Fosigotifator

Calico Life Sciences, the San Francisco-based Alphabet-founded research organization focused on aging and age-related diseases, announced receipt of US FDA Breakthrough Therapy Designation (BTD) for fosigotifator (ABBV-CLS-7262), an investigational eIF2B activator, for the treatment of Vanishing White Matter (VWM) disease. The designation applies across adult, pediatric, and infant patients, covering the full age spectrum of a condition that currently has no approved treatment. The BTD provides Calico with intensive FDA guidance, organizational commitment from senior agency staff, and eligibility for rolling review — benefits that become material given the complexity of designing trials in an ultra-rare pediatric leukodystrophy. The designation follows fosigotifator’s earlier selection for the FDA’s Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program in June 2024, which provided enhanced communication with FDA review staff on clinical study design, endpoint selection, and patient population definition. VWM is an ultra-rare, progressive leukoencephalopathy caused by loss-of-function variants in any of the five subunits of eIF2B, a guanine nucleotide exchange factor essential for protein synthesis and a central regulator of the integrated stress response (ISR). Pathogenic eIF2B variants reduce enzymatic activity, causing chronic ISR activation in the brain that leads to white matter degeneration. Symptoms — which include progressive motor impairment, cognitive decline, and seizures — typically emerge between ages 2 and 6, though onset can occur at any age. Stressors such as fever or mild head trauma can precipitate episodes of rapid neurological deterioration. The disease course is uniformly progressive and life-shortening. Fosigotifator directly binds eIF2B and increases its enzymatic activity in complexes carrying VWM-associated pathogenic variants, thereby attenuating chronic ISR activation in the central nervous system. In preclinical VWM mouse models, the compound demonstrated reductions in ISR signaling in the brain and spinal cord, improvements in coordination and motor function, and extended lifespan. The Phase I/II trial (NCT05757141) — the first administration of an eIF2B activator to humans with VWM — is evaluating safety, tolerability, pharmacokinetics, and exploratory efficacy across adult, pediatric, and infant subjects. Calico’s announcement cited preliminary clinical data as the basis for the BTD but did not disclose specific efficacy figures, patient numbers, or data cutoff dates. The program was developed by Calico in collaboration with AbbVie, pursuant to a 2014 research collaboration. The BTD announcement, however, identifies only Calico as the sponsoring entity, with no mention of AbbVie’s current role — a shift from the 2024 START Program announcement, which referenced both companies jointly. Fosigotifator is also under investigation in two separate ongoing studies in amyotrophic lateral sclerosis (ALS), indicating broader interest in ISR modulation across neurodegeneration. The VWM therapeutic landscape is nascent. San Francisco-based ReviR Therapeutics dosed the first participant in a Phase I healthy volunteer study of RTX-117 in March 2026, an oral eIF2B activator discovered using AI-assisted drug design in collaboration with XtalPi. RTX-117 has received FDA Investigational New Drug clearance and Orphan Drug Designation for CMT, with IND clearance also secured in China for VWM. Unlike fosigotifator, RTX-117 has not yet been administered to VWM patients, and the Phase I study is evaluating safety in healthy subjects as a precursor to disease-specific trials. Both compounds share the same molecular target and mechanistic rationale — eIF2B activation to suppress pathological ISR signaling — but fosigotifator holds a meaningful clinical lead, being the first eIF2B activator to enter patients with VWM and now the first to receive BTD in the indication. This article was generated with AI assistance and reviewed and edited by the AllSci editorial team Explore more at AllSci News: https://allsci.com/news/ Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.

iStock, Deagreez Calico will leverage 9MW3811’s anti-inflammatory mechanism to advance its mission of addressing aging-related diseases. Alphabet’s aging-focused subsidiary Calico Life Sciences has entered into an exclusive licensing agreement with Mabwell Bioscience to advance the Shanghai biotech’s anti-IL-11 monoclonal antibodies for age-related diseases. Under the terms of the collaboration, Calico will make an upfront payment of $25 million and commit up to $571 million in development, regulatory and commercial milestone payments, according to an automated translation of Thursday’s Chinese-language filing . The star of Thursday’s partnership is Mabwell’s investigational antibody 9MW3811, which according to the biotech’s website targets and blocks the IL-11 cytokine, in turn disabling its downstream signaling pathway. As a result, 9MW3811’s mechanism of action suppresses the body’s inflammatory response. Mabwell is currently studying 9MW3811 for idiopathic pulmonary fibrosis, with approvals to initiate trials in China, the U.S. and Australia. The FDA cleared the molecule’s Investigational New Drug application in this indication in June 2023. For Calico, however, 9MW3811’s mechanism could present a novel pathway for addressing aging and age-related disorders. Calico will gain the exclusive right to develop, manufacture and commercialize the asset outside the Greater China region. The California-based biotech was founded in September 2013 by Alphabet, the parent company of internet search giant Google. The aging-focused startup started making waves in the industry a year later, in September 2014, when it partnered with AbbVie to establish an R&D center in Illinois. Both parties at the time committed to an initial funding of $250 million each, with the potential to pitch in $500 million more. The companies upped the agreement in June 2018, with each putting in $500 million toward the goal of developing treatments for age-related diseases. In January this year, however, this deep-pocketed alliance ran into a clinical hurdle when their drug candidate fosigotifator, an inhibitor of the eukaryotic initiation factor 2B, failed to significantly slow disease progression in patients with amyotrophic lateral sclerosis, according to topline findings from the HEALEY ALS platform trial. According to its website , Calico looks at the underlying biology of aging to identify novel pharmaceutical targets—those “that are not currently being pursued by many others,” the company noted. Elsewhere in the aging space, BioAge in January shelved its lead asset azelaprag after safety concerns over liver damage. The biotech was studying azelaprag as a treatment for obesity. Results from the Phase II STRIDES study in December 2024 showed that patients treated with the molecule had elevated levels of liver enzymes, leading the company to suspend the study.