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Fosgonimeton is an injectable prodrug of dihexa, developed for Alzheimer's disease and taken through a 549-patient phase 2/3 trial that missed every endpoint. It is the most thoroughly tested member of a family whose founding mechanism papers were retracted for fabricated data. The chemistry is worth stating plainly because it is rarely stated at all: fosgonimeton is dihexa carrying a phosphate group on one hydroxyl and nothing else. The phosphate makes it soluble enough to inject; the body removes it, and what circulates and enters the brain is dihexa. Anyone reading about dihexa is therefore reading about a molecule whose active form has already been given to hundreds of patients.
- The only member of this chemistry ever tested properly in humans, which makes it the most informative entry in the family
- Reassuring safety on the things that usually stop a drug: no deaths, no liver signal, fewer serious events than placebo
- Genuine neurotrophic and anti-inflammatory activity in cell and animal work published after the retracted papers
- Injection site reactions in 57 percent at 40 mg and 73 percent at 70 mg, against 14 percent on placebo
- Withdrawal for adverse events rose with dose to 21.5 percent at 70 mg
- Eosinophilia in about 7 percent of both drug arms and none on placebo, usually alongside an injection reaction
- Two of the five treatment-related serious events were angioedema, so a hypersensitivity reading is reasonable
Mechanism
Fosgonimeton is a phosphate . Its own is roughly 0.3 hours; it is cleaved to the active species, which the developer calls fosgo-AM or ATH-1001 and which is dihexa, with a half-life of about 1.5 hours [3]. In rats given fosgonimeton under the skin, the active reached every brain region measured with a peak at 10 minutes, while fosgonimeton itself was undetectable in brain tissue [2]. The does not cross into the brain; only what it releases does.
The claimed mechanism is positive modulation of the hepatocyte growth factor and MET system rather than agonism. The molecule is said to strengthen HGF's own action at MET, raising MET phosphorylation and driving and along with MAPK and ERK, with downstream effects on positioning and [2].
⚠️ No potency constant exists for this compound, or for any member of its chemical series. There is no published Ki, Kd, IC50 or EC50 against MET, HGF or anything else; ChEMBL returns no bioactivity and no mechanism records, and the primary pharmacology paper contains none of those terms. What is reported is significance at particular concentrations: MET phosphorylation rose in cells given a subthreshold amount of HGF plus the compound, and a cell-scattering assay reached significance at 10 picomolar, 100 picomolar and 1 nanomolar [2]. Those are activity observations, not target-engagement measurements, and the difference matters here more than usual.
⚠️ It matters because the papers that once supplied the missing numbers were retracted. The account of this chemistry as a mimic of HGF's dimerisation domain, and every picomolar affinity figure attached to it, comes from work withdrawn in 2025 after the originating university found falsified and fabricated data [4][5]. The developer's later papers do not restore it; they report that phosphorylated MET rises and that downstream pathways activate, and never a binding measurement.
In cell and animal work the compound protects neurons against several insults and lengthens neurites, and reduces inflammatory output from macrophages given bacterial endotoxin [2]. Those results are real and were produced after the retracted work, but they describe what the molecule does to cells rather than what it binds.
receptor fingerprint
/ and MAPK/ERK signalling (downstream)Pathway activation
MET / c-Met receptor tyrosine kinase (HGF receptor)Claimed positive modulator, not agonist
Hepatocyte growth factor (HGF)Direct binding; source retracted
Evidencehow good the literature is
The clinical record is unusually complete for a compound at this stage, and unusually negative.
LIFT-AD was a randomised, placebo-controlled phase 2/3 across 90 United States sites, 26 weeks, with the primary analysis in 287 participants not taking cholinesterase inhibitors and 549 dosed overall [1]. It missed its primary endpoint and every secondary one. The combined cognition and function score differed by 0.08 points (p 0.70). ADAS-Cog11 differed by 0.70 points (p 0.35) and the daily-living scale by 0.67 points (p 0.61), both favouring the drug and neither close to significance. A single exploratory blood marker, p-tau217, fell 13.7 percent with a nominal p below 0.01; it was not protected against multiple comparisons and was the only result in the whole trial under 0.05.
⚠️ The trial's own authors name the confound: the placebo group did not decline. Both arms improved for the first six weeks and drifted back, which they attribute to a milder population than intended and to daily injections influencing caregiver-rated scales. That makes the trial less informative than its size suggests, in both directions.
⚠️ Two earlier trials are widely described as positive and neither result is actually in the public record. The phase 2 in Alzheimer's disease shows posted results on the registry, but every posted outcome is a baseline value with no treatment effect; the same is true of a phase 2 in dementia with Lewy bodies, which was terminated for design limitations. Neither has a primary publication. What circulates instead is a press release describing a post hoc subgroup with a 3.3-point cognitive difference, no subgroup size and no p-values, and the registered primary endpoint of that trial was missed.
⚠️ The most-quoted supporting number in the whole programme, a p of 0.027 on an evoked-potential latency measure, comes from seven people on drug against four on placebo over eight days, uncorrected for multiplicity [3]. The phase 2 designed to reproduce that exact endpoint did not.
An open-label extension was terminated when the parent trial failed.
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
Safety is the part of this programme with the most data behind it, because the phase 2/3 dosed 549 people for 26 weeks and posted its results [1].
There were no deaths in any arm. Serious adverse events were less common on the drug than on placebo, 4.2 percent against 6.9 percent. No clinically meaningful liver enzyme elevations appeared, and the few large ALT rises were balanced between groups.
⚠️ The dominant problem was the injection itself. Injection site reactions affected 57.1 percent of the 40 mg arm and 72.9 percent of the 70 mg arm against 14.2 percent on placebo, and withdrawal for adverse events rose with dose, from 4.6 percent on placebo to 10.7 and then 21.5 percent.
⚠️ A hypersensitivity signal is visible and worth naming. Eosinophilia occurred in about 7 percent of both drug arms and in none of the placebo group, and 20 of those 24 cases happened alongside an injection site reaction. Most were mild, transient and reversible, but two of the five treatment-related serious events across the trial were angioedema. Read together, that pattern looks like an immune response to the injected material rather than a coincidence.
An earlier phase 1 found no maximum tolerated dose up to 90 mg as a single injection, with no accumulation over nine days of dosing and no effect of age or sex on exposure [3].
History
The chemistry traces to Washington State University and reached the clinic through a Seattle company later renamed Athira Pharma.
⚠️ The programme's scientific foundations came apart in stages. In 2021 the chief executive was placed on leave and then resigned after an internal review found altered images in her doctoral dissertation and in several papers published between 2011 and 2014. In January 2025 the company agreed to pay just over four million dollars to resolve allegations under the False Claims Act that it had failed to report research misconduct allegations to its federal funder; the settlement carried no admission of liability. In April 2025 three of the underlying papers were retracted [4][5].
The clinical failure came in between. Topline results from the phase 2/3 were announced in September 2024; two weeks later the company cut about 70 percent of its staff, paused this compound including the open-label extension, and moved its attention to a different molecule for ALS. The company was renamed again in January 2026 and fosgonimeton no longer appears in its pipeline.
Resources
This entry is here for reference.
Research
- 2022first citedSafety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/M…
- 2025most recentFosgonimeton in mild-to-moderate Alzheimer's disease
- 1.Fosgonimeton in mild-to-moderate Alzheimer's disease
- 2.Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia
- 3.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.
- 4.Retraction notice to "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 351 (2014) 390-402].
- 5.Retraction notice to "Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers" [J Pharmacol Exp Ther 340 (2012) 539-548].
5 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is fosgonimeton the same thing as dihexa?
Almost. Fosgonimeton is dihexa with a phosphate group attached to one hydroxyl, added to make it soluble enough to inject. The body removes the phosphate and what circulates is dihexa. They are the same molecule separated by one modification, which is why the human trial result applies to both.
Does the failed trial mean dihexa does not work?
Not exactly, and the distinction is worth keeping. The trial tested 26 weeks of treatment in older adults with Alzheimer's disease, which is a hard problem that has defeated much stronger candidates. It does not test whether the compound does anything for cognition in a healthy person. What it does mean is that the best-designed test this chemistry has received found nothing, and that the animal results now stand without the mechanism that was meant to explain them.
Why is the mechanism described so cautiously here?
Because the papers that established it were retracted in 2025 after the originating university found falsified and fabricated data. Later work from the developer shows the compound raises MET phosphorylation and activates downstream pathways, which is real, but no measurement of what it actually binds survives in an unretracted paper.
Limitations of the evidence
- Missed its primary endpoint and every secondary endpoint, with p between 0.35 and 0.70
- The placebo group did not decline, which the trial's own authors name as a confound
- No binding constant exists for it or any compound in its series, in any unretracted publication
- The papers establishing its mechanism were retracted in 2025 for falsified and fabricated data
- Development is paused and the sponsor has removed it from its pipeline
- The two earlier phase 2 trials have no published results; the registry holds only baseline values
Adverse effects
- Injection site reactions in 57 percent at 40 mg and 73 percent at 70 mg, against 14 percent on placebo
- Withdrawal for adverse events rose with dose to 21.5 percent at 70 mg
- Eosinophilia in about 7 percent of both drug arms and none on placebo, usually alongside an injection reaction
- Two of the five treatment-related serious events were angioedema, so a hypersensitivity reading is reasonable