Therapeutics

ALX-001

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Overview

Name: ALX-001
Synonyms: BMS-984923
Chemical Name: (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Allyx Therapeutics, Inc.

Background

ALX-001 is an allosteric modulator of the metabotropic glutamate receptor type 5 (mGluR5). Originally developed by Bristol Myers Squibb as a potential treatment for schizophrenia, the compound is now in testing for AD.

The rationale for this drug stems from mGluR5’s role as a co-receptor for Aβ oligomers, and a mediator of their synaptotoxcity (e.g., see Um et al., 2013; Hamilton et al., 2016).

In experiments performed in the Strittmatter lab at Yale University, this compound prevented Aβ oligomer-induced mGluR5 activation and synapse loss, without affecting physiological glutamate signaling. A one-month regimen improved synapse density and function, and memory behaviors in APP/PS1 mice with amyloidosis (Haas et al., 2017). The compound may work by inhibiting astrocyte-mediated synapse destruction. Pharmacokinetic studies in rodents and nonhuman primates reported nearly full occupancy of brain mGluR5 receptors after oral dosing, as judged by PET imaging with the mGluR5 ligand 18FFPEB. No toxicity resulted from doses up to 250 times higher than those needed to achieve binding to half of brain receptors. In mice, the brain concentration of drug reached twice that in blood (Spurrier et al., 2022). 

In 2021, the Yale-founded biotech company Allyx Therapeutics licensed BMS-984923 from Bristol Myers Squibb, and is developing it for cognitive impairment due to neurodegeneration, under the name ALX-001 (press release).

Findings

From March 2021 to April 2022, a Phase 1, single-dose-escalation study, conducted at Yale, enrolled 36 cognitively normal older adults, who received 10, 40, 70, 100, 150, or 200 mg ALX-001, to assess safety and pharmacokinetics. Some participants also underwent 18FFPEB PET imaging to ascertain brain mGluR5 receptor occupancy. According to results presented at the October 2023 CTAD conference, doses up to 200 mg were safe. Mild adverse events were deemed related to drug, including brief oral sensations and transient dizziness or headache. Plasma levels increased linearly with dose, and were sufficient to achieve 80 percent brain mGluR5 occupancy. Full results are posted on clinicaltrials.gov.

From January to February 2023, an additional Phase 1 study tested food effects on safety and pharmacokinetics in 12 healthy older adults.

In March 2023, a Phase 1b multiple ascending dose study began. The first part plans to enroll healthy older adults for 10 days of twice-daily 50, 100, 150, or 225 mg capsules, or placebo. A second part will enroll Alzheimer’s disease patients for 28 days of 150 or 225 mg twice daily. The primary outcome is safety, with pharmacokinetics as a secondary. In the AD patients, other secondary outcomes include change from baseline in synaptic density on PET, and cognition on the ADAS-COG14. The study plans to enroll 50 participants, and finish in late 2024.

For details on ALX-001/BMS-984923 trials, see clinicaltrials.gov.

Last Updated: 22 Nov 2023

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References

Paper Citations

  1. Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron. 2013 Sep 4;79(5):887-902. PubMed.
  2. Hamilton A, Vasefi M, Vander Tuin C, McQuaid RJ, Anisman H, Ferguson SS. Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model. Cell Rep. 2016 May 31;15(9):1859-65. Epub 2016 May 19 PubMed.
  3. Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO, Herber CS, Degnan AP, Balakrishnan A, Macor JE, Albright CF, Strittmatter SM. Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes. Cell Rep. 2017 Jul 5;20(1):76-88. PubMed.
  4. Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, Siegert TR, Laird W, Allnutt MA, Chiasseu M, Brody AH, Takahashi H, Nies SH, Cañamás AP, Sadasivam P, Lee S, Li S, Zhang L, Huang YH, Carson RE, Cai Z, Strittmatter SM. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci Transl Med. 2022 Jun;14(647):eabi8593. PubMed.

External Citations

  1. results are posted
  2. clinicaltrials.gov
  3. press release

Further Reading

No Available Further Reading