Phase 1/2 Trial of APB-102, Gene Therapy for Familial ALS, Cleared to Open

Clearance was given to open a Phase 1/2 trial evaluating APB-102, a potential gene therapy for amyotrophic lateral sclerosis (ALS) patients who carry mutations in the SOD1 gene, its developer Apic Bio announced.

The trial is scheduled to begin later this year or early next year, following U.S. Food and Drug Administration (FDA) approval of its design as detailed in an investigational new drug (IND) application.

“FDA IND clearance for our drug candidate APB-102 to treat SOD1 ALS is a significant milestone for Apic Bio and takes us one step closer to bringing potentially disease-modifying therapies to patients with genetic diseases,” John Reilly, company CEO and co-founder, said in a press release.

The multicenter Phase 1/2 clinical trial will have three parts. In part 1, participants will receive single but ascending doses of APB-102, administered via an injection into the spinal canal (intrathecal injection), to determine an optimal treatment dose.

Part 2 will randomly assign patients to either a placebo or APB-102 at the dose determined in part 1; part 3 will an extended follow-up of enrolled patients.

“Despite SOD1 gene mutations being well understood as a cause of genetic ALS for decades, we don’t yet have an approved treatment option that targets the disorder at the source. I am pleased to see APB-102 progress” as a potential  “long-term disease modifying gene therapy option,” said Robert Brown, PhD, MD, a neurology professor at the University of Massachusetts Medical School and a scientific co-founder of Apic Bio.

Mutations in the SOD1 gene are among the most common causes of familial ALS, accounting for 15% to 20% of all such cases. These mutations are also found in 1–2% of sporadic ALS cases.

This gene contains the instructions for an enzyme of the same name, SOD1, which helps regulate the production of free radicals that can damage cells. In the presence of SOD1 mutations, this protein is prone to misfolding and clumping, triggering various cellular processes that drive the disease.

In an earlier study, Brown and his team discovered that the mutated SOD1 gene can be silenced in ALS patients using a molecule known as microRNA. These are molecules that prevent specific proteins from being made by latching onto intermediate RNA molecules that carry instructions for protein production.

The researchers developed an artificial microRNA that recognized a portion of the SOD1 RNA sequence that can be found in almost all SOD1 mutations. They did so to maximize the number of patients for whom this approach might work.

A proof-of-concept study that followed successfully delivered the microRNA via intrathecal injection — using an engineered adeno-associated virus (AAV) — to two ALS patients. Results showed lower SOD1 levels in their brain and spinal cord.

The approach formed the basis for APB-102, a one-time, AAV-delivered gene therapy designed to shut down the activity of the mutated SOD1 gene, and prolong the survival of motor neurons — the nerve cells that are progressively lost in ALS.

“The clinical development of APB-102 is rooted in nearly 30 years of gene therapy research demonstrating the link between the SOD1 gene mutation and ALS and the strong potential of AAV-delivered SOD1 targeting miRNA to slow down or reverse the progression of ALS in patients with SOD1 mutations,” Brown said.

APB-102 was granted orphan drug status by the FDA in July 2019. This designation aims to encourage therapies for rare and serious diseases through benefits such as seven years of market exclusivity if approved and exemption from FDA application fees.

“ALS is a devastating, fatal neurogenerative disorder, where mutations in the SOD1 gene account for one-fifth of all inherited forms of the disease,” said Jorge Quiroz, chief medical officer of Apic Bio. “We believe that APB-102 may provide therapeutic benefit for these patients by targeting the underlying pathophysiology of the disease.”