Therapy Type: Combination, Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis, Alzheimer's Disease
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2), Alzheimer's Disease (Phase 2)
Company: Amylyx Pharmaceuticals Inc
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).
No preclinical data on AMX0035 have been published to show its superiority over PB and TUDCA given individually. 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). Following on those results, investigators in February 2019 began a Phase 3 trial of TUDCA. It is enrolling 440 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 is set to end in December 2022.
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.
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. 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 for six months. 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.
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 (Pagnanoni et al., 2021; Paganoni et al., 2022). The study was completed in 2021.
From August 2018 to April 2021, Amylyx ran PEGASUS, a Phase 2 trial in Alzheimer’s disease. Conducted at 11 sites in the U.S., the study enrolled 95 participants with a biomarker-confirmed diagnosis of probable Alzheimer’s disease or mild cognitive impairment, and randomized them to an undisclosed dose of AMX0035 or placebo for 24 weeks. The primary outcome is safety; secondary outcomes include volumetric and functional MRI, cognition, and psychiatric symptoms, as well as unspecified CSF and plasma biomarkers.
In November 2020, Amylyx started a compassionate use program for 40 people and, in August 2021, started a Phase 1/2 drug exposure/pharmacodynamic study in 14 people with ALS.
In October 2021, Amylyx began PHOENIX, a 600-participant Phase 3 trial comparing a 48-week course of an undisclosed dose of AMX0035 to placebo. 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. The trial listed 33 sites; as of April 2022, only three were recruiting. The trial is expected to run until November 2023, with topline results expected in 2024. 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 tracheostome/ventilation-free survival and delayed first hospitalization in the PEGASUS 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 contigent on the outcome of the ongoing PHOENIX trial (see Notice of Compliance).
For details on AMX0035 trials, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
|Amylyx Pharmaceuticals Inc||NCT03533257||
Last Updated: 17 Jun 2022
Research Models Citations
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