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Calico Life Sciences’ investigational eIF2B activator fosigotifator (ABBV-CLS-7262), for Vanishing White Matter (VWM) disease, is one of several drugs accepted into the U.S. Food and Drug Administration (FDA) new Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program. The program was created to accelerate new treatment development for rare diseases through more frequent communication with FDA staff to address issues including clinical study design, choice of control group, and fine-tuning the choice of patient population. 

Calico and partners AbbVie are conducting a Phase Ib/II trial of fosigotifator, which is the first time an eIF2B activator has been administered to people with VWM disease. 

The rare disease/orphan drug market has grown dramatically over the last decade, especially as drug makers have found they can charge much higher prices, even for treatments for extremely rare diseases. The market is valued at more than $200B and over 1000 drugs for orphan diseases have been approved.

FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) initiated the START Pilot Program. It’s not clear how many companies will be invited to participate, but the initial reports were that each agency would select three.

Earlier last week, several other companies announced they had products selected for START:  

  • Neurogene said its gene therapy candidate for Rett syndrome, NGN-401, has been chosen for the program. That treatment delivers a full-length MECP2 gene using an adeno-associated virus serotype 9 (AAV9) vector via intracerebroventricular infusion. It is currently being evaluated in a Phase I/II clinical trial. 
  • Grace Science announced that its GS-100 gene therapy candidate for NGLY1 deficiency was selected. GS-100 delivers a full-length version of the NGLY1 gene using an AAV9 vector and is also administered intracerebroventricularly. The company says the second NGLY1 Deficiency patient was successfully treated with GS-100 in May.
  • Also chosen was Larimar Therapeutics’ protein replacement therapy nomlabofusp for Friedreich’s ataxia. Larimar expects to submit a biologics license application for this drug next year. 
  • Denali Therapeutics also had a drug selectedDNL126, an investigational enzyme replacement therapy is being developed as a treatment for the rare genetic lysosomal storage disease MPS III type A. Denali is conducting a Phase I/II study of DNL126 for children with the disease.

It’s not clear how many companies will be in the pilot. However, the agency has said CBER and CDER would each select up to three drug sponsors to participate in the pilot.

“The inclusion of fosigotifator [in the START program] underscores the potential of this investigational therapy in addressing the unmet needs of individuals and families affected by Vanishing White Matter Disease,” said Arthur D. Levinson, PhD, founder and CEO of Calico. 

VWM disease is an ultra-rare progressive leukoencephalopathy caused by variations in any of the five subunits of an essential enzyme in cells called eIF2B. Variations in eIF2B cause a reduction in its enzymatic activity that may lead to chronic activation of the integrated stress response (ISR). Chronic activation of the ISR in the brain causes the white matter to degenerate causing such symptoms, such as impaired muscle movement, cognitive decline, seizures, and shortened lifespan. 

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.

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