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 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, but PB and TUDCA individually 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). It also protected 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 TUDCA trial. It is enrolling 440 ALS patients 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. Results are expected in summer 2021.
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 6 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). The benefit appeared over and above any effects of riluzole and edaravarone.
No significant differences were noted in secondary outcomes. The most common side effects were diarrhea and abdominal pain, which occurred in five percent of participants and lessened with time. Ninety-eight out of 137 participants completed the trial.
Between March 2018 and September 2019, the 90 CENTAUR completers went on to an open-label extension trial. An analysis of survival in this phase found that people who had originally been randomized to drug lived 6.5 months longer 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. The difference was statistically significant (Pagnanoni et al., 2020).
In August 2018, Amylyx began PEGASUS, a Phase 2 trial in Alzheimer’s disease. Conducted at 10 sites in the U.S., the study is enrolling 100 participants with a biomarker-confirmed diagnosis of probable Alzheimer’s disease or mild cognitive impairment, and randomizes 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. Results are expected in summer 2020.
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: 16 Oct 2020
Research Models Citations
- Kubota K, Niinuma Y, Kaneko M, Okuma Y, Sugai M, Omura T, Uesugi M, Uehara T, Hosoi T, Nomura Y. Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem. 2006 Jun;97(5):1259-68. Epub 2006 Mar 15 PubMed.
- Daruich A, Picard E, Boatright JH, Behar-Cohen F. Review: The bile acids urso- and tauroursodeoxycholic acid as neuroprotective therapies in retinal disease. Mol Vis. 2019;25:610-624. Epub 2019 Oct 14 PubMed.
- Wiley JC, Pettan-Brewer C, Ladiges WC. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell. 2011 Jun;10(3):418-28. PubMed.
- Sturm E, Fellner L, Krismer F, Poewe W, Wenning GK, Stefanova N. Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy. Neurotherapeutics. 2016 Oct;13(4):871-879. PubMed.
- Ono K, Ikemoto M, Kawarabayashi T, Ikeda M, Nishinakagawa T, Hosokawa M, Shoji M, Takahashi M, Nakashima M. A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P + A53T transgenic mice. Parkinsonism Relat Disord. 2009 Nov;15(9):649-54. PubMed.
- Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D'Hooge R, Rodrigues CM. TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice. Mol Neurobiol. 2012 Mar 23; PubMed.
- Ackerman HD, Gerhard GS. Bile Acids in Neurodegenerative Disorders. Front Aging Neurosci. 2016;8:263. Epub 2016 Nov 22 PubMed.
- Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ, . Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler. 2009 Apr;10(2):99-106. PubMed.
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