Amylyx Announces Latest Statistical Analysis of New ALS Drugs

Recently, Amylyx announced the results of the long-term survival analysis of AMX0035 in the treatment of amyotrophic lateral sclerosis (ALS) phase 2 CENTAUR trial adjusted for placebo crossover. Post hoc analyses showed that AMX0035 demonstrated a greater survival benefit compared with placebo, with median survival of 10.6 to 18.8 months after adjustment for placebo crossover; , AMX0035 extended median survival by only 6.8 months compared to placebo. The results were published in the peer-reviewed medical journal Muscle & Nerve.

In clinical trials of rapidly fatal diseases such as ALS, a design that crosses over placebo to active treatment is critical; however, this design may underestimate the clinical effect of active treatment. In the post hoc analysis described above, Amylyx was assessed using a rank-preserving structural failure time model (RPSFTM), an analytical method frequently used in oncology drug evaluations to account for placebo crossover.

This post hoc analysis incorporated updated patient vital status information from a previous interim ITT analysis. The final dataset compared the date of randomization from the phase 2 CENTAUR trial to the data cutoff date of July 20, 2020 (longest follow-up, 35 months after randomization) and the final open-label extension (OLE) patient follow-up date ( March 1, 2021, 42 months after randomization) time to death (all-cause mortality). The vital status of all but one patient was censored at the last follow-up visit. Post hoc analyses included RPSFTM and subgroup analyses.

Results of the final overall survival ITT analysis showed that as of July 2020, patients initially randomized to AMX0035 had a significantly longer median survival of 6.9 months compared with patients initially randomized to placebo (HR = 0.57; 95% CI : 0.35-0.92; p=0.023). As of March 2021, patients initially randomized to AMX0035 had a significantly longer median survival of 4.8 months compared with patients initially randomized to placebo (HR=0.64; 95% CI: 0.42-1.00; p=0.048 ).

A significant survival benefit was observed with AMX0035 compared to the ITT analysis with statistical method results considering treatment crossover (RPSFTM and subgroup analysis). The RPSFTM analysis modeled the placebo survival outcome if patients had not crossed over to AMX0035 treatment in the OLE phase, showing a greater survival benefit for AMX0035 compared to placebo.

Specifically, as of July 2020, patients initially randomized to AMX0035 had a median survival of 25.8 months, compared with a median RPSFTM-adjusted survival of 15.2 months for patients initially randomized to placebo, a difference was 10.6 months (HR=0.39; 95%CI: 0.17-0.88; p=0.023). As of March 2021, the RPSFTM analysis showed consistent results.

In addition, as of the July 2020 cutoff date, subgroup post hoc analysis assessments based on randomization group and OLE phase enrollment indicated that patients randomized to AMX0035 from the start of the trial and continued into the open compared with patients who never received AMX0035 Patients treated with AMX0035 during the label extension phase (OLE) had a median survival of 18.8 months (p<0.0001).

The results of the long-term analysis described above provide further evidence that AMX0035 has the potential to deliver a survival benefit to patients with ALS, as well as provide insights into potential new ways to analyze survival data in ALS clinical trials. As a serious and deadly disease, time is invaluable to ALS patients and their families, and any treatment that might provide more time to live is very important.

AMX0035 (PB-TURSO) is a proprietary oral fixed-dose combination formulation consisting of sodium phenylbutyrate (PB) and taurine diol (TURSO). PB is a small molecular chaperone designed to reduce the unfolded protein response (UPR) and prevent cell death due to UPR. TURSO is a Bax inhibitor designed to reduce cell death through apoptosis. PB and TURSO were combined in a fixed-dose formulation to reduce neuronal death and dysfunction. AMX0035 is designed to target endoplasmic reticulum and mitochondria-dependent neuronal degeneration pathways in ALS and other neurodegenerative diseases.

It is worth noting that at the end of March this year, the U.S. FDA Advisory Committee voted 6 against and 4 in favor, finding that Amylyx failed to clearly demonstrate the effectiveness of AMX0035 in the treatment of ALS in the above-mentioned Phase 2 CENTAUR trial, resulting in the drug's approval. There is little hope of a batch listing. It is reported that the FDA will make a final review decision on June 29 this year.