Background

AMX0035 is a proprietary, oral combination of two drugs already in use, sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA). PB is prescribed under the brand name Buphenyl to treat urea cycle disorders. It acts as a scavenger to facilitate the excretion of excess nitrogen. Interest in repurposing PB to treat neurodegenerative diseases stems from its action as a chemical chaperone, which inhibits endoplasmic reticulum stress responses and neuronal cell death induced by accumulation of misfolded or mutant proteins (Kubota et al., 2006). PB also epigenetically regulates gene expression by inhibiting histone deacetylase.

TUDCA is a naturally occurring bile acid with anti-apoptotic and neuroprotective effects. TUDCA has been used for centuries in Asian medicine, and is widely available over the counter as a nutritional supplement. It is used clinically to help dissolve gallstones, and treat some forms of liver disease. TUDCA inhibits mitochondria-mediated apoptosis and the formation of reactive oxygen species, and blocks apoptosis caused by ER stress (reviewed in Daruich et al., 2019).

The only preclinical data comparing AMX0035 to PB and TUDCA individually describes gene expression and metabolomic changes in ALS patient-derived primary skin cells (Fels et al., 2022). The combination changed more genes and different genes than did PB or TUDCA alone. Both compounds show activity in mouse models of neurodegeneration. PB resulted in fewer plaques and better performance in a spatial memory task in APPswePS1delta9 (Wiley et al., 2011). PB prolonged survival in an ALS mouse model, both when given alone and together with riluzole (Ryu et al., 2005; Del Signore et al., 2009). PB was also reported to protect against neurodegeneration in models of α-synuclein toxicity and Parkinson’s disease (Sturm et al., 2016; Ono et al., 2009). TUDCA reduced amyloid deposition and improved cognition in APP/PS1 mice (Nunes et al., 2012). It also improved pathology and behavior in mouse models of Parkinson’s disease, HD, and ALS (reviewed by Ackerman and Gerhard, 2016).

In a clinical study conducted 10 years ago in Milan, Italy, TUDCA alone reportedly had a treatment benefit in ALS. In a Phase 2 trial in 34 ALS patients, treatment with 2 g per day for one year slowed deterioration on the ALS Functional Rating Scale (ALSFRS-R) compared with placebo (Elia et al., 2015). Post hoc analysis suggested a reduced risk of death during the trial (Reggiardo et al., 2023). Following those results, investigators in February 2019 began a Phase 3 trial of TUDCA (Albanese et al., 2022). It has enrolled 337 ALS patients at 25 sites in seven European Union countries, for an 18-month course of 2 g daily plus riluzole. The primary outcome will be change on the ALSFRS-R; the trial was set to end in December 2023.

In another trial, PB was judged safe and well-tolerated after open-label dose escalation in 40 ALS patients (Cudkowicz et al., 2009). No efficacy measures were included, but PB at 9 g/day was sufficient to induce changes in histone acetylation in patients’ blood cells. PB was also evaluated in Huntington’s (PHEN-HD trial) and Parkinson’s diseases; results are not published.

Findings

In June 2017, Amylyx began CENTAUR, a Phase 2 safety and efficacy study of AMX0035 in people with ALS. Funded by foundations and conducted at 25 academic centers in the U.S., the trial enrolled 137 patients aged 18-80 who had been symptomatic for 18 months or less. Participants were randomized 2 to 1 to take either 3 grams PB plus 1 g TUDCA twice daily, or placebo for six months. They could also take edaravone or riluzole. Primary outcomes were disease progression, measured as change on the ALSFRS-R compared with placebo, adverse events, and number of people who stayed on AMX0035. Secondary outcomes included measures of muscle strength, vital lung capacity, survival, need for tracheostomy, and hospitalizations. Other secondary endpoints were plasma phosphorylated neurofilament H and unspecified imaging biomarkers. The study was completed in September 2019.

According to published trial results, AMX0035 slowed decline on the ALSFRS-R. The treated group lost 1.24 points per month compared to 1.66 for placebo (Sep 2020 news on Paganoni et al., 2020). The benefit appeared over and above any effects of riluzole and edaravarone. No significant differences between AMX0035 and placebo were noted in secondary outcomes. The most common side effects were diarrhea and abdominal pain, which occurred in 5 percent of participants and lessened with time. Ninety-eight out of 137 participants completed the trial. A post hoc analysis comparing long-term survival of the active drug participants to matched external controls found a 10-month survival advantage with treatment (Paganoni et al., 2023).

Between March 2018 and September 2019, 95 CENTAUR completers went on to an open-label extension study, whose primary outcome was adverse events. An analysis of survival in this phase concluded that people who originally had been randomized to drug lived 6.5 months longer than those originally in the placebo group. The participants from the active drug group survived a median of 24 months after randomization, compared to 18.5 months for the placebo group, a statistically significant difference (Paganoni et al., 2021; Paganoni et al., 2022). 

In this trial, AMX0035 treatment were reported to have reduced levels of inflammatory biomarkers YKL-40 and CRP in plasma by 20 and 30 percent, respectively (Bowser et al., 2023).

From August 2018 to April 2021, Amylyx ran PEGASUS, a Phase 2 trial in Alzheimer’s disease. Conducted at 10 sites in the U.S., the study enrolled 95 participants with a biomarker-confirmed diagnosis of probable Alzheimer’s disease or mild cognitive impairment due to AD, and randomized them to an undisclosed dose of AMX0035 or placebo for 24 weeks. The primary outcome was safety; secondary outcomes include volumetric and functional MRI, cognition, and psychiatric symptoms, as well as unspecified CSF and plasma biomarkers. The company reported topline results at the November 2021 CTAD conference (press release). AMX0035 met safety and tolerability endpoints, with gastrointestinal side effects in line with previous clinical trials. The trial was not powered to detect efficacy and clinical endpoints revealed none. Treatment led to a significant reduction in CSF AD biomarkers Tau and pTau181, and an increased Aβ42/40 ratio. A marker of DNA damage, 8-hydroxy-2'-deoxyguanosine, was higher in the treated group. At the December 2022 CTAD conference, the company reported changes favoring drug in CSF biomarkers neurogranin, fABP3, and YKL40, but not in NfL, GFAP, an inflammation composite, soluble insulin receptor, or 24S-OH-cholesterol.

From November 2020 to January 2023, Amylyx sponsored a compassionate-use program for 28 people with ALS. In August 2021, the company started a Phase 1/2 drug exposure/pharmacodynamic study in 14 people with ALS.

In October 2021, Amylyx began PHOENIX, a 664-participant, international Phase 3 trial in ALS, comparing a 48-week course of an undisclosed dose of AMX0035 to placebo. The drug is to be delivered by mouth or feeding tube once daily for three weeks, then twice daily for the rest of the study. Primary outcomes are slope change on the ALS-FRS and survival, adverse events, and number of people able to complete the trial; secondary outcomes include various functional and quality-of-life measures but not biomarkers such as neurofilament light or others. Ongoing at around 70 sites in the U.S. and Europe, the trial is expected to run until November 2023, with topline results expected in 2024. An open-label extension began in December 2022; an expanded access program exists, as well.

On March 30, 2022, after a day-long meeting, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted 6 to 4 against approving AMX0035 for the treatment of ALS based on the data submitted to the agency. In its briefing document issued prior to this AdComs meeting, the FDA had registered concerns with the statistical analysis method chosen for the primary endpoint, with the accounting of deaths that occurred during the study, center effects, group imbalances in incident concomitant medications, and other weaknesses in the data. For the purposes of the AdComs meeting, the briefing document concluded that the available evidence did not amount to substantial evidence of effectiveness. A decision was initially expected in June 2022, but the FDA pushed it back to September, citing a need for more time to evaluate the data.

In May 2022, company scientists published data claiming that AMX0035 treatment lengthened tracheostomy/ventilation-free survival and delayed first hospitalization in the CENTAUR trial (Paganoni et al., 2022). 

On June 10, AMX0035, brand name Albrioza, received conditional marketing approval from Health Canada, the country's drug regulatory agency. The approval is contingent on the outcome of the ongoing PHOENIX trial (see Notice of Compliance).

On July 5, 2022, Amylyx announced the U.S. FDA would reconvene the advisory committee to discuss a "major amendment" to the AMX0035 application (press release). In this rare second meeting, the committee voted in favor of the drug. The decision came after new analysis of data from the CENTAUR Phase 2 trial and long-term extension, and a pledge from Amylyx to voluntarily withdraw the drug if it fails to show efficacy in its ongoing Phase 3 trial (Endpoints News). On September 29, the FDA approved Albrioza, which is marketed in the U.S. as Relyvrio (Oct 2022 news). For review and commentary, see Sun et al., 2023; and Flynn et al., 2023.

In March 2023, the company began a 12-patient pilot study of AMX0035 in adults with Wolfram Syndrome, a genetic disorder characterized by diabetes, optic nerve atrophy, and deafness. The company began a 600-patient Phase 3 trial in progressive supranuclear palsy in December 2023.

On June 22, 2023, the European Medicines Agency rejected this drug, citing unconvincing data on its efficacy at slowing progression or prolonging survival (EMA statement). The company appealed, seeking conditional approval, but was rejected again in October (Endpoints News; company press release).

On March 8, 2024, Amylyx announced that the 664-patient PHOENIX trial had failed to meet its endpoints (press release; Mar 2024 news). Relyvrio did not change disease progression on the ALSFRS-R compared to placebo (p=0.667), nor did it change any secondary outcomes. The company said it would take eight weeks to decide the drug’s fate, and would continue to provide it to current users for that time. The open-label extension to PEGASUS will continue in Europe, as will the studies in Wolfram syndrome and Progressive Supranuclear Palsy. The trial result may reverse Relyvrio’s conditional approval in Canada.

On April 4, the company announced it would withdraw Relyvrio from the market in the U.S. and Canada (press release). No new patients will be able to start therapy. Patients already taking the drug are eligible to transition to the PHOENIX open-label extension for free. Development for Wolfram syndrome and PSP will continue.

For details on AMX0035 trials, see clinicaltrials.gov.

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