrinologist with MultiCare in Spokane, Wash.

Sotagliflozin “will be a cardiology drug,” and will “have a hard time” competing with the SGLT2 inhibitors, she predicted.

Dr. Bhatt agreed that sotagliflozin “will be perceived as a drug for cardiologists to prescribe. I don’t see endocrinologists, nephrologists, and primary care physicians reaching for this drug if it has a heart failure label.” But, he added, “my hope is that the company files for additional indications. It deserves an indication for glycemic control.”

The evidence for a heart failure benefit from sotagliflozin is “valid and compelling,” and “having this option is great,” commented Mikhail N. Kosiborod, MD, a cardiologist, vice president of research at Saint Luke’s Health System, and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. But, he added, “it will be a reasonably tall task for sotagliflozin to come from behind and be disruptive in a space where there are already two well-established SGLT2 inhibitors” approved for preventing heart failure hospitalizations, “with a lot of data to back them up,”

The feature that sets sotagliflozin apart from the approved SGLT2 inhibitors is the “really compelling decrease” it produced in rates of MIs and strokes “that we simply do not see with SGLT2 inhibitors,” Dr. Kosiborod said in an interview.

He also cited results from SCORED that suggest “a meaningful reduction in A1c” when indirectly compared with SGLT2 inhibitors, especially in patients with more severe CKD. The lack of a dedicated A1c-lowering trial or an approved type 2 diabetes indication “will not be a problem for cardiologists,” he predicted, but also agreed that it is less likely to be used by primary care physicians in low-risk patients.

“I can see myself prescribing sotagliflozin,” said Dr. Kosiborod, a SCORED coinvestigator, especially for patients with coexisting type 2 diabetes, heart failure, CKD, and atherosclerotic cardiovascular disease. These patients may get “more bang for the buck” because of a reduced risk for MI and stroke, making sotagliflozin “a solid consideration in these patients if the economic factors align.”

Like others, Dr. Kosiborod cited the big impact pricing will have, especially if, as expected, a generic SGLT2 inhibitor soon comes onto the U.S. market. “Access and affordability are very important.”

SOLOIST-WHF and SCORED were sponsored initially by Sanofi and later by Lexicon after Sanofi pulled out of sotagliflozin development. Dr. Butler has been a consultant for Lexicon as well as for AstraZeneca (which markets Farxiga), Boehringer Ingelheim and Lilly (which jointly market Jardiance), and Janssen (which markets Invokana), as well as for numerous other companies. Dr. Packer has been a consultant for AstraZeneca, Boehringer Ingelheim, Lilly, and numerous other companies. Dr. Bhatt was lead investigator for SOLOIST-WHF and SCORED and has been an adviser for Boehringer Ingelheim and Janssen and numerous other companies. Dr. Wysham has been an adviser, speaker, and consultant for AstraZeneca, Boehringer Ingelheim, Lilly, Janssen, Novo Nordisk, and Sanofi, an adviser for Abbott, and a speaker for Insulet. Dr. Kosiborod was a member of the SCORED Steering Committee and has been a consultant for Lexicon, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and numerous other companies.

A version of this article first appeared on Medscape.com.

Sotagliflozin, a novel agent that inhibits sodium-glucose cotransporter 1 as well as SGLT2, has received marketing approval from the Food and Drug Administration for reducing the risk for cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with heart failure, and also for preventing these same events in patients with type 2 diabetes, chronic kidney disease (CKD), and other cardiovascular disease risk factors.

This puts sotagliflozin in direct competition with two SGLT2 inhibitors, dapagliflozin (Farxiga) and empagliflozin (Jardiance), that already have indications for preventing heart failure hospitalizations in patients with heart failure as well as approvals for type 2 diabetes and preservation of renal function.

Officials at Lexicon Pharmaceuticals, the company that developed and will market sotagliflozin under the trade name Inpefa, said in a press release that they expect U.S. sales of the agent to begin before the end of June 2023. The release also highlighted that the approval broadly covered use in patients with heart failure across the full range of both reduced and preserved left ventricular ejection fractions.

Lexicon officials also said that the company will focus on marketing sotagliflozin for preventing near-term rehospitalizations of patients discharged after an episode of acute heart failure decompensation.

They base this niche target for sotagliflozin on results from the SOLOIST-WHF trial, which randomized 1,222 patients with type 2 diabetes recently hospitalized for worsening heart failure and showed a significant 33% reduction in the rate of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure, compared with control patients during a median 9 months of follow-up. Nearly half of the enrolled patients received their first dose while still hospitalized, while the other half received their first dose a median of 2 days after hospital discharge. The drug appeared safe.
 

Cutting heart failure rehospitalizations in half

An exploratory post hoc analysis of SOLOIST-WHF showed that treatment with sotagliflozin cut the rate of rehospitalizations roughly in half after both 30 and 90 days compared with control patients, according to an abstract presented at the 2022 annual scientific sessions of the AHA that has not yet been published in a peer-reviewed journal.

The only SGLT2 inhibitor tested so far when initiated in patients during hospitalization for heart failure is empagliflozin, in the EMPULSE trial, which randomized 530 patients. EMPULSE also showed that starting an SGLT2 inhibitor in this setting was safe and resulted in significant clinical benefit, the study’s primary endpoint, defined as a composite of death from any cause, number of heart failure events, and time to first heart failure event, or a 5-point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days.

In the DELIVER trial, which tested dapagliflozin in patients with heart failure with preserved ejection fraction, roughly 10% of patients started study treatment during or within 30 days of heart failure hospitalization, and in this subgroup, dapagliflozin appeared as effective as it was in the other 90% of patients who did not start the drug during an acute or subacute phase.

Despite the SOLOIST-WHF evidence for sotagliflozin’s safety and efficacy in this economically important clinical setting, some experts say the drug faces an uphill path as it contends for market share against two solidly established, albeit dramatically underused, SGLT2 inhibitors. (Recent data document that 20% or fewer of U.S. patients eligible for treatment with an SGLT2 inhibitor receive it, such as a review of 49,000 patients hospitalized during 2021-2022 with heart failure with reduced ejection fraction.)

Others foresee a clear role for sotagliflozin, particularly because of additional facets of the drug’s performance in trials that they perceive give it an edge over dapagliflozin and empagliflozin. This includes evidence that sotagliflozin treatment uniquely (within the SGLT2 inhibitor class) cuts the rate of strokes and myocardial infarctions, as well as evidence of its apparent ability to lower hemoglobin A1c levels in patients with type 2 diabetes and with an estimated glomerular filtration rate below 30 mL/min per 1.73 m², a property likely linked to inhibition of SGLT1 in the gut that dampens intestinal glucose absorption.
 

Sotagliflozin uptake ‘will be a challenge’

“It will be a challenge” for sotagliflozin uptake, given the head start that both dapagliflozin and empagliflozin have had as well-documented agents for patients with heart failure, commented Javed Butler, MD, a heart failure clinician and trialist who is president of the Baylor Scott & White Research Institute in Dallas.

Given the position dapagliflozin and empagliflozin currently have in U.S. heart failure management – with the SGLT2 inhibitor class called out in guidelines as foundational for treating patients with heart failure with reduced ejection fraction and likely soon for heart failure with preserved ejection fraction as well – “I can’t imagine [sotagliflozin] will be considered a preferred option,” Dr. Butler said in an interview.

Another expert was even more dismissive of sotagliflozin’s role.

“There is no persuasive evidence that sotagliflozin has any advantages, compared with the SGLT2 inhibitors, for the treatment of heart failure,” said Milton Packer, MD, a heart failure specialist and trialist at Baylor University Medical Center, Dallas. “I do not see why U.S. physicians might pivot from established SGLT2 inhibitors to sotagliflozin,” unless it was priced “at a very meaningful discount to available SGLT2 inhibitors.”

At the time it announced the FDA’s approval, Lexicon did not provide details on how it would price sotagliflozin. Existing retail prices for dapagliflozin and empagliflozin run about $550-$600/month, a price point that has contributed to slow U.S. uptake of the drug class. But experts anticipate a dramatic shake-up of the U.S. market for SGLT2 inhibitors with expected introduction of a generic SGLT2 inhibitor formulation by 2025, a development that could further dampen sotagliflozin’s prospects.

Other experts are more optimistic about the new agent’s uptake, perhaps none more than Deepak L. Bhatt, MD, MPH, who led both pivotal trials that provide the bulk of sotagliflozin’s evidence package.

copyright CYIM

In addition to SOLOIST-WHF, Dr. Bhatt also headed the SCORED trial, with 10,584 patients with type 2 diabetes, CKD, and risks for cardiovascular disease randomized to sotagliflozin or placebo and followed for a median of 16 months. The primary result showed that sotagliflozin treatment cut the combined rate of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure by a significant 26% relative to control patients.
 

A clear MACE benefit

“The data from SOLOIST-WHF and SCORED look at least as good as the data for the SGLT2 inhibitors for heart failure, and what appears to be different are the rates for MI and stroke in SCORED,” said Dr. Bhatt, director of Mount Sinai Heart, New York.

“I believe the rate of major adverse cardiovascular events [MACE] were reduced [in SCORED], and this is different from the SGLT2 inhibitors,” he said in an interview.

In 2022, Dr. Bhatt reported results from a prespecified secondary analysis of SCORED that showed that treatment with sotagliflozin cut the rate of MACE by a significant 21%-26%, compared with placebo. This finding was, in part, driven by the first data to show a substantial benefit from an SGLT inhibitor on stroke rates.

And while SCORED did not report a significant benefit for slowing progression of CKD, subsequent post hoc analyses have suggested this advantage also in as-yet-unpublished findings, Dr. Bhatt added.

But he said he doubted nephrologists will see it as a first-line agent for slowing CKD progression – an indication already held by dapagliflozin, pending for empagliflozin, and also in place for a third SGLT2 inhibitor, canagliflozin (Invokana) – because sotagliflozin lacks clear significant and prespecified evidence for this effect.

Dr. Bhatt also acknowledged the limitation of sotagliflozin compared with the SGLT2 inhibitors as an agent for glucose control, again because of no evidence for this effect from a prospective analysis and no pending indication for type 2 diabetes treatment. But the SCORED data showed a clear A1c benefit, even in patients with severely reduced renal function.
 

Mostly for cardiologists? ‘Compelling’ reductions in MIs and strokes

That may mean sotagliflozin “won’t get much use by endocrinologists nor by primary care physicians,” commented Carol L. Wysham, MD, an endocrinologist with MultiCare in Spokane, Wash.

Sotagliflozin “will be a cardiology drug,” and will “have a hard time” competing with the SGLT2 inhibitors, she predicted.

Dr. Bhatt agreed that sotagliflozin “will be perceived as a drug for cardiologists to prescribe. I don’t see endocrinologists, nephrologists, and primary care physicians reaching for this drug if it has a heart failure label.” But, he added, “my hope is that the company files for additional indications. It deserves an indication for glycemic control.”

The evidence for a heart failure benefit from sotagliflozin is “valid and compelling,” and “having this option is great,” commented Mikhail N. Kosiborod, MD, a cardiologist, vice president of research at Saint Luke’s Health System, and codirector of the Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. But, he added, “it will be a reasonably tall task for sotagliflozin to come from behind and be disruptive in a space where there are already two well-established SGLT2 inhibitors” approved for preventing heart failure hospitalizations, “with a lot of data to back them up,”

The feature that sets sotagliflozin apart from the approved SGLT2 inhibitors is the “really compelling decrease” it produced in rates of MIs and strokes “that we simply do not see with SGLT2 inhibitors,” Dr. Kosiborod said in an interview.

He also cited results from SCORED that suggest “a meaningful reduction in A1c” when indirectly compared with SGLT2 inhibitors, especially in patients with more severe CKD. The lack of a dedicated A1c-lowering trial or an approved type 2 diabetes indication “will not be a problem for cardiologists,” he predicted, but also agreed that it is less likely to be used by primary care physicians in low-risk patients.

“I can see myself prescribing sotagliflozin,” said Dr. Kosiborod, a SCORED coinvestigator, especially for patients with coexisting type 2 diabetes, heart failure, CKD, and atherosclerotic cardiovascular disease. These patients may get “more bang for the buck” because of a reduced risk for MI and stroke, making sotagliflozin “a solid consideration in these patients if the economic factors align.”

Like others, Dr. Kosiborod cited the big impact pricing will have, especially if, as expected, a generic SGLT2 inhibitor soon comes onto the U.S. market. “Access and affordability are very important.”

SOLOIST-WHF and SCORED were sponsored initially by Sanofi and later by Lexicon after Sanofi pulled out of sotagliflozin development. Dr. Butler has been a consultant for Lexicon as well as for AstraZeneca (which markets Farxiga), Boehringer Ingelheim and Lilly (which jointly market Jardiance), and Janssen (which markets Invokana), as well as for numerous other companies. Dr. Packer has been a consultant for AstraZeneca, Boehringer Ingelheim, Lilly, and numerous other companies. Dr. Bhatt was lead investigator for SOLOIST-WHF and SCORED and has been an adviser for Boehringer Ingelheim and Janssen and numerous other companies. Dr. Wysham has been an adviser, speaker, and consultant for AstraZeneca, Boehringer Ingelheim, Lilly, Janssen, Novo Nordisk, and Sanofi, an adviser for Abbott, and a speaker for Insulet. Dr. Kosiborod was a member of the SCORED Steering Committee and has been a consultant for Lexicon, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and numerous other companies.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved extended-release injection buprenorphine (Brixadi, Braeburn) for the treatment of moderate to severe opioid use disorder (OUD).

Olivier Le Moal/Getty Images

The medication comes in two formulations: a weekly and a monthly version. The weekly treatment is indicated in patients who have initiated treatment with a single dose of transmucosal buprenorphine or who are already being treated with the drug. The monthly version is for patients already receiving buprenorphine.

“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, MD, in a release. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework,” Dr. Califf added.

The Substance Abuse and Mental Health Services Administration reports that patients receiving medication for OUD have their risk for all-cause mortality cut by 50%.

In its release, the FDA said that it remains committed to increasing treatment options for OUD. Earlier this month, the agency issued a joint letter with SAMHSA to underscore the importance of counseling and other services as part of a comprehensive treatment plan the disorder. It also emphasized that receiving buprenorphine should not be contingent on participating in such services.

Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for patients who do not tolerate higher doses of extended-release buprenorphine that are currently available.

The drug will be available through a Risk Evaluation and Mitigation Strategy program and administered only by health care providers in a health care setting.

The most common adverse reactions associated with the drug include injection-site pain, headache, constipation, nausea, injection-site erythema, injection-site pruritus, insomnia, and urinary tract infections. The FDA reports that such side effects occur in at least 5% of patients.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has approved extended-release injection buprenorphine (Brixadi, Braeburn) for the treatment of moderate to severe opioid use disorder (OUD).

Olivier Le Moal/Getty Images

The medication comes in two formulations: a weekly and a monthly version. The weekly treatment is indicated in patients who have initiated treatment with a single dose of transmucosal buprenorphine or who are already being treated with the drug. The monthly version is for patients already receiving buprenorphine.

“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, MD, in a release. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework,” Dr. Califf added.

The Substance Abuse and Mental Health Services Administration reports that patients receiving medication for OUD have their risk for all-cause mortality cut by 50%.

In its release, the FDA said that it remains committed to increasing treatment options for OUD. Earlier this month, the agency issued a joint letter with SAMHSA to underscore the importance of counseling and other services as part of a comprehensive treatment plan the disorder. It also emphasized that receiving buprenorphine should not be contingent on participating in such services.

Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for patients who do not tolerate higher doses of extended-release buprenorphine that are currently available.

The drug will be available through a Risk Evaluation and Mitigation Strategy program and administered only by health care providers in a health care setting.

The most common adverse reactions associated with the drug include injection-site pain, headache, constipation, nausea, injection-site erythema, injection-site pruritus, insomnia, and urinary tract infections. The FDA reports that such side effects occur in at least 5% of patients.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has approved extended-release injection buprenorphine (Brixadi, Braeburn) for the treatment of moderate to severe opioid use disorder (OUD).

Olivier Le Moal/Getty Images

The medication comes in two formulations: a weekly and a monthly version. The weekly treatment is indicated in patients who have initiated treatment with a single dose of transmucosal buprenorphine or who are already being treated with the drug. The monthly version is for patients already receiving buprenorphine.

“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, MD, in a release. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework,” Dr. Califf added.

The Substance Abuse and Mental Health Services Administration reports that patients receiving medication for OUD have their risk for all-cause mortality cut by 50%.

In its release, the FDA said that it remains committed to increasing treatment options for OUD. Earlier this month, the agency issued a joint letter with SAMHSA to underscore the importance of counseling and other services as part of a comprehensive treatment plan the disorder. It also emphasized that receiving buprenorphine should not be contingent on participating in such services.

Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for patients who do not tolerate higher doses of extended-release buprenorphine that are currently available.

The drug will be available through a Risk Evaluation and Mitigation Strategy program and administered only by health care providers in a health care setting.

The most common adverse reactions associated with the drug include injection-site pain, headache, constipation, nausea, injection-site erythema, injection-site pruritus, insomnia, and urinary tract infections. The FDA reports that such side effects occur in at least 5% of patients.

A version of this article originally appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
 

Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”

The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.

“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.

The citrate-free formulation is thought to lead to less pain on injection.

Yuflyma will be available in prefilled syringe and autoinjector administration options.

Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.

Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.

If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.

Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.

In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.

The full prescribing information for Yuflyma is available here.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
 

Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”

The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.

“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.

The citrate-free formulation is thought to lead to less pain on injection.

Yuflyma will be available in prefilled syringe and autoinjector administration options.

Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.

Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.

If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.

Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.

In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.

The full prescribing information for Yuflyma is available here.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the biosimilar adalimumab-aaty (Yuflyma) in a citrate-free, high-concentration formulation, the manufacturer, Celltrion USA, announced today. It is the ninth biosimilar of adalimumab (Humira) to be approved in the United States.
 

Yuflyma is approved for the treatment of adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. It is also approved for polyarticular juvenile idiopathic arthritis for patients aged 2 years or older, as well as for Crohn’s disease in adults and in pediatric patients aged 6 years or older.

Wikimedia Commons/FitzColinGerald/Creative Commons License

The formulation was approved on the basis of a comprehensive data package of analytic, preclinical, and clinical studies, according to Celltrion USA, “demonstrating that Yuflyma is comparable to the reference product Humira in terms of efficacy, safety, pharmacokinetics, and immunogenicity up to 24 weeks and 1 year following treatment.”

The company conducted a double-blind, randomized phase 3 trial that compared switching from reference adalimumab to Yuflyma with continuing either reference adalimumab or Yuflyma for patients with active rheumatoid arthritis. In that trial, the efficacy, pharmacokinetics, safety, and immunogenicity of Yuflyma and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to Yuflyma.

“Currently, more than 80% of patients treated with Humira in the United States rely on a high-concentration and citrate-free formulation of this medication. The availability of a high-concentration and citrate-free formulation adalimumab biosimilar provides an important treatment option for patients with inflammatory diseases who benefit from this effective therapy,” said Jonathan Kay, MD, of the University of Massachusetts, Worcester, in the press release.

The citrate-free formulation is thought to lead to less pain on injection.

Yuflyma will be available in prefilled syringe and autoinjector administration options.

Celltrion USA plans to market the drug in the United States in July 2023. Following the initial launch of 40 mg/0.4 mL, the company plans to launch dose forms of 80 mg/0.8 mL and 20 mg/0.2 mL.

Celltrion USA is also seeking an interchangeability designation from the FDA following the completion of an interchangeability trial of 366 patients with chronic plaque psoriasis. The interchangeability designation would mean that patients successfully switched from Humira to Yuflyma multiple times in the trial. The interchangeability designation would allow pharmacists to autosubstitute Humira with Yuflyma. In these cases, individual state laws control how and whether physicians will be notified of this switch.

If interchangeability is approved for Yuflyma, which the company tentatively expects in the fourth quarter of 2024, it would be just the third interchangeable biosimilar approved by the FDA overall and the second adalimumab biosimilar to be designated as such, after adalimumab-adbm (Cyltezo) in October 2021.

Yuflyma was approved in Canada in December 2021 for 10 indications: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, adult ulcerative colitis, hidradenitis suppurativa, plaque psoriasis, adult uveitis, and pediatric uveitis.

In February 2022, the European Commission granted marketing authorization for Yuflyma across those 10 indications, as well as for nonradiographic axial spondyloarthritis, pediatric plaque psoriasis, and pediatric Crohn’s disease.

In April 2022, Celltrion USA signed a licensing agreement with AbbVie, the manufacturer of Humira. Under that agreement, Celltrion will pay royalties to AbbVie on sales of their individual biosimilars, and AbbVie agreed to drop all patent litigation.

The full prescribing information for Yuflyma is available here.

A version of this article first appeared on Medscape.com.

PARIS – The EfficAPSI study showed with real-world data that sublingual immunotherapy (SLIT) reduces the risks for asthma onset and the worsening of asthma symptoms for patients with allergic rhinitis. The research was presented at the 18th French-language allergy conference.

These results confirm that allergen immunotherapy, or “desensitization,” is indeed an etiologic treatment of this allergic condition.

SLIT encompasses personalized solutions created for an individual specifically for allergies to dust mites, grass, birch, cats, and so on. These preparations are commonly used by allergy specialists when establishing an AIT treatment plan.

In 2017, the French Health Authority published a report indicating that there was insufficient clinical proof regarding the efficacy of SLIT. It subsequently removed injectable forms of these allergen extracts from the list of drugs reimbursed by the state and reduced state reimbursement of sublingual SLIT preparations from 30% to 15%, a step it confirmed in March 2018 and that led to outrage from allergy specialists. The chair of the French allergy society at the time, Jocelyne Just, MD, PhD, argued that conducting double-blind, placebo-controlled studies for all types (grass pollen, birch pollen, dust mites, asthma, allergic rhinitis, subcutaneous injections, sublingual treatments, tablets, liquid preparations) would take decades. Furthermore, meta-analyses on the subject, despite being heterogeneous and unable to answer all questions, are indeed pointing to the effectiveness of SLIT. To supplement existing data and to answer the queries raised by the HAS, several studies have been launched, including EfficAPSI.

The pharmacoepidemiologic EfficAPSI study is the largest retrospective, real-world, longitudinal cohort study ever carried out regarding liquid SLIT using data stored in the French National Health Data System (SNDS). The primary objective of the study was to evaluate the real-world impact of liquid SLIT on the onset and worsening of asthma for patients with allergic rhinitis and to evaluate the impact of sublingual treatments on public health.

A cohort analysis of patients treated with SLIT and control patients treated for allergic rhinitis with or without treatment for asthma was carried out. The patients treated with SLIT for at least 2 consecutive years were anonymously selected from the SNDS using the Stallergenes Greer prescription database.

In all, 99,538 patients who received SLIT were compared with 333,082 control patients (those who had received treatment for allergic rhinitis without taking SLIT). Participants were stratified according to their treatment history for asthma and were paired using a propensity score to minimize comparison bias.

The main definition of the onset of asthma included the first prescription of an asthma medication, hospital admission for asthma, or a diagnosis of chronic asthma. The secondary definition omitted the prescription of any treatment, and the third (sensitive and specific) took into consideration an initial prescription of omalizumab or a prescription of three inhaled corticosteroids (ICSs) associated with or without a long-acting beta-2 agonist (LABA) for a period of 1 year, admission to the hospital, or chronic asthma.
 

Asthma risk reduced

Among patients with allergic rhinitis without preexisting asthma, liquid SLIT was associated with a significantly lower risk of asthma onset in comparison with the control group (primary hazard ratio: 0.77; secondary HR: 0.66; and tertiary HR: 0.62).

The risk reductions were significant and were consistent regardless of the allergens analyzed (tertiary HR, dust mites: 0.57; grass: 0.52) for all age groups. These new results that were based on the tertiary definition corroborate the results from the primary and secondary definitions.

“Overall, these results suggest a more than 20% reduction in the risk of asthma onset observed in patients treated with liquid SLIT and symptomatic drugs, compared to patients treated with symptomatic drugs only,” said study co-author Philippe Devillier, MD, PhD, research director at the respiratory tract diseases center of Foch Hospital, Paris. “These results are consistent with previous studies in the same French health care database, as well as in a German database with SLIT preparations in tablet form. This not only confirms the soundness of the methodology but also the benefit of liquid SLIT as an etiological treatment of respiratory allergies.”
 

Risk for worsening

Furthermore, in the same study, liquid SLIT treatment was associated with a 27% reduced risk for worsening asthma and a 36% reduced risk for severe asthma. Among patients with allergic rhinitis and preexisting asthma, liquid SLIT was associated with a significantly lower risk for worsening of asthma, compared with the control group (primary HR: 0.73; secondary HR: 0.61; and tertiary HR: 0.64). The primary definition was an initial prescription of an ICS-LABA combination in a patient treated with ICS alone, severe exacerbation of asthma symptoms, hospital admission, or a diagnosis of chronic asthma.

“The risk reductions were significant and consistent for the allergens analyzed,” said study co-author Pascal Demoly, MD, PhD, head of pulmonology at Montpellier University Hospital, France (tertiary HR, dust mites: 0.66; grass: 0.59; birch: 0.34; and cats: 0.77). “This was across all age groups,” he added.

“The results of the EfficAPSI real-world study on health data from the SNDS are consistent with outcomes from clinical trials, suggestive of a reduced risk of asthma onset in patients with allergic rhinitis receiving liquid SLIT, as well as a reduced risk of worsening of preexisting asthma,” said Devillier. “SLIT, in this case in the form of a liquid, thus appears to be an effective etiological treatment, since the use of symptomatic drugs, in particular preventer inhalers, but also reliever inhalers, is lower in patients treated with SLIT over at least two consecutive years, compared with paired control subjects. And it’s the same for the risk of treating asthma in nonasthmatic patients at the start of the study. EfficAPSI is the largest study using data from a comprehensive state drug reimbursement database, allowing us to assess the impact of liquid SLIT on public health. These results, also obtained with other allergen preparations, particularly in tablet form in French and German studies using data from health care databases, demonstrate the consistency of the data regarding the efficacy of SLIT.”

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

PARIS – The EfficAPSI study showed with real-world data that sublingual immunotherapy (SLIT) reduces the risks for asthma onset and the worsening of asthma symptoms for patients with allergic rhinitis. The research was presented at the 18th French-language allergy conference.

These results confirm that allergen immunotherapy, or “desensitization,” is indeed an etiologic treatment of this allergic condition.

SLIT encompasses personalized solutions created for an individual specifically for allergies to dust mites, grass, birch, cats, and so on. These preparations are commonly used by allergy specialists when establishing an AIT treatment plan.

In 2017, the French Health Authority published a report indicating that there was insufficient clinical proof regarding the efficacy of SLIT. It subsequently removed injectable forms of these allergen extracts from the list of drugs reimbursed by the state and reduced state reimbursement of sublingual SLIT preparations from 30% to 15%, a step it confirmed in March 2018 and that led to outrage from allergy specialists. The chair of the French allergy society at the time, Jocelyne Just, MD, PhD, argued that conducting double-blind, placebo-controlled studies for all types (grass pollen, birch pollen, dust mites, asthma, allergic rhinitis, subcutaneous injections, sublingual treatments, tablets, liquid preparations) would take decades. Furthermore, meta-analyses on the subject, despite being heterogeneous and unable to answer all questions, are indeed pointing to the effectiveness of SLIT. To supplement existing data and to answer the queries raised by the HAS, several studies have been launched, including EfficAPSI.

The pharmacoepidemiologic EfficAPSI study is the largest retrospective, real-world, longitudinal cohort study ever carried out regarding liquid SLIT using data stored in the French National Health Data System (SNDS). The primary objective of the study was to evaluate the real-world impact of liquid SLIT on the onset and worsening of asthma for patients with allergic rhinitis and to evaluate the impact of sublingual treatments on public health.

A cohort analysis of patients treated with SLIT and control patients treated for allergic rhinitis with or without treatment for asthma was carried out. The patients treated with SLIT for at least 2 consecutive years were anonymously selected from the SNDS using the Stallergenes Greer prescription database.

In all, 99,538 patients who received SLIT were compared with 333,082 control patients (those who had received treatment for allergic rhinitis without taking SLIT). Participants were stratified according to their treatment history for asthma and were paired using a propensity score to minimize comparison bias.

The main definition of the onset of asthma included the first prescription of an asthma medication, hospital admission for asthma, or a diagnosis of chronic asthma. The secondary definition omitted the prescription of any treatment, and the third (sensitive and specific) took into consideration an initial prescription of omalizumab or a prescription of three inhaled corticosteroids (ICSs) associated with or without a long-acting beta-2 agonist (LABA) for a period of 1 year, admission to the hospital, or chronic asthma.
 

Asthma risk reduced

Among patients with allergic rhinitis without preexisting asthma, liquid SLIT was associated with a significantly lower risk of asthma onset in comparison with the control group (primary hazard ratio: 0.77; secondary HR: 0.66; and tertiary HR: 0.62).

The risk reductions were significant and were consistent regardless of the allergens analyzed (tertiary HR, dust mites: 0.57; grass: 0.52) for all age groups. These new results that were based on the tertiary definition corroborate the results from the primary and secondary definitions.

“Overall, these results suggest a more than 20% reduction in the risk of asthma onset observed in patients treated with liquid SLIT and symptomatic drugs, compared to patients treated with symptomatic drugs only,” said study co-author Philippe Devillier, MD, PhD, research director at the respiratory tract diseases center of Foch Hospital, Paris. “These results are consistent with previous studies in the same French health care database, as well as in a German database with SLIT preparations in tablet form. This not only confirms the soundness of the methodology but also the benefit of liquid SLIT as an etiological treatment of respiratory allergies.”
 

Risk for worsening

Furthermore, in the same study, liquid SLIT treatment was associated with a 27% reduced risk for worsening asthma and a 36% reduced risk for severe asthma. Among patients with allergic rhinitis and preexisting asthma, liquid SLIT was associated with a significantly lower risk for worsening of asthma, compared with the control group (primary HR: 0.73; secondary HR: 0.61; and tertiary HR: 0.64). The primary definition was an initial prescription of an ICS-LABA combination in a patient treated with ICS alone, severe exacerbation of asthma symptoms, hospital admission, or a diagnosis of chronic asthma.

“The risk reductions were significant and consistent for the allergens analyzed,” said study co-author Pascal Demoly, MD, PhD, head of pulmonology at Montpellier University Hospital, France (tertiary HR, dust mites: 0.66; grass: 0.59; birch: 0.34; and cats: 0.77). “This was across all age groups,” he added.

“The results of the EfficAPSI real-world study on health data from the SNDS are consistent with outcomes from clinical trials, suggestive of a reduced risk of asthma onset in patients with allergic rhinitis receiving liquid SLIT, as well as a reduced risk of worsening of preexisting asthma,” said Devillier. “SLIT, in this case in the form of a liquid, thus appears to be an effective etiological treatment, since the use of symptomatic drugs, in particular preventer inhalers, but also reliever inhalers, is lower in patients treated with SLIT over at least two consecutive years, compared with paired control subjects. And it’s the same for the risk of treating asthma in nonasthmatic patients at the start of the study. EfficAPSI is the largest study using data from a comprehensive state drug reimbursement database, allowing us to assess the impact of liquid SLIT on public health. These results, also obtained with other allergen preparations, particularly in tablet form in French and German studies using data from health care databases, demonstrate the consistency of the data regarding the efficacy of SLIT.”

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

PARIS – The EfficAPSI study showed with real-world data that sublingual immunotherapy (SLIT) reduces the risks for asthma onset and the worsening of asthma symptoms for patients with allergic rhinitis. The research was presented at the 18th French-language allergy conference.

These results confirm that allergen immunotherapy, or “desensitization,” is indeed an etiologic treatment of this allergic condition.

SLIT encompasses personalized solutions created for an individual specifically for allergies to dust mites, grass, birch, cats, and so on. These preparations are commonly used by allergy specialists when establishing an AIT treatment plan.

In 2017, the French Health Authority published a report indicating that there was insufficient clinical proof regarding the efficacy of SLIT. It subsequently removed injectable forms of these allergen extracts from the list of drugs reimbursed by the state and reduced state reimbursement of sublingual SLIT preparations from 30% to 15%, a step it confirmed in March 2018 and that led to outrage from allergy specialists. The chair of the French allergy society at the time, Jocelyne Just, MD, PhD, argued that conducting double-blind, placebo-controlled studies for all types (grass pollen, birch pollen, dust mites, asthma, allergic rhinitis, subcutaneous injections, sublingual treatments, tablets, liquid preparations) would take decades. Furthermore, meta-analyses on the subject, despite being heterogeneous and unable to answer all questions, are indeed pointing to the effectiveness of SLIT. To supplement existing data and to answer the queries raised by the HAS, several studies have been launched, including EfficAPSI.

The pharmacoepidemiologic EfficAPSI study is the largest retrospective, real-world, longitudinal cohort study ever carried out regarding liquid SLIT using data stored in the French National Health Data System (SNDS). The primary objective of the study was to evaluate the real-world impact of liquid SLIT on the onset and worsening of asthma for patients with allergic rhinitis and to evaluate the impact of sublingual treatments on public health.

A cohort analysis of patients treated with SLIT and control patients treated for allergic rhinitis with or without treatment for asthma was carried out. The patients treated with SLIT for at least 2 consecutive years were anonymously selected from the SNDS using the Stallergenes Greer prescription database.

In all, 99,538 patients who received SLIT were compared with 333,082 control patients (those who had received treatment for allergic rhinitis without taking SLIT). Participants were stratified according to their treatment history for asthma and were paired using a propensity score to minimize comparison bias.

The main definition of the onset of asthma included the first prescription of an asthma medication, hospital admission for asthma, or a diagnosis of chronic asthma. The secondary definition omitted the prescription of any treatment, and the third (sensitive and specific) took into consideration an initial prescription of omalizumab or a prescription of three inhaled corticosteroids (ICSs) associated with or without a long-acting beta-2 agonist (LABA) for a period of 1 year, admission to the hospital, or chronic asthma.
 

Asthma risk reduced

Among patients with allergic rhinitis without preexisting asthma, liquid SLIT was associated with a significantly lower risk of asthma onset in comparison with the control group (primary hazard ratio: 0.77; secondary HR: 0.66; and tertiary HR: 0.62).

The risk reductions were significant and were consistent regardless of the allergens analyzed (tertiary HR, dust mites: 0.57; grass: 0.52) for all age groups. These new results that were based on the tertiary definition corroborate the results from the primary and secondary definitions.

“Overall, these results suggest a more than 20% reduction in the risk of asthma onset observed in patients treated with liquid SLIT and symptomatic drugs, compared to patients treated with symptomatic drugs only,” said study co-author Philippe Devillier, MD, PhD, research director at the respiratory tract diseases center of Foch Hospital, Paris. “These results are consistent with previous studies in the same French health care database, as well as in a German database with SLIT preparations in tablet form. This not only confirms the soundness of the methodology but also the benefit of liquid SLIT as an etiological treatment of respiratory allergies.”
 

Risk for worsening

Furthermore, in the same study, liquid SLIT treatment was associated with a 27% reduced risk for worsening asthma and a 36% reduced risk for severe asthma. Among patients with allergic rhinitis and preexisting asthma, liquid SLIT was associated with a significantly lower risk for worsening of asthma, compared with the control group (primary HR: 0.73; secondary HR: 0.61; and tertiary HR: 0.64). The primary definition was an initial prescription of an ICS-LABA combination in a patient treated with ICS alone, severe exacerbation of asthma symptoms, hospital admission, or a diagnosis of chronic asthma.

“The risk reductions were significant and consistent for the allergens analyzed,” said study co-author Pascal Demoly, MD, PhD, head of pulmonology at Montpellier University Hospital, France (tertiary HR, dust mites: 0.66; grass: 0.59; birch: 0.34; and cats: 0.77). “This was across all age groups,” he added.

“The results of the EfficAPSI real-world study on health data from the SNDS are consistent with outcomes from clinical trials, suggestive of a reduced risk of asthma onset in patients with allergic rhinitis receiving liquid SLIT, as well as a reduced risk of worsening of preexisting asthma,” said Devillier. “SLIT, in this case in the form of a liquid, thus appears to be an effective etiological treatment, since the use of symptomatic drugs, in particular preventer inhalers, but also reliever inhalers, is lower in patients treated with SLIT over at least two consecutive years, compared with paired control subjects. And it’s the same for the risk of treating asthma in nonasthmatic patients at the start of the study. EfficAPSI is the largest study using data from a comprehensive state drug reimbursement database, allowing us to assess the impact of liquid SLIT on public health. These results, also obtained with other allergen preparations, particularly in tablet form in French and German studies using data from health care databases, demonstrate the consistency of the data regarding the efficacy of SLIT.”

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved avapritinib (AYVAKIT, Blueprint Medicines) for the treatment of adults with indolent systemic mastocytosis. The new approval, which expands use of the drug to patients with indolent systemic mastocytosis, represents the “first and only approved medicine” to treat this disease, according to the company press statement.

Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.

The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.

The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.

The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).

Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.

“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.

A version of this article first appeared on Medscape.com.

Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.

The U.S. Food and Drug Administration has approved avapritinib (AYVAKIT, Blueprint Medicines) for the treatment of adults with indolent systemic mastocytosis. The new approval, which expands use of the drug to patients with indolent systemic mastocytosis, represents the “first and only approved medicine” to treat this disease, according to the company press statement.

Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.

The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.

The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.

The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).

Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.

“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.

A version of this article first appeared on Medscape.com.

Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.

The U.S. Food and Drug Administration has approved avapritinib (AYVAKIT, Blueprint Medicines) for the treatment of adults with indolent systemic mastocytosis. The new approval, which expands use of the drug to patients with indolent systemic mastocytosis, represents the “first and only approved medicine” to treat this disease, according to the company press statement.

Avapritinib, a selective KIT mutation-targeted tyrosine kinase inhibitor, was approved in 2021 to treat advanced systemic mastocytosis, a rare and potentially fatal hematologic disorder. Nonadvanced forms include indolent or smoldering disease; advanced disease can progress to leukemia. The expanded approval now covers patients with indolent disease, which represents the majority of patients with systemic mastocytosis.

The drug is also approved for adults with unresectable or metastatic GIST that harbors a platelet-derived growth factor receptor alpha exon 18 mutation.

The approval is based on data from the phase 2 PIONEER trial. In the trial, 222 patients with moderate to severe indolent, systemic mastocytosis* were randomly assigned in a 2:1 ratio to receive either avapritinib 25 mg once daily plus best supportive care or placebo plus best supportive care.

The findings, published in February, revealed that patients who received avapritinib experienced significantly greater improvements in total symptom scores at 24 weeks (–15.6 vs. –9.2 for control patients). Significantly more patients in the avapritinib arm achieved greater than or equal to 50% reductions in serum tryptase (54% vs. 0%), bone marrow mast cell aggregates (53% vs. 23%), and KIT D816V variant allele fraction (68% vs. 6%).

Most adverse reactions were mild to moderate in severity and included eye edema, dizziness, peripheral edema, and flushing. Fewer than 1% of patients discontinued treatment because of serious adverse reactions.

“People with indolent systemic mastocytosis are significantly impacted by their disease symptoms, and many individuals self-isolate at home to protect against unpredictable external triggers,” Judith Kain Emmel, board chair of the Mast Cell Disease Society, said in the company press release. “Today’s approval is a historic moment for the [systemic mastocytosis] community and offers new hope for patients and their families.

A version of this article first appeared on Medscape.com.

Correction, 5/23/23: An earlier version of this article mischaracterized these patients' conditions. They had moderate to severe indolent, systemic mastocytosis.

The U.S. Food and Drug Administration has approved pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases/Protalix BioTherapeutics), an enzyme replacement therapy (ERT) to treat adults with confirmed Fabry disease.

Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme alpha-galactosidase A (GLA), which leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, the heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems.

Elfabrio delivers a functional version of GLA. It’s given by intravenous infusion every 2 weeks.

Evidence for safety, tolerability, and efficacy of Elfabrio stems from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.

It has been studied in both ERT-naïve and ERT-experienced patients. In one head-to-head trial, Elfabrio was non-inferior in safety and efficacy to agalsidase beta (Fabrazyme, Sanofi Genzyme), the companies said in a press statement announcing approval.

“The totality of clinical data suggests that Elfabrio has the potential to be a long-lasting therapy,” Dror Bashan, president and CEO of Protalix, said in the statement.

Patients treated with Elfabrio have experienced hypersensitivity reactions, including anaphylaxis. In clinical trials, 20 (14%) patients treated with Elfabrio experienced hypersensitivity reactions; 4 patients (3%) experienced anaphylaxis reactions that occurred within 5-40 minutes of the start of the initial infusion.

Before administering Elfabrio, pretreatment with antihistamines, antipyretics, and/or corticosteroids should be considered, the label advises.

Patients and caregivers should be informed of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and instructed to seek medical care immediately if such symptoms occur.

A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials. Monitoring serum creatinine and urinary protein-to-creatinine ratio is advised. If glomerulonephritis is suspected, treatment should be stopped until a diagnostic evaluation can be conducted.

Full prescribing information is available online.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases/Protalix BioTherapeutics), an enzyme replacement therapy (ERT) to treat adults with confirmed Fabry disease.

Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme alpha-galactosidase A (GLA), which leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, the heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems.

Elfabrio delivers a functional version of GLA. It’s given by intravenous infusion every 2 weeks.

Evidence for safety, tolerability, and efficacy of Elfabrio stems from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.

It has been studied in both ERT-naïve and ERT-experienced patients. In one head-to-head trial, Elfabrio was non-inferior in safety and efficacy to agalsidase beta (Fabrazyme, Sanofi Genzyme), the companies said in a press statement announcing approval.

“The totality of clinical data suggests that Elfabrio has the potential to be a long-lasting therapy,” Dror Bashan, president and CEO of Protalix, said in the statement.

Patients treated with Elfabrio have experienced hypersensitivity reactions, including anaphylaxis. In clinical trials, 20 (14%) patients treated with Elfabrio experienced hypersensitivity reactions; 4 patients (3%) experienced anaphylaxis reactions that occurred within 5-40 minutes of the start of the initial infusion.

Before administering Elfabrio, pretreatment with antihistamines, antipyretics, and/or corticosteroids should be considered, the label advises.

Patients and caregivers should be informed of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and instructed to seek medical care immediately if such symptoms occur.

A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials. Monitoring serum creatinine and urinary protein-to-creatinine ratio is advised. If glomerulonephritis is suspected, treatment should be stopped until a diagnostic evaluation can be conducted.

Full prescribing information is available online.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases/Protalix BioTherapeutics), an enzyme replacement therapy (ERT) to treat adults with confirmed Fabry disease.

Fabry disease is a rare inherited X-linked lysosomal disorder caused by a deficiency of the enzyme alpha-galactosidase A (GLA), which leads to the buildup of globotriaosylceramide (GL-3) in blood vessels, kidneys, the heart, nerves, and other organs, increasing the risk for kidney failure, myocardial infarction, stroke, and other problems.

Elfabrio delivers a functional version of GLA. It’s given by intravenous infusion every 2 weeks.

Evidence for safety, tolerability, and efficacy of Elfabrio stems from a comprehensive clinical program in more than 140 patients with up to 7.5 years of follow up treatment.

It has been studied in both ERT-naïve and ERT-experienced patients. In one head-to-head trial, Elfabrio was non-inferior in safety and efficacy to agalsidase beta (Fabrazyme, Sanofi Genzyme), the companies said in a press statement announcing approval.

“The totality of clinical data suggests that Elfabrio has the potential to be a long-lasting therapy,” Dror Bashan, president and CEO of Protalix, said in the statement.

Patients treated with Elfabrio have experienced hypersensitivity reactions, including anaphylaxis. In clinical trials, 20 (14%) patients treated with Elfabrio experienced hypersensitivity reactions; 4 patients (3%) experienced anaphylaxis reactions that occurred within 5-40 minutes of the start of the initial infusion.

Before administering Elfabrio, pretreatment with antihistamines, antipyretics, and/or corticosteroids should be considered, the label advises.

Patients and caregivers should be informed of the signs and symptoms of hypersensitivity reactions and infusion-associated reactions and instructed to seek medical care immediately if such symptoms occur.

A case of membranoproliferative glomerulonephritis with immune depositions in the kidney was reported during clinical trials. Monitoring serum creatinine and urinary protein-to-creatinine ratio is advised. If glomerulonephritis is suspected, treatment should be stopped until a diagnostic evaluation can be conducted.

Full prescribing information is available online.

A version of this article first appeared on Medscape.com.