Proteostasis Therapeutics (PTI) has completed patient enrollment in a Phase 2 clinical trial evaluating its cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination therapies in cystic fibrosis (CF) patients who have at least one copy of the F508del mutation in the CFTR gene (the defective gene in CF patients).
The most common mutation in CF patients is the F508del mutation, which impairs the ability of the CFTR protein to move salts across the cell membrane.
CF patients can either be homozygous (both the maternal and the paternal copy of the CFTR gene has the mutation) or heterozygous (only one of the copies of the gene has the mutation) for the F508del mutation.
This Phase 2 clinical trial (NCT03500263) is a global, randomized, placebo-controlled study designed to assess the effectiveness, safety, and tolerability of PTI’s combination therapy over a period of four weeks in CF patients homozygous or heterozygous for F508del (up to 30 patients in each group).
The goals of the study include safety, changes in sweat chloride concentration (a measure of CFTR function), and changes in percent predicted FEV1 (ppFEV1, a measure of lung function).
The combination treatment includes 600 mg of PTI-801 (third-generation CFTR corrector), 300 mg of PTI-808 (a CFTR potentiator), with or without 10 mg of PTI-428 (a CFTR amplifier). These doses were selected based on previous data gathered from approximately 250 CF patients.
CFTR amplifiers are a new type of medicine that help increase CFTR protein levels in cells and tissues. CFTR potentiators are drugs that can help overcome gating defects that are caused by certain mutations of the CFTR gene. CFTR correctors help the CFTR protein form the right 3D shape so it can properly move to the cell surface.
“We are working hard to introduce the power of choice to the CF community, and the completion of enrollment in our global Phase 2 study is an important step forward to completing that mission,” Geoffrey Gilmartin, MD, MMSc, chief medical officer of Proteostasis, said in a press release.
“We heard loud and clear at our recently hosted Cystic Fibrosis Summit, as well as at the [recent] North American CF Conference, that the community urgently demands options to address the inequity in access, variability in clinical response and genetic disparity amongst people with CF,” Gilmartin said.
Due to speedy enrollment from clinical centers across the United States, Canada, Western Europe, and New Zealand, top-line results from the study are anticipated by the end of 2019, instead of early 2020, as initially expected.
This Phase 2 study follows on the heels of positive results from a previous 14-day Phase 1 clinical study testing PTI’s double and triple combination therapy in F508del homozygous patients, including those prone to a quick decline in lung function.
The data indicated a favorable safety and tolerability profile for these therapeutic combinations, and a significant improvement in ppFEV1 and sweat chloride concentration, when compared to available standard-of-care treatment.
Of note, the triple combo (PTI-801, PTI-808, and PTI-428) received fast track designation by the U.S. Food and Drug Administration (FDA) in 2018.