New Promising Results from Phase 3 of Combination Therapy

Findings from a phase 3 trial evaluating the efficacy and safety of tezacaftor in combination with ivacaftor in patients with cystic fibrosis (CF) who were homozygous for the Phe508del mutation were published in the New England Journal of Medicine.

The Phe508del mutation has been known to result in greatly reduced conductance regulator (CFTR) protein activity and a loss of chloride secretion, which can lead to impaction of mucus in the airways, gastrointestinal tract, and exocrine organs, with the potential for severe clinical consequences including gradual loss of lung function, nutritional deficits, pulmonary exacerbations, and respiratory failure. It is the most prevalent CFTR mutation worldwide, and affects approximately 46% of American CF patients.

Previous data has shown Ivacaftor’s association with a rate of progressive decline in lung function that is lower than that in untreated patients. In a phase 2 clinical trial involving patients who were homozygous for the Phe508del mutation or heterozygous for the Phe508del and G551D mutations, when combined with the investigational CFTR corrector tezacaftor, it has exhibited enhanced CFTR function and improved lung function.

In August, just one month removed from Vertex’s announcement of positive datafrom Phase 1 and Phase 2 studies, Rare Disease Report covered the acceptance of applications for the use of the tezacaftor/ivacaftor combination treatment in this patient population by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

The phase 3 trial enrolled a total of 510 patients 12 years and older with CF who were homozygous for the Phe508del CFTR mutation at 91 sites in the U.S., Canada, and Europe from January 30, 2015 to January 20, 2017. Patients were randomly assigned to be administered either tezacaftor and ivacaftor (administered as a fixed-dose combination tablet containing 100 mg of tezacaftor and 150 mg of ivacaftor in the morning and a tablet containing 150 mg of ivacaftor in the evening) combination therapy or placebo for 24 weeks.

In total, 475 patients completed the full 24 weeks of the trial, with 93.6% (n=235) in the tezacaftor-ivacaftor group and 93% (n=240) in the placebo group. While no significant difference in the body mass index (BMI) was experienced between the groups at week 24, the use of the combination therapy led to a significantly greater absolute change from baseline in the predicted forced expiratory volume in 1 second (FEV1) than placebo. Despite advances in standard-of-care therapy, patients with CF continue to lose lung function at a rate of an estimated 1% to 3% per year. This trial exhibited a significant effect of the combination therapy compared to the placebo, as the mean absolute change from baseline in FEV1 through week 24 was 3.4 percentage points in the former, compared to 0.6 in the latter.

The most common adverse events (AEs) among the enrolled patients included infective pulmonary exacerbation, cough, headache, nasopharyngitis, increased sputum production, pyrecia, hemoptysis, oropharyngeal pain, and fatigue. The incidence of AEs was similar in both the group for combination therapy and the placebo group, however, those treated with lumacaftor-ivacaftor in the phase 3 did not experience an increased incidence of respiratory events (33 patients [13.1%] vs. 41 patients [15.9%]).

This improved safety profile of the tezacaftor-ivacaftor combination supports its use in a broad range of patients with CF, and, if approved, the therapy will be the third of Vertex’s drugs approved for CF patients, and the second intended specifically to treat patients with F508del mutations (Orkami [lumacaftor/ivacaftor]).

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A Brief Historical Timeline of CF Research to Date

Cystic fibrosis care has seen such rapid advances that the average CF patient has experienced a dramatic evolution in treatment strategies in their lifetime. Here are some of the biggest milestones that shaped modern-day CF treatments.

Continue reading A Brief Historical Timeline of CF Research to Date

Positive Results for Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced that the New England Journal of Medicine (NEJM) published two articles with results from two Phase 3 studies of the tezacaftor/ivacaftor combination treatment, a medicine in development that is designed to treat the underlying cause of cystic fibrosis (CF) in people ages 12 and older who have certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Continue reading Positive Results for Phase 3 Studies of the Tezacaftor/Ivacaftor Combination Treatment

Live Stream the North American CF Conference Tomorrow for Free!

The North American CF Conference (NACFC) provides a collaborative and educational forum for all CF professionals. The educational elements of the meeting program are targeted to physicians, nurses, research scientists, respiratory therapists, physical therapists, nutritionists, social workers, and pharmacists. Continue reading Live Stream the North American CF Conference Tomorrow for Free!

Phase 1b Trial of QR-010

ProQR Completes Dosing of Cystic Fibrosis Patients in QR-010 Phase 1b Trial

Key Updates
• Last patient received their final dose in the PQ-010-001 Phase 1b clinical trial of QR-010 in CF patients with the F508del mutation.
Top-line trial data are expected to be issued in a press release Continue reading Phase 1b Trial of QR-010

Vertex Drug Gets Priority Review for Cystic Fibrosis

Tezacaftor/Ivacaftor Gets Priority Review for Cystic Fibrosis

The Food and Drug Administration (FDA) has granted Priority Review to the New Drug Application (NDA) of tezacaftor/ivacaftor (Vertex) for the treatment of patients ≥12yrs old with cystic fibrosis (CF) who have two copies of the F508del mutation or one F508del mutation and one residual function mutation.

The NDA submission was based on positive results from 2 global Phase 3 trials, which showed statistically significant improvements in lung function (percent predicted forced expiratory volume in one second, or ppFEV1) in patients treated with tezacaftor/ivacaftor.

The combination treatment consists of ivacaftor (marketed under the brand name Kalydeco), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, and tezacaftor, a novel CFTR corrector. Tezacaftor is designed to address the processing defect of F508del-CFTR to enable it to reach the cell surface, where ivacaftor can further enhance the protein’s function.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target date of February 28, 2018 to make a decision on the NDA.

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Rare mutation cell collection (RARE) (RARE-OB-16)

This study is taking place at multiple care centers across the U.S. Researchers will collect and make available for study cells from people with rare CFTR mutations.

This study will consist of a single visit where researchers will collect nasal cells and a blood sample. CFTR genotype will be confirmed and a repository of rare CFTR mutation specimens will be established and made available to other researchers for further study.

This study is for people with CF over the age of 2 who have a rare CFTR mutation. This study may require nasal swabs and/or other methods of cell collection.

FDA Approves Kalydeco for Cystic Fibrosis Patients Ages 2 and Up

The U.S. Food and Drug Administration (FDA) continues to provide new indications for Vertex’s Kalydeco (ivacaftor) for Cystic Fibrosis (CF) patients. Earlier today, it was approved for use in more than 600 patients ages 2 and older who have 1 of 5 residual function mutations that results in a splicing Continue reading FDA Approves Kalydeco for Cystic Fibrosis Patients Ages 2 and Up

Phase 1 and 2 results with promising new data

Proteostasis Therapeutics Announces Progression of PTI-428 and PTI-801 to Longer Duration Studies in CF Subjects

Proteostasis Therapeutics, Inc. (NASDAQ:PTI), a biopharmaceutical company developing small molecule therapeutics to treat diseases caused by dysfunctional protein processing such as cystic fibrosis (CF), announced updates across the Company’s later stage development programs in CF, including PTI-428, a cystic fibrosis transmembrane conductance regulator (CFTR) amplifier, PTI-801, a new generation CFTR corrector, and PTI-808, a CFTR potentiator.

Proteostasis announced that it has completed dosing of 19 patients as part of the ongoing Phase 1/2 study designed to evaluate the safety and pharmacokinetics of PTI-428, the Company’s CFTR amplifier. PTI-428 was administered together with background Orkambi® (lumacaftor/ivacaftor) or as the only CFTR modulator therapy in CF subjects over a 14-day period (7-day dosing followed by 7-day follow-up period). The trial met its primary safety and pharmacokinetic endpoints, confirming PTI-428’s safety, tolerability and lack of clinically meaningful drug-drug interaction with ivacaftor and lumacaftor.

“Preliminary data suggests that PTI-428 continues to demonstrate a favorable safety and pharmacokinetic profile, which has enabled the initiation of Phase 2, enrolling CF subjects on background Orkambi® taking PTI-428 or placebo for 28 days,” said Meenu Chhabra, President and CEO of Proteostasis Therapeutics. “We continue to make meaningful progress with all three components of our proprietary triple combination: with the support of US and EU patient advocacy groups for the PTI-801 protocol, we are eligible to begin screening and enrolling CF subjects on background Orkambi® and 40 clinical sites in the US, Canada and EU have been identified or are in process of activation; enrollment continues in our 28-day study of PTI-428 across 14 active clinical sites in the US, with activation of another 23 sites in both the US and EU in process; and we have initiated a Phase 1 study of PTI-808 in healthy volunteers.”

In the Phase 1 portion of the PTI-428 study, 11 subjects in the Orkambi® cohort and eight in the PTI-428 monotherapy cohort were enrolled, with each group enrolling 2 placebo subjects. All adverse events (AEs) were mild or moderate and none occurred in more than one subject. There were no hematology-related adverse events and no serious adverse events (SAEs) reported. Safety endpoints evaluated included lung function as measured by forced expiratory volume in one second (FEV1), although the study was not designed to show a statistically significant difference. In the subjects who received PTI-428 in addition to their background Orkambi, there was no significant improvement of FEV1 compared to placebo, although there was a numerical increase in FEV1 at day 7. Measurements of sweat chloride and mRNA in nasal mucosa were used as exploratory biomarkers but the changes were not significant nor correlated with lung function changes.

Ms. Chhabra added, “While confirming the safety of PTI-428, the phase 1 portion of this study was not expected to demonstrate efficacy over a 7-day dosing period, as PTI-428, as a CFTR amplifier, is designed to deliver substrate to correctors and was investigated in combination with Orkambi®, whose signal of efficacy required a 28-day study. As a result, we look forward to generating data in our 28-day proof-of-concept study to begin understanding the activity profile of PTI-428.” Proteostasis is enrolling patients in the Phase 2 safety and efficacy portion of the study, which explores PTI-428 dosed over a 28-day period, and preliminary data is expected in Q4 2017.

Po-Shun Lee, M.D., Executive Vice President, Chief Medical Officer, added: “This is a very exciting time for the CF community, with the potential of next generation CFTR modulator therapies and combinations just beginning to emerge inclusive of doublets, triplets and quadruplets. We believe that PTI-428, PTI-801 and PTI-808 have the potential to play a pivotal role in emerging next generation therapies as proprietary combinations and as add-ons to the evolving standard of care. In fact, recent clinical data published with triple combinations of CFTR modulators confirms that in vitro assays have high translational value correlating with improvements in lung function beyond what had been observed to date. This continues to reinforce the correlation between in vitro chloride transport and FEV1 and further suggests a ceiling on lung function improvement has not yet been established.”

Proteostasis also announced today that the protocol for the CF portion of its Phase 1/2 study of PTI-801, a new generation CFTR corrector with Fast Track designation from the FDA, has been endorsed by the Cystic Fibrosis Foundation Therapeutics Development Network (TDN) Protocol Review Committee and the European Cystic Fibrosis Society Clinical Trial Network (CTN). Screening of CF subjects for 14-day dosing in this study is in the process of being initiated, with initial data expected in Q4 2017. A total of 52 healthy volunteers have participated and completed the study. All AEs in the healthy volunteer portion of the study that have been reported to date were of mild or moderate intensity. No AEs were reported in more than one subject and no SAEs were reported. PTI-801 was found to be generally well tolerated. Preliminary PK assessments indicated that PTI-801 was well absorbed following single and multiple oral administrations, and suggest that it could be suitable for once daily dosing. In vitro studies have shown that the addition of PTI-801 to either a lumacaftor/ivacaftor or tezacaftor/ivacaftor combination increased the effect of both combinations by approximately three-fold.

The Company also announced today that its Investigational New Drug application with the U.S. Food and Drug Administration for PTI-808, a CFTR potentiator, is now active and that the Company has initiated a Phase 1 study in healthy volunteers. If positive efficacy results are achieved in the PTI-428 and PTI-801 programs, Proteostasis intends to initiate a triple combination study at the end of 2017 with all three agents (also known as PTI-NC-733). The study will explore different doses of PTI-808 with fixed dose combination of PTI-428 and PTI-801 in an F508del homozygous population who are not taking Orkambi®.

About Proteostasis Therapeutics, Inc.
Proteostasis Therapeutics, Inc. is a biopharmaceutical company dedicated to the discovery of groundbreaking therapies to treat diseases caused by dysfunctional protein processing, such as cystic fibrosis (CF). Headquartered in Cambridge, MA, the Proteostasis Therapeutics team focuses on identifying therapies that restore protein function. In addition to its multiple programs in cystic fibrosis, Proteostasis Therapeutics has formed a collaboration with Astellas Pharma, Inc. to research and identify therapies targeting the Unfolded Protein Response (UPR) pathway. For more information, visit