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, according to the full results of the RESPONSE phase 3 study.
“At a dose of 10 mg daily, 1 in 4 patients normalize their alkaline phosphatase level,” chief investigator Gideon Hirschfield, PhD, BM BChir, with the Toronto Center for Liver Disease at Toronto General Hospital, Toronto, Ontario, Canada, said in an interview.
The study data are “genuinely exciting...and support the potential for seladelpar to raise the bar in PBC treatment,” Dr. Hirschfield added in a news release.
Seladelpar is being developed by CymaBay Therapeutics, which funded the study.
The results were published online in The New England Journal of Medicine.
Topline data from the study were presented in November at The Liver Meeting 2023: American Association for the Study of Liver Diseases.
‘Unequivocal’ Progress
Up to 40% of patients with PBC have an inadequate response to first-line therapy with ursodeoxycholic acid (UDCA) and are at a high risk for disease progression. More than half of patients with the disease fail to respond to second-line therapy with obeticholic acid.
Seladelpar, and the dual PPAR-alpha and PPAR-delta agonist elafibranor, are an “unequivocal sign of progress, marking the arrival of a new era in which PBC treatment is expected to provide both biochemical benefits and amelioration of symptoms for patients,” David N. Assis, MD, with the Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, wrote in a linked editorial.
In the RESPONSE study, 193 patients with PBC who had an inadequate response to or a history of unacceptable side effects with UDCA were randomly allocated to either oral seladelpar 10 mg daily or placebo for 12 months. The vast majority (93.8%) continued UDCA as standard-of-care background therapy.
The primary endpoint was a biochemical response, which was defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at 12 months.
After 12 months, 61.7% of patients taking seladelpar met the primary endpoint vs 20% of patients taking placebo.
In addition, significantly more patients taking seladelpar than placebo had normalization of the ALP level (25% vs 0%). The average decrease in ALP from baseline was 42.4% in the seladelpar group vs 4.3% in the placebo group.
At 12 months, alanine aminotransferase and gamma-glutamyl transferase levels were reduced by 23.5% and 39.1%, respectively, in the seladelpar group compared with 6.5% and 11.4%, respectively, in the placebo group.
“In PBC, we use target endpoints, so the trial was not powered or able to show yet clinical outcomes because the pace of the disease is quite slow. But we believe that the normalization of liver tests and improvement in quality of life will change the disease trajectory over time,” Dr. Hirschfield said.
Significant Reduction in Pruritus
A key secondary endpoint was change in patient-reported pruritus.
At baseline, 38.3% of patients in the seladelpar group and 35.4% of those in the placebo group had moderate to severe pruritus, with a daily numerical rating scale (NRS) score of 4 or higher out of 10.
Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater with seladelpar than with placebo (change from baseline, −3.2 points vs −1.7 points). These improvements were sustained through 12 months.
Improvements on the 5-D Itch Scale in both the moderate to severe pruritus population and the overall population also favored seladelpar over placebo for itch relief, which had a positive impact on sleep. Similar results demonstrating reductions in itch and improvements in sleep were observed using the PBC-40 questionnaire.
Adverse events that led to discontinuation of seladelpar or placebo were rare, and there was no between-group difference in the incidence of serious adverse events.
“No worrisome adverse events affecting the muscles were observed, including among patients receiving statins. Certain gastrointestinal events — abdominal pain, abdominal distention, and nausea — were reported more frequently in the seladelpar group than in the placebo group,” the study authors wrote.
The most common adverse events that occurred in ≥ 5% of patients in either group were COVID-19 and pruritus. A greater percentage of patients treated with placebo reported pruritus (15.4% vs 4.7%) as an adverse event — a finding consistent with the positive effect of seladelpar on reducing pruritus.
The researchers noted that 96.4% of patients who participated in the RESPONSE trial chose to enroll in the extension trial to evaluate long-term safety and the side-effect profile of seladelpar.
Potential First-Line Treatment?
In Dr. Assis’ view, the RESPONSE trial, coupled with the recently reported ELATIVE trial of the dual PPAR-alpha and PPAR-delta agonist elafibranor in PBC, “cement the role of PPAR agonists as the preferred second-line treatment in primary biliary cholangitis.”
“The reduction in serum cholestatic markers and the safety profiles of elafibranor and seladelpar offer clear advantages beyond what was previously shown with obeticholic acid. These trials also cement a new treatment goal for primary biliary cholangitis in which a reduction in pruritus should be expected as part of anticholestatic treatment,” Dr. Assis wrote.
“The results of these trials suggest that the use of PPAR agonists in primary biliary cholangitis could improve treatment outcomes while also improving quality of life, which is a highly desirable alignment of clinician and patient goals,” Dr. Assis added.
Looking ahead, Dr. Hirschfield sees a potential role for seladelpar earlier in the course of PBC treatment, he said in an interview.
“Over time, the way we treat patients will not be to wait to fail. It will be treat to target and treat to success,” Dr. Hirschfield said.
Earlier this month, the US Food and Drug Administration accepted CymaBay Therapeutics’ new drug application for seladelpar for the treatment of PBC, including pruritus in adults without cirrhosis or with compensated cirrhosis (Child Pugh A) who fail to respond adequately or cannot tolerate UDCA. Seladelpar for PBC was granted breakthrough designation in October 2023.
The study was funded by CymaBay Therapeutics. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article appeared on Medscape.com.
, according to the full results of the RESPONSE phase 3 study.
“At a dose of 10 mg daily, 1 in 4 patients normalize their alkaline phosphatase level,” chief investigator Gideon Hirschfield, PhD, BM BChir, with the Toronto Center for Liver Disease at Toronto General Hospital, Toronto, Ontario, Canada, said in an interview.
The study data are “genuinely exciting...and support the potential for seladelpar to raise the bar in PBC treatment,” Dr. Hirschfield added in a news release.
Seladelpar is being developed by CymaBay Therapeutics, which funded the study.
The results were published online in The New England Journal of Medicine.
Topline data from the study were presented in November at The Liver Meeting 2023: American Association for the Study of Liver Diseases.
‘Unequivocal’ Progress
Up to 40% of patients with PBC have an inadequate response to first-line therapy with ursodeoxycholic acid (UDCA) and are at a high risk for disease progression. More than half of patients with the disease fail to respond to second-line therapy with obeticholic acid.
Seladelpar, and the dual PPAR-alpha and PPAR-delta agonist elafibranor, are an “unequivocal sign of progress, marking the arrival of a new era in which PBC treatment is expected to provide both biochemical benefits and amelioration of symptoms for patients,” David N. Assis, MD, with the Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, wrote in a linked editorial.
In the RESPONSE study, 193 patients with PBC who had an inadequate response to or a history of unacceptable side effects with UDCA were randomly allocated to either oral seladelpar 10 mg daily or placebo for 12 months. The vast majority (93.8%) continued UDCA as standard-of-care background therapy.
The primary endpoint was a biochemical response, which was defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at 12 months.
After 12 months, 61.7% of patients taking seladelpar met the primary endpoint vs 20% of patients taking placebo.
In addition, significantly more patients taking seladelpar than placebo had normalization of the ALP level (25% vs 0%). The average decrease in ALP from baseline was 42.4% in the seladelpar group vs 4.3% in the placebo group.
At 12 months, alanine aminotransferase and gamma-glutamyl transferase levels were reduced by 23.5% and 39.1%, respectively, in the seladelpar group compared with 6.5% and 11.4%, respectively, in the placebo group.
“In PBC, we use target endpoints, so the trial was not powered or able to show yet clinical outcomes because the pace of the disease is quite slow. But we believe that the normalization of liver tests and improvement in quality of life will change the disease trajectory over time,” Dr. Hirschfield said.
Significant Reduction in Pruritus
A key secondary endpoint was change in patient-reported pruritus.
At baseline, 38.3% of patients in the seladelpar group and 35.4% of those in the placebo group had moderate to severe pruritus, with a daily numerical rating scale (NRS) score of 4 or higher out of 10.
Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater with seladelpar than with placebo (change from baseline, −3.2 points vs −1.7 points). These improvements were sustained through 12 months.
Improvements on the 5-D Itch Scale in both the moderate to severe pruritus population and the overall population also favored seladelpar over placebo for itch relief, which had a positive impact on sleep. Similar results demonstrating reductions in itch and improvements in sleep were observed using the PBC-40 questionnaire.
Adverse events that led to discontinuation of seladelpar or placebo were rare, and there was no between-group difference in the incidence of serious adverse events.
“No worrisome adverse events affecting the muscles were observed, including among patients receiving statins. Certain gastrointestinal events — abdominal pain, abdominal distention, and nausea — were reported more frequently in the seladelpar group than in the placebo group,” the study authors wrote.
The most common adverse events that occurred in ≥ 5% of patients in either group were COVID-19 and pruritus. A greater percentage of patients treated with placebo reported pruritus (15.4% vs 4.7%) as an adverse event — a finding consistent with the positive effect of seladelpar on reducing pruritus.
The researchers noted that 96.4% of patients who participated in the RESPONSE trial chose to enroll in the extension trial to evaluate long-term safety and the side-effect profile of seladelpar.
Potential First-Line Treatment?
In Dr. Assis’ view, the RESPONSE trial, coupled with the recently reported ELATIVE trial of the dual PPAR-alpha and PPAR-delta agonist elafibranor in PBC, “cement the role of PPAR agonists as the preferred second-line treatment in primary biliary cholangitis.”
“The reduction in serum cholestatic markers and the safety profiles of elafibranor and seladelpar offer clear advantages beyond what was previously shown with obeticholic acid. These trials also cement a new treatment goal for primary biliary cholangitis in which a reduction in pruritus should be expected as part of anticholestatic treatment,” Dr. Assis wrote.
“The results of these trials suggest that the use of PPAR agonists in primary biliary cholangitis could improve treatment outcomes while also improving quality of life, which is a highly desirable alignment of clinician and patient goals,” Dr. Assis added.
Looking ahead, Dr. Hirschfield sees a potential role for seladelpar earlier in the course of PBC treatment, he said in an interview.
“Over time, the way we treat patients will not be to wait to fail. It will be treat to target and treat to success,” Dr. Hirschfield said.
Earlier this month, the US Food and Drug Administration accepted CymaBay Therapeutics’ new drug application for seladelpar for the treatment of PBC, including pruritus in adults without cirrhosis or with compensated cirrhosis (Child Pugh A) who fail to respond adequately or cannot tolerate UDCA. Seladelpar for PBC was granted breakthrough designation in October 2023.
The study was funded by CymaBay Therapeutics. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article appeared on Medscape.com.
, according to the full results of the RESPONSE phase 3 study.
“At a dose of 10 mg daily, 1 in 4 patients normalize their alkaline phosphatase level,” chief investigator Gideon Hirschfield, PhD, BM BChir, with the Toronto Center for Liver Disease at Toronto General Hospital, Toronto, Ontario, Canada, said in an interview.
The study data are “genuinely exciting...and support the potential for seladelpar to raise the bar in PBC treatment,” Dr. Hirschfield added in a news release.
Seladelpar is being developed by CymaBay Therapeutics, which funded the study.
The results were published online in The New England Journal of Medicine.
Topline data from the study were presented in November at The Liver Meeting 2023: American Association for the Study of Liver Diseases.
‘Unequivocal’ Progress
Up to 40% of patients with PBC have an inadequate response to first-line therapy with ursodeoxycholic acid (UDCA) and are at a high risk for disease progression. More than half of patients with the disease fail to respond to second-line therapy with obeticholic acid.
Seladelpar, and the dual PPAR-alpha and PPAR-delta agonist elafibranor, are an “unequivocal sign of progress, marking the arrival of a new era in which PBC treatment is expected to provide both biochemical benefits and amelioration of symptoms for patients,” David N. Assis, MD, with the Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, wrote in a linked editorial.
In the RESPONSE study, 193 patients with PBC who had an inadequate response to or a history of unacceptable side effects with UDCA were randomly allocated to either oral seladelpar 10 mg daily or placebo for 12 months. The vast majority (93.8%) continued UDCA as standard-of-care background therapy.
The primary endpoint was a biochemical response, which was defined as an alkaline phosphatase (ALP) level < 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at 12 months.
After 12 months, 61.7% of patients taking seladelpar met the primary endpoint vs 20% of patients taking placebo.
In addition, significantly more patients taking seladelpar than placebo had normalization of the ALP level (25% vs 0%). The average decrease in ALP from baseline was 42.4% in the seladelpar group vs 4.3% in the placebo group.
At 12 months, alanine aminotransferase and gamma-glutamyl transferase levels were reduced by 23.5% and 39.1%, respectively, in the seladelpar group compared with 6.5% and 11.4%, respectively, in the placebo group.
“In PBC, we use target endpoints, so the trial was not powered or able to show yet clinical outcomes because the pace of the disease is quite slow. But we believe that the normalization of liver tests and improvement in quality of life will change the disease trajectory over time,” Dr. Hirschfield said.
Significant Reduction in Pruritus
A key secondary endpoint was change in patient-reported pruritus.
At baseline, 38.3% of patients in the seladelpar group and 35.4% of those in the placebo group had moderate to severe pruritus, with a daily numerical rating scale (NRS) score of 4 or higher out of 10.
Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater with seladelpar than with placebo (change from baseline, −3.2 points vs −1.7 points). These improvements were sustained through 12 months.
Improvements on the 5-D Itch Scale in both the moderate to severe pruritus population and the overall population also favored seladelpar over placebo for itch relief, which had a positive impact on sleep. Similar results demonstrating reductions in itch and improvements in sleep were observed using the PBC-40 questionnaire.
Adverse events that led to discontinuation of seladelpar or placebo were rare, and there was no between-group difference in the incidence of serious adverse events.
“No worrisome adverse events affecting the muscles were observed, including among patients receiving statins. Certain gastrointestinal events — abdominal pain, abdominal distention, and nausea — were reported more frequently in the seladelpar group than in the placebo group,” the study authors wrote.
The most common adverse events that occurred in ≥ 5% of patients in either group were COVID-19 and pruritus. A greater percentage of patients treated with placebo reported pruritus (15.4% vs 4.7%) as an adverse event — a finding consistent with the positive effect of seladelpar on reducing pruritus.
The researchers noted that 96.4% of patients who participated in the RESPONSE trial chose to enroll in the extension trial to evaluate long-term safety and the side-effect profile of seladelpar.
Potential First-Line Treatment?
In Dr. Assis’ view, the RESPONSE trial, coupled with the recently reported ELATIVE trial of the dual PPAR-alpha and PPAR-delta agonist elafibranor in PBC, “cement the role of PPAR agonists as the preferred second-line treatment in primary biliary cholangitis.”
“The reduction in serum cholestatic markers and the safety profiles of elafibranor and seladelpar offer clear advantages beyond what was previously shown with obeticholic acid. These trials also cement a new treatment goal for primary biliary cholangitis in which a reduction in pruritus should be expected as part of anticholestatic treatment,” Dr. Assis wrote.
“The results of these trials suggest that the use of PPAR agonists in primary biliary cholangitis could improve treatment outcomes while also improving quality of life, which is a highly desirable alignment of clinician and patient goals,” Dr. Assis added.
Looking ahead, Dr. Hirschfield sees a potential role for seladelpar earlier in the course of PBC treatment, he said in an interview.
“Over time, the way we treat patients will not be to wait to fail. It will be treat to target and treat to success,” Dr. Hirschfield said.
Earlier this month, the US Food and Drug Administration accepted CymaBay Therapeutics’ new drug application for seladelpar for the treatment of PBC, including pruritus in adults without cirrhosis or with compensated cirrhosis (Child Pugh A) who fail to respond adequately or cannot tolerate UDCA. Seladelpar for PBC was granted breakthrough designation in October 2023.
The study was funded by CymaBay Therapeutics. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE