Q&A: Finding a treatment for rare cystic fibrosis splicing mutation

Key takeaways:

• Few patients with cystic fibrosis have a copy of the 3849+10kb C-to-T splicing mutation.
• Research is planned to assess the efficacy of inhaled antisense oligonucleotide in this population.

Although inhaled antisense oligonucleotide treatment is safe, its efficacy needs to be determined in patients with the cystic fibrosis splicing mutation 3849+10kb C-to-T, according to a press release from the Cystic Fibrosis Foundation.

In an effort to uncover how this drug performs in this specific patient population, SpliSense is conducting a phase 2 trial on its antisense oligonucleotide (ASO) therapy, thanks in part to funding from the Cystic Fibrosis Foundation.

Healio spoke with Steven M. Rowe, MD, executive vice president and chief scientific officer of the Cystic Fibrosis Foundation, to learn more about the 3849+10kb C-to-T splicing mutation, the ASO drug and phase 2 trial details.

Healio: How common is the splicing mutation 3849+10kb C-to-T?

Rowe: This splicing mutation is a rare mutation in CF. About 1.9% of people with CF (614 people) in the U.S. had at least one copy of this mutation, according to the 2022 CF Foundation Patient Registry Annual Data Report. This mutation represents one of more than 1,700 CF-causing mutations.

Healio: What is the current treatment for patients with this mutation?

Rowe: In the U.S. and some other countries, people with this splicing mutation are approved to take the CF transmembrane conductance regulator (CFTR) modulators Kalydeco (Vertex) and Symdeko (Vertex), which target the underlying cause of CF — a dysfunctional CFTR protein. However, researchers believe people with this splicing mutation could have more benefit in the lungs with an ASO treatment compared with modulators. In addition to CFTR modulators, people with this mutation — like all other CF mutations — rely on symptomatic treatments such as antibiotics, anti-inflammatories and pancreatic enzyme replacement therapies.

Healio: What are the limitations of this treatment?

Rowe: The ASO therapy binds to the RNA molecule, which is quickly broken down inside cells. People with this splicing mutation would need to take repeated inhaled treatments to see improvements in lung function. In addition, this treatment is unlikely to provide benefits to other organs affected by CF.

Healio: How does an ASO improve treatment for patients?

Rowe: Although this mutation can be treated with modulators, ASO therapy may be more effective than modulator treatment for this mutation.

If successful, the ASO would result in functional CFTR protein in the lungs, which would help restore the proper balance of salt and fluids in the lungs of people with this splicing mutation. The thick, sticky mucus found in the lungs and other organs would return to its normal consistency, allowing people with this mutation to breathe easier and clear germs from their airways. However, the medicine would not be able to reverse existing lung damage and is targeted only to the lungs, so it is unlikely to address the effects of CF in other organs.

Healio: How will the phase 2 trial build on phase 1?

Rowe: The phase 1 trials indicated that the potential ASO therapy was safe and well tolerated in healthy volunteers. The phase 2 trial will test its efficacy in people with CF with the 3849+10kb C-to-T mutation.

The most important part of this upcoming clinical trial is to generate a proof-of-concept for ASO technology in CF. If the clinical trial is successful, it could validate the use of ASO therapy to treat rare CF mutations for which CFTR modulators aren’t effective. In addition, the work that we are funding for CF may help SpliSense advance research in using ASOs to treat other pulmonary diseases. ASOs already are used in the treatment of spinal muscular atrophy, certain forms of muscular dystrophy and other genetic diseases.

Healio: What other treatments are being studied under the Path to a Cure initiative?

Rowe: The CF Foundation established our Path to a Cure initiative to bring transformative therapies, and ultimately a cure, to all people with CF regardless of mutation. In support of the initiative, the CF Foundation is funding research into several types of genetic therapies, which could potentially benefit everyone with CF.

One strategy is to provide either a correct messenger RNA (mRNA therapy) or a correct CFTR gene (gene therapy) to cells. Another approach is to use gene editing, which uses the cell’s own DNA repair machinery to correct the mutation in the cell’s DNA. The Foundation also is investing in research into ways to deliver these genetic therapies into cells (gene delivery) — initially in the lungs and then to other organs in the body. Currently, the CF Foundation is supporting three mRNA therapies and one gene therapy for CF in early-stage clinical trials.

The Foundation will continue this work until every person with the disease has a cure.

Healio: What are the advantages of pursuing multiple treatments?

Rowe: The success rate of any drug making it through the approval process is between 10% to 15%, so it is critical to pursue multiple treatments to get a viable treatment option to patients.

With genetic therapies, many companies are trying different approaches because of the challenges of getting genetic therapies past the body’s natural immune response and the thick mucus in the lungs of people with CF. In addition, each individual responds differently to treatments, so it is important to offer options in case the side effects of a new therapy are too severe for some or if other medicines that a patient takes might interact negatively.

Reference:

• CF Foundation provides up to $8.5M to SpliSense to support a clinical trial for a potential treatment for splicing mutations. https://www.cff.org/press-releases/2024-04/foundation-provides-8-5m-splisense-support-clinical-trial. Published April 3, 2024. Accessed April 5, 2024.