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FDA OKs Subcutaneous Vedolizumab for Crohn’s Maintenance Therapy
The move follows the FDA’s approval last year of subcutaneous vedolizumab for maintenance treatment of adults with moderately to severely active ulcerative colitis (UC).
The humanized immunoglobulin G1 monoclonal antibody is available as a single-dose prefilled pen (Entyvio Pen).
The FDA first approved the IV formulation of the biologic in 2014 for patients with moderate to severe UC and CD who cannot tolerate other therapies or in whom such therapies have failed.
The approval of subcutaneous vedolizumab for maintenance treatment of CD is based on the phase 3, randomized, double-blind, placebo-controlled VISIBLE 2 trial.
The trial enrolled 409 adult patients with moderately to severely active CD who had clinical response at week 6 following two doses of open-label IV vedolizumab at weeks 0 and 2.
At week 6, they were randomly allocated in a 2:1 ratio to receive vedolizumab 108 mg administered by subcutaneous injection or placebo every 2 weeks. The primary endpoint was clinical remission at week 52, which was defined as a total Crohn’s Disease Activity Index score ≤ 150.
The results showed that significantly more patients receiving subcutaneous vedolizumab than placebo achieved long-term clinical remission (48% vs 34%; P < .01), the company said in a news release.
The safety profile of subcutaneous vedolizumab is generally consistent with the known safety profile of IV vedolizumab, with the addition of injection-site reactions (including injection-site erythema, rash, pruritus, swelling, bruising, hematoma, pain, urticaria, and edema).
“Crohn’s disease is a complex and usually progressive disease for which an appropriate management plan is critical. My primary goal as a clinician is always to get patients to achieve remission,” Timothy Ritter, MD, senior medical director, GI Alliance Research, and assistant professor of medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, said in the news release.
“In VISIBLE 2, about half of patients treated with Entyvio SC achieved long-term clinical remission. The data from VISIBLE 2 reaffirm the well-established efficacy profile of Entyvio, regardless of route of administration,” Dr. Ritter added.
A version of this article appeared on Medscape.com.
The move follows the FDA’s approval last year of subcutaneous vedolizumab for maintenance treatment of adults with moderately to severely active ulcerative colitis (UC).
The humanized immunoglobulin G1 monoclonal antibody is available as a single-dose prefilled pen (Entyvio Pen).
The FDA first approved the IV formulation of the biologic in 2014 for patients with moderate to severe UC and CD who cannot tolerate other therapies or in whom such therapies have failed.
The approval of subcutaneous vedolizumab for maintenance treatment of CD is based on the phase 3, randomized, double-blind, placebo-controlled VISIBLE 2 trial.
The trial enrolled 409 adult patients with moderately to severely active CD who had clinical response at week 6 following two doses of open-label IV vedolizumab at weeks 0 and 2.
At week 6, they were randomly allocated in a 2:1 ratio to receive vedolizumab 108 mg administered by subcutaneous injection or placebo every 2 weeks. The primary endpoint was clinical remission at week 52, which was defined as a total Crohn’s Disease Activity Index score ≤ 150.
The results showed that significantly more patients receiving subcutaneous vedolizumab than placebo achieved long-term clinical remission (48% vs 34%; P < .01), the company said in a news release.
The safety profile of subcutaneous vedolizumab is generally consistent with the known safety profile of IV vedolizumab, with the addition of injection-site reactions (including injection-site erythema, rash, pruritus, swelling, bruising, hematoma, pain, urticaria, and edema).
“Crohn’s disease is a complex and usually progressive disease for which an appropriate management plan is critical. My primary goal as a clinician is always to get patients to achieve remission,” Timothy Ritter, MD, senior medical director, GI Alliance Research, and assistant professor of medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, said in the news release.
“In VISIBLE 2, about half of patients treated with Entyvio SC achieved long-term clinical remission. The data from VISIBLE 2 reaffirm the well-established efficacy profile of Entyvio, regardless of route of administration,” Dr. Ritter added.
A version of this article appeared on Medscape.com.
The move follows the FDA’s approval last year of subcutaneous vedolizumab for maintenance treatment of adults with moderately to severely active ulcerative colitis (UC).
The humanized immunoglobulin G1 monoclonal antibody is available as a single-dose prefilled pen (Entyvio Pen).
The FDA first approved the IV formulation of the biologic in 2014 for patients with moderate to severe UC and CD who cannot tolerate other therapies or in whom such therapies have failed.
The approval of subcutaneous vedolizumab for maintenance treatment of CD is based on the phase 3, randomized, double-blind, placebo-controlled VISIBLE 2 trial.
The trial enrolled 409 adult patients with moderately to severely active CD who had clinical response at week 6 following two doses of open-label IV vedolizumab at weeks 0 and 2.
At week 6, they were randomly allocated in a 2:1 ratio to receive vedolizumab 108 mg administered by subcutaneous injection or placebo every 2 weeks. The primary endpoint was clinical remission at week 52, which was defined as a total Crohn’s Disease Activity Index score ≤ 150.
The results showed that significantly more patients receiving subcutaneous vedolizumab than placebo achieved long-term clinical remission (48% vs 34%; P < .01), the company said in a news release.
The safety profile of subcutaneous vedolizumab is generally consistent with the known safety profile of IV vedolizumab, with the addition of injection-site reactions (including injection-site erythema, rash, pruritus, swelling, bruising, hematoma, pain, urticaria, and edema).
“Crohn’s disease is a complex and usually progressive disease for which an appropriate management plan is critical. My primary goal as a clinician is always to get patients to achieve remission,” Timothy Ritter, MD, senior medical director, GI Alliance Research, and assistant professor of medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, said in the news release.
“In VISIBLE 2, about half of patients treated with Entyvio SC achieved long-term clinical remission. The data from VISIBLE 2 reaffirm the well-established efficacy profile of Entyvio, regardless of route of administration,” Dr. Ritter added.
A version of this article appeared on Medscape.com.
Approved Therapy for ALS Is Withdrawn When New Study Shows No Benefit
DENVER —
As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.
Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.
PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
ALSFRS-R Served as Primary Endpoint in Both Trials
In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).
The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.
In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.
For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.
Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.
As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
Differences Between Two Trials Were Evaluated
The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.
When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.
An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.
Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
‘Unfortunate’ Results
Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.
Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.
In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.
“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.
However, he believes that the study will still have value for better understanding ALS.
“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”
Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.
DENVER —
As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.
Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.
PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
ALSFRS-R Served as Primary Endpoint in Both Trials
In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).
The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.
In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.
For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.
Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.
As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
Differences Between Two Trials Were Evaluated
The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.
When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.
An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.
Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
‘Unfortunate’ Results
Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.
Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.
In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.
“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.
However, he believes that the study will still have value for better understanding ALS.
“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”
Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.
DENVER —
As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.
Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.
PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
ALSFRS-R Served as Primary Endpoint in Both Trials
In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).
The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.
In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.
For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.
Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.
As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
Differences Between Two Trials Were Evaluated
The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.
When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.
An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.
Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
‘Unfortunate’ Results
Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.
Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.
In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.
“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.
However, he believes that the study will still have value for better understanding ALS.
“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”
Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.
FROM AAN 2024
Positive Results From Phase 2 Trial Support Potential New Option for Control of CIDP
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
FROM AAN 2024
The Obesogenic Environment of Preschool and Day Care
Thirty years ago I had an experience in the office that influenced my approach to obesity for the rest of my career. The patient was a 4-year-old whom I had been seeing since her birth. At her annual well-child visit her weight had jumped up significantly from the previous year’s visit. She appeared well, but the change in her growth trajectory prompted a bit more in-depth history taking.
It turned out that finances had forced the family to employ one of the child’s grandmothers as the day care provider. Unfortunately, this grandmother’s passion was cooking and she was particularly adept at baking. She had no other hobbies and a sore hip limited her mobility, so she seldom went outside. When I eventually met her she was a cheerful, overweight, and delightful woman.
Deconstructing this obesogenic environment without disrupting this otherwise healthy family was an exercise that required tact, patience, and creativity. Fortunately, the young girl’s mother had already harbored some concerns about her child’s weight and was more than willing to participate in this environmental re-engineering project. It’s a long story, but she and I achieved our goals and the child eventually coasted back toward her previous growth curve.
I have always suspected that this scenario is being replayed hundreds of thousands of time across this country. But, sadly most don’t share this one’s happy ending. Parents don’t alway perceive the seriousness of the problem. The economic hurdles are often too steep to overcome, even when the most creative minds are involved.
How prevalent are obesogenic day care environments? We certainly know childhood obesity is a problem and the statistics in the preschool age group are particularly concerning. More than 14 million children are in non-parental early care and education programs; these environments would seem to be a logical place to target our prevention strategies. Understandably, there seems to be a hesitancy to point fingers, but how many day care providers are similar to the well-intentioned grandmother in the scenario I described? We must at least suspect that the example set by the adults in the preschool and day care environment might be having some influence on the children under their care.
There has been some research that sheds some light on this question. A paper from the University of Oklahoma has looked at the predictors of overweight and obesity in early care and education (ECE) teachers in hopes of “finding modifiable opportunities to enhance the health of this critical workforce.” In their paper, the investigators refer to other research that has found the prevalence of overweight and obesity among ECE teachers is higher than our national average and their waist circumference is significantly greater than the standard recommendation for women.
A study from Norway has looked at the association between preschool staff’s activity level and that of the children under their care using accelerometers. This particular investigation couldn’t determine whether it was the staff’s activity level that influenced the children or vice versa because it wasn’t an observational study. Common sense would lead one to believe it was the staff’s relative inactivity that was being reflected in the children’s.
It is interesting that in this Norwegian study when the teachers were asked about their attitudes toward activity and their self-perception of their own activity, there was no relationship between the staff’s and the children’s level of activity. In other words, the educators and caregivers bought into the importance of activity but had difficulty translating this philosophy into own behavior.
So where does this leave us? It turns out my experience decades ago was not a one-off event, but instead represents the tip of very large iceberg. Should we immediately create a system of day care provider boot camps? Let’s remember that each educator and caregiver is one of us. They may be slight outliers but not a group of individuals deserving of forced marches and half-rations to get them in shape.
ECEs have listened to the same message we have all heard about diet and activity and their importance for a child’s health. It’s for their own health and that of their charges. This could be as simple as providing accelerometers or step-counting smartwatches. Or, by having physical educators perform on-site audits that could then be used to create site-specific plans for increasing both teacher and student activity.
Modifying the educators’ diet is a more complex procedure and can quickly become entangled in the socio-economic background of each individual teacher. A healthy diet is not always equally available to everyone. The solution may involve providing the teachers with food to be eaten at work and to be prepared at home. But, creative answers can be found if we look for them.
Before we get too far down the obesity-is-a-disease pathway, we must take a closer look at the role the early care and early school milieu are playing in the obesity problem. A little common sense behavior modification when children are in the controlled environment of school/day care may allow us to be less reliant on the those new wonder drugs in the long run.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Thirty years ago I had an experience in the office that influenced my approach to obesity for the rest of my career. The patient was a 4-year-old whom I had been seeing since her birth. At her annual well-child visit her weight had jumped up significantly from the previous year’s visit. She appeared well, but the change in her growth trajectory prompted a bit more in-depth history taking.
It turned out that finances had forced the family to employ one of the child’s grandmothers as the day care provider. Unfortunately, this grandmother’s passion was cooking and she was particularly adept at baking. She had no other hobbies and a sore hip limited her mobility, so she seldom went outside. When I eventually met her she was a cheerful, overweight, and delightful woman.
Deconstructing this obesogenic environment without disrupting this otherwise healthy family was an exercise that required tact, patience, and creativity. Fortunately, the young girl’s mother had already harbored some concerns about her child’s weight and was more than willing to participate in this environmental re-engineering project. It’s a long story, but she and I achieved our goals and the child eventually coasted back toward her previous growth curve.
I have always suspected that this scenario is being replayed hundreds of thousands of time across this country. But, sadly most don’t share this one’s happy ending. Parents don’t alway perceive the seriousness of the problem. The economic hurdles are often too steep to overcome, even when the most creative minds are involved.
How prevalent are obesogenic day care environments? We certainly know childhood obesity is a problem and the statistics in the preschool age group are particularly concerning. More than 14 million children are in non-parental early care and education programs; these environments would seem to be a logical place to target our prevention strategies. Understandably, there seems to be a hesitancy to point fingers, but how many day care providers are similar to the well-intentioned grandmother in the scenario I described? We must at least suspect that the example set by the adults in the preschool and day care environment might be having some influence on the children under their care.
There has been some research that sheds some light on this question. A paper from the University of Oklahoma has looked at the predictors of overweight and obesity in early care and education (ECE) teachers in hopes of “finding modifiable opportunities to enhance the health of this critical workforce.” In their paper, the investigators refer to other research that has found the prevalence of overweight and obesity among ECE teachers is higher than our national average and their waist circumference is significantly greater than the standard recommendation for women.
A study from Norway has looked at the association between preschool staff’s activity level and that of the children under their care using accelerometers. This particular investigation couldn’t determine whether it was the staff’s activity level that influenced the children or vice versa because it wasn’t an observational study. Common sense would lead one to believe it was the staff’s relative inactivity that was being reflected in the children’s.
It is interesting that in this Norwegian study when the teachers were asked about their attitudes toward activity and their self-perception of their own activity, there was no relationship between the staff’s and the children’s level of activity. In other words, the educators and caregivers bought into the importance of activity but had difficulty translating this philosophy into own behavior.
So where does this leave us? It turns out my experience decades ago was not a one-off event, but instead represents the tip of very large iceberg. Should we immediately create a system of day care provider boot camps? Let’s remember that each educator and caregiver is one of us. They may be slight outliers but not a group of individuals deserving of forced marches and half-rations to get them in shape.
ECEs have listened to the same message we have all heard about diet and activity and their importance for a child’s health. It’s for their own health and that of their charges. This could be as simple as providing accelerometers or step-counting smartwatches. Or, by having physical educators perform on-site audits that could then be used to create site-specific plans for increasing both teacher and student activity.
Modifying the educators’ diet is a more complex procedure and can quickly become entangled in the socio-economic background of each individual teacher. A healthy diet is not always equally available to everyone. The solution may involve providing the teachers with food to be eaten at work and to be prepared at home. But, creative answers can be found if we look for them.
Before we get too far down the obesity-is-a-disease pathway, we must take a closer look at the role the early care and early school milieu are playing in the obesity problem. A little common sense behavior modification when children are in the controlled environment of school/day care may allow us to be less reliant on the those new wonder drugs in the long run.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Thirty years ago I had an experience in the office that influenced my approach to obesity for the rest of my career. The patient was a 4-year-old whom I had been seeing since her birth. At her annual well-child visit her weight had jumped up significantly from the previous year’s visit. She appeared well, but the change in her growth trajectory prompted a bit more in-depth history taking.
It turned out that finances had forced the family to employ one of the child’s grandmothers as the day care provider. Unfortunately, this grandmother’s passion was cooking and she was particularly adept at baking. She had no other hobbies and a sore hip limited her mobility, so she seldom went outside. When I eventually met her she was a cheerful, overweight, and delightful woman.
Deconstructing this obesogenic environment without disrupting this otherwise healthy family was an exercise that required tact, patience, and creativity. Fortunately, the young girl’s mother had already harbored some concerns about her child’s weight and was more than willing to participate in this environmental re-engineering project. It’s a long story, but she and I achieved our goals and the child eventually coasted back toward her previous growth curve.
I have always suspected that this scenario is being replayed hundreds of thousands of time across this country. But, sadly most don’t share this one’s happy ending. Parents don’t alway perceive the seriousness of the problem. The economic hurdles are often too steep to overcome, even when the most creative minds are involved.
How prevalent are obesogenic day care environments? We certainly know childhood obesity is a problem and the statistics in the preschool age group are particularly concerning. More than 14 million children are in non-parental early care and education programs; these environments would seem to be a logical place to target our prevention strategies. Understandably, there seems to be a hesitancy to point fingers, but how many day care providers are similar to the well-intentioned grandmother in the scenario I described? We must at least suspect that the example set by the adults in the preschool and day care environment might be having some influence on the children under their care.
There has been some research that sheds some light on this question. A paper from the University of Oklahoma has looked at the predictors of overweight and obesity in early care and education (ECE) teachers in hopes of “finding modifiable opportunities to enhance the health of this critical workforce.” In their paper, the investigators refer to other research that has found the prevalence of overweight and obesity among ECE teachers is higher than our national average and their waist circumference is significantly greater than the standard recommendation for women.
A study from Norway has looked at the association between preschool staff’s activity level and that of the children under their care using accelerometers. This particular investigation couldn’t determine whether it was the staff’s activity level that influenced the children or vice versa because it wasn’t an observational study. Common sense would lead one to believe it was the staff’s relative inactivity that was being reflected in the children’s.
It is interesting that in this Norwegian study when the teachers were asked about their attitudes toward activity and their self-perception of their own activity, there was no relationship between the staff’s and the children’s level of activity. In other words, the educators and caregivers bought into the importance of activity but had difficulty translating this philosophy into own behavior.
So where does this leave us? It turns out my experience decades ago was not a one-off event, but instead represents the tip of very large iceberg. Should we immediately create a system of day care provider boot camps? Let’s remember that each educator and caregiver is one of us. They may be slight outliers but not a group of individuals deserving of forced marches and half-rations to get them in shape.
ECEs have listened to the same message we have all heard about diet and activity and their importance for a child’s health. It’s for their own health and that of their charges. This could be as simple as providing accelerometers or step-counting smartwatches. Or, by having physical educators perform on-site audits that could then be used to create site-specific plans for increasing both teacher and student activity.
Modifying the educators’ diet is a more complex procedure and can quickly become entangled in the socio-economic background of each individual teacher. A healthy diet is not always equally available to everyone. The solution may involve providing the teachers with food to be eaten at work and to be prepared at home. But, creative answers can be found if we look for them.
Before we get too far down the obesity-is-a-disease pathway, we must take a closer look at the role the early care and early school milieu are playing in the obesity problem. A little common sense behavior modification when children are in the controlled environment of school/day care may allow us to be less reliant on the those new wonder drugs in the long run.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Drug Prototype Shows Promise for Stem Cell Treatment of Pulmonary Disease
A drug prototype known as NZ-97 showed promise for treating pulmonary disease by stimulating growth of new stem cells to repair damaged tissue, based on data from a new proof-of-concept study.
In many pulmonary diseases, insufficient stem cells allow damage to progress, but researchers have developed a lung-targeted, drug-like small molecule to stimulate the growth of lung stem cells, according to data published in Proceedings of the National Academy of Sciences.
Michael J. Bollong, PhD, associate professor in the department of chemistry at Scripps Research, San Diego, and colleagues used ReFRAME, a drug repurposing library and database created by the Calibr-Skaggs Institute for Innovative Medicines (the drug discovery arm of Scripps Research) to test existing drugs as foundations to promote stem cell growth and repair in the lungs.
“At present, there are no drugs which promote regenerative repair of the lung,” Dr. Bollong said in an interview. “This is especially important in idiopathic pulmonary fibrosis, as this disease is driven by an insufficiency of the stem cell population of the lower airway, alveolar type 2 cells (AEC2s), to proliferate and to regenerate the gas exchange epithelium,” he said.
The researchers identified dipeptidyl peptidase 4 (DPP4) inhibitors as potential tools to help promote production of stem cells in the lower airway called AEC2s. Dysfunction of AEC2 is thought to play a key role in the pathogenesis of idiopathic pulmonary fibrosis, the researchers noted in the study. They created a new and highly soluble DPP4 inhibitor known as NZ-97 that could be administered via intratracheal injection.
In addition, 1 month of treatment with 0.5 mg/kg of NZ-97 every fourth day showed no detectable changes in alveolar structure, increased inflammation, or cellular hyperplasia.
The current research “identifies a novel mechanism for promoting alveolar repair” and treating not only idiopathic pulmonary fibrosis (IPF) but potentially other pulmonary diseases, such as chronic obstructive pulmonary disease, Dr. Bollong said.
“Here we reported a drug prototype, NZ-97, a locally delivered and lung-retained molecule that inhibits DPP4 in the lumen of the lung,” Bollong explained. The NZ-97 prototype drug is chemically similar to CMR316, a new clinical drug candidate from researchers at Calibr-Skaggs that is scheduled to start a phase 1 clinical trial later in the summer of 2024, according to Dr. Bollong.
CMR316 is designed to be delivered once a week in mist form via a nebulizer. “If CMR316 demonstrates ameliorative efficacy in IPF, it could provide a novel avenue for regenerating the lung and could be added on top of standard-of-care anti-fibrotic drugs to delay or potentially even reverse disease progression,” Dr. Bollong told this news organization.
“The key challenge will be understanding if the identified regenerative mechanism will show ameliorative efficacy in a clinical trial,” Dr. Bollong said. “While we have shown effects in animal models and patient-derived cells, the degree and duration of the ameliorative effect in patients will ultimately be determined in the clinic.”
Looking ahead, the CMR316 phase 1 clinical trial is designed to evaluate safety and target engagement, Dr. Bollong said. Dr. Bollong’s lab continues to collaborate with Calibr to develop other regenerative approaches to the treatment of disease in other organs, he said.
Meeting the Need for Regenerative Treatment
The current study and the ongoing research into NZ-97 address the need for regenerative therapies in pulmonary disease, Dharani K. Narendra, MD, of Baylor College of Medicine, Houston, Texas, said in an interview.
“Identifying DPP4 inhibitors, particularly NZ-97, as potential agents for expanding type 2 alveolar epithelial cells (AEC2s) represents a promising therapeutic strategy to stimulate the regeneration of damaged alveolar epithelium,” she said. “The AEC2s play a crucial role in lung repair, and targeting these could potentially ameliorate various lung diseases that currently lack effective treatments,” she explained.
“DPP4 inhibitors are well-established in diabetes management and have known biological actions; however, the successful repurposing and effectiveness of NZ-97 in promoting lung repair are surprising to some extent,” said Dr. Narendra. “This surprise stems from this medication’s novel application and efficacy in a pulmonary context, showing significant potential where traditional DPP4 inhibitors required higher, potentially unsafe doses to achieve similar effects,” she said.
Should research prove successful, NZ-97 could offer substantial clinical benefits for treating pulmonary diseases such as IPF and other conditions involving alveolar damage. By enhancing AEC2 proliferation, NZ-97 may improve patient outcomes by mitigating lung damage and promoting regenerative repair, possibly reducing the dependency on more invasive treatments like lung transplantation.
More research on NZ-97 is needed in order to identify potential barriers to its use, Dr. Narendra said. “Further studies are needed to evaluate the long-term effects of NZ-97, understand its mechanisms in human lung tissue, and determine its safety and efficacy in clinical settings.”
Dr. Narendra had no financial conflicts to disclose but served on the Editorial Board of Chest Physician.
A version of this article appeared on Medscape.com.
A drug prototype known as NZ-97 showed promise for treating pulmonary disease by stimulating growth of new stem cells to repair damaged tissue, based on data from a new proof-of-concept study.
In many pulmonary diseases, insufficient stem cells allow damage to progress, but researchers have developed a lung-targeted, drug-like small molecule to stimulate the growth of lung stem cells, according to data published in Proceedings of the National Academy of Sciences.
Michael J. Bollong, PhD, associate professor in the department of chemistry at Scripps Research, San Diego, and colleagues used ReFRAME, a drug repurposing library and database created by the Calibr-Skaggs Institute for Innovative Medicines (the drug discovery arm of Scripps Research) to test existing drugs as foundations to promote stem cell growth and repair in the lungs.
“At present, there are no drugs which promote regenerative repair of the lung,” Dr. Bollong said in an interview. “This is especially important in idiopathic pulmonary fibrosis, as this disease is driven by an insufficiency of the stem cell population of the lower airway, alveolar type 2 cells (AEC2s), to proliferate and to regenerate the gas exchange epithelium,” he said.
The researchers identified dipeptidyl peptidase 4 (DPP4) inhibitors as potential tools to help promote production of stem cells in the lower airway called AEC2s. Dysfunction of AEC2 is thought to play a key role in the pathogenesis of idiopathic pulmonary fibrosis, the researchers noted in the study. They created a new and highly soluble DPP4 inhibitor known as NZ-97 that could be administered via intratracheal injection.
In addition, 1 month of treatment with 0.5 mg/kg of NZ-97 every fourth day showed no detectable changes in alveolar structure, increased inflammation, or cellular hyperplasia.
The current research “identifies a novel mechanism for promoting alveolar repair” and treating not only idiopathic pulmonary fibrosis (IPF) but potentially other pulmonary diseases, such as chronic obstructive pulmonary disease, Dr. Bollong said.
“Here we reported a drug prototype, NZ-97, a locally delivered and lung-retained molecule that inhibits DPP4 in the lumen of the lung,” Bollong explained. The NZ-97 prototype drug is chemically similar to CMR316, a new clinical drug candidate from researchers at Calibr-Skaggs that is scheduled to start a phase 1 clinical trial later in the summer of 2024, according to Dr. Bollong.
CMR316 is designed to be delivered once a week in mist form via a nebulizer. “If CMR316 demonstrates ameliorative efficacy in IPF, it could provide a novel avenue for regenerating the lung and could be added on top of standard-of-care anti-fibrotic drugs to delay or potentially even reverse disease progression,” Dr. Bollong told this news organization.
“The key challenge will be understanding if the identified regenerative mechanism will show ameliorative efficacy in a clinical trial,” Dr. Bollong said. “While we have shown effects in animal models and patient-derived cells, the degree and duration of the ameliorative effect in patients will ultimately be determined in the clinic.”
Looking ahead, the CMR316 phase 1 clinical trial is designed to evaluate safety and target engagement, Dr. Bollong said. Dr. Bollong’s lab continues to collaborate with Calibr to develop other regenerative approaches to the treatment of disease in other organs, he said.
Meeting the Need for Regenerative Treatment
The current study and the ongoing research into NZ-97 address the need for regenerative therapies in pulmonary disease, Dharani K. Narendra, MD, of Baylor College of Medicine, Houston, Texas, said in an interview.
“Identifying DPP4 inhibitors, particularly NZ-97, as potential agents for expanding type 2 alveolar epithelial cells (AEC2s) represents a promising therapeutic strategy to stimulate the regeneration of damaged alveolar epithelium,” she said. “The AEC2s play a crucial role in lung repair, and targeting these could potentially ameliorate various lung diseases that currently lack effective treatments,” she explained.
“DPP4 inhibitors are well-established in diabetes management and have known biological actions; however, the successful repurposing and effectiveness of NZ-97 in promoting lung repair are surprising to some extent,” said Dr. Narendra. “This surprise stems from this medication’s novel application and efficacy in a pulmonary context, showing significant potential where traditional DPP4 inhibitors required higher, potentially unsafe doses to achieve similar effects,” she said.
Should research prove successful, NZ-97 could offer substantial clinical benefits for treating pulmonary diseases such as IPF and other conditions involving alveolar damage. By enhancing AEC2 proliferation, NZ-97 may improve patient outcomes by mitigating lung damage and promoting regenerative repair, possibly reducing the dependency on more invasive treatments like lung transplantation.
More research on NZ-97 is needed in order to identify potential barriers to its use, Dr. Narendra said. “Further studies are needed to evaluate the long-term effects of NZ-97, understand its mechanisms in human lung tissue, and determine its safety and efficacy in clinical settings.”
Dr. Narendra had no financial conflicts to disclose but served on the Editorial Board of Chest Physician.
A version of this article appeared on Medscape.com.
A drug prototype known as NZ-97 showed promise for treating pulmonary disease by stimulating growth of new stem cells to repair damaged tissue, based on data from a new proof-of-concept study.
In many pulmonary diseases, insufficient stem cells allow damage to progress, but researchers have developed a lung-targeted, drug-like small molecule to stimulate the growth of lung stem cells, according to data published in Proceedings of the National Academy of Sciences.
Michael J. Bollong, PhD, associate professor in the department of chemistry at Scripps Research, San Diego, and colleagues used ReFRAME, a drug repurposing library and database created by the Calibr-Skaggs Institute for Innovative Medicines (the drug discovery arm of Scripps Research) to test existing drugs as foundations to promote stem cell growth and repair in the lungs.
“At present, there are no drugs which promote regenerative repair of the lung,” Dr. Bollong said in an interview. “This is especially important in idiopathic pulmonary fibrosis, as this disease is driven by an insufficiency of the stem cell population of the lower airway, alveolar type 2 cells (AEC2s), to proliferate and to regenerate the gas exchange epithelium,” he said.
The researchers identified dipeptidyl peptidase 4 (DPP4) inhibitors as potential tools to help promote production of stem cells in the lower airway called AEC2s. Dysfunction of AEC2 is thought to play a key role in the pathogenesis of idiopathic pulmonary fibrosis, the researchers noted in the study. They created a new and highly soluble DPP4 inhibitor known as NZ-97 that could be administered via intratracheal injection.
In addition, 1 month of treatment with 0.5 mg/kg of NZ-97 every fourth day showed no detectable changes in alveolar structure, increased inflammation, or cellular hyperplasia.
The current research “identifies a novel mechanism for promoting alveolar repair” and treating not only idiopathic pulmonary fibrosis (IPF) but potentially other pulmonary diseases, such as chronic obstructive pulmonary disease, Dr. Bollong said.
“Here we reported a drug prototype, NZ-97, a locally delivered and lung-retained molecule that inhibits DPP4 in the lumen of the lung,” Bollong explained. The NZ-97 prototype drug is chemically similar to CMR316, a new clinical drug candidate from researchers at Calibr-Skaggs that is scheduled to start a phase 1 clinical trial later in the summer of 2024, according to Dr. Bollong.
CMR316 is designed to be delivered once a week in mist form via a nebulizer. “If CMR316 demonstrates ameliorative efficacy in IPF, it could provide a novel avenue for regenerating the lung and could be added on top of standard-of-care anti-fibrotic drugs to delay or potentially even reverse disease progression,” Dr. Bollong told this news organization.
“The key challenge will be understanding if the identified regenerative mechanism will show ameliorative efficacy in a clinical trial,” Dr. Bollong said. “While we have shown effects in animal models and patient-derived cells, the degree and duration of the ameliorative effect in patients will ultimately be determined in the clinic.”
Looking ahead, the CMR316 phase 1 clinical trial is designed to evaluate safety and target engagement, Dr. Bollong said. Dr. Bollong’s lab continues to collaborate with Calibr to develop other regenerative approaches to the treatment of disease in other organs, he said.
Meeting the Need for Regenerative Treatment
The current study and the ongoing research into NZ-97 address the need for regenerative therapies in pulmonary disease, Dharani K. Narendra, MD, of Baylor College of Medicine, Houston, Texas, said in an interview.
“Identifying DPP4 inhibitors, particularly NZ-97, as potential agents for expanding type 2 alveolar epithelial cells (AEC2s) represents a promising therapeutic strategy to stimulate the regeneration of damaged alveolar epithelium,” she said. “The AEC2s play a crucial role in lung repair, and targeting these could potentially ameliorate various lung diseases that currently lack effective treatments,” she explained.
“DPP4 inhibitors are well-established in diabetes management and have known biological actions; however, the successful repurposing and effectiveness of NZ-97 in promoting lung repair are surprising to some extent,” said Dr. Narendra. “This surprise stems from this medication’s novel application and efficacy in a pulmonary context, showing significant potential where traditional DPP4 inhibitors required higher, potentially unsafe doses to achieve similar effects,” she said.
Should research prove successful, NZ-97 could offer substantial clinical benefits for treating pulmonary diseases such as IPF and other conditions involving alveolar damage. By enhancing AEC2 proliferation, NZ-97 may improve patient outcomes by mitigating lung damage and promoting regenerative repair, possibly reducing the dependency on more invasive treatments like lung transplantation.
More research on NZ-97 is needed in order to identify potential barriers to its use, Dr. Narendra said. “Further studies are needed to evaluate the long-term effects of NZ-97, understand its mechanisms in human lung tissue, and determine its safety and efficacy in clinical settings.”
Dr. Narendra had no financial conflicts to disclose but served on the Editorial Board of Chest Physician.
A version of this article appeared on Medscape.com.
CRC Screening in Primary Care: The Blood Test Option
Last year, I concluded a commentary for this news organization on colorectal cancer (CRC) screening guidelines by stating that between stool-based tests, flexible sigmoidoscopy, and colonoscopy, “the best screening test is the test that gets done.” But should that maxim apply to the new blood-based screening test, Guardant Health Shield? This proprietary test, which costs $895 and is not generally covered by insurance, identifies alterations in cell-free DNA that are characteristic of CRC.
Shield’s test characteristics were recently evaluated in a prospective study of more than 10,000 adults aged 45-84 at average risk for CRC. The test had an 87.5% sensitivity for stage I, II, or III colorectal cancer but only a 13% sensitivity for advanced precancerous lesions. Test specificity was 89.6%, meaning that about 1 in 10 participants without CRC or advanced precancerous lesions on colonoscopy had a false-positive result.
Although the Shield blood test has a higher rate of false positives than the traditional fecal immunochemical test (FIT) and lower sensitivity and specificity than a multitarget stool DNA (FIT-DNA) test designed to improve on Cologuard, it meets the previously established criteria set forth by the Centers for Medicare & Medicaid Services (CMS) to be covered for Medicare beneficiaries at 3-year intervals, pending FDA approval.
A big concern, however, is that the availability of a blood test may cause patients who would have otherwise been screened with colonoscopy or stool tests to switch to the blood test. A cost-effectiveness analysis found that offering a blood test to patients who decline screening colonoscopy saves additional lives, but at the cost of more than $377,000 per life-year gained. Another study relying on three microsimulation models previously utilized by the US Preventive Services Task Force (USPSTF) found that annual FIT results in more life-years gained at substantially lower cost than blood-based screening every 3 years “even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT.” As a result, a multidisciplinary expert panel concluded that blood-based screening should not substitute for established CRC screening tests, but instead be offered only to patients who decline those tests.
In practice, this will increase the complexity of the CRC screening conversations we have with patients. We will need to be clear that the blood test is not yet endorsed by the USPSTF or any major guideline group and is a second-line test that will miss most precancerous polyps. As with the stool tests, it is essential to emphasize that a positive result must be followed by diagnostic colonoscopy. To addend the cancer screening maxim I mentioned before, the blood test is not the best test for CRC, but it’s probably better than no test at all.
Dr. Lin is a family physician and associate director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania. He blogs at Common Sense Family Doctor.
A version of this article appeared on Medscape.com.
Last year, I concluded a commentary for this news organization on colorectal cancer (CRC) screening guidelines by stating that between stool-based tests, flexible sigmoidoscopy, and colonoscopy, “the best screening test is the test that gets done.” But should that maxim apply to the new blood-based screening test, Guardant Health Shield? This proprietary test, which costs $895 and is not generally covered by insurance, identifies alterations in cell-free DNA that are characteristic of CRC.
Shield’s test characteristics were recently evaluated in a prospective study of more than 10,000 adults aged 45-84 at average risk for CRC. The test had an 87.5% sensitivity for stage I, II, or III colorectal cancer but only a 13% sensitivity for advanced precancerous lesions. Test specificity was 89.6%, meaning that about 1 in 10 participants without CRC or advanced precancerous lesions on colonoscopy had a false-positive result.
Although the Shield blood test has a higher rate of false positives than the traditional fecal immunochemical test (FIT) and lower sensitivity and specificity than a multitarget stool DNA (FIT-DNA) test designed to improve on Cologuard, it meets the previously established criteria set forth by the Centers for Medicare & Medicaid Services (CMS) to be covered for Medicare beneficiaries at 3-year intervals, pending FDA approval.
A big concern, however, is that the availability of a blood test may cause patients who would have otherwise been screened with colonoscopy or stool tests to switch to the blood test. A cost-effectiveness analysis found that offering a blood test to patients who decline screening colonoscopy saves additional lives, but at the cost of more than $377,000 per life-year gained. Another study relying on three microsimulation models previously utilized by the US Preventive Services Task Force (USPSTF) found that annual FIT results in more life-years gained at substantially lower cost than blood-based screening every 3 years “even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT.” As a result, a multidisciplinary expert panel concluded that blood-based screening should not substitute for established CRC screening tests, but instead be offered only to patients who decline those tests.
In practice, this will increase the complexity of the CRC screening conversations we have with patients. We will need to be clear that the blood test is not yet endorsed by the USPSTF or any major guideline group and is a second-line test that will miss most precancerous polyps. As with the stool tests, it is essential to emphasize that a positive result must be followed by diagnostic colonoscopy. To addend the cancer screening maxim I mentioned before, the blood test is not the best test for CRC, but it’s probably better than no test at all.
Dr. Lin is a family physician and associate director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania. He blogs at Common Sense Family Doctor.
A version of this article appeared on Medscape.com.
Last year, I concluded a commentary for this news organization on colorectal cancer (CRC) screening guidelines by stating that between stool-based tests, flexible sigmoidoscopy, and colonoscopy, “the best screening test is the test that gets done.” But should that maxim apply to the new blood-based screening test, Guardant Health Shield? This proprietary test, which costs $895 and is not generally covered by insurance, identifies alterations in cell-free DNA that are characteristic of CRC.
Shield’s test characteristics were recently evaluated in a prospective study of more than 10,000 adults aged 45-84 at average risk for CRC. The test had an 87.5% sensitivity for stage I, II, or III colorectal cancer but only a 13% sensitivity for advanced precancerous lesions. Test specificity was 89.6%, meaning that about 1 in 10 participants without CRC or advanced precancerous lesions on colonoscopy had a false-positive result.
Although the Shield blood test has a higher rate of false positives than the traditional fecal immunochemical test (FIT) and lower sensitivity and specificity than a multitarget stool DNA (FIT-DNA) test designed to improve on Cologuard, it meets the previously established criteria set forth by the Centers for Medicare & Medicaid Services (CMS) to be covered for Medicare beneficiaries at 3-year intervals, pending FDA approval.
A big concern, however, is that the availability of a blood test may cause patients who would have otherwise been screened with colonoscopy or stool tests to switch to the blood test. A cost-effectiveness analysis found that offering a blood test to patients who decline screening colonoscopy saves additional lives, but at the cost of more than $377,000 per life-year gained. Another study relying on three microsimulation models previously utilized by the US Preventive Services Task Force (USPSTF) found that annual FIT results in more life-years gained at substantially lower cost than blood-based screening every 3 years “even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT.” As a result, a multidisciplinary expert panel concluded that blood-based screening should not substitute for established CRC screening tests, but instead be offered only to patients who decline those tests.
In practice, this will increase the complexity of the CRC screening conversations we have with patients. We will need to be clear that the blood test is not yet endorsed by the USPSTF or any major guideline group and is a second-line test that will miss most precancerous polyps. As with the stool tests, it is essential to emphasize that a positive result must be followed by diagnostic colonoscopy. To addend the cancer screening maxim I mentioned before, the blood test is not the best test for CRC, but it’s probably better than no test at all.
Dr. Lin is a family physician and associate director, Family Medicine Residency Program, Lancaster General Hospital, Lancaster, Pennsylvania. He blogs at Common Sense Family Doctor.
A version of this article appeared on Medscape.com.
Semaglutide Trial for Knee Osteoarthritis Shows Improvements in Pain, Physical Function
VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024 World Congress.
From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).
As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.
“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.
Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
Not Approved in OA
Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.
“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.
“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.
“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
Previous Work
The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.
Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.
“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.
“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
STEP 9 Study Design
No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.
STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.
In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.
A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.
Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.
Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
Other Findings
In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.
“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.
Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.
“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.
Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.
The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024 World Congress.
From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).
As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.
“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.
Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
Not Approved in OA
Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.
“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.
“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.
“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
Previous Work
The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.
Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.
“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.
“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
STEP 9 Study Design
No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.
STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.
In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.
A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.
Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.
Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
Other Findings
In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.
“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.
Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.
“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.
Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.
The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024 World Congress.
From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).
As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.
“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.
Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
Not Approved in OA
Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.
“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.
“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.
“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
Previous Work
The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.
Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.
“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.
“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
STEP 9 Study Design
No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.
STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.
In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.
A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.
Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.
Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
Other Findings
In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.
“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.
Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.
“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.
Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.
The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.
A version of this article appeared on Medscape.com.
FROM OARSI 2024
Are Carbs Really the Enemy?
Recent headlines scream that we have an obesity problem and that carbs are the culprit for the problem. That leads me to ask: How did we get to blaming carbs as the enemy in the war against obesity?
First, a quick review of the history of diet and macronutrient content.
A long time ago, prehistoric humans foraged and hunted for food. Protein and fat were procured from animal meat, which was very important for encephalization, or evolutionary increase in the complexity or relative size of the brain. Most of the requirements for protein and iron were satisfied by hunting and eating land animals as well as consuming marine life that washed up on shore.
Carbohydrates in the form of plant foods served as the only sources of energy available to prehistoric hunter-gatherers, which offset the high protein content of the rest of their diet. These were only available during spring and summer.
Then, about 10,000 years ago, plant and animal agriculture began, and humans saw a permanent shift in the macronutrient content of our daily intake so that it was more consistent and stable. Initially, the nutrient characteristic changes were subtle, going from wild food to cultivated food with the Agricultural Revolution in the mid-17th century. Then, it changed even more rapidly less than 200 years ago with the Industrial Revolution, resulting in semiprocessed and ultraprocessed foods.
This change in food intake altered human physiology, with major changes in our digestive, immune, and neural physiology and an increase in chronic disease prevalence. The last 50 years has seen an increase in obesity in the United States, along with increases in chronic disease such as type 2 diabetes, which leads cardiovascular disease and certain cancers.
Back to Carbohydrates: Do We Need Them? How Much? What Kind?
Unfortunately, ultraprocessed foods have become a staple of the standard American or Western diet.
Ultraprocessed foods such as cakes, cookies, crackers, sugary breakfast cereals, pizza, potato chips, soft drinks, and ice cream are eons away from our prehistoric diet of wild game, nuts, fruits, and berries, at which time, our digestive immune and nervous systems evolved. The pace at which ultraprocessed foods have entered our diet outpaces the time necessary for adaptation of our digestive systems and genes to these foods. They are indeed pathogenic in this context.
So when was the time when humans consumed an “optimal” diet? This is hard to say because during the time of brain evolution, we needed protein and iron and succumbed to infections and trauma. In the early 1900s, we continued to succumb to infection until the discovery of antibiotics. Soon thereafter, industrialization and processed foods led to weight gain and the chronic diseases of the cardiovascular system and type 2 diabetes.
Carbohydrates provide calories and fiber and some micronutrients, which are needed for energy, metabolism, and bowel and immune health. But how much do we need?
Currently in the United States, the percentage of total food energy derived from the three major macronutrients is: carbohydrates, 51.8%; fat, 32.8%; and protein, 15.4%. Current advice for a healthy diet to lower risk for cardiovascular disease is to limit fat intake to 30% of total energy, protein to 15%, and to increase complex carbohydrates to 55%-60% of total energy. But we also need to qualify this in terms of the quality of the macronutrient, particularly carbohydrates.
In addition to the quality, the macronutrient content of the diet has varied considerably from our prehistoric times when dietary protein intakes were high at 19%-35% of energy at the expense of carbohydrate (22%-40% of energy).
If our genes haven’t kept up with industrialization, then why do we need so many carbohydrates to equate to 55%-60% of energy? Is it possible that we are confusing what is available with what we actually need? What do I mean by this?
We certainly have changed the landscape of the world due to agriculture, which has allowed us to procreate and feed ourselves, and certainly, industrialization has increased the availability of accessible cheap food. Protein in the form of meat, fish, and fowl are harder to get in industrialized nations as are fruits and vegetables. These macronutrients were the foods of our ancestors. It may be that a healthy diet is considered the one that is available.
For instance, the Mediterranean diet is somewhat higher in fat content, 40%-50% fat (mostly mono and unsaturated), and similar in protein content but lower in carbohydrate content than the typical Western diet. The Dietary Approaches to Stop Hypertension (DASH) diet is lower in fat at 25% total calories, is higher in carbohydrates at 55%, and is lower in protein, but this diet was generated in the United States, therefore it is more Western.
We need high-quality protein for organ and muscle function, high-quality unsaturated and monounsaturated fats for brain function and cellular functions, and high-quality complex carbohydrates for energy and gut health as well as micronutrients for many cellular functions. A ketogenic diet is not sustainable in the long-term for these reasons: chiefly the need for some carbohydrates for gut health and micronutrients.
How much carbohydrate content is needed should take into consideration energy expenditure as well as micronutrients and fiber intake. Protein and fat can contribute to energy production but not as readily as carbohydrates that can quickly restore glycogen in the muscle and liver. What’s interesting is that our ancestors were able to hunt and run away from danger with the small amounts of carbohydrates from plants and berries plus the protein and fat intake from animals and fish — but the Olympics weren’t a thing then!
It may be another 200,000 years before our genes catch up to ultraprocessed foods and the simple carbohydrates and sugars contained in these products. Evidence suggests that ultraprocessed foods cause inflammation in organs like the liver, adipose tissue, the heart, and even the brain. In the brain, this inflammation may be what’s causing us to defend a higher body weight set point in this environment of easily obtained highly palatable ultraprocessed foods.
Let’s not wait until our genes catch up and our bodies tolerate junk food without disease progression. It could be like waiting for Godot!
Dr. Apovian is professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, Massachusetts. She disclosed ties to Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, and L-Nutra.
A version of this article appeared on Medscape.com.
Recent headlines scream that we have an obesity problem and that carbs are the culprit for the problem. That leads me to ask: How did we get to blaming carbs as the enemy in the war against obesity?
First, a quick review of the history of diet and macronutrient content.
A long time ago, prehistoric humans foraged and hunted for food. Protein and fat were procured from animal meat, which was very important for encephalization, or evolutionary increase in the complexity or relative size of the brain. Most of the requirements for protein and iron were satisfied by hunting and eating land animals as well as consuming marine life that washed up on shore.
Carbohydrates in the form of plant foods served as the only sources of energy available to prehistoric hunter-gatherers, which offset the high protein content of the rest of their diet. These were only available during spring and summer.
Then, about 10,000 years ago, plant and animal agriculture began, and humans saw a permanent shift in the macronutrient content of our daily intake so that it was more consistent and stable. Initially, the nutrient characteristic changes were subtle, going from wild food to cultivated food with the Agricultural Revolution in the mid-17th century. Then, it changed even more rapidly less than 200 years ago with the Industrial Revolution, resulting in semiprocessed and ultraprocessed foods.
This change in food intake altered human physiology, with major changes in our digestive, immune, and neural physiology and an increase in chronic disease prevalence. The last 50 years has seen an increase in obesity in the United States, along with increases in chronic disease such as type 2 diabetes, which leads cardiovascular disease and certain cancers.
Back to Carbohydrates: Do We Need Them? How Much? What Kind?
Unfortunately, ultraprocessed foods have become a staple of the standard American or Western diet.
Ultraprocessed foods such as cakes, cookies, crackers, sugary breakfast cereals, pizza, potato chips, soft drinks, and ice cream are eons away from our prehistoric diet of wild game, nuts, fruits, and berries, at which time, our digestive immune and nervous systems evolved. The pace at which ultraprocessed foods have entered our diet outpaces the time necessary for adaptation of our digestive systems and genes to these foods. They are indeed pathogenic in this context.
So when was the time when humans consumed an “optimal” diet? This is hard to say because during the time of brain evolution, we needed protein and iron and succumbed to infections and trauma. In the early 1900s, we continued to succumb to infection until the discovery of antibiotics. Soon thereafter, industrialization and processed foods led to weight gain and the chronic diseases of the cardiovascular system and type 2 diabetes.
Carbohydrates provide calories and fiber and some micronutrients, which are needed for energy, metabolism, and bowel and immune health. But how much do we need?
Currently in the United States, the percentage of total food energy derived from the three major macronutrients is: carbohydrates, 51.8%; fat, 32.8%; and protein, 15.4%. Current advice for a healthy diet to lower risk for cardiovascular disease is to limit fat intake to 30% of total energy, protein to 15%, and to increase complex carbohydrates to 55%-60% of total energy. But we also need to qualify this in terms of the quality of the macronutrient, particularly carbohydrates.
In addition to the quality, the macronutrient content of the diet has varied considerably from our prehistoric times when dietary protein intakes were high at 19%-35% of energy at the expense of carbohydrate (22%-40% of energy).
If our genes haven’t kept up with industrialization, then why do we need so many carbohydrates to equate to 55%-60% of energy? Is it possible that we are confusing what is available with what we actually need? What do I mean by this?
We certainly have changed the landscape of the world due to agriculture, which has allowed us to procreate and feed ourselves, and certainly, industrialization has increased the availability of accessible cheap food. Protein in the form of meat, fish, and fowl are harder to get in industrialized nations as are fruits and vegetables. These macronutrients were the foods of our ancestors. It may be that a healthy diet is considered the one that is available.
For instance, the Mediterranean diet is somewhat higher in fat content, 40%-50% fat (mostly mono and unsaturated), and similar in protein content but lower in carbohydrate content than the typical Western diet. The Dietary Approaches to Stop Hypertension (DASH) diet is lower in fat at 25% total calories, is higher in carbohydrates at 55%, and is lower in protein, but this diet was generated in the United States, therefore it is more Western.
We need high-quality protein for organ and muscle function, high-quality unsaturated and monounsaturated fats for brain function and cellular functions, and high-quality complex carbohydrates for energy and gut health as well as micronutrients for many cellular functions. A ketogenic diet is not sustainable in the long-term for these reasons: chiefly the need for some carbohydrates for gut health and micronutrients.
How much carbohydrate content is needed should take into consideration energy expenditure as well as micronutrients and fiber intake. Protein and fat can contribute to energy production but not as readily as carbohydrates that can quickly restore glycogen in the muscle and liver. What’s interesting is that our ancestors were able to hunt and run away from danger with the small amounts of carbohydrates from plants and berries plus the protein and fat intake from animals and fish — but the Olympics weren’t a thing then!
It may be another 200,000 years before our genes catch up to ultraprocessed foods and the simple carbohydrates and sugars contained in these products. Evidence suggests that ultraprocessed foods cause inflammation in organs like the liver, adipose tissue, the heart, and even the brain. In the brain, this inflammation may be what’s causing us to defend a higher body weight set point in this environment of easily obtained highly palatable ultraprocessed foods.
Let’s not wait until our genes catch up and our bodies tolerate junk food without disease progression. It could be like waiting for Godot!
Dr. Apovian is professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, Massachusetts. She disclosed ties to Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, and L-Nutra.
A version of this article appeared on Medscape.com.
Recent headlines scream that we have an obesity problem and that carbs are the culprit for the problem. That leads me to ask: How did we get to blaming carbs as the enemy in the war against obesity?
First, a quick review of the history of diet and macronutrient content.
A long time ago, prehistoric humans foraged and hunted for food. Protein and fat were procured from animal meat, which was very important for encephalization, or evolutionary increase in the complexity or relative size of the brain. Most of the requirements for protein and iron were satisfied by hunting and eating land animals as well as consuming marine life that washed up on shore.
Carbohydrates in the form of plant foods served as the only sources of energy available to prehistoric hunter-gatherers, which offset the high protein content of the rest of their diet. These were only available during spring and summer.
Then, about 10,000 years ago, plant and animal agriculture began, and humans saw a permanent shift in the macronutrient content of our daily intake so that it was more consistent and stable. Initially, the nutrient characteristic changes were subtle, going from wild food to cultivated food with the Agricultural Revolution in the mid-17th century. Then, it changed even more rapidly less than 200 years ago with the Industrial Revolution, resulting in semiprocessed and ultraprocessed foods.
This change in food intake altered human physiology, with major changes in our digestive, immune, and neural physiology and an increase in chronic disease prevalence. The last 50 years has seen an increase in obesity in the United States, along with increases in chronic disease such as type 2 diabetes, which leads cardiovascular disease and certain cancers.
Back to Carbohydrates: Do We Need Them? How Much? What Kind?
Unfortunately, ultraprocessed foods have become a staple of the standard American or Western diet.
Ultraprocessed foods such as cakes, cookies, crackers, sugary breakfast cereals, pizza, potato chips, soft drinks, and ice cream are eons away from our prehistoric diet of wild game, nuts, fruits, and berries, at which time, our digestive immune and nervous systems evolved. The pace at which ultraprocessed foods have entered our diet outpaces the time necessary for adaptation of our digestive systems and genes to these foods. They are indeed pathogenic in this context.
So when was the time when humans consumed an “optimal” diet? This is hard to say because during the time of brain evolution, we needed protein and iron and succumbed to infections and trauma. In the early 1900s, we continued to succumb to infection until the discovery of antibiotics. Soon thereafter, industrialization and processed foods led to weight gain and the chronic diseases of the cardiovascular system and type 2 diabetes.
Carbohydrates provide calories and fiber and some micronutrients, which are needed for energy, metabolism, and bowel and immune health. But how much do we need?
Currently in the United States, the percentage of total food energy derived from the three major macronutrients is: carbohydrates, 51.8%; fat, 32.8%; and protein, 15.4%. Current advice for a healthy diet to lower risk for cardiovascular disease is to limit fat intake to 30% of total energy, protein to 15%, and to increase complex carbohydrates to 55%-60% of total energy. But we also need to qualify this in terms of the quality of the macronutrient, particularly carbohydrates.
In addition to the quality, the macronutrient content of the diet has varied considerably from our prehistoric times when dietary protein intakes were high at 19%-35% of energy at the expense of carbohydrate (22%-40% of energy).
If our genes haven’t kept up with industrialization, then why do we need so many carbohydrates to equate to 55%-60% of energy? Is it possible that we are confusing what is available with what we actually need? What do I mean by this?
We certainly have changed the landscape of the world due to agriculture, which has allowed us to procreate and feed ourselves, and certainly, industrialization has increased the availability of accessible cheap food. Protein in the form of meat, fish, and fowl are harder to get in industrialized nations as are fruits and vegetables. These macronutrients were the foods of our ancestors. It may be that a healthy diet is considered the one that is available.
For instance, the Mediterranean diet is somewhat higher in fat content, 40%-50% fat (mostly mono and unsaturated), and similar in protein content but lower in carbohydrate content than the typical Western diet. The Dietary Approaches to Stop Hypertension (DASH) diet is lower in fat at 25% total calories, is higher in carbohydrates at 55%, and is lower in protein, but this diet was generated in the United States, therefore it is more Western.
We need high-quality protein for organ and muscle function, high-quality unsaturated and monounsaturated fats for brain function and cellular functions, and high-quality complex carbohydrates for energy and gut health as well as micronutrients for many cellular functions. A ketogenic diet is not sustainable in the long-term for these reasons: chiefly the need for some carbohydrates for gut health and micronutrients.
How much carbohydrate content is needed should take into consideration energy expenditure as well as micronutrients and fiber intake. Protein and fat can contribute to energy production but not as readily as carbohydrates that can quickly restore glycogen in the muscle and liver. What’s interesting is that our ancestors were able to hunt and run away from danger with the small amounts of carbohydrates from plants and berries plus the protein and fat intake from animals and fish — but the Olympics weren’t a thing then!
It may be another 200,000 years before our genes catch up to ultraprocessed foods and the simple carbohydrates and sugars contained in these products. Evidence suggests that ultraprocessed foods cause inflammation in organs like the liver, adipose tissue, the heart, and even the brain. In the brain, this inflammation may be what’s causing us to defend a higher body weight set point in this environment of easily obtained highly palatable ultraprocessed foods.
Let’s not wait until our genes catch up and our bodies tolerate junk food without disease progression. It could be like waiting for Godot!
Dr. Apovian is professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, Massachusetts. She disclosed ties to Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, and L-Nutra.
A version of this article appeared on Medscape.com.
Menopause, RSV, and More: 4 New Meds to Know
BOSTON — The US Food and Drug Administration (FDA) approved 55 new medications in 2023 and 11 more in 2024 to date.
A New First-Line for GERD?
Vonoprazan, an oral potassium-competitive acid blocker — which received FDA approval in November 2023 — may be a good alternative for patients whose symptoms continue to linger despite taking medications designated to treat gastroesophageal reflux disease (GERD).
GERD is the most common gastrointestinal symptom encountered by primary care physicians. Proton-pump inhibitors (PPIs) are the first-line treatment for the condition but can have long-term side effects such as Clostridioides difficile infection and kidney lesions.
“We know that not all patients are going to have symptom relief with H2 blockers and PPIs, so there’s an opportunity for patients who don’t get full symptom relief,” Dr. Smetana told attendees.
Vonoprazan blocks potassium binding to ATPase proton pumps and inhibits the secretion of gastric acid.
The approval of vonoprazan for erosive GERD was based on results from the phase 3 PHALCON-EE study, a randomized, double-blind, multicenter study that found the drug to be more effective than lansoprazole in treating erosive esophagitis.
Vonoprazan “has more rapid absorption than PPIs [and a] longer half-life and is more potent than PPIs, so theoretically it could be more effective in certain settings,” Dr. Smetana said.
Vonoprazan is FDA approved for only 6 months of use. Despite its efficacy, cost may be a barrier to many patients. H2 blockers generally cost patients less than $10 for 1 month’s supply, whereas vonoprazan can cost up to $650.
Nonhormonal Drug for Menopause
Fezolinetant, the first neurokinin receptor antagonist to receive approval from the FDA to treat vasomotor symptoms, may be an option for women concerned about hormone-based therapy for menopausal hot flashes.
“[Fezolinetant] specifically works in the area of the brain that’s involved in body temperature regulation and sweating,” Dr. Smetana said.
Results from the SKYLIGHT 1 randomized controlled trial of fezolinetant found the medication reduced the frequency and severity of hot flashes. Some of the side effects include abdominal pain, diarrhea, and insomnia.
Other nonestrogen treatments, including selective serotonin reuptake inhibitors (SSRIs), gabapentin, cognitive-behavioral therapy, and hypnosis, are modestly effective, according to the North American Menopause Society.
“[Fezolinetant] offers a different option that physicians may be more comfortable prescribing,” Dr. Smetana said. “And I think this will be an important addition to nonhormonal therapy.”
RSV Vaccine for Everyone
Once considered an illness that is more prevalent in young children, respiratory syncytial virus (RSV) has become more prevalent and severe among older adults. Between 60,000 and 120,000 older adults are hospitalized and 6000-10,000 die of RSV infection each year, according to the US Centers for Disease Control and Prevention.
The FDA has approved two RSV vaccines approved for older adults, but clinicians may find it challenging to get older patients vaccinated for this and other preventable illnesses.
Patients who received the RSV vaccine had an 83% relative risk reduction for the illness, according to a recent study, and an overall lower risk for hospitalization.
Moderna is developing an mRNA vaccine for RSV that is similar to many COVID-19 vaccines. A study published in 2023 in The New England Journal of Medicine found no cases of neuroinflammatory disorders among patients who received the mRNA RSV vaccine, with a median follow-up of 112 days.
“This is important given ongoing concerns of neurological safety,” among older adults who receive the RSV vaccine, Dr. Smetana said.
As of March 2024, the CDC recommends shared decision-making for adults older than 60 years and for healthcare providers to “consider” rather than “recommend” the vaccine for their patients. The agency’s Adult RSV Work Group plans to meet at June 2024 to reconsider whether shared clinical decision-making remains the preferred policy option.
New Antidepressants
A medication thrice rejected by the FDA is now heading a new class of drugs to treat major depressive disorder.
Gepirone, a 5-HT1A receptor agonist, has a different mechanism of action from that of SSRIs, which are currently considered the first-line treatment for depression.
Gepirone was rejected by the FDA in 2002, 2004, and 2007, with concerns that the efficacy studies were too small. In 2015, an FDA advisory committee agreed that the evidence to date did not support approval of an extended-release form of the drug. But the agency decided to approve the medication in September 2023.
“So why is this medication worth discussing now?” Dr. Smetana said. “It’s because the side effect profile is different from existing antidepressants.”
Many patients may stop using SSRIs because of side effects such as insomnia and loss of libido, Dr. Smetana said. Gepirone has the potential to avoid activation of other 5-HT receptors that mediate side effects, he said.
Studies suggest that gepirone reduces both anxiety and depression scores on the Hamilton Depression Rating Scale in patients who have both conditions and decreases rates of depression relapse compared with placebo through at least 48 weeks. The drug also may be less likely than SSRIs to cause sexual dysfunction in men, Dr. Smetana said.
Gepirone will be available to prescribe to patients in fall 2024.
Dr. Smetana reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
BOSTON — The US Food and Drug Administration (FDA) approved 55 new medications in 2023 and 11 more in 2024 to date.
A New First-Line for GERD?
Vonoprazan, an oral potassium-competitive acid blocker — which received FDA approval in November 2023 — may be a good alternative for patients whose symptoms continue to linger despite taking medications designated to treat gastroesophageal reflux disease (GERD).
GERD is the most common gastrointestinal symptom encountered by primary care physicians. Proton-pump inhibitors (PPIs) are the first-line treatment for the condition but can have long-term side effects such as Clostridioides difficile infection and kidney lesions.
“We know that not all patients are going to have symptom relief with H2 blockers and PPIs, so there’s an opportunity for patients who don’t get full symptom relief,” Dr. Smetana told attendees.
Vonoprazan blocks potassium binding to ATPase proton pumps and inhibits the secretion of gastric acid.
The approval of vonoprazan for erosive GERD was based on results from the phase 3 PHALCON-EE study, a randomized, double-blind, multicenter study that found the drug to be more effective than lansoprazole in treating erosive esophagitis.
Vonoprazan “has more rapid absorption than PPIs [and a] longer half-life and is more potent than PPIs, so theoretically it could be more effective in certain settings,” Dr. Smetana said.
Vonoprazan is FDA approved for only 6 months of use. Despite its efficacy, cost may be a barrier to many patients. H2 blockers generally cost patients less than $10 for 1 month’s supply, whereas vonoprazan can cost up to $650.
Nonhormonal Drug for Menopause
Fezolinetant, the first neurokinin receptor antagonist to receive approval from the FDA to treat vasomotor symptoms, may be an option for women concerned about hormone-based therapy for menopausal hot flashes.
“[Fezolinetant] specifically works in the area of the brain that’s involved in body temperature regulation and sweating,” Dr. Smetana said.
Results from the SKYLIGHT 1 randomized controlled trial of fezolinetant found the medication reduced the frequency and severity of hot flashes. Some of the side effects include abdominal pain, diarrhea, and insomnia.
Other nonestrogen treatments, including selective serotonin reuptake inhibitors (SSRIs), gabapentin, cognitive-behavioral therapy, and hypnosis, are modestly effective, according to the North American Menopause Society.
“[Fezolinetant] offers a different option that physicians may be more comfortable prescribing,” Dr. Smetana said. “And I think this will be an important addition to nonhormonal therapy.”
RSV Vaccine for Everyone
Once considered an illness that is more prevalent in young children, respiratory syncytial virus (RSV) has become more prevalent and severe among older adults. Between 60,000 and 120,000 older adults are hospitalized and 6000-10,000 die of RSV infection each year, according to the US Centers for Disease Control and Prevention.
The FDA has approved two RSV vaccines approved for older adults, but clinicians may find it challenging to get older patients vaccinated for this and other preventable illnesses.
Patients who received the RSV vaccine had an 83% relative risk reduction for the illness, according to a recent study, and an overall lower risk for hospitalization.
Moderna is developing an mRNA vaccine for RSV that is similar to many COVID-19 vaccines. A study published in 2023 in The New England Journal of Medicine found no cases of neuroinflammatory disorders among patients who received the mRNA RSV vaccine, with a median follow-up of 112 days.
“This is important given ongoing concerns of neurological safety,” among older adults who receive the RSV vaccine, Dr. Smetana said.
As of March 2024, the CDC recommends shared decision-making for adults older than 60 years and for healthcare providers to “consider” rather than “recommend” the vaccine for their patients. The agency’s Adult RSV Work Group plans to meet at June 2024 to reconsider whether shared clinical decision-making remains the preferred policy option.
New Antidepressants
A medication thrice rejected by the FDA is now heading a new class of drugs to treat major depressive disorder.
Gepirone, a 5-HT1A receptor agonist, has a different mechanism of action from that of SSRIs, which are currently considered the first-line treatment for depression.
Gepirone was rejected by the FDA in 2002, 2004, and 2007, with concerns that the efficacy studies were too small. In 2015, an FDA advisory committee agreed that the evidence to date did not support approval of an extended-release form of the drug. But the agency decided to approve the medication in September 2023.
“So why is this medication worth discussing now?” Dr. Smetana said. “It’s because the side effect profile is different from existing antidepressants.”
Many patients may stop using SSRIs because of side effects such as insomnia and loss of libido, Dr. Smetana said. Gepirone has the potential to avoid activation of other 5-HT receptors that mediate side effects, he said.
Studies suggest that gepirone reduces both anxiety and depression scores on the Hamilton Depression Rating Scale in patients who have both conditions and decreases rates of depression relapse compared with placebo through at least 48 weeks. The drug also may be less likely than SSRIs to cause sexual dysfunction in men, Dr. Smetana said.
Gepirone will be available to prescribe to patients in fall 2024.
Dr. Smetana reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
BOSTON — The US Food and Drug Administration (FDA) approved 55 new medications in 2023 and 11 more in 2024 to date.
A New First-Line for GERD?
Vonoprazan, an oral potassium-competitive acid blocker — which received FDA approval in November 2023 — may be a good alternative for patients whose symptoms continue to linger despite taking medications designated to treat gastroesophageal reflux disease (GERD).
GERD is the most common gastrointestinal symptom encountered by primary care physicians. Proton-pump inhibitors (PPIs) are the first-line treatment for the condition but can have long-term side effects such as Clostridioides difficile infection and kidney lesions.
“We know that not all patients are going to have symptom relief with H2 blockers and PPIs, so there’s an opportunity for patients who don’t get full symptom relief,” Dr. Smetana told attendees.
Vonoprazan blocks potassium binding to ATPase proton pumps and inhibits the secretion of gastric acid.
The approval of vonoprazan for erosive GERD was based on results from the phase 3 PHALCON-EE study, a randomized, double-blind, multicenter study that found the drug to be more effective than lansoprazole in treating erosive esophagitis.
Vonoprazan “has more rapid absorption than PPIs [and a] longer half-life and is more potent than PPIs, so theoretically it could be more effective in certain settings,” Dr. Smetana said.
Vonoprazan is FDA approved for only 6 months of use. Despite its efficacy, cost may be a barrier to many patients. H2 blockers generally cost patients less than $10 for 1 month’s supply, whereas vonoprazan can cost up to $650.
Nonhormonal Drug for Menopause
Fezolinetant, the first neurokinin receptor antagonist to receive approval from the FDA to treat vasomotor symptoms, may be an option for women concerned about hormone-based therapy for menopausal hot flashes.
“[Fezolinetant] specifically works in the area of the brain that’s involved in body temperature regulation and sweating,” Dr. Smetana said.
Results from the SKYLIGHT 1 randomized controlled trial of fezolinetant found the medication reduced the frequency and severity of hot flashes. Some of the side effects include abdominal pain, diarrhea, and insomnia.
Other nonestrogen treatments, including selective serotonin reuptake inhibitors (SSRIs), gabapentin, cognitive-behavioral therapy, and hypnosis, are modestly effective, according to the North American Menopause Society.
“[Fezolinetant] offers a different option that physicians may be more comfortable prescribing,” Dr. Smetana said. “And I think this will be an important addition to nonhormonal therapy.”
RSV Vaccine for Everyone
Once considered an illness that is more prevalent in young children, respiratory syncytial virus (RSV) has become more prevalent and severe among older adults. Between 60,000 and 120,000 older adults are hospitalized and 6000-10,000 die of RSV infection each year, according to the US Centers for Disease Control and Prevention.
The FDA has approved two RSV vaccines approved for older adults, but clinicians may find it challenging to get older patients vaccinated for this and other preventable illnesses.
Patients who received the RSV vaccine had an 83% relative risk reduction for the illness, according to a recent study, and an overall lower risk for hospitalization.
Moderna is developing an mRNA vaccine for RSV that is similar to many COVID-19 vaccines. A study published in 2023 in The New England Journal of Medicine found no cases of neuroinflammatory disorders among patients who received the mRNA RSV vaccine, with a median follow-up of 112 days.
“This is important given ongoing concerns of neurological safety,” among older adults who receive the RSV vaccine, Dr. Smetana said.
As of March 2024, the CDC recommends shared decision-making for adults older than 60 years and for healthcare providers to “consider” rather than “recommend” the vaccine for their patients. The agency’s Adult RSV Work Group plans to meet at June 2024 to reconsider whether shared clinical decision-making remains the preferred policy option.
New Antidepressants
A medication thrice rejected by the FDA is now heading a new class of drugs to treat major depressive disorder.
Gepirone, a 5-HT1A receptor agonist, has a different mechanism of action from that of SSRIs, which are currently considered the first-line treatment for depression.
Gepirone was rejected by the FDA in 2002, 2004, and 2007, with concerns that the efficacy studies were too small. In 2015, an FDA advisory committee agreed that the evidence to date did not support approval of an extended-release form of the drug. But the agency decided to approve the medication in September 2023.
“So why is this medication worth discussing now?” Dr. Smetana said. “It’s because the side effect profile is different from existing antidepressants.”
Many patients may stop using SSRIs because of side effects such as insomnia and loss of libido, Dr. Smetana said. Gepirone has the potential to avoid activation of other 5-HT receptors that mediate side effects, he said.
Studies suggest that gepirone reduces both anxiety and depression scores on the Hamilton Depression Rating Scale in patients who have both conditions and decreases rates of depression relapse compared with placebo through at least 48 weeks. The drug also may be less likely than SSRIs to cause sexual dysfunction in men, Dr. Smetana said.
Gepirone will be available to prescribe to patients in fall 2024.
Dr. Smetana reported no relevant financial conflicts of interest.
A version of this article appeared on Medscape.com.
New Screening Protocol May Improve Prostate Cancer Detection
TOPLINE:
according to preliminary findings from the Finnish ProScreen randomized clinical trial.
METHODOLOGY:
- Prostate-specific antigen (PSA) screening is currently recommended for men in the United States starting at age 55. However, the test is controversial, in large part because it often detects prostate cancer that is not clinically relevant and may lead to overtreatment of men with low-grade disease.
- The current ProScreen trial assessed a screening intervention that aims to reduce unnecessary diagnoses of prostate cancer but still catch relevant cancers and reduce prostate cancer mortality.
- The researchers randomized 60,745 eligible men aged 50-63 years to be invited to a three-phase screening intervention (n = 15,201) or to be part of a control group that was not invited to screen (n = 45,544).
- The screening group who agreed to participate (n = 7744) first underwent a PSA test. Those with a PSA of ≥ 3.0 ng/mL then underwent a four-kallikrein panel to identify high-grade prostate cancer. Those with a kallikrein panel risk score of 7.5% or higher underwent an MRI of the prostate gland.
- Targeted biopsies were performed in those with abnormal prostate gland findings on MRI. Most patients with a negative MRI were not recommended for systematic biopsy unless they had a PSA density of ≥ 0.15 ng/mL.
TAKEAWAY:
- Among the 7744 invited men who agreed to the three-phase screening protocol (51%), ultimately 209 (2.7% of all screened participants) had a targeted transrectal prostate biopsy. Overall, 136 of the biopsies (65%) detected cancer — 32 low-grade and 128 high-grade prostate cancers, for cumulative incidence rates of 0.41% and 1.65%, respectively.
- Over a 3.2-year median follow-up among the 7457 invited men who refused screening, seven low-grade and 44 high-grade prostate cancers were detected (cumulative incidence rates, 0.1% and 0.6%, respectively).
- Among the entire invited screening group, 39 low-grade (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected.
- Among men in the control group, 65 low-grade prostate cancers were ultimately identified and 282 high-grade. The risk difference between the invited screening group and control group was 0.11% for low-grade disease and 0.51% for high-grade disease. Compared with the control group, the intervention led to the detection of one additional low-grade prostate cancer per 909 men invited to screen and one additional high-grade prostate cancer per 196 men invited.
IN PRACTICE:
The three-phase screening approach used in this study detected additional cancers, compared with a control group not invited for screening, but “these results are descriptive and should be interpreted provisionally pending results from the trial on the primary outcomes of prostate cancer mortality,” the investigators said.
SOURCE:
This study was conducted by the ProScreen Trial Investigators, including first author Anssi Auvinen, MD, PhD, of Tampere University, Tampere, Finland, and was published online in JAMAalongside an accompanying editorial.
LIMITATIONS:
Absolute differences between the two randomized groups in this study were small and had unclear clinical importance. Prior screening was reported by several participants and may have reduced cancer detection. The results are based on a single invitation for screening, meaning some high-grade cancers were likely missed; subsequent screening invitations may identify missed cancers. No data were available on cancers missed at screening, and interval cancer incidence is needed to assess sensitivity of the screening protocol used in the study.
DISCLOSURES:
The ProScreen trial is funded by grants from the Academy of Finland, the Finnish Cancer Foundation, the Jane and Aatos Erkko Foundation, the Finland State Research Funding, Helsinki University Hospital, the Sigrid Jusélius Foundation, and the Päivikki and Sakari Sohlberg Foundation. Dr. Auvinen reported having no disclosures. Multiple co-authors reported associations outside the submitted work. The full list of author disclosures is included with the full text of the article.
A version of this article appeared on Medscape.com.
TOPLINE:
according to preliminary findings from the Finnish ProScreen randomized clinical trial.
METHODOLOGY:
- Prostate-specific antigen (PSA) screening is currently recommended for men in the United States starting at age 55. However, the test is controversial, in large part because it often detects prostate cancer that is not clinically relevant and may lead to overtreatment of men with low-grade disease.
- The current ProScreen trial assessed a screening intervention that aims to reduce unnecessary diagnoses of prostate cancer but still catch relevant cancers and reduce prostate cancer mortality.
- The researchers randomized 60,745 eligible men aged 50-63 years to be invited to a three-phase screening intervention (n = 15,201) or to be part of a control group that was not invited to screen (n = 45,544).
- The screening group who agreed to participate (n = 7744) first underwent a PSA test. Those with a PSA of ≥ 3.0 ng/mL then underwent a four-kallikrein panel to identify high-grade prostate cancer. Those with a kallikrein panel risk score of 7.5% or higher underwent an MRI of the prostate gland.
- Targeted biopsies were performed in those with abnormal prostate gland findings on MRI. Most patients with a negative MRI were not recommended for systematic biopsy unless they had a PSA density of ≥ 0.15 ng/mL.
TAKEAWAY:
- Among the 7744 invited men who agreed to the three-phase screening protocol (51%), ultimately 209 (2.7% of all screened participants) had a targeted transrectal prostate biopsy. Overall, 136 of the biopsies (65%) detected cancer — 32 low-grade and 128 high-grade prostate cancers, for cumulative incidence rates of 0.41% and 1.65%, respectively.
- Over a 3.2-year median follow-up among the 7457 invited men who refused screening, seven low-grade and 44 high-grade prostate cancers were detected (cumulative incidence rates, 0.1% and 0.6%, respectively).
- Among the entire invited screening group, 39 low-grade (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected.
- Among men in the control group, 65 low-grade prostate cancers were ultimately identified and 282 high-grade. The risk difference between the invited screening group and control group was 0.11% for low-grade disease and 0.51% for high-grade disease. Compared with the control group, the intervention led to the detection of one additional low-grade prostate cancer per 909 men invited to screen and one additional high-grade prostate cancer per 196 men invited.
IN PRACTICE:
The three-phase screening approach used in this study detected additional cancers, compared with a control group not invited for screening, but “these results are descriptive and should be interpreted provisionally pending results from the trial on the primary outcomes of prostate cancer mortality,” the investigators said.
SOURCE:
This study was conducted by the ProScreen Trial Investigators, including first author Anssi Auvinen, MD, PhD, of Tampere University, Tampere, Finland, and was published online in JAMAalongside an accompanying editorial.
LIMITATIONS:
Absolute differences between the two randomized groups in this study were small and had unclear clinical importance. Prior screening was reported by several participants and may have reduced cancer detection. The results are based on a single invitation for screening, meaning some high-grade cancers were likely missed; subsequent screening invitations may identify missed cancers. No data were available on cancers missed at screening, and interval cancer incidence is needed to assess sensitivity of the screening protocol used in the study.
DISCLOSURES:
The ProScreen trial is funded by grants from the Academy of Finland, the Finnish Cancer Foundation, the Jane and Aatos Erkko Foundation, the Finland State Research Funding, Helsinki University Hospital, the Sigrid Jusélius Foundation, and the Päivikki and Sakari Sohlberg Foundation. Dr. Auvinen reported having no disclosures. Multiple co-authors reported associations outside the submitted work. The full list of author disclosures is included with the full text of the article.
A version of this article appeared on Medscape.com.
TOPLINE:
according to preliminary findings from the Finnish ProScreen randomized clinical trial.
METHODOLOGY:
- Prostate-specific antigen (PSA) screening is currently recommended for men in the United States starting at age 55. However, the test is controversial, in large part because it often detects prostate cancer that is not clinically relevant and may lead to overtreatment of men with low-grade disease.
- The current ProScreen trial assessed a screening intervention that aims to reduce unnecessary diagnoses of prostate cancer but still catch relevant cancers and reduce prostate cancer mortality.
- The researchers randomized 60,745 eligible men aged 50-63 years to be invited to a three-phase screening intervention (n = 15,201) or to be part of a control group that was not invited to screen (n = 45,544).
- The screening group who agreed to participate (n = 7744) first underwent a PSA test. Those with a PSA of ≥ 3.0 ng/mL then underwent a four-kallikrein panel to identify high-grade prostate cancer. Those with a kallikrein panel risk score of 7.5% or higher underwent an MRI of the prostate gland.
- Targeted biopsies were performed in those with abnormal prostate gland findings on MRI. Most patients with a negative MRI were not recommended for systematic biopsy unless they had a PSA density of ≥ 0.15 ng/mL.
TAKEAWAY:
- Among the 7744 invited men who agreed to the three-phase screening protocol (51%), ultimately 209 (2.7% of all screened participants) had a targeted transrectal prostate biopsy. Overall, 136 of the biopsies (65%) detected cancer — 32 low-grade and 128 high-grade prostate cancers, for cumulative incidence rates of 0.41% and 1.65%, respectively.
- Over a 3.2-year median follow-up among the 7457 invited men who refused screening, seven low-grade and 44 high-grade prostate cancers were detected (cumulative incidence rates, 0.1% and 0.6%, respectively).
- Among the entire invited screening group, 39 low-grade (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected.
- Among men in the control group, 65 low-grade prostate cancers were ultimately identified and 282 high-grade. The risk difference between the invited screening group and control group was 0.11% for low-grade disease and 0.51% for high-grade disease. Compared with the control group, the intervention led to the detection of one additional low-grade prostate cancer per 909 men invited to screen and one additional high-grade prostate cancer per 196 men invited.
IN PRACTICE:
The three-phase screening approach used in this study detected additional cancers, compared with a control group not invited for screening, but “these results are descriptive and should be interpreted provisionally pending results from the trial on the primary outcomes of prostate cancer mortality,” the investigators said.
SOURCE:
This study was conducted by the ProScreen Trial Investigators, including first author Anssi Auvinen, MD, PhD, of Tampere University, Tampere, Finland, and was published online in JAMAalongside an accompanying editorial.
LIMITATIONS:
Absolute differences between the two randomized groups in this study were small and had unclear clinical importance. Prior screening was reported by several participants and may have reduced cancer detection. The results are based on a single invitation for screening, meaning some high-grade cancers were likely missed; subsequent screening invitations may identify missed cancers. No data were available on cancers missed at screening, and interval cancer incidence is needed to assess sensitivity of the screening protocol used in the study.
DISCLOSURES:
The ProScreen trial is funded by grants from the Academy of Finland, the Finnish Cancer Foundation, the Jane and Aatos Erkko Foundation, the Finland State Research Funding, Helsinki University Hospital, the Sigrid Jusélius Foundation, and the Päivikki and Sakari Sohlberg Foundation. Dr. Auvinen reported having no disclosures. Multiple co-authors reported associations outside the submitted work. The full list of author disclosures is included with the full text of the article.
A version of this article appeared on Medscape.com.