SPL84 therapy on FDA fast track for CF due to splicing mutation

Phase 2 trial in Alabama recruiting CF patients with specific mutation

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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The U.S. Food and Drug Administration (FDA) has granted fast track designation to SPL84, an experimental inhalation therapy for people with cystic fibrosis (CF) caused by the 3849+10 kb C-to-T mutation in the CFTR gene.

The designation is given to accelerate the development and review of therapies meant to address unmet medical needs in serious conditions. It provides access to more frequent communications with the FDA throughout the drug development process.

“Fast track designation for SPL84 is an important acknowledgement by the FDA of the critical need to find an effective treatment for CF patients carrying the 3849+10 kilobase (Kb) C->T mutation,” Gili Hart, PhD, CEO of SpliSense, which is developing the treatment, said in a company press release.

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Fast track to speed ‘potentially life-changing treatment’ for certain CF patients

The designation will help quicken the development “of a potentially life-changing treatment for people with CF carrying the 3849+10 Kb C->T mutation,” she added.

CF is caused by mutations in the CFTR gene, resulting in missing or dysfunctional CFTR protein. Therefore, cells cannot properly regulate the flow of chloride, resulting in sticky mucus, particularly in the lungs, pancreas, or liver. Patients with the 3849+10 kb C-to-T mutation are not eligible for treatment with CFTR modulators, which work to increase the protein’s functionality.

Genes contain exons — the parts that provide instructions for making a protein— and introns, regions that help regulate gene activity but do not actually code for a protein.

When a gene is read to produce the protein, its sequence is copied into a temporary molecule called messenger RNA (mRNA). Then, mRNA undergoes splicing, a process whereby introns are removed and exons form a mature sequence used as a template to make the protein.

The 3849+10 kb C-to-T mutation alters the splicing process, resulting in a shorter and dysfunctional CFTR protein.

SPL84 is an RNA-based therapy designed to correct the splicing deficit in patients carrying this specific mutation, allowing for the production of a fully functional CFTR protein. The therapy is given via inhalation, so that it goes directly to the lungs.

The therapy has been shown to restore the levels and function of CFTR in lab-grown cells derived from CF patients carrying the 3849+10 kb C-to-T mutation, and to have a good safety profile in a Phase 1 trial (NCT06217952) involving healthy volunteers.

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Phase 2 trial recruiting adults with CF caused by 3849+10 kb C-to-T mutation

Recently, the FDA cleared a Phase 2 trial (NCT06429176) trial that is evaluating the therapy in adults with CF carrying the 3849+10 kb C-to-T mutation. The trial is currently recruiting patients at a site in Alabama.

The trial is expected to enroll 24 patients randomly assigned to receive either SPL84 or a placebo, given weekly for nine weeks.

Its main goal is to assess safety and tolerability, by looking into adverse events, breathing rate, heart rate, blood pressure, and blood levels of oxygen. Lung function, heart health, and general physical appearance will also be examined.

Secondary measures include the therapy’s pharmacokinetics, or its movement into, through, and out of the body, and preliminary measures of efficacy, including changes in respiratory symptoms, body weight, and the need for antibiotics.

The therapy has also been granted orphan drug designation in the U.S. and Europe. That designation aims to speed the development of treatments for rare diseases.