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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Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr.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