Calico Life Sciences LLC (Calico) announced that its investigational eIF2B activator fosigotifator (ABBV-CLS-7262) has been accepted into the U.S. Food and Drug Administration (FDA) Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program. Fosigotifator is being developed by Calico and AbbVie pursuant to their 2014 collaboration as a potential treatment for Vanishing White Matter (VWM) disease. FDA's Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) initiated the START Pilot Program to help further accelerate the development of novel drug and biological products for rare diseases.

Selected participants will be able to obtain frequent advice and enhanced communication with FDA review staff to address program-specific development issues, including, but not limited, to clinical study design, choice of control group, and fine-tuning the choice of patient population. VWM disease is an ultra-rare progressive leukoencephalopathy - a disease of the brain's white matter - caused by variations in any of the five sub units of an essential enzyme in cells called eIF2B. VWM variations in eIF2B cause a reduction in its enzymatic activity that may lead to chronic activation of the integrated stress response (ISR).

The ISR plays a critical role in protein homeostasis and organismal resilience, both of which are implicated in the biology of aging. In VWM, chronic activation of the ISR in the brain causes the white matter to degenerate. Individuals with VWM disease commonly have symptoms such as impaired muscle movement, cognitive decline, seizures, and have a shortened lifespan.

While symptoms often begin to appear between ages 2 and 6, the disease can present at any age. The disease course is chronic and progressive, and stressors such as fever, infection, and mild head trauma may cause episodes of rapid deterioration. There is currently no cure and no treatment approved for VWM disease.

Fosigotifator targets eIF2B, a guanine nucleotide exchange factor that is essential for protein synthesis and a key regulator of the ISR. In preclinical studies in a mouse model of VWM, fosigotifator blunted the persistent ISR in the brain and spinal cord, primarily in cell types that are known to be severely affected by the human form of VWM, and corrected coordination and movement problems in these mice. Calico and AbbVie are currently conducting a Phase 1b/2 trial of fosigotifator to evaluate the safety, tolerability, and pharmacokinetics of fosigotifator in participants diagnosed with VWM disease. This study is the first time an eIF2B activator has been administered to people with VWM disease.