Sionna Therapeutics (NASDAQ:SION) used its presentation at the Guggenheim Emerging Outlook Biotech Summit 2026 to outline its strategy to develop next-generation cystic fibrosis (CF) therapies centered on NBD1 stabilization, and to preview multiple mid-2026 clinical catalysts.
Company background and focus on NBD1 stabilization
Chief Executive Officer Mike Cloonan said Sionna’s mission is to “revolutionize the treatment paradigm” in CF by leveraging what he described as “unique and first-in-class NBD1 stabilizers.” Cloonan traced the origins of the science behind the company’s programs back more than 15 years to Genzyme, continuing through Sanofi after the merger. Sionna was formed in late 2019 as a dedicated CF company to advance those programs, and it now has “multiple NBD1 programs” in the clinic along with complementary mechanisms intended for combination use.
According to Cloonan, the biology has long suggested NBD1 as a key target, but the chemistry has been difficult due to “very shallow binding pockets.” He referenced a 2016 paper from Pfizer that concluded NBD1 was “undruggable” for this reason, and said Vertex has also stated it tried to stabilize NBD1 but could not optimize the target.
New preclinical data on CFTR protein half-life
Chief Medical Officer Charlotte McKee highlighted data recently presented at the North American CF Conference. She said that beyond impaired folding and reduced trafficking to the cell surface, F508del CFTR that does reach the cell surface has “a much reduced half-life” and is turned over more quickly than normal.
McKee said Sionna researchers used pulse-chase experiments to show that NBD1 stabilizers, either alone or in combination with complementary mechanisms, could restore CFTR protein half-life to the “normal wild-type range.” She characterized the work as a complex assay set that provides another piece of evidence supporting the company’s approach.
Mid-2026 catalyst: Phase 2a PreciSION-CF add-on study with SION-719
Cloonan said 2026 is a pivotal year for the company, with multiple readouts expected mid-year. The first is the Phase 2a PreciSION-CF proof-of-concept study evaluating the NBD1 stabilizer SION-719 on top of TRIKAFTA. He described it as the “first patient study with NBD1” designed to demonstrate improvement in sweat chloride when adding 719 to TRIKAFTA, and as the first opportunity to assess translation of the company’s CFHBE assay in patients.
McKee provided details on the trial design, describing it as a sweat chloride-based, randomized, double-blind crossover study in F508del homozygous patients who are stable on physician-prescribed TRIKAFTA. Patients remain on TRIKAFTA throughout the study and receive two 14-day dosing periods—TRIKAFTA plus SION-719 (at a lower dose range) and TRIKAFTA plus placebo—separated by a 28-day washout. She said each patient serves as their own control, and the study is powered to detect at least a 10 mmol/L improvement in sweat chloride above baseline.
McKee said the company chose F508del homozygous patients to make the proof-of-concept “clear-cut” and reduce genotype variability. She added that eligibility criteria were set to enroll patients in the middle of real-world baseline sweat chloride values for those on TRIKAFTA—patients who are not yet at normal CFTR function but have shown some benefit and still have room to improve.
Why Sionna set a 10 mmol/L sweat chloride threshold
In response to questions about why the study is powered for a 10 mmol/L change, Cloonan said the company selected that level based on feedback from the CF community as the point where improvement above standard of care begins to be viewed as clinically meaningful. He also said the company believes a 10 mmol/L sweat chloride change implies a potential FEV1 improvement “in the order of three percentage points,” though he emphasized PreciSION-CF is not designed to show FEV1.
McKee added that when sweat chloride improvements are in the single digits, they may translate to FEV1 “but just as often they haven’t,” describing that range as a “noisy, risky zone.”
The discussion also addressed comparisons with ALYFTREK in different genotypes. McKee said that in F508del homozygous patients, ALYFTREK’s Phase III data showed about a 3 mmol/L change versus TRIKAFTA, while an 8 mmol/L difference was observed in a separate Phase III study in compound heterozygous patients (FMF genotype).
Dual-combination program: SION-451 with complementary correctors
Sionna’s second mid-2026 catalyst is a healthy volunteer dual-combination study evaluating a different NBD1 stabilizer, SION-451, combined with two complementary mechanisms: SION-2222 (a TMD1 corrector) and SION-109 (an ICL4 corrector). Cloonan said the readout is expected mid-2026 and is intended to assess combination tolerability and pharmacokinetics, with the goal of selecting the best dual combination to progress.
McKee explained that SION-719 and SION-451 were both advanced into Phase 1 with the expectation of selecting one, but the company chose to deploy both based on differences in potency and exposure. She said 719 appeared “a little bit” more potent at low doses suited for add-on use with TRIKAFTA, while 451 achieved higher exposures that may be advantageous in a two-drug regimen where the NBD1 component must provide more of the effect.
On the purpose of the healthy volunteer dual-combination study, McKee said it is designed to evaluate pharmacokinetics and safety/tolerability of the combinations and to support selection of the preferred dual combination for future patient studies. When asked about potential safety differences between the TMD1 and ICL4 combinations, McKee said there was no preclinical differentiation and that the Phase 1 combination study should help determine which is preferred.
Cloonan also said that after PreciSION-CF data, Sionna expects to evaluate whether to pursue both an add-on path and the dual-combination path, noting it would depend in part on capital availability. McKee added that if Sionna progresses an add-on approach, it would “absolutely explore” different background standards of care, and noted that ALYFTREK and TRIKAFTA share the same mechanisms of action.
Chief Financial Officer Elena Ridloff said the CF market is about $12 billion today and is expected to grow to $15 billion to $17 billion over the next five years. Ridloff also said the company ended the third quarter with $325 million in cash, providing runway into 2028.
About Sionna Therapeutics (NASDAQ:SION)
Sionna Therapeutics is a clinical-stage biotechnology company dedicated to developing next-generation RNA therapeutics for oncology and immunology indications. Leveraging proprietary lipid nanoparticle and coacervate delivery technologies, the company aims to overcome key challenges associated with stability, targeting and immune activation that have historically limited the clinical performance of mRNA-based medicines. Its strategic focus spans both solid tumors and hematological malignancies, as well as selected autoimmune disorders, reflecting a broad ambition to harness the power of messenger RNA in diverse therapeutic areas.
At the heart of Sionna’s approach is a platform that combines optimized ionizable lipids with bespoke surface chemistries to enhance payload delivery, intracellular release and endosomal escape.
