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.