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Treatment with <a href="https://alsnewstoday.com/amx0035/">Relyvrio</a> (sodium phenylbutyrate and taurursodiol) in the CENTAUR trial significantly extended the median survival — by 10.4 months — of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients compared with an historical patient control group, a post-hoc analysis of study data reported.
This finding more than doubles the 4.8 months of extended survival initially observed in treated patients versus those randomized to a placebo in the 24-week trial, a majority of whom then were given Relyvrio in an open-label extension study.
The new analysis also found treatment lowered the risk of death over follow-up by 52% relative to the study’s external control group. The earlier analysis comparing treated CENTAUR patients with those who moved from placebo to Relyvrio reported a 36% lower risk of death.
“This [post-hoc] analysis is important because the survival difference seen helps support the robustness and clinical meaningfulness of the ITT [intent-to-treat] overall survival analysis on CENTAUR,” Machelle Manuel, PhD, head of global medical affairs at <a href="https://www.amylyx.com/">Amylyx Pharmaceuticals</a>, the treatment&#8217;s developer, said in a <a href="https://www.businesswire.com/news/home/20231010489409/en/Amylyx-Pharmaceuticals-Announces-Publication-of-Survival-Analysis-Comparing-CENTAUR-to-Historical-Clinical-Trial-Control">company press release</a>.
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<h3>ALS patients with rapid progression treated in CENTAUR and extension study</h3>
The study “<a href="https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.51915">Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls</a>,” was published in the journal <a href="https://onlinelibrary.wiley.com/journal/23289503">Annals of Clinical and Translational Neurology</a>.
In this post hoc analysis of CENTAUR data, patients given the oral medication were compared with matched control participants from previously completed clinical trials.
These controls were part of the <a href="https://ncri1.partners.org/proact">Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database</a>, the largest publicly available collection of ALS clinical trial data. It currently contains nearly 12,000 de-identified patient records from 29 Phase 2 and 3 trials.
“Analyses like the one &#8230; further our shared mission of accelerating the discovery of treatments and a cure for ALS,” said Alex Sherman, leader of the team that created the PRO-ACT database.
Relyvrio contains a fixed-dose combination of tauroursodeoxycholic acid and sodium phenylbutyrate, two compounds believed to protect nerve cells from certain forms of cellular stress.
Approved in the U.S. and in Canada — where it is sold as Albrioza — it is designed to slow disease progression and potentially extend survival.
Relyvrio&#8217;s approval was supported by data from the <a href="https://clinicaltrials.gov/ct2/show/NCT03127514">CENTAUR Phase 2 trial (NCT03127514)</a>, which evaluated the treatment&#8217;s safety and efficacy against a placebo in adults recently diagnosed with rapidly progressing ALS.
Its 137 participants randomly were assigned to either Relyvrio or a placebo for six months. Then, a total of 90 patients who completed the main trial chose to enter an <a href="https://clinicaltrials.gov/ct2/show/NCT03488524">open-label extension (OLE) study (NCT03488524)</a>, in which all were treated for up to 30 months, or about 2.5 years.
Analyses spanning about 42 months in both the CENTAUR and OLE studies demonstrated that patients given Relyvrio in the main trial lived about 4.8 months longer than those who moved from a placebo to the active treatment. This meant that starting Relyvrio six months earlier lowered the risk of death by 36%.
<h3>Majority of placebo group patients opted for Relyvrio in long-term extension</h3>
However, such an analysis is unable to determine exactly how much longer patients survive when given Relyvrio versus those not using this treatment, as most placebo patients — 71% — entered the OLE and received Relyvrio.
To have a better idea of the therapy’s true effectiveness, researchers at the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute (NCRI) at Massachusetts General Hospital conducted a post hoc analysis of CENTAUR data.
This analysis, done after the trial finished and all the data had been gathered, was funded by Amylyx. It specifically compared survival outcomes among Relyvrio-treated patients in CENTAUR with a matched group of patients from PRO-ACT — which includes <a href="https://alsnewstoday.com/news/amylyx-donates-centaur-records-pro-act-trials-database-als/">data from CENTAUR&#8217;s placebo arm</a>.
“The PRO-ACT initiative merges data from existing publicly and privately conducted ALS clinical trials to generate an invaluable resource for accelerating discovery in the field of ALS. This database allows anyone interested in moving ALS research forward an aid to do so quickly,” said Sherman, who also is director of the Center for Innovation and Biomedical Informatics at the NCRI.
In total, the post-hoc analysis included 89 ALS patients treated with Relyvrio and 85 controls from PRO-ACT, who were matched for factors such as disease duration, rate of disease progression, lung function, and age.
Notably, this control group had a similar rate of disease progression as the placebo group in CENTAUR — a monthly decline of 1.66 points in ALS Functional Rating Scale-Revised (ALSFRS-R) scores.
After a follow-up of 42 months, the median survival time in the Relyvrio group was found to be 23.54 months, significantly longer than the 13.15 months observed for the PRO-ACT control group.
Here, Relyvrio resulted in a 10.39-month longer survival, and a 52% lower risk of death compared with the PRO-ACT controls.
Overall, these findings are consistent with a <a href="https://alsnewstoday.com/news/amx0035-survival-als-patients-centaur-clinical-trial-analysis-amylyx/">previous CENTAUR analysis</a>, where researchers estimated the likely survival of placebo group patients had they stayed on placebo in the OLE. In that analysis, Relyvrio resulted in a 10.6-month survival gain, which translated in a 61% reduction in the risk of death.
“The PRO-ACT database is comprised of thousands of harmonized longitudinal records from ALS clinical trials and helps advance scientific research by providing access to robust longitudinal participant data,” said Sabrina Paganoni, MD, PhD, with the Sean M. Healey and AMG Center for ALS &amp; the Neurological Clinical Research Institute at Massachusetts General Hospital, and Melanie Quintana, PhD, a senior statistical scientist with Berry Consultants.
“Analyses using well-matched external controls may provide additional context for evaluating survival effects in future ALS trials,” added the scientists, both lead authors of the study.

Tag: post-hoc analyses

Relyvrio extends survival by 10.4 months versus external ALS group