Fosigotifator
ABBV-CLS-7262 · fosigotifator sodium tromethamine
Last updated
At a glance
Overview
What Fosigotifator Is — and Why It's on Biomogging at All#
Fosigotifator (ABBV-CLS-7262) is an orally bioavailable, CNS-penetrant eIF2B activator — the most clinically advanced molecule ever developed in the ISRIB lineage. By stabilizing the active eIF2B decamer, it blocks the Integrated Stress Response (ISR) from collapsing global protein translation when cells fire the eIF2α-phosphorylation alarm. In rodents, ISRIB-class activity has produced the kind of endpoints that catch a nootropic reader's eye: enhanced long-term memory consolidation, reversal of TBI-induced cognitive deficits, and rescued translation in neurodegeneration models.
The catch — and this profile is honest about it up front — is that fosigotifator is not procurable. The entire molecule has only ever existed as AbbVie/Calico IND-restricted clinical supply. The Phase 2/3 HEALEY ALS Platform Trial (Regimen F) missed its primary endpoint in January 2025, and AbbVie wound down the Calico collaboration in November 2025. No peptide vendor, research-chemical supplier, or Chinese API broker carries it. Anything sold under this name is, almost certainly, mislabeled ISRIB or worse.
"The main rationale for fosigotifator was to provide an orally bioavailable, systemically and centrally acting eIF2B activator suitable for chronic dosing in neurodegenerative disorders." — AlzForum Therapeutics Monograph (2025)
This page is therefore a reference profile, not a protocol page. The sections below cover the eIF2B / ISR mechanism in detail, the (limited) human PK and tolerability data from the Phase 1 and HEALEY programs, the clinical dose structure that was actually run, what the broader ISRIB-class literature implies for cognition and neuroprotection, and a frank read on sourcing reality and the ISRIB-vs-fosigotifator decision the nootropic community keeps circling back to.
How Fosigotifator works
eIF2B Activation — Releasing the Translation Brake#
Fosigotifator is a phosphate prodrug; in plasma, alkaline phosphatase cleaves the phosphate group to liberate the active CNS-penetrant parent molecule, a small-molecule activator of eukaryotic initiation factor 2B (eIF2B). eIF2B is the guanine-nucleotide exchange factor (GEF) that recycles GDP-bound eIF2 back to its GTP-bound active state, gating every round of cap-dependent translation initiation in the cell.
The active parent binds at the symmetric interface of the eIF2B decameric assembly, stabilizing the active (βγδε)₂ holoenzyme. This stabilization is the structural pivot point of the entire mechanism — it locks eIF2B into a conformation that resists inhibition by its endogenous brake, phospho-eIF2α.
"Fosigotifator, a phosphate prodrug of a CNS-penetrant eIF2B activator, was designed to combine high in vitro potency with the physicochemical properties necessary for oral dosing in humans." — Frost JM, Tong Y, Xu X, et al. Journal of Medicinal Chemistry (2026)
For the reader: this is the same chemotype as ISRIB, but engineered for actual drug-like exposure rather than gram-per-day in vitro tool-compound behavior.
Integrated Stress Response (ISR) Suppression#
Under cellular stress — misfolded protein load, viral dsRNA, amino-acid scarcity, heme deficiency — four sensor kinases (PERK, PKR, GCN2, HRI) phosphorylate eIF2α at Ser51. Phospho-eIF2α flips its function: instead of being eIF2B's substrate, it becomes a competitive inhibitor. Global cap-dependent translation collapses, and ribosomes shunt onto upstream open reading frames that drive translation of ATF4 and other stress transcripts. This is the Integrated Stress Response (ISR).
The ISR is adaptive in acute settings but pathologic when chronic — it is implicated in neurodegeneration, memory consolidation deficits, vanishing white-matter disease, and traumatic-brain-injury cognitive decline. By stabilizing eIF2B against phospho-eIF2α, fosigotifator restores normal translation initiation even when the ISR is firing.
"eIF2B activators such as ISRIB and its clinical derivatives protect against ISR-induced translational repression, with preclinical evidence supporting cognitive benefits and neuroprotection across neurodegeneration models." — Stoian II, Nistor D, Levai MC, Popa DI, Popescu R. Biomedicines (2026)
The practical translation: in models, ISR blockade rescues long-term memory consolidation, reverses TBI-induced cognitive deficits, and improves motor-neuron survival in SOD1/TDP-43 ALS models. This is the mechanistic basis for the nootropic interest in the chemotype.
CNS Penetration via Prodrug Engineering#
The parent eIF2B activator is highly lipophilic with poor aqueous solubility — the same property that limited ISRIB to in vitro and intracerebroventricular work. Fosigotifator solves this with a phosphate prodrug strategy: the phosphate ester is appended for aqueous solubility and oral dissolution, then cleaved by gut and hepatic alkaline phosphatases to release the lipophilic, blood-brain-barrier-crossing parent.
The CNS exposure achieved is the headline pharmacology criterion of the discovery program — without it, the molecule would be just another in vitro tool. With it, the parent reaches CNS compartments at concentrations sufficient to engage eIF2B in neurons, oligodendrocytes, and microglia.
"The main rationale for fosigotifator was to provide an orally bioavailable, systemically and centrally acting eIF2B activator suitable for chronic dosing in neurodegenerative disorders." — AlzForum, AlzForum Therapeutics Monograph (2025)
The Phase 1 program confirmed this translated to humans: clean PK, no meaningful food effect, and no dose-dependent AE signal across single- and multiple-ascending-dose cohorts.
"ABBV-CLS-7262 was generally safe and well tolerated across all cohorts, with similar PK and safety profiles observed following single and multiple oral doses, and minimal food effect." — Cho W, Jeong A, Malik P, Boiser J, Huang X, Rosebraugh M. Neurology (2023)
Downstream Effects on ATF4 and Synaptic Plasticity#
When ISR firing is dampened, ATF4 translation drops — and ATF4 is the master transcription factor for many stress-response genes including CHOP, GADD34, and a suite of proteins that, in chronic activation, drive synaptic pruning and neuronal apoptosis. Reducing chronic ATF4 tone is the proposed mechanism by which the chemotype enhances long-term memory consolidation in rodent work (Sidrauski 2013) and reverses TBI cognitive deficits (Chou 2017).
For the bodybuilding and looksmaxxing reader, this is where the mechanism sounds tantalizing — a clean molecular handle on the very translation-control node that limits memory formation. But the practical handoff has not happened: no human cognition data for fosigotifator has been published, the ALS trial missed its primary endpoint with only a nominally significant strength-loss signal at the exploratory high dose, and the program has been discontinued.
"While Regimen F (fosigotifator) did not meet the primary endpoint of the study, treatment was generally well tolerated and a nominally significant reduction in upper and lower extremity strength loss was observed in the exploratory high dose group." — HEALEY ALS Platform Trial — Regimen F, Massachusetts General Hospital/Healey Center (2025)
Why None of This Reaches the Recovery or Hypertrophy Axis#
Fosigotifator has no documented activity on androgen, estrogen, or progesterone receptors; no effect on the HPG axis; no engagement with GH, IGF-1, or insulin signaling; no action on mTOR, AMPK, or the canonical hypertrophy translation control pathways. Its translation effects are upstream of eIF2 — global initiation gating under stress — not the eIF4F/mTORC1 axis that governs muscle-protein synthesis. There is no mechanistic route by which an eIF2B activator would accelerate lean-mass accrual, fat loss, or strength.
The interest for the physique-focused reader is strictly cognitive and neuroprotective — the same reasons the broader nootropic community has tracked ISRIB for a decade. Fosigotifator is the cleanest pharmacologic embodiment of that mechanism to date, even if its sourcing reality (IND-restricted clinical supply, never on the vendor market, program now terminated) keeps it firmly in the reference-literature category rather than the protocol category.
Protocol
Cycle length & outcomes
Documented cycle
24 weeks
Cycle Notes#
Fosigotifator is documented here as a mechanistic reference, not as a runnable protocol. The compound never reached approval, the HEALEY ALS Regimen F trial missed its primary endpoint in January 2025, and AbbVie terminated the Calico collaboration in November 2025. No vendor channel — peptide, research-chemical, or otherwise — carries authentic ABBV-CLS-7262. The "cycle" data below is what the clinical program actually ran, included so users evaluating the eIF2B / ISR mechanism understand the real exposure ranges that were tested.
Documented Clinical Exposure#
| Program | Population | Duration | Dose Level | Schedule |
|---|---|---|---|---|
| Phase 1 SAD (NCT04948645) | Healthy subjects | Single dose | Ascending, undisclosed mg | Oral, fed + fasted arms |
| Phase 1 MAD | Healthy subjects | 14 days | Ascending, undisclosed mg | Oral once-daily |
| HEALEY Regimen F (NCT05740813) | ALS | 24 weeks | Primary dose (n=155) | Oral once-daily |
| HEALEY Regimen F high arm | ALS | 24 weeks | Exploratory high dose (n=79) | Oral once-daily |
| VWM open-label (NCT05757141) | Adult + pediatric ≥6mo | Up to 4 years | Weight-banded, undisclosed | Oral once-daily |
Numeric mg values were never published. AbbVie/Calico kept both the primary and the exploratory-high doses proprietary throughout the program, and with the asset now discontinued they are unlikely to be released. What is public is the schedule architecture: once-daily oral, no loading phase, no taper, no titration, no food restriction.
"ABBV-CLS-7262 was generally safe and well tolerated across all cohorts, with similar PK and safety profiles observed following single and multiple oral doses, and minimal food effect." — Cho et al., Neurology (2023)
Onset Timing & Cycle Architecture#
The molecule is a phosphate prodrug — alkaline phosphatase in gut and liver liberates the active eIF2B-stabilizing parent within the first pass. Pharmacodynamic onset at the eIF2B holoenzyme is effectively immediate; what is slow is the downstream consequence. Translation rebalancing, ATF4 transcript suppression, and any neuronal-protection readout require sustained daily exposure on the order of weeks to months. The HEALEY trial chose a 24-week treatment window precisely because shorter exposures are unlikely to register against the noise of neurodegenerative decline.
"Fosigotifator, a phosphate prodrug of a CNS-penetrant eIF2B activator, was designed to combine high in vitro potency with the physicochemical properties necessary for oral dosing in humans." — Frost et al., J. Med. Chem. (2026)
No loading dose was used. No taper was used. eIF2B activators do not engage receptor-downregulation feedback in the way that, say, dopaminergic or opioid ligands do, and abrupt discontinuation in clinical protocols was uneventful. The cycle is functionally on or off.
Bloodwork Cadence (As Run in Trial)#
The HEALEY protocol monitored standard chemistry, hematology, and liver panels at baseline and at intervals across the 24-week treatment window, plus ALS-specific functional endpoints (ALSFRS-R, slow vital capacity, hand-held dynamometry). No dose-dependent laboratory signal emerged across the active arms.
"While Regimen F (fosigotifator) did not meet the primary endpoint of the study, treatment was generally well tolerated and a nominally significant reduction in upper and lower extremity strength loss was observed in the exploratory high dose group." — HEALEY ALS Platform Trial Regimen F update, Massachusetts General Hospital (2025)
The exploratory-high arm produced a 32% slower upper-extremity strength decline and a 62% slower lower-extremity strength decline vs. pooled placebo on dynamometry — nominally significant, secondary endpoint, in a failed primary trial. That signal is the only dose-response hint in the public record, and it pointed toward more rather than less exposure being where the mechanism lives.
Why There Is No Community Cycle#
The eIF2B / ISR mechanism is genuinely interesting for cognition, memory consolidation, and TBI recovery — the rodent ISRIB literature is strong. But fosigotifator itself has zero community footprint:
- No vendor stocks it. Searches across SwissChems, peptide vendors, and Chinese-API listings return nothing authentic. Any listing using the name "fosigotifator" or "ABBV-CLS-7262" should be assumed mislabeled — most likely ISRIB, possibly a structural analog with unknown PK, possibly nothing.
- No human cognition data exists. Every published endpoint is safety, PK, or ALS-specific motor function. There is no MDD readout, no healthy-volunteer cognition readout, no sleep architecture data.
- No off-label dosing convention has formed. Unlike modafinil, semax, or even ISRIB, fosigotifator has never circulated outside IND-restricted clinical supply, so there is no log culture, no nootropic-stack convention, and no empirical mg/day to anchor to.
Users drawn to the ISR mechanism for cognitive purposes have historically routed through ISRIB sourced from chemical-reagent suppliers rather than chasing fosigotifator. ISRIB has its own problems — miserable aqueous solubility was the entire reason the fosigotifator prodrug program existed — but it is at least obtainable and has the bulk of the preclinical cognitive literature attached to it.
"The main rationale for fosigotifator was to provide an orally bioavailable, systemically and centrally acting eIF2B activator suitable for chronic dosing in neurodegenerative disorders." — AlzForum, Therapeutics Monograph (2025)
Stacking#
Not applicable. There is no documented co-administration data, no community stack convention, and no mechanistic reason to pair an eIF2B activator with the standard nootropic adjuncts (racetams, choline donors, adaptogens) outside of speculation. The eIF2B / ISR axis sits upstream of essentially all stress-responsive translation, so meaningful stack design would require human PD biomarkers that simply do not exist for this molecule.
Bottom Line#
Fosigotifator is a closed chapter. The mechanism — eIF2B stabilization, ISR brake-release, restored translation under stress — remains one of the more compelling cognitive and neuroprotective targets in the literature, and the molecule was the best-engineered clinical probe of that pathway to date. But the program is discontinued, the supply chain never existed outside clinical trials, and the realistic path for anyone interested in the mechanism is reading the ISRIB literature, not running fosigotifator.
Risks & mistakes
Common (most users)#
Across the only public human safety dataset — 125 active subjects in the Phase 1 SAD/MAD program and 234 active subjects in HEALEY Regimen F over 24 weeks — fosigotifator's tolerability profile was essentially indistinguishable from placebo (treatment-related TEAEs: 25.2% active vs. 26.2% placebo). What did show up was mild, transient, and proportionate to what any oral CNS-active molecule produces:
- Headache — most common across the class. Typically resolves within the first 1–2 weeks of continuous dosing. No dose-dependent escalation was observed.
- Mild GI upset — nausea or loose stools, generally tied to the phosphate prodrug load rather than the active parent. The Phase 1 program showed no meaningful food effect, so administration with or without a high-fat meal is mechanically equivalent.
- Fatigue / drowsiness — low incidence, transient. Not a stimulant-class compound and not associated with sleep disruption in any published trial.
- Dizziness — uncommon, mild, no orthostatic signal in the trial cohorts.
"ABBV-CLS-7262 was generally safe and well tolerated across all cohorts, with similar PK and safety profiles observed following single and multiple oral doses, and minimal food effect." — Cho et al., Neurology (2023)
Uncommon (dose-dependent or individual)#
The Phase 1 SAD/MAD design tested escalating single and 14-day repeat doses and explicitly looked for dose-dependent toxicity signals. None emerged. Despite that, a few considerations are worth flagging for any subject in a chronic protocol:
- Liver enzyme drift — not reported in the published trial data, but the phosphate-prodrug architecture relies on alkaline-phosphatase cleavage and the active parent is a CNS-penetrant small molecule with hepatic clearance contributions. ALT/AST monitoring at baseline and every 6–8 weeks is appropriate on any chronic protocol.
- CBC / metabolic panel shifts — Phase 1 reported no clinically meaningful laboratory abnormalities, but baseline + periodic monitoring is standard for any chronic CNS investigational compound.
- Tolerance / diminishing subjective effect — mechanistically possible if eIF2B activation is sustained at saturating concentrations. The HEALEY high-dose arm did produce a nominally significant signal at week 24, suggesting the mechanism does not run out on that timescale, but pulsed protocols (week-on / week-off) have a theoretical rationale that has not been clinically tested.
Rare but serious#
No serious adverse events attributable to fosigotifator have been published. The relevant rare-but-serious considerations come from the class (chronic ISR suppression) and should be taken seriously even though the human data is reassuring:
- Sustained-suppression risk to physiologic stress responses — the ISR is a protective program. In one APPswe Alzheimer rodent model, daily ISRIB dosing was associated with significant mortality (Briggs et al., 2017) — likely model-specific, but a reminder that indefinite pharmacologic blunting of a stress-defense pathway is not biologically free. Long-term human safety beyond 24 weeks is uncharacterized.
- Unanticipated CNS effects on chronic dosing — mood shifts, cognitive blunting, or paradoxical fatigue would be the warning signs. Discontinuation is the appropriate response; the molecule has no withdrawal syndrome described.
- Hepatotoxicity — not reported in trials, but rising transaminases (>3× ULN) on follow-up bloodwork is a stop signal for any chronic oral compound.
"While Regimen F (fosigotifator) did not meet the primary endpoint of the study, treatment was generally well tolerated and a nominally significant reduction in upper and lower extremity strength loss was observed in the exploratory high dose group." — HEALEY ALS Platform Trial (2025)
Hard contraindications#
These are non-negotiable based on the clinical-trial protocol language and the reproductive-toxicology gap in the public record:
- Pregnancy — excluded from all clinical protocols. Reproductive toxicology has not been publicly disclosed.
- Lactation / breastfeeding — excluded in trial protocols.
- Sperm donation / active conception attempts — trial protocols barred sperm donation during dosing and for ≥30 days post-last-dose. Conception attempts fall in the same exclusion window.
- Concurrent investigational compounds — fosigotifator itself is investigational; stacking with other unapproved CNS-active molecules is uncharted and inadvisable.
- Vendor-sourced "fosigotifator" — flatly: it does not exist on the gray market. Any vendor listing this name is almost certainly shipping mislabeled ISRIB, a structural analog with unknown PK, or nothing at all. Third-party HPLC/MS analytics would be mandatory before any subject in a research protocol could trust the identity of such material — and the realistic identification result is ISRIB-class material rather than the actual phosphate prodrug.
Sex-specific and reproductive considerations#
Fosigotifator has no documented activity at steroid receptors, no effect on the HPG axis, and no reported impact on GH/IGF-1 — so PCT is not applicable, and the compound is mechanistically sex-neutral on the endocrine axis. The hard line is reproductive: clinical protocols mandated contraception throughout dosing and for ≥30 days post-last-dose in both male and female subjects, with explicit exclusion of pregnancy, breastfeeding, and sperm donation in the same window. Reproductive toxicology has not been published, and that gap should be treated as a contraindication rather than an open question. No PCT is required after discontinuation; no recovery protocol applies.
FAQ — Fosigotifator
Research & citations
5 studies cited on this page.
Conclusion
Fosigotifator is a prime example of a mechanistically intriguing, clinically developed nootropic that remains out of reach for community research — but its literature leaves a well-mapped trail for those tracking eIF2B/ISR modulation.
Key takeaways:
- Oral, once-daily phosphate prodrug engineered for CNS bioavailability
- All clinical dosing data are proprietary; no mg values or sourcing routes exist for independent research
- No community or performance/aesthetics protocols are documented anywhere — procurement outside IND channels is not possible
- Mechanism: robust eIF2B activation, ISR suppression, and preclinical neuroprotection in models of memory, TBI, and white-matter disease (Frost et al., 2026; Stoian et al., 2026)
- Headline benefit in trials: well-tolerated safety profile, with a nominal signal for slower motor decline in ALS — but no effect on primary endpoints (HEALEY ALS, 2025)
- Users interested in the ISRIB/eIF2B pathway will find more actionable options with classic research compounds like ISRIB itself
Bottom line: fosigotifator defines the cutting edge of integrated stress response modulation, but its place in the research landscape is reference-only — not a practical or available protocol for cognitive enhancement or neuroprotection.