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The investigational combination of sodium phenylbutyrate and taurursodiol (AMX0035) offered significant functional and survival benefits in adults with amyotrophic lateral sclerosis (ALS), according to an updated analysis of the CENTAUR trial.

Median time to first hospitalization was not reached for the 89 patients taking sodium phenylbutyrate-taurursodiol, an oral combination of sodium phenylbutyrate and taurursodiol, as compared to 62.4 weeks among 48 patients assigned to placebo (P=0.034), reported Sabrina Paganoni, MD, PhD, of Massachusetts General Hospital in Boston.

The median time to death or need for tracheostomy/permanent assisted ventilation was 103.6 weeks with sodium phenylbutyrate-taurursodiol versus 80.4 weeks with placebo (P=0.025), she stated during a press conference at the American Academy of Neurology virtual meeting.

Paganoni also reported that participants who enrolled in the open-label extension (OLE) part of the trial saw extended survival, despite the fact that a majority "received AMX0035 with a 6-month delayed start in the OLE."

"The drug that we tested in the CENTAUR trial is the first to show a combination of both functional and survival benefits for people living with ALS," Paganoni said. "People with ALS have progressive muscle weakness and this means that they lose the ability to do the things that we do every day, that we take for granted, such as walking or talking. Typically, they die within a couple of years after diagnosis. ALS is really a tragic disease."

In a July 2020 overall survival analysis of all participants, the mean hazard of death was 44% lower in the group originally randomized to sodium phenylbutyrate-taurursodiol versus placebo (HR 0.56, 95% CI 0.34-0.92, P=0.023), according to Paganoni and colleagues. Additional trial data were reported in September and October 2020.

In the 24-week CENTAUR trial, ALS patients were randomized 2:1 to sodium phenylbutyrate (3 g) and taurursodiol (1 g) or to placebo by mouth or feeding tube. The study agent is designed to reduce neuronal death in people with ALS by simultaneously mitigating endoplasmic reticulum stress and mitochondrial dysfunction, Paganoni explained, noting that the sodium phenylbutyrate-taurursodiol combination was "very easy to administer...and does not require laboratory or echocardiogram monitoring."

"The excitement is that people who took AMX0035 in the trial retained physical functions longer such as speaking, swallowing, and walking," she stated. "From a patient perspective, this means better function with the activities of daily living."

"The results of the CENTAUR trial show substantial evidence that support the role of AMX0035 in ALS," Paganoni added. "If approved, I expect that AMX0035 will be widely used for the treatment of ALS. The next steps will depend on discussions with regulatory agencies."

Press conference moderator Natalia Rost, MD, also of Massachusetts General, but not involved in the trial, told 番茄社区app that she was "impressed by the relentless pursuit of breakthroughs in treatment options for this terrible, deadly disease. In the CENTAUR trial, the authors, first, were able to demonstrate the efficacy of the new compound on survival and functional disability in ALS as compared to placebo."

"Secondly, they advanced their methodology in the way they ascertained the vital status in this complex patient population and were able to validate their findings in the extended follow-up," Rost said. "The reason why this is important is the field of neurological research is long overdue for a novel ALS therapy."

Rost added "Let's monitor carefully what the next phase in this compound's development brings."

Drug developer Amylyx Pharmaceuticals of Cambridge, Massachusetts, said the FDA has requested more data from a placebo-controlled trial.

"To fulfill the FDA's request...Amylyx plans to initiate a Phase 3 clinical trial in Europe and the United States," the company said in a . "The trial is expected to begin enrollment in Q3 2021. The FDA also expressed that it would continue to discuss with Amylyx how regulatory requirements may be met in the most expeditious way possible."

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