Cystic Fibrosis Compound to Stabilize CFTR Protein Advances in Clinical Study

Cystic Fibrosis Compound to Stabilize CFTR Protein Advances in Clinical Study

Nivalis Therapeutics, Inc., recently announced an expanded clinical development plan for N91115, the company’s first-in-class stabilizer of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is defective in patients with cystic fibrosis (CF).

An independent Data Monitoring Committee (DMC) completed a review of interim safety results from the ongoing double-blind, randomized, placebo-controlled, and parallel-group Phase 2 clinical trial (NCT02589236). This study is evaluating the efficacy and safety of N91115 in CF adults who are homozygous for the F508del-CFTR mutation and being treated with lumacaftor/ivacaftor (Orkambi).

No safety concerns were found, and the DMC determined the trial may continue to recruit and randomize patients for a higher N91115 dose (400 mg). The trial began with a dose of 200 mg late last year, and is now comparing 200 mg to 400 mg of N91115, administered twice a day in addition to Orkambi.

Nivalis Therapeutics will also commence a Phase 2, proof-of-concept trial to assess the efficacy and safety of N91115 in patients carrying one copy of the F508del mutation and a second mutation that causes a gating defect in the CFTR protein, and who are being treated with Kalydeco (ivacaftor).

This trial is expected to soon start enrolling patients in the U.S. About 20 participants will be randomly assigned to receive treatment with N91115 plus Kalydeco, or with placebo plus Kalydeco. Its primary endpoint is the absolute change from baseline in lung function, assessed as percent predicted FEV1 (ppFEV1).

“Enrollment of the ongoing Phase 2 study has been encouraging, and we are pleased that the DMC has validated the initial clinical safety of N91115 with its recent approval of the higher dose arm,” said Jon Congleton, president and chief executive officer of Nivalis, in a press release. “We also look forward to initiating our second Phase 2 study which aims to show the additional benefit of N91115 in people with different CF mutations, as we believe multiple mechanisms of action will be required to fully achieve optimal clinical outcomes for patients living with CF.”

CFTR is a membrane protein encoded by the CFTR gene that conducts chloride and thiocyanate ions across epithelial cell membranes. Gene mutations affecting chloride ion channel function lead to the dysregulation of epithelial fluid transport in the lung, pancreas, and other organs.

N91115 leads to a S-nitrosoglutathione reductase (GSNOR) inhibition and modulates the mutated CFTR protein by modifying the chaperones that lead to the protein’s degradation. In preclinical studies, the stabilizing effect of N91115 was found to increase and prolong CFTR activity when added to other CFTR modulators.

One comment

  1. Tat-beclin-1 says:

    It seems that CFTR can provide evidence that the major cystic fibrosis mutation DeltaF508 leads to defective protein folding in the endoplasmic reticulum, which prevents its processing and targeting to the cell surface.

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