Therapeutics

Fosgonimeton

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Overview

Name: Fosgonimeton
Synonyms: ATH-1017, NDX-1017
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Dementia with Lewy Bodies, Parkinson's Disease Dementia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Dementia with Lewy Bodies (Discontinued), Parkinson's Disease Dementia (Discontinued)
Company: Athira Pharma

Background

NDX-1017 is a brain-penetrant small molecule that activates signaling via the hepatocyte growth factor (HGF)/MET receptor system (Moebius and Church, 2023). HGF promotes proliferation and survival of neurons, enhances hippocampal synaptic plasticity, and boosts learning and memory (Akimoto et al., 2004; Kato et al., 2012). NDX-1017 is being developed as a subcutaneous once-daily injection.

Hippocampal expression of MET receptors is diminished in Alzheimer’s disease (Hamasaki et al., 2014). Conversely, expression of HGF by gene transfer improved Aβ-induced cognitive deficits in mice, and prevented motor symptoms and neuron loss in a rat model of parkinsonism (Takeuchi et al., 2008; Koike et al., 2006).

Direct, intrathecal administration of hepatocyte growth factor itself has been studied in a rat model of ALS and a marmoset model of traumatic brain injury, and is being investigated clinically for ALS in Japan (Aoki et al., 2019). 

Fosgonimeton is a prodrug formulation of a small molecule originally identified in a screen for positive modulators of HGF/MET signaling (Johnston et al., 2023). The small molecule, fosgonimeton-active metabolite (fosgo-AM), was reported to be neurotrophic and neuroprotective in primary rat neurons, and to reverse scopolamine-induced learning deficits in rats. To improve its pharmacokinetics, the company developed the prodrug formulation, which generated higher blood and brain levels of fosgo-AM than were possible with direct delivery of the metabolite. In a mouse model of cognitive impairment due to acute inflammation, fosgonimeton partly reversed cognitive deficits. It was also reported to prevent Aβ42 toxicity and protect dopamine neurons against 6-OHDA (2023 AD/PD conference poster, Reda et al., 2024).

This drug may be related to N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, aka DihexaU.S. Patent 8598118B2. This small-molecule, brain-penetrant angiotensin IV analog was invented by researchers at Washington State University, Pullman. Dihexa activates HGF/MET signaling to stimulate dendritic arborization and synaptogenesis, and improves learning/memory in aged rats, and in rats with scopolamine-induced amnesia (ScienceDaily news storyMcCoy et al., 2013; Benoist et al., 2014; reviewed in Wright and Harding, 2015). 

M3 Biotechnology was founded to commercialize Dihexa (see WSU article). The company told Alzforum that further development led to NDX-1017. M3 Biotechnology in 2019 was renamed Athira Pharma, and NDX-107 in 2020 was renamed ATH-1017 and, in March 2022, fosgonimeton.

Findings

In October 2017, the company began a first-in-human, Phase 1 safety study of single- and multiple-ascending doses in 88 healthy people and AD patients. Funded by ADDF and others, the placebo-controlled trial tested doses from 2 to 90 mg, injected subcutaneously. Outcomes were drug-related adverse events and pharmacokinetics.

Results were presented at the 2019 CTAD conference (Dec 2019 conference news). In the single-ascending-dose portion, 48 healthy men received up to 90 mg and no drug-related adverse events were seen. Likewise, multiple dosing of 29 healthy elderly and 11 AD patients with up to 80 or 40 mg/day, respectively, for nine days raised no safety issues, with dose-proportional pharmacokinetics in all groups.

Quantitative electroencephalography (qEEG) and event-related potential (ERP) measures were evaluated as noninvasive markers of brain penetration and target engagement by NDX-1017. EEG gamma power is associated with learning, memory, and executive functions, while ERP P300 latency is a marker of cognitive processing speed. In people with AD, gamma power is reduced, and P300 latency is lengthened. In the trial, NDX-1017 was reported to cause a dose-related increase in gamma power in healthy people; in the AD group, multiple dosing led to improvements in gamma power and p300 latency. The trial included no cognitive assessments. Trial results were published after peer review (Hua et al., 2022NeurologyLive).

In September 2020, the company began a Phase 2 trial called LIFT-AD. It planned to enroll 300 participants with clinically diagnosed mild to moderate AD, and compare two doses of drug to placebo, given once daily using prefilled syringes, for six months. The primary outcome will be the Global Statistical Test, a combination of scores from the ADAS-Cog11 and the ADCS-Clinical Global Impression of Change. Secondary endpoints will include ADAS-Cog11, ADCS CGIC, and ADCS-ADL. In early 2022, the company increased enrollment to 420, and reclassified the trial to Phase 3. In 2023, enrollment was further increased to 475, with completion expected in January 2024.

In November 2021, another Phase 2 study called ACT-AD began to assess the relationship between ERP changes and cognition in 77 people with mild to moderate AD. Participants received 40 or 70 mg ATH-1017 or placebo daily for six months, with an optional six-month open-label extension. The primary outcome was ERP P300 latency; secondary outcomes included ADAS-Cog11, global clinical change, ADCS-ADL, and drug pharmacokinetics. The trial was completed in May 2022. In June, the company announced the trial had failed to meet its primary endpoint (press release). A prespecified subgroup analysis suggested that use of cholinesterase inhibitors by 60 percent of participants may have diminished the effects of fosgonimeton. A post hoc analysis of people taking only fosgonimeton indicated improvements in ERP P300 latency and ADAS-Cog11 endpoints, the company reported. There were no serious adverse events or deaths in the study. The most common adverse event was injection site reaction. Results were presented at meetings in 2022 (e.g. see AAIC slides). The company presented additional post hoc analyses at the April 2023 American Academy of Neurology conference (slides). They reported that fosgonimeton, in the absence of acetylcholinesterase inhibitors, improved MMSE scores by 1.6 points from baseline; however, the change compared to placebo was not statistically significant. Decreases in biomarkers NfL and GFAP correlated with clinical outcomes in people taking only fosgonimeton. The company presented data suggesting that acetylcholinesterase inhibitors antagonize the effect of fosgonimeton on HGF/MET signaling.

Both ACT-AD and LIFT-AD offer a two-year, open-label safety extension.

In June 2021, the company placed CEO Leen Kawas on temporary leave amid questions about research integrity related to her doctoral dissertation, which laid the foundations for work on ATH-1017 (Seattle Times news story). According to news reports, Washington State University is conducting an investigation of multiple papers from her time as a researcher there, after comments on PubPeer noted irregularities in figures and data (Puget Sound Business Journal newsSTAT news). Kawas resigned in October 2021, after an independent investigation found altered images in her dissertation and at least four publications related to her graduate work (company release).

In January 2022, Athira began a Phase 2 trial testing 26 weeks of fosgonimeton on cognition in people with Parkinson’s disease dementia or dementia with Lewy bodies (DLB). Seventy-five participants were to be randomized to 40 or 70 mg fosgonimeton or placebo, injected daily, against a primary outcome of a combined score of the ADAS-Cog 13 and P300 latency. By December 2022, the trial had stopped recruiting at 28 participants, and was expected to finish in May 2023. In a December 2023 press release, the company announced that this trial had failed on the primary endpoint. Results were presented at the March 2024 AD/PD conference (poster). An apparent improvement in the ADAS-Cog13 with 40 mg fosgonimeton compared to placebo was difficult to interpret due to baseline differences between the groups. The treatment appeared safe, but four of 10 participants in the higher dose arm dropped out because of adverse events. The most common side effect was injection site reaction.

From July to October 2022, a study of absorption, metabolism, and excretion of a single dose of [14C]-fosgonimeton was conducted in eight male volunteers.

Athira is developing additional small-molecule modulators of HGF/MET signaling that, unlike fosgonimeton, are orally available (Taylor et al., 2022).

In April 2024, the company completed a Phase 1 trial in 32 healthy adults of ATH-1020 (Berthiaume et al., 2022, poster).

In February 2024, company scientists reported beneficial effects of ATH-1105 in cell culture and in animal models of ALS (Berthiaume et al., 2024). In May 2024, the company listed a Phase 1 trial to test single and multiple daily doses of ATH-1105 in healthy volunteers in Dallas.

On September 3, 2024, Athira announced that the Phase 2/3 LIFT-AD trial had failed to meet its primary endpoint of improvement in the Global Statistical Test after 26 weeks treatment (press release, slides). Treatment also missed the key secondary endpoints of the ADAS-Cog11 or ADCS-ADL23. The company reported numerical improvements on cognitive and biomarker endpoints, but none were statistically significant. The trial had enrolled 549 participants, but the efficacy analysis covered only 287. Participants who took acetylcholinesterase inhibitors were excluded from the analysis, and the higher dose arm had been discontinued because of injection site reactions. Plans for an additional study have been canceled, the company told news sources (Endpoints News).

For details on NDX-1017/ATH-1017 trials, see clinicaltrials.gov.

Clinical Trial Timeline

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Athira Pharma NCT04488419
N=300
Athira Pharma NCT04491006
N=75
Athira Pharma NCT04886063
N=300
Athira Pharma NCT04831281
N=75

Last Updated: 10 Sep 2024

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References

News Citations

  1. At CTAD, Early Failures and Hints of Success, from Small Trials

Paper Citations

  1. . Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial. J Alzheimers Dis. 2022;86(3):1399-1413. PubMed.
  2. . Development of stable, orally bioavailable small molecule positive modulators of HGF/MET signaling for the treatment of cognitive impairment. 10.1002/alz.063440 Alzheimer's & Dementia
  3. . ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS. Front Neurosci. 2024;18:1348157. Epub 2024 Feb 8 PubMed.
  4. . The Case for a Novel Therapeutic Approach to Dementia: Small Molecule Hepatocyte Growth Factor (HGF/MET) Positive Modulators. J Alzheimers Dis. 2023;92(1):1-12. PubMed.
  5. . Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus. Neuroscience. 2004;128(1):155-62. PubMed.
  6. . Hepatocyte growth factor overexpression in the nervous system enhances learning and memory performance in mice. J Neurosci Res. 2012 Sep;90(9):1743-55. PubMed.
  7. . Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains. Neuropathology. 2014 Jun;34(3):284-90. Epub 2014 Jan 21 PubMed.
  8. . Alleviation of Abeta-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model. Gene Ther. 2008 Apr;15(8):561-71. PubMed.
  9. . Prevention of onset of Parkinson's disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson's disease. Gene Ther. 2006 Dec;13(23):1639-44. Epub 2006 Jun 22 PubMed.
  10. . [Application of Hepatocyte Growth Factor for Amyotrophic Lateral Sclerosis]. Brain Nerve. 2019 Nov;71(11):1253-1260. PubMed.
  11. . Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia. Neurotherapeutics. 2023 Mar;20(2):431-451. Epub 2022 Dec 20 PubMed.
  12. . Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. PubMed.
  13. . The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. Epub 2014 Sep 3 PubMed. Expression of concern.
  14. . The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. PubMed.

External Citations

  1. NeurologyLive
  2. press release
  3. AAIC slides
  4. slides
  5. Seattle Times news story
  6. Puget Sound Business Journal news
  7. STAT news
  8. company release
  9. press release
  10. poster
  11. Phase 1 trial
  12. Berthiaume et al., 2022, poster)
  13. Phase 1 trial
  14. press release
  15. slides
  16. Endpoints News
  17. clinicaltrials.gov
  18. conference poster
  19. Reda et al., 2024
  20. Dihexa
  21. U.S. Patent 8598118B2
  22. ScienceDaily news story
  23. WSU article

Further Reading

Papers

  1. . Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Neurosci Biobehav Rev. 2018 Sep;92:209-225. Epub 2018 May 4 PubMed.
  2. . The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Prog Neurobiol. 2015 Feb;125:26-46. Epub 2014 Nov 29 PubMed.