(662) Novel CFTR Modulator Combinations that Address the NBD1 Defect Central to ΔF508 Dysfunction Enable Full Correction of CFTR

Background: Cystic Fibrosis (CF) results from Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, the most prevalent being ΔF508-CFTR. Approved CFTR modulators increase its function, providing eligible patients with clinical benefits. Despite advances, current modulators do not provide most CF patients with normal levels of CFTR function, indicated by the fact that in most eligible patient groups mean sweat chloride levels do not reach the normal range. ΔF508-CFTR results in the loss of phenylalanine F508 within CFTR’s first Nucleotide Binding Domain (NBD1). ΔF508 causes NBD1 destabilization: a key driver of the impaired folding, trafficking, half-life, and function of ΔF508-CFTR [1-4]. Thus, full ΔF508-CFTR correction may require NBD1 stabilization. F508 also participates in the interface of NBD1 and the fourth intracellular loop of CFTR’s second transmembrane domain (ICL4). ΔF508 weakens this interface, further adding to ΔF508-CFTR’s molecular pathology [5,6]. Consistent with this, suppressor mutations that stabilize NBD1, when combined with others that improve CFTR assembly, can correct ΔF508-CFTR to wild-type levels [8,9]. Without NBD1 stabilization, correction is significantly reduced. Drugs that stabilize NBD1 thus have the potential to improve patient health, yet no current drugs meaningfully address this key defect. After unsuccessful discovery efforts by Pfizer and others, NBD1 was considered likely undruggable [10].

Methods: For over 12 years, our science team has focused on the discovery of NBD1 stabilizers and complementary modulators to restore wild-type function to ΔF508-CFTR. Using functional and biochemical assays, we demonstrate the activity of Sionna’s NBD1 stabilizers alone and in combination with Sionna’s ICL4- and TMD1-directed correctors, and standard-of-care CFTR modulators.

Results: We show that Sionna NBD1 stabilizers can restore ΔF508-CFTR maturation, trafficking, and function to wild-type levels when combined with mechanistically complementary agents, including both Sionna and current standard-of-care modulators. Data from the clinically predictive CFHBE model suggest Sionna NBD1 stabilizers enable multiple potential paths to full restoration of CFTR function for most CF patients.

Conclusions: To develop a more effective therapy for most CF patients, Sionna is advancing small molecules that robustly stabilize the CFTR NBD1 domain, a new and mechanistically-novel therapeutic class, and TMD1- and ICL4-directed CFTR correctors that complement NBD1 stabilization. With novel NBD1-stabilizers as their base, Sionna combinations can provide unprecedented improvement in ΔF508-CFTR maturation, trafficking, and function.

Acknowledgements: This work was supported by Sionna Therapeutics and the CFF with past support from Genzyme and Sanofi.

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