TL;DR
Famous for "millions of times more potent than BDNF." 2014 mechanism paper retracted in April 2025. Clinical analog failed Phase 2/3.
What is it? Hexapeptide peptidomimetic derived from angiotensin IV at Washington State University. Orally active, blood-brain-barrier permeable. Picomolar spinogenesis in hippocampal culture drives the BDNF marketing claim.
What does it do? Positioned as a positive allosteric modulator of HGF at c-Met, amplifying synaptogenesis and neurite outgrowth. The in-vivo human case is unverified.
Does the evidence hold up? WSU foundation is compromised: Benoist 2014 retracted; McCoy 2013 carries an expression of concern. Independent preclinical work exists (Uribe 2015, Sun 2021). Athira's fosgonimeton prodrug missed the LIFT-AD Phase 2/3 endpoint in late 2024.
Who uses it? A small crowd ordering oral capsules from research-chemical vendors at 8–25 mg/day.
Bottom line? Hype exceeds the evidence. The best human translation already failed.
What It Is
Dihexa (developmental code PNB-0408; chemical name N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a synthetic hexapeptide-like molecule — formally a peptidomimetic — derived from a two-decade structure-activity-relationship campaign on the C-terminal end of angiotensin IV. It was developed at Washington State University (WSU) by Joseph W. Harding, Ph.D., Jay Wright, Ph.D., and collaborators working on the procognitive properties of angiotensin IV analogs. Its key engineered properties are oral bioavailability, blood-brain-barrier permeability, and metabolic stability — characteristics that earlier angiotensin IV peptides lacked.
The dihexa headline that made it famous in the optimization community is the claim that it is "approximately 10 million times more potent than BDNF" at promoting new synapse formation. That claim originates from in vitro hippocampal-culture data showing measurable spinogenesis at picomolar concentrations of dihexa, compared with the nanomolar concentrations conventionally needed for BDNF. The seven-orders-of-magnitude potency comparison is a specific in vitro readout — not a demonstration of in vivo equivalence — and the foundational papers behind it have a complicated and now-compromised provenance.
Dihexa was licensed from WSU in 2013 to a company originally called M3 Biotechnology (later renamed Athira Pharma). M3 / Athira did not advance dihexa itself into clinical trials. Instead it advanced a related phosphate prodrug called fosgonimeton (development codes NDX-1017 and ATH-1017), positioned as a clinically optimized HGF/c-Met positive modulator. Fosgonimeton ran a Phase 1 trial in healthy volunteers and Alzheimer's subjects, the ACT-AD Phase 2 trial (mild-to-moderate AD on standard-of-care AChEIs), the SHAPE Phase 2 trial in Parkinson's disease dementia and dementia with Lewy bodies, and the LIFT-AD Phase 2/3 trial in mild-to-moderate AD. The LIFT-AD trial reported topline results in late 2024 and did not meet its primary endpoint (Global Statistical Test). Athira's stock collapsed; the program was reframed as a "broad neuroprotective mechanism with biomarker signal" rather than a Phase 3 success.
Compounding the clinical problem is a serious research-integrity issue. In 2021, four foundational papers from the Harding/Wright lab — co-authored by then-Athira CEO Leen Kawas (formerly a WSU PhD student in Harding's lab) — received expressions of concern after PubPeer commenters and STAT News reporting flagged image manipulation in western blot data. An Athira special-committee investigation concluded that Kawas altered images in her 2011 doctoral dissertation and at least four research papers published 2011–2014. Kawas resigned as CEO of Athira in October 2021. In April 2025, the 2014 Benoist et al. paper that established dihexa's HGF/c-Met mechanism was formally retracted. In January 2025, Athira agreed to pay approximately four million dollars to settle False Claims Act allegations brought by a whistleblower over NIH grant applications that referenced the compromised research. None of this proves dihexa does not work — it has not been independently disproven — but it does mean the original WSU evidence base must be read with appropriate skepticism. This profile presents dihexa with both the underlying claims and the integrity record visible side-by-side.
Mechanism of Action
The proposed mechanism — based on the WSU papers, with the caveat that the central mechanism paper (Benoist 2014) has been retracted — is hepatocyte growth factor (HGF) / c-Met receptor positive modulation. The path from angiotensin IV to dihexa to HGF/c-Met evolved through a two-decade research arc.
- Angiotensin IV (AngIV) parent — Endogenous AngIV (a hexapeptide derived from angiotensin II) was shown across the 1990s and 2000s to enhance learning and memory in rodent spatial-memory tasks (Morris water maze, radial-arm maze, scopolamine-amnesia models). Early work attributed this to a putative "AT4 receptor." Subsequent work from the Harding group reinterpreted the binding site as the c-Met receptor — the receptor for hepatocyte growth factor (HGF). This receptor reassignment is foundational to the entire dihexa mechanistic story.
- Modification rationale — Native AngIV has very poor pharmacokinetics: rapid enzymatic degradation, no oral bioavailability, no blood-brain barrier penetration. McCoy et al. 2013 (J Pharmacol Exp Ther; PMID 23055539) screened a library of N-acyl-Tyr-Ile-(6)-aminohexanoic-amide analogs for cognitive activity and HGF interaction. The N-hexanoic acyl group plus the 6-aminohexanoic-amide tail produced a metabolically stabilized, orally active, BBB-permeant compound — dihexa.
- HGF binding and c-Met phosphorylation (retracted paper) — Benoist et al. 2014 (J Pharmacol Exp Ther; PMID 25187433; RETRACTED April 2025) reported that dihexa binds with high affinity to HGF and that, in the presence of subthreshold HGF concentrations, dihexa augments HGF-mediated c-Met phosphorylation, downstream signaling, and HGF-dependent cell scattering. The proposal: dihexa is a positive allosteric modulator of HGF/c-Met signaling, not an HGF mimetic and not a direct c-Met agonist. The retraction of this paper is the single most important caveat to this mechanism.
- Synaptogenesis claim (picomolar potency) — In hippocampal culture, dihexa was reported to induce dendritic spinogenesis at concentrations as low as 10⁻¹² M (picomolar). For comparison, BDNF requires nanomolar concentrations to elicit comparable structural plasticity changes. This is the source of the "10 million times more potent than BDNF" claim. Important caveat: this is an in vitro structural endpoint at a specific dose-comparator relationship, not a demonstration that dihexa is therapeutically equivalent to BDNF in vivo.
- HGF/c-Met biology in CNS — Independent of the dihexa controversy, HGF and its receptor c-Met are expressed throughout the CNS. HGF promotes neuronal survival, neurite outgrowth, synaptogenesis, and possibly neurogenesis. The HGF system has been independently identified by other groups as a plausible therapeutic target in Alzheimer's, Parkinson's, ALS, and stroke. This larger HGF biology is not dependent on the dihexa-specific findings; it provides at least some independent rationale for the therapeutic hypothesis.
- Downstream signaling — c-Met activation engages PI3K/Akt, MAPK/ERK, and STAT3 pathways downstream of receptor dimerization. Sun et al. (2021, Brain Sci) reported that dihexa-mediated cognitive rescue in APP/PS1 transgenic Alzheimer's mice tracked with PI3K/Akt activation in hippocampus — an independent (non-Kawas) report providing some support for the downstream signaling story.
- BBB permeability — Dihexa was specifically engineered for BBB permeability via lipophilicity tuning (the N-hexanoic acyl group is the key lipid handle). This is an unusual property for a hexapeptide-like molecule and is the practical reason dihexa was prioritized over earlier AngIV analogs.
- What this is not — Dihexa is not a nootropic in the classical sense. It does not engage acetylcholine, dopamine, NMDA, or GABA receptors. The mechanism, if it is real, is purely neurotrophic / synaptogenic.
- What we do not know — Whether dihexa actually engages HGF/c-Met in vivo at doses humans use, whether it crosses the human BBB at physiologically relevant concentrations, and whether picomolar in vitro potency translates to any clinically meaningful synaptogenesis in the human brain. These questions are unanswered, and the largest clinical attempt to answer them (Athira's fosgonimeton) failed.
What the Research Shows
Dihexa research falls into three buckets: the original WSU preclinical campaign (now partially compromised), independent preclinical work, and the indirect human evidence from fosgonimeton (Athira's clinical analog).
- Foundational dihexa papers (WSU, partly compromised) — McCoy 2013 (PMID 23055539) — orally active dihexa improved performance in scopolamine-amnesia and aged-rat cognitive models; received an expression of concern in 2021. Benoist 2014 (PMID 25187433) — HGF/c-Met mechanism paper; retracted April 2025. Wright & Harding 2015 reviews (PMID 25649658, 25455861) — synthesize the mechanistic story; not retracted but rest on the now-questioned underlying data.
- Independent preclinical — hair cell preservation — Uribe et al. 2015 (Front Cell Neurosci; PMID 25674052) — dihexa attenuates aminoglycoside-induced hair cell death in zebrafish and mouse models through an HGF-dependent mechanism. Independent of the Kawas issue. A meaningful independent confirmation that dihexa engages HGF biology in at least one non-WSU experimental system.
- Independent preclinical — APP/PS1 Alzheimer's mouse model — Sun et al. 2021 (Brain Sci; PMID 34827487) — dihexa rescues cognitive impairment in APP/PS1 transgenic mice via the PI3K/AKT signaling pathway. Independent of the Harding/Kawas group; partially supports the cognitive-rescue claim.
- Stem cell / hepatic differentiation — Siller et al. 2015 Stem Cell Reports (PMID 25937370) — dihexa appears in cocktails for small-molecule-driven hepatocyte differentiation from human pluripotent stem cells. Tangential to cognition but provides corroboration that dihexa has cellular activity at physiologically relevant doses.
- Peripheral nerve repair — A 2022 paper in Stem Cell Research & Therapy (PMID 35410439) reported dihexa (2–4 mg/kg in rats over 16 weeks) as a candidate adjunct for limb functional recovery after surgical nerve repair via HGF-dependent mechanisms. Independent group.
- Fosgonimeton Phase 1 (NCT03298672) — Phase 1 in healthy volunteers and AD subjects. Safe, well-tolerated, dose-proportional pharmacokinetics, no sex effect or accumulation over 9 days. qEEG showed sustained gamma-power induction; ERP P300 latency improved after multiple dosing.
- ACT-AD Phase 2 (NCT04491006, fosgonimeton) — Mild-to-moderate AD on standard-of-care acetylcholinesterase inhibitors. Did not meet primary endpoint (ERP P300 latency change) when used adjunctively. Monotherapy subgroup analysis suggested benefit (ADAS-Cog11 change of −3.3 points; ERP P300 latency change of −28 ms). Athira reframed the trial design and pursued LIFT-AD.
- SHAPE Phase 2 (NCT04831281, fosgonimeton) — 28 subjects with Parkinson's disease dementia or dementia with Lewy bodies. Originally designed for ~75 subjects; truncated to 28 to redirect resources to LIFT-AD. Exploratory positive cognitive signal at 40 mg dose; the 70 mg arm showed inconsistent results with high dropout.
- LIFT-AD Phase 2/3 (NCT04488419, fosgonimeton) — the headline failure — Late 2024 topline: did not meet primary endpoint (Global Statistical Test). 26 weeks, 40 mg subcutaneous fosgonimeton vs placebo. Athira attributed the miss to lack of clinical decline in the placebo group and short study duration. Numerically greater treatment effect in APOE4 carriers, but not statistically significant. Athira has effectively wound down the AD program.
- Cognition in healthy animals — Some dihexa marketing materials cite a "40–60% improvement in Morris water maze in non-impaired rats." This claim does not appear in a peer-reviewed, independently replicated form meeting the standards we apply elsewhere on Kalios. Treat with skepticism.
Critical Context — A Compromised Evidence Base
The dihexa story is the clearest example in the optimization community of a compound whose published evidence base is partly compromised by research-integrity findings AND whose largest clinical translation (fosgonimeton) failed its pivotal trial. The HGF/c-Met biology is real and independently studied; the case that dihexa is the right molecule to engage it for human cognition is now considerably weaker than 2018-era summaries suggest. Anyone using dihexa today is doing so on the strength of a 2013 paper with an expression of concern, a 2014 mechanism paper that has been retracted, a few independent supporting studies, and a failed fosgonimeton clinical program.
Human Data
There is no published human trial of dihexa itself. All clinical evidence comes from fosgonimeton (Athira's prodrug analog), which is structurally related but pharmacokinetically distinct.
- NCT03298672 — Fosgonimeton Phase 1 — Healthy volunteers and AD subjects. Safety, PK, qEEG, ERP P300 latency. Reported as safe and tolerated; gamma-power induction observed.
- NCT04491006 — ACT-AD Phase 2 (fosgonimeton) — 77 patients with mild-to-moderate AD. Failed primary endpoint (ERP P300 latency) in adjunct-therapy population; monotherapy subgroup signal was not powered to be statistically definitive but informed LIFT-AD design.
- NCT04831281 — SHAPE Phase 2 (fosgonimeton in PDD/DLB) — Truncated at 28 of 75 planned subjects. Exploratory positive cognitive signal at 40 mg.
- NCT04488419 — LIFT-AD Phase 2/3 (fosgonimeton) — ~475 subjects, 26-week double-blind, 40 mg fosgonimeton vs placebo. Did not meet primary endpoint (Global Statistical Test). Primary endpoint change of −0.08 with fosgonimeton (P=0.70). Athira reported topline in late 2024.
- NCT04886063 — additional fosgonimeton extension / supportive program — Various follow-on trials and extensions; outcomes consistent with parent trials.
- None of these studied dihexa itself — Fosgonimeton is a phosphate-modified prodrug with different oral bioavailability, plasma protein binding, BBB permeability, and metabolic profile. Translating fosgonimeton clinical results to dihexa is not straightforward in either direction. Negative fosgonimeton results do not strictly disprove dihexa, but they are the most direct human translation of the HGF/c-Met cognitive hypothesis to date.
- No dihexa human trial registered as of April 2026 — A search of ClinicalTrials.gov returns no active or completed trials of dihexa specifically.
In practice: zero published controlled human data on dihexa as administered by the optimization community (oral capsules from research-chemical vendors, transdermal preparations, sublingual). The closest human translation — fosgonimeton — failed its pivotal trial. Any user-reported benefit from dihexa is therefore entirely uncontrolled, with high placebo, expectancy, and reporter-selection bias.
Dosing from the Literature
No FDA-approved dose exists for dihexa. The doses below are extrapolated from animal studies and from community practice. This is not medical advice.
| Route / Context | Dose Range | Frequency | Notes |
|---|
| Animal (oral, McCoy 2013) | 2 mg/kg/day | Daily | Standard procognitive dose in rats. Allometric human-scaling predicts ~20–25 mg/day for a 70 kg adult — higher than typical community use. |
| Animal (peripheral nerve repair, 2022) | 2–4 mg/kg/day | Daily, 16 weeks | Used in rat sciatic nerve repair studies via HGF-dependent mechanism. |
| Community oral (typical reported) | 8–25 mg/day | Once daily, oral | Most common community-reported range. Often cited as 10 mg or 20 mg as round numbers. No clinical trial supports any specific human dose. |
| Community transdermal / sublingual | Variable | — | Some vendors offer transdermal or sublingual preparations. No PK data exists for these routes in humans. |
| Cycle length | 4–12 weeks | — | Practitioner reports vary widely. No tachyphylaxis or downregulation data exists. |
| Fosgonimeton Phase 2/3 (LIFT-AD, for reference only) | 40 mg SubQ | Once daily | Not directly applicable to dihexa — fosgonimeton is a prodrug with different PK. Listed only as the closest clinically tested reference. |
Dosing Disclaimer
Dihexa has never been formally dose-finding-studied in humans. Community doses (8–25 mg/day oral) are taken from vendor recommendations and forum aggregation, not clinical evidence. The animal-allometry-derived dose (~20–25 mg/day for a 70 kg adult) is in the same range but is itself extrapolated from a 2013 paper that received an expression of concern. Anyone considering dihexa should weigh the absence of human dose-response data, the failed fosgonimeton clinical program, and the c-Met-cancer theoretical risk before initiating.
Reconstitution & Storage
Dihexa is supplied either as a lyophilized powder (commonly 30 mg or 60 mg vials) for reconstitution and oral administration, or as pre-formulated oral capsules (commonly 8 mg or 25 mg). Some vendors also sell transdermal preparations. Unlike injectable peptides, dihexa is administered orally — there is no reason to reconstitute for injection.
| Form | Strength | Storage | Shelf Life |
|---|
| Lyophilized powder (research) | 30 mg or 60 mg vials | −20°C, desiccated, dark | 24+ months sealed |
| Oral capsule (typical) | 8 mg or 25 mg | Room temperature, dry, dark | 12–24 months |
| Reconstituted oral solution | Variable | 2–8°C refrigerated | Use within 14 days |
| Transdermal / sublingual prep | Variable | 2–8°C refrigerated | Per manufacturer |
- Oral administration only — Dihexa was specifically engineered for oral bioavailability and BBB permeability. There is no rationale for injection. Do not inject dihexa.
- Bioavailability — Oral bioavailability in rodents is sufficient to produce CNS effects at 2 mg/kg/day. Human PK data does not exist.
- BBB permeability — Engineered via the lipophilic N-hexanoic acyl group. Confirmed in rodent studies. Not directly characterized in humans.
- Stability — Lyophilized powder is stable at −20°C for 2+ years. Reconstituted solutions should be refrigerated and used within ~14 days.
→ Use the Kalios Dosing Calculator for dihexa scheduling
Side Effects & Risks
Important
The foundational mechanism paper was retracted in April 2025 and the fosgonimeton analog missed its LIFT-AD primary endpoint in late 2024. c-Met is dysregulated in many human cancers; pharmacologically activating the pathway carries theoretical oncogenic concerns. Worth discussing with your doctor before starting, especially with any cancer history.
The dihexa side-effect profile in humans is essentially unknown — no formal human safety study of dihexa has been published. The fosgonimeton clinical program reported a generally favorable tolerability profile (injection site reactions most common; no treatment-related serious adverse events in the published Phase 1/2 reports). Dihexa-specific community reports include the items below.
- HGF/c-Met activation and theoretical cancer risk — the central concern — c-Met is dysregulated in many human cancers, where it drives proliferation, motility, invasion, and metastasis. Pharmacologically activating c-Met in a generalized way is the opposite direction of much of oncology drug development (which inhibits c-Met). Dihexa is positioned as a positive modulator that augments existing HGF signaling rather than a direct agonist, which theoretically limits the off-target stimulation of cells without baseline HGF exposure — but this is a theoretical risk-mitigation, not a tested one. The single most important contraindication for dihexa is any history of cancer or precancerous lesion. Screen for this before initiation.
- Headache — The most commonly reported community side effect. Typically dose-related.
- Fatigue / lethargy — Reported in a minority of community users.
- Mood changes — Anxious, irritable, or low mood reported anecdotally. No mechanism established.
- GI discomfort — Mild nausea reported in some users; no characterized GI signal in animal studies.
- Sleep changes — Both insomnia and increased dream vividness anecdotally reported.
- Drug interactions — Largely unstudied. Theoretical concern about combining with other neurotrophic agents (semax, selank, cerebrolysin) or with stimulants.
- WADA — Not specifically named on the WADA Prohibited List. As a neurotrophic peptidomimetic with c-Met positive modulator activity, dihexa would plausibly fall under S2 (peptide hormones, growth factors, related substances and mimetics) for tested athletes.
- Sourcing risk — The most variable practical risk. Dihexa is sold by online research-chemical vendors with highly variable purity. Independent COA (HPLC + mass spec) is the practical floor for due diligence. Counterfeit, underdosed, and contaminated material is common in unvetted markets.
- Long-term safety unknown — Zero long-term human safety data. Even Athira's largest fosgonimeton trial only followed patients for 26 weeks.
Bloodwork & Monitoring
No formal monitoring guideline exists. Given the c-Met / cancer concern and the absence of safety data, conservative monitoring is warranted:
- Cancer screening (pre-initiation, age-appropriate) — The most important pre-treatment assessment. Skin check, colon screening per age guidelines, breast/prostate per age, complete blood work to rule out occult hematologic abnormality. Anyone with a history of cancer, dysplasia, or precancerous lesion should not initiate.
- CMP (comprehensive metabolic panel) — Baseline and at 8 weeks. Liver enzymes, kidney function, glucose. No characterized organ toxicity but baseline establishment is prudent.
- CBC with differential — Baseline and at 8 weeks. Watch for any unexpected hematological changes given the broad regenerative mechanism.
- Cognitive baseline (objective) — Most users take dihexa for perceived cognitive benefit. A baseline cognitive assessment (e.g., Cambridge Brain Sciences test battery, or a standardized clinical screen) gives an objective comparator. Subjective "I feel sharper" reports are heavily placebo-confounded.
- Periodic re-screening for cancer markers — Long-term users should consider age-appropriate cancer screening at recommended intervals while on the compound, not deferred or skipped because of the protocol.
- Mood / sleep tracking — Subjective tracking can reveal changes that bloodwork cannot.
Commonly Stacked With
ACTH(4-10) analog. Mechanistically distinct from dihexa (BDNF upregulation vs HGF/c-Met). Some community protocols pair dihexa with intranasal semax for "different neurotrophic axes" but no published evidence supports the combination.
Tuftsin analog with anxiolytic and immune-modulatory activity. Mechanistically distinct. Sometimes combined with dihexa for "calm focus" — but again, no published evidence supports the specific combination, and selank has its own evidence base on its own merits.
Lion's Mane (Hericium erinaceus)
Mushroom extract with NGF-modulating compounds (hericenones, erinacines). Some preliminary human evidence for mild cognitive benefit in older adults. Mechanistically orthogonal to dihexa. Often paired in nootropic stacks.
Creatine + omega-3 + sleep optimization
The non-peptide foundation. If the goal is cognitive performance, creatine (3–5 g/day), omega-3 (2 g EPA+DHA), and 7–9 hours of sleep have larger effect sizes and stronger evidence than any peptide. Building a peptide cognitive stack on top of unaddressed sleep deprivation is inverted-priority.
Porcine brain peptide hydrolysate with 200+ clinical trials in stroke and dementia. A more evidence-backed neurotrophic-class alternative to dihexa for users seeking that biological category. Available in many ex-US markets.
→ Check compound compatibility in the Stack Builder
Regulatory Status
Current Status — April 2026
Dihexa is not FDA-approved for any indication and has not been the direct subject of any registered human clinical trial. It exists as a research-only compound. Its closest clinical translation, fosgonimeton (Athira Pharma's phosphate prodrug analog), failed its primary endpoint in the LIFT-AD Phase 2/3 trial in late 2024 and is no longer being advanced in Alzheimer's. Athira has effectively wound down the AD program.
Dihexa is not on the FDA Category 2 Bulk Drug Substances peptide list targeted by HHS Secretary Robert F. Kennedy Jr.'s February 2026 reclassification announcement. As a peptidomimetic small molecule, dihexa would be regulated through the conventional NDA pathway if any sponsor pursued approval — and as of April 2026, no sponsor is publicly doing so.
WSU still holds the dihexa patent (WO2008/156865), licensed exclusively to what is now Athira Pharma. In January 2025, Athira agreed to pay approximately four million dollars to settle False Claims Act allegations related to NIH grant applications referencing the compromised research. In April 2025, the foundational 2014 Benoist et al. mechanism paper was formally retracted.
WADA: Not specifically named on the WADA Prohibited List. Athletes should consult their sport-specific federation; a peptidomimetic with c-Met positive modulator activity could plausibly be evaluated under S2.
Cost & Access
Dihexa is not approved for human use. It is available through research suppliers for laboratory research purposes only.
U.S. compounding pharmacies cannot legally compound dihexa under current FDA bulk-substance rules. Online research-chemical channels list dihexa in capsule and bulk-powder form with sharp variance in pricing, purity, and documentation. Untested or low-tier vendors have been documented selling underdosed or impure material — particularly problematic for a compound where users have no perceptible acute signal to verify activity.
Dihexa is not currently among the peptides under HHS Secretary Robert F. Kennedy Jr.'s February 2026 reclassification review, which applies specifically to Category 2 peptide bulk substances. Dihexa is a peptidomimetic small molecule and falls outside that review's scope. Absent a sponsor advancing dihexa specifically through the NDA pathway, it will remain in the research-only category for the foreseeable future. Following the LIFT-AD failure, the prospect of a major sponsor re-entering the dihexa clinical space is presently low.
Estimated pricing as of April 2026. Actual costs vary by provider, location, and prescription status. Kalios does not sell compounds.
Related Compounds
Other cognitive-signal peptides weighed against dihexa:
Cerebrolysin-derived synthetic peptide engineered to retain the neurotrophic core activity.
Phenothiazine dye and mitochondrial electron-transport alternative carrier. Nootropic and antimicrobial.
Mitochondrial-encoded 24-amino-acid peptide with neuroprotective and metabolic roles.
Key References
- McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, Harding JW. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. PMID: 23055539. PMCID: PMC3533412. (Foundational dihexa paper — received expression of concern in 2021.)
- Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW. 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. PMID: 25187433. PMCID: PMC4201273. RETRACTED April 2025 following investigation into image manipulation.
- Wright JW, Harding JW. 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. PMID: 25649658. (Mechanistic review.)
- Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Prog Neurobiol. 2015 Feb;125:26-46. PMID: 25455861. (Comprehensive Wright/Harding review.)
- Uribe PM, Kawas LH, Harding JW, Coffin AB. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Front Cell Neurosci. 2015 Jan 28;9:3. PMID: 25674052. PMCID: PMC4309183. (Independent dihexa hair-cell preservation study.)
- Siller R, Greenhough S, Naumovska E, Sullivan GJ. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Reports. 2015 May 12;4(5):939-52. PMID: 25937370.
- Sun X, Deng Y, Liang J, Lin Y, Song J, Zhao S, Zhuang G, Jia Z. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci. 2021 Oct 28;11(11):1421. PMID: 34827487. (Independent Chinese group; APP/PS1 model.)
- Stem Cell Research & Therapy. Dihexa as adjunct in peripheral nerve repair. 2022 Apr 11;13(1):159. PMID: 35410439. PMCID: PMC8996222.
- Hua X, Church K, Walker W, L'Hostis P, Viardot G, Danjou P, Hendrix S, Moebius HJ. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease. (Fosgonimeton Phase 1 — NCT03298672.)
- Johnston JL, Reda SM, Setti SE, Taylor RW, Berthiaume AA, Walker WE, Wu W, Moebius HJ, Church KJ. 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.
- Athira Pharma, Inc. Topline Results from Phase 2/3 LIFT-AD Clinical Trial of Fosgonimeton for Mild-to-Moderate Alzheimer's Disease. Press release, late 2024. (NCT04488419 — primary endpoint not met.)
- Athira Pharma, Inc. Topline Results from ACT-AD Phase 2 Proof of Concept Study of Fosgonimeton in Mild-to-Moderate Alzheimer's Disease. Press release, 2022. (NCT04491006.)
- Athira Pharma, Inc. Results from SHAPE Phase 2 Clinical Trial of Fosgonimeton in Parkinson's Disease Dementia and Dementia with Lewy Bodies. Press release, December 2023. (NCT04831281.)
- Retraction Watch. Four papers by Athira CEO earn expressions of concern. September 24, 2021.
- Retraction Watch. Biotech company agrees to pay four million dollars to settle data falsification allegations. January 7, 2025.
- U.S. Department of Justice. Athira Pharma Agrees to Pay Multi-Million-Dollar Sum to Settle False Claims Act Allegations. Press release, January 2025.
- U.S. Patent — WSU dihexa patent (WO2008/156865) — exclusively licensed to Athira Pharma.
- FDA. Bulk Drug Substances Nominated for Use in Compounding — 503A and 503B Categories. FDA.gov. Updated 2025–2026.
Last updated: April 2026 | Profile authored by Kalios Peptides research team