NBD1 stabilizers safe in healthy volunteers, Sionna says
Company says it will advance development of SION-719, SION-451
SION-719 and SION-451, two NBD1 stabilizers Sionna Therapeutics is developing to restore CFTR protein function in cystic fibrosis (CF), will advance to the next stages of clinical development after positive safety results in Phase 1 clinical trials.
Sionna tested both compounds in healthy volunteers to assess safety and pharmacokinetics, or how the medications move into, through, and out of the body. With positive data in both categories, the company plans to test one compound as an addition to standard-of-care CF therapies and the other in combination with a second, proprietary therapy.
“Today’s announcement brings us one step closer to our vision of developing novel NBD1-led proprietary dual combinations to transform the treatment paradigm for CF patients,” Mike Cloonan, president and CEO of Sionna, said in a company press release. “The successful completion of two NBD1 Phase 1 trials and being the first company to bring NBD1 compounds into the clinic are important milestones.”
CF is caused by genetic mutations that lead to no or impaired production of the CFTR protein and as a result mucus that is thick and sticky. A variety of CF symptoms, including respiratory, digestive, and reproductive challenges, can develop as this mucus builds up in organs.
Restoring CFTR function
CF treatment may ease symptoms and slow progression, but not all patients tolerate, respond to, or are eligible for available CFTR modulators.
“While advances in CF treatments have improved the lives of CF patients over the past decade, there still remains a large unmet need,” said Patrick Flume, MD, a pulmonologist and professor at the Medical University of South Carolina. “The majority of CF patients on approved modulators do not have normal CFTR function and many patients discontinue or reduce dosages due to tolerability issues.”
To address this issue, Sionna aims to develop medications that restore CFTR function. SION-719 and SION-451 both focus on a region of CFTR called NBD1, where the most common CF-causing mutation is found. This leads to instability that causes the protein to fold incorrectly, reducing function.
Both therapies are designed to keep NBD1 stable. Preclinical trials demonstrated that each medication, in combination with one or more CFTR modulators, successfully restored protein function.
Testing doses, formulations
In the trials (ACTRN12624000849594, ACTRN12624000739516), the company tested the safety of each compound alone in healthy volunteers. The first two parts of the trials examined different doses of the medications in single- or multiple-dose formulations.
Across 210 participants, there were no serious adverse events. No participants discontinued use because of side effects related to treatment.
A third part of the studies established that a tablet formulation is biologically equivalent to an oral suspension. Results also indicated that dosing can occur either in a fasted or fed state.
Twice-daily dosing, at multiple dose levels, allowed each therapy to reach target concentrations. These targets were based on preclinical testing, which established the level of exposure for clinically meaningful changes.
“Based on these encouraging data, we are fortunate to have the option to advance the clinical development of both NBD1 stabilizers while maintaining our timelines and cash runway into 2028,” Cloonan said.
For SION-719, the next step will be a Phase 2a clinical trial evaluating the compound as an add-on to standard-of-care therapies. The U.S. Food and Drug Administration accepted an investigational new drug application to start the SION-719 trial, according to Sionna.
The company is on track to start the trial in the second half of this year. Before taking this step, it will complete a study testing drug-drug interactions to confirm whether SION-719 can be given in combination with standard-of-care therapies.
SION-451 will advance to another Phase 1 healthy volunteer trial, also expected to start later this year. It will test SION-451 combined with SION-222 (galicaftor) and SION-109. Both of these medications are CFTR correctors — a type of CFTR modulator that helps the protein fold correctly so it can reach the cell surface to function properly — targeting other parts of CFTR. The company intends to choose one of these combinations to test in a Phase 2b trial in participants with CF.
For the Phase 2a SION-719 trial and the Phase 1 SION-451 trial, Sionna expects top-line results in mid-2026.
“It is exciting to hear that both NBD1 stabilizers will progress into the next stage of clinical development with the goal of providing new options for CF patients,” Flume said.
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