New study phase tests add-on therapy for adults with rare CF mutation

Splisense has begun testing its inhaled therapy SPL84 alongside standard treatment in adults with cystic fibrosis (CF) who carry a specific genetic mutation.

This second phase of an ongoing Phase 2 clinical trial is evaluating whether SPL84 can offer extra benefits when paired with the approved CFTR modulators Trikafta (sold as Kaftrio in Europe) or Alyftrek. The study (NCT06429176) plans to enroll about 40 adults carrying the 3849+10 kb C-to-T mutation who are currently taking one of these modulator therapies.

Participants will be randomly assigned to receive a 50 mg dose of inhaled SPL84 or a placebo once weekly for about three months. While the trial’s main goal is to monitor safety, researchers will also measure how the combination impacts lung function and symptom severity. Recruitment is active across sites in the U.S.

“We look forward to the Phase 2b topline results, expected in the second half of next year,” Gili Hart, PhD, the company’s CEO, said in a press release.

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How SPL84 targets genetic splicing errors

CF is caused by mutations in the CFTR gene, which provides instructions for building the CFTR protein. This protein is normally needed to regulate mucus production. In CF, the protein is absent or dysfunctional, leading to thick, sticky mucus that builds up in the lungs and other organs, driving most disease symptoms.

When the CFTR gene is read to produce CFTR protein, the genetic code is copied from the cell’s DNA into a temporary molecule called messenger RNA (mRNA). The 3849+10 kb C-to-T mutation leads to a splicing defect in the premature mRNA molecule. SPL84 is designed to correct the splicing defect, essentially unscrambling the mRNA code to allow production of functional CFTR protein.

In early testing with healthy volunteers, SPL84 demonstrated a strong safety profile, prompting Splisense to advance to the Phase 2 trial in CF patients carrying the target mutation. The first phase of the study tested multiple doses in patients who were not taking CFTR modulators. It demonstrated solid safety alongside encouraging signs of efficacy, with up to 70% of participants showing improvements on lung function tests.

“We selected the 50 mg dose [for the Phase 2b part of the trial] based on the favorable Phase 2a safety profile and the consistent encouraging clinical activity observed at this dose,” Hart said.

CFTR modulators — including the triple-combination therapies Trikafta and Alyftrek, both sold by Vertex Pharmaceuticals — are a class of treatments that can increase the activity of the dysfunctional CFTR protein in people with CF caused by certain mutations.

“Given SPL84’s RNA-level mechanism, which is distinct from CFTR modulators, we believe there is a strong scientific rationale for evaluating the combination,” Hart said.

“Following the favorable safety and efficacy profile demonstrated in the Phase 2a study, we are excited to initiate the Phase 2b study, designed to determine whether once-weekly SPL84 can provide additional clinical benefit for people with the 3849+10kb C→T mutation who are already receiving standard-of-care CFTR modulator therapy,” Hart added.