Greatest ppFEV1 Improvement Shown in High Dose Triplet with Mean Absolute Improvement in ppFEV1 of 8 Percentage Points at 14 Days Compared to Placebo (p<0.05) in Subjects with Two F508del Mutations (F/F) Not Predisposed to Rapid Pulmonary Decline

All Combinations Studied Were Well-Tolerated, Including in Difficult to Treat Patients Predisposed to Rapid Pulmonary Decline

Phase 2 Doses Identified for Proprietary Combination, On Track for Mid 2020 Phase 3 Launch

BOSTON, MA, USA I March 25, 2019 I Proteostasis Therapeutics, Inc. (NASDAQ:PTI), a clinical stage biopharmaceutical company dedicated to the discovery and development of groundbreaking therapies to treat cystic fibrosis (CF) and other diseases caused by dysfunctional protein processing, today announced results from Phase 1 clinical studies of its proprietary cystic fibrosis transmembrane conductance regulator (CFTR) modulators: PTI-801, a third-generation CFTR corrector; PTI-808, a novel CFTR potentiator; and PTI-428, a novel CFTR amplifier. This comprehensive data set includes efficacy and safety data from 14-day studies of PTI’s proprietary combination therapy (PTI-808, PTI-801 and PTI-428), as well as separate studies of PTI-801 over 14 days and PTI-428 over 28 days as add-on treatments to background tezacaftor/ivacaftor therapy, in CF subjects. Endpoints including safety, changes in sweat chloride (SC) concentration and in percent predicted FEV1 (ppFEV1) were assessed and evaluated.

“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. These studies are expected to complete by year-end 2019 with preliminary data readouts thereafter, in anticipation of our mid-2020 Phase 3 launch timeline,” said Meenu Chhabra, President and Chief Executive Officer of Proteostasis. Ms. Chhabra added, “Recruiting patients to earlier-stage studies in a highly competitive clinical trial environment is challenging. I’m very proud of the PTI team and the continued execution resulting in dosing of more than 240 subjects since 2016.”

“As we continue to advance our understanding of CF and the wide distribution of patients’ responses to available CFTR modulator therapies, it is becoming increasingly important to have access to additional disease modifying treatment options,” said Jennifer Taylor-Cousar, M.D., M.S.C.S., Associate Professor of Medicine and Pediatrics, and Co-Director and CF Therapeutics Development Network Director of the Adult CF Program at National Jewish Health. “Data with dual and triple combinations from PTI fuels hope within the CF treatment community that we might soon be able, if approved, to expand our armamentarium with additional CFTR modulators that will allow us to tailor treatment. We look forward to understanding the full potential of these molecules in longer duration studies.”

Proprietary Combination Results in Detail

For PTI’s proprietary triple combination study, 31 subjects were randomized and treated in two dose cohorts determined as part of a pharmacokinetic-pharmacodynamic (PK-PD) model designed to address the combination rule under established regulatory guidance for dose selection in a Phase 3 study, or received placebo.  Both active cohorts included the same dose of PTI-428 (30mg) and either a low dose of PTI-801 (200 mg) and a high-dose-tested of PTI-808 (300mg), or a high-dose-tested of PTI-801 (600mg) and a mid-dose of PTI-808 (150 mg).  PTI-808 or placebo was administered in a 7-day lead-in period, which was followed by a 14-day triple combination treatment period and a subsequent 7-day washout period. PK results were as expected and reconfirmed a once-a-day dosing profile for a triple combination of PTI-801, PTI-808 and PTI-428.

The compounds were generally well tolerated and there were no serious adverse events or discontinuations reported during the triple combination treatment period. The majority of adverse events reported were mild to moderate in severity. A broad set of inclusion criteria, endorsed by the CF Foundation as a way to enable recruitment due to limited patient availability, were used in the study, resulting in the enrollment of the highest number of subjects predisposed to rapid pulmonary function decline (n=7) across all of the Company’s proprietary combination studies to date.

In a per protocol analysis (PPA) (n=27, limited to subjects compliant to the protocol), a PTI-801 dose-dependent improvement in ppFEV1 and SC concentration was observed across cohorts. Further, improvement in ppFEV1 did not reach a plateau by day 14, unlike the response profile in the Company’s previously reported mid-dose doublet (300mg PTI-801 and 300mg PTI-808) and in reported results from non-PTI triple combinations, a finding that affirms PTI’s plan for longer duration studies.

In the PPA population, a statistically significant (p<0.001) mean absolute increase in ppFEV1 at day 14 of 5 percentage points versus baseline was observed in the 600 mg PTI-801 cohort. This cohort also showed a statistically significant decrease in sweat chloride concentration at day 14 of -19 mM (p<0.00001) compared to baseline and -24 mM (p<0.001) compared to placebo with individual improvements of up to 50 mM.  Adjusting for subjects predisposed to rapid pulmonary decline (subjects who would be ineligible for other CFTR modulators combination studies), the 600 mg PTI-801 cohort saw an improvement in ppFEV1 of +6 (p<0.005) versus baseline, and +8 (p<0.05) versus baseline compared to placebo.

In the Company’s doublet study, enrollment remains ongoing in the cohort of 400 mg PTI-801 and 300 mg PTI-808, with 7 subjects recruited to date.  As support for the Company’s PK-PD model, a group unblinding of the sweat chloride endpoint was performed, and demonstrated a mean improvement of -20 mM versus baseline (p<0.0005).  Factoring in a broad new dataset that includes all double and triple combination 14-day studies, the Company’s PK-PD model shows a strong positive relationship between sweat chloride, ppFEV1 improvements and dose levels.  This points to a potential best in class doublet combination backbone of 600 mg of PTI-801 and 300 mg of PTI-808, which will be further studied and could be used with or without PTI-428.    

Phase 2 Trials Planned

Based on the totality of data, the Company will be launching three new Phase 2, 28-day studies in CF subjects with at least one F508del mutation.  The studies will employ entry criteria comparable to those used in other CFTR modulator combination studies. They will include a placebo controlled, triple and double combination trial in up to 30 patients exploring PTI-801 (600 mg) and PTI-808 (300 mg) with or without PTI-428 over a 28-day treatment period.  PTI’s CFTR modulators will also be evaluated in a homogeneous population over a longer duration. These studies will provide insight on the magnitude of PTI-428 contribution to efficacy and include:

  • PTI-801/808/428 28-day study in CF subjects (F508del homozygotes)
  • PTI-801/808 28-day study in CF subjects (F508del homozygotes)
  • PTI-801/808/428 28-day study in CF subjects (F508del heterozygotes)

These studies will position the Company to complete Phase 2 enrollment in 2019 and initiate Phase 3 studies in mid-2020, as previously guided. 

Add-On Study Results in Detail

For PTI’s two separate add-on studies, a total of 56 CF subjects who were on background tezacaftor/ivacaftor were randomized and treated with either PTI-801 (400 mg) or placebo for 14 days (n=18), or PTI-428 (10 mg or 30 mg) or placebo for 28 days (n=38).

Similar to the Company’s proprietary combination cohorts, these studies were designed with broad entry criteria, endorsed by the CF Foundation as a way to enable recruitment due to limited patient availability. Review of patient medical history records revealed that they experienced an average decline in ppFEV1 of 3 points despite initiating tezacaftor/ivacaftor therapy; approximately a third of the population had 3 or more pulmonary exacerbations in the 12 months prior to screening, and almost half had previously discontinued lumacaftor/ivacaftor for reasons that included intolerability and lack of benefit.  These factors all suggest a strong recruitment bias towards CFTR modulator non-responders for these studies.

Subjects receiving PTI-801 experienced an average sweat chloride improvement of -20 mM (p<0.05) compared to baseline, with individual improvements approaching or exceeding -40 mM during the treatment period.  These subjects did not, however, demonstrate a statistically significant improvement in ppFEV1 at the end of 14 days of treatment.

Consistent with PTI-428’s mechanism of action, patients at both the 10 mg and 30 mg doses achieved the targeted increase of CFTR protein expression of approximately 50% (p<0.05) through 28 days compared to baseline. These results were obtained via a proprietary CFTR protein ELISA that analyzes samples from the nasal mucosa of study subjects and is an established biomarker for CFTR amplifiers. Similar to the PTI-801 add on study, PTI-428 subjects did not demonstrate a statistically significant improvement in ppFEV1 at the end of 28 days of treatment.

Conference Call and Webcast

Proteostasis will hold a conference call and accompanying webcast today, March 25, 2019, at 8:00 AM ET to discuss the data announced today.  The conference call can be accessed by dialing (844) 534-7315 from the United States or (574) 990-3007 from outside the United States and referring to conference ID 5397635. A live webcast and accompanying slide presentation will be available on the Investor Events page in the Investors & Media section of the company’s website, A replay of the webcast will be available on the company’s website shortly after the conclusion of the conference call.

About Proteostasis Therapeutics, Inc.

Proteostasis Therapeutics, Inc. is a clinical stage biopharmaceutical company developing small molecule therapeutics to treat cystic fibrosis and other diseases caused by dysfunctional protein processing. Headquartered in Boston, MA, the Proteostasis Therapeutics team focuses on identifying therapies that restore protein function. For more information, visit

SOURCE: Proteostasis Therapeutics