Nivalis Therapeutics recently announced the expansion of the clinical development plan for N91115, the company’s investigational, first-in-class stabilizer of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is defective in patients with cystic fibrosis.
Boulder, Colorado-based Nivalis is a clinical stage pharmaceutical dedicated to treating people with cystic fibrosis. The company developed N91115 – which works through a novel mechanism of action called snitrosoglutathione reductase (GSNOR) inhibition – that is presumed to modulate the unstable and defective CFTR protein, which is responsible for cystic fibrosis.
GSNOR inhibition works by modifying the chaperones responsible for CFTR protein degradation through restoring GSNO levels, leading to a stabilizing effect that increases the CFTR chloride channel function and thus, a net chloride secretion. This effect is predicted to be complementary and agnostic to other CFTR modulators, like Orkambi.
The review of the interim safety data from Nivalis’ ongoing 12-week, double-blind, randomized, placebo-controlled, parallel group Phase 2 clinical trial to evaluate the safety and efficacy of N91115 in adults who have two copies of the F508del mutation in the CFTR gene, and are currently under treatment with Orkambi, has now been completed by an independent data monitoring committee.
The committee found no safety concerns and concluded that the study may proceed with enrollment and randomization of patients in a bigger cohort, testing 400 mg of N91115 to be compared with 200 mg, administered twice a day in addition to Orkambi.
A new Phase 2, proof-of-concept clinical trial will be launched by Nivalis to evaluate N91115 in patients with one copy of the F508del mutation, and in patients with a second mutation that results in a gating defect in the CFTR protein. These patients would also receive treatment with Kalydeco (ivacaftor).
This multicenter clinical study will begin enrolling patients in the U.S. in the first half of 2016. The trial will randomize nearly 20 cystic fibrosis patients into two groups: one receiving N91115 with Kalydeco, and one receiving a placebo with Kalydeco. The primary efficacy endpoint is the absolute alteration from baseline in lung function (assessed by ppFEV) in the group receiving N91115 .
“Enrollment of the ongoing Phase 2 study has been encouraging, and we are pleased that the [data monitoring committee] has validated the initial clinical safety of N91115 with its recent approval of the higher-dose arm,” Nivalis President and CEO Jon Congleton said 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 cystic fibrosis mutations, as we believe multiple mechanisms of action will be required to fully achieve optimal clinical outcomes for patients living with cystic fibrosis.”