Proteostasis Therapeutics Inc. investors keen to compare its experimental cystic fibrosis triplet therapy to combinations in development by Vertex Pharmaceuticals Inc. appeared rattled by phase I data Monday. Proteostasis reported its triplet improving a measure of lung function at two weeks with no plateau in sight. The outcome helped it identify doses of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators to use in planned phase II trials. But analysts suggested the data offered little challenge to Vertex's triplet, which they said has outshone the Proteostasis combo on the same measure. Proteostasis shares (NASDAQ:PTI) fell 67.8 percent in heavy trading Monday to close at $1.31 on Monday. Vertex shares (NASDAQ:VRTX) inched higher, closing up 1.3 percent at $183.85.

On Monday, Proteostasis shared data from phase I studies of both its CFTR corrector PTI-801 and its CFTR amplifier PTI-428 as add-on treatments to Vertex's Symdeko (tezacaftor/ivacaftor) therapy. But its key focus ­– as well as that of investors in the company and Vertex – seemed to be on 14-day data from the phase I study of its triplet therapy, combining PTI-801, PTI-428 and the CFTR potentiator PTI-808.

The latter study, which randomized 31 patients to one of two dose cohorts, provided participants with either PTI-808 or placebo during a seven-day lead-in period, followed by a 14-day triple combination treatment period and a subsequent 7-day washout period. Among those participants who stuck to the trial's protocol, a statistically significant (p<0.001) mean absolute increase in percent predicted forced expiratory volume in one second (ppFEV1) at two weeks of 5 percentage points vs. baseline was observed in the 600-mg PTI-801 cohort.

Proteostasis President and CEO Meenu Chhabra told analysts that, in "a comparable patient population set to the Vertex studies," that number would be closer to a 6 percentage point change vs. baseline. But that message didn't seem to resonate with a group looking at data from Vertex's combinations, which have included recent phase III tests of two different CFTR correctors – VX-445 and VX-659 – in combination with tezacaftor and ivacaftor, both of which appeared to deliver significantly greater increases in ppFEV1. (See BioWorld, March 7, 2019)

In a phase III study of 402 CF patients with one F508del mutation and one minimal function mutation, treatment with Vertex's VX-445-lead triplet for four weeks produced a mean absolute improvement in ppFEV1 of 13.8 percentage points from baseline compared to placebo (p<0.0001). Data released in November showed VX-659 plus tezacaftor and ivacaftor produced a mean absolute improvement in ppFEV1 of 14 percentage points from baseline to week four of treatment compared to placebo in a similar population of 380 CF patients (p<0.0001).

The Vertex data, some observers pointed out, has focused on four-week data. "But the VRTX phase II publications show 14-day data that's similar to the four weeks," J.P. Morgan analyst Cory Kasimov wrote. "Bigger picture, today's underwhelming data update for PTI further reinforces our belief that VRTX will remain a dominant player in the CF space for the foreseeable future," he wrote.

Other analysts, such as Jefferies' Michael Yee expressed similar sentiments about the data, while adding fuel to the fire that burned Proteostasis shares Monday with a comment on the challenges of recruiting and enrolling patients to participate in its trials. The competitive issue for the company, more than just data, he wrote, is that "it's very difficult to enroll patients in studies due to the clear priority preference for patients to be on VRTX drugs – and patients who are getting on clinical trials are going to be poor performers, sick patients, patients who failed VRTX therapy, and/or patients who were not eligible for VRTX drugs."

Outlining the company's progress during a conference call held to discuss its findings, Chhabra addressed that issue and others, saying that her team has "built a better understanding of available subjects for the next phase of clinical development." She also framed the company's progress less in terms of comparison than market choice, saying that the new data represented "the culmination of a great deal of work under challenging circumstances and has delivered several important outcomes that allow us to cross the threshold into becoming a potential second entrant into the CFTR modulator arena and finally being able to deliver the promise of choice back to the patients."

In addition to the headline ppFEV1 data, the company noted that improvement in that measure for per-protocol participants didn't plateau by the two week mark and that, for the same group, there was statistically significant decrease in sweat chloride concentration at day 14 of -19 mM (p<0.00001) vs. baseline.

"With no plateau in ppFEV1 improvement reached over 14 days in our triplet combination study, we look forward to studying what we believe are the optimal doses for our corrector and potentiator through longer duration trials in subjects who are not predisposed to rapid pulmonary decline," Chhabra said. "These studies are expected to complete by year-end 2019 with preliminary data readouts thereafter, in anticipation of our mid-2020 phase III launch timeline," she said.

All three compounds in the Proteostasis triplet were generally well-tolerated with no serious adverse events or discontinuations reported during the combination treatment period, the company said.

Add-on studies don't pan out

The company also reported the results of two separate add-on studies Monday. They enrolled 56 CF subjects who were on Symdeko randomized and treated with either PTI-801 (400 mg) or placebo for 14 days or PTI-428 (10 mg or 30 mg) or placebo for 28 days.

In the first study, participants receiving PTI-801 experienced an average sweat chloride improvement of -20 mM (p<0.05) compared to baseline, the company reported, but they did not see a statistically significant improvement in ppFEV1 at the end of 14 days of treatment.

In the second study, patients at both the 10 mg and 30 mg doses of PTI-428 achieved the targeted increase of CFTR protein expression of about 50 percent (p<0.05) through 28 days compared to baseline. But, similar to the PTI-801 add on study, PTI-428-treated participants failed to see a statistically significant improvement in ppFEV1 at the end of the treatment period.