Proteostasis’ CFTR Modulators Show Potential in Improving Effectiveness of Orkambi

Alice Melão, MSc avatar

by Alice Melão, MSc |

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CFTR modulators

Clinical trials on all three Proteostasis Therapeutics’ investigational cystic fibrosis modulators — PTI-428, PTI-801, and PTI-808 — have demonstrated they are safe and have the potential to improve the effectiveness of Orkambi in patients with cystic fibrosis (CF).

The positive clinical data supports the initiation of new clinical trials evaluating the drug candidates in doublet and triplet combinations in CF patients.

Cystic fibrosis patients have a defective CFTR gene which results in the defective production of CFTR protein — an important channel for the transport of chloride ions in and out of cells, to help control the movement of water in tissues.

PTI-428 is a CFTR protein amplifier that increases the levels of the immature form of the CFTR protein. PTI-801, on the other hand, is a CFTR corrector, meaning it addresses the malfunctioning of the protein.

The company is also developing a CFTR potentiator, PTI-808, which was designed to improve the performance of other CFTR-based therapies.

All three therapies were engineered to help restore the normal activity of the CFTR protein.

Results from the recently completed, 28-day treatment, Phase 2 clinical trial (NCT02718495) on the CFTR amplifier in combination with Vertex’s Orkambi (lumacaftor/ivacaftor) have demonstrated that PTI-428 can effectively improve CF symptoms.

Patients who received 50 mg once-daily of PTI-428 as an add-on to Orkambi treatment showed a significantly improved lung function, measured as percent predicted of forced expiratory volume in 1 second (ppFEV1) — the improvement was by 5.2 percent points from baseline compared to Orkambi alone. This beneficial effect was observed after only 14 days of treatments and sustained until the 28 days of treatment was completed.

These results were compared to previous Orkambi Phase 3 TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949) data, and confirmed that PTI-428 can improve Orkambi’s effect in patients who respond to the treatment.

In addition to these positive results, the investigators also found that treatment with PTI-428 promoted an increase in CFTR protein levels. However, no correlation was found between changes in sweat chloride — a hallmark of CF — and lung function improvements.

“This is an important first step toward translating the scientific potential of the first and only genotype agnostic CFTR modulator in development, and its ability to enhance Orkambi by selectively increasing the production of the CFTR protein,” Patrick Flume, MD, investigator at the Medical University of South Carolina, a CF Foundation Therapeutics Development Network center, who is participating in the PTI-428 and PTI-801 clinical studies, said in a press release.

During the 28-day study, PTI-428 was shown to be safe and well tolerated by the patients. No meaningful interactions with other drugs were reported. Treatment with PTI-428 was not associated with serious adverse events. One mild case of low platelet levels was reported.

“The ability to capture an improvement in absolute ppFEV1 along with a targeted increase in the CFTR protein at 50 mg of PTI-428 indicates that we have been able to identify a starting dose that will guide us for future dose optimization in combination studies with our proprietary potentiator and corrector,” said Meenu Chhabra, president and CEO of Proteostasis.

The company has also initiated a Phase 1 trial (NCT03140527) to evaluate the safety and efficacy of PTI-801 compared to placebo in healthy volunteers and cystic fibrosis patients undergoing treatment with Orkambi. The trial is currently enrolling participants. For more information, visit the clinical trial web page here.

Preliminary data collected from four patients who were treated with 100 mg of PTI-801 once a day, and who completed the pre-established 14 days of treatment, showed mean absolute improvements in ppFEV1 of about 4 percentage points from baseline.

“This initial data begins to validate the in vitro profile of PTI-801 and its potential to bolster efficacy for subjects on Orkambi. We are eager to explore a dose response in the next planned cohort with 200 mg of once-a-day dosing,” Chhabra said.

Regarding PTI-808, it was shown to be safe and well-tolerated, with only mild or moderate adverse events being reported in healthy volunteers.

In addition, data from initial testing of co-administration of PTI-428, PTI-808, and PTI-801 in 20 healthy volunteers revealed that these therapies, when combined, continued to be safe for people. No serious safety issues associated with the combo treatment were reported, or clinically meaningful drug-drug interactions.

“The Phase 2 data with PTI-428, along with initial clinical evidence with PTI-801 and the completion of co-administration safety and PK [pharmacokinetic] studies with all three CFTR modulators in healthy volunteers, further cements our progress toward combination development with our proprietary compounds in the CF patient population,” Chhabra said.

“We look forward to initiating a doublet study of PTI-801 and PTI-808 in CF subjects and progressing toward a triple combination study in CF subjects in 2018,” Chhabra added.