Triple Combo of Proteostasis’ CFTR Modulators May Benefit CF Patients, Phase 1 Trial Shows

Alice Melão, MSc avatar

by Alice Melão, MSc |

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Treatment with Proteostasis Therapeutics’ triple combo therapy regimen may significantly improve the lung function of patients with cystic fibrosis (CF), results from a Phase 1 clinical trial suggest.

The therapy includes the company’s three investigational modulators of the CFTR genePTI-428, which is an amplifierPTI-801, which is a corrector; and PTI-808, which is a potentiator. This combination is designed to overcome the impact of CF-causing mutations in this gene.

“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,” Jennifer Taylor-Cousar, MD, co-director of the Adult CF Program at National Jewish Health, said in a press release.

The trial (NCT03500263) included 31 patients with CF who were randomized to receive either the triple treatment combination or a placebo. The triple combo was given daily with a fixed dose of PTI-428 (30 mg) plus either a low dose of PTI-801 (200 mg) and a high-dose-tested of PTI-808 (300 mg), or a high-dose-tested of PTI-801 (600 mg) and a mid-dose of PTI-808 (150 mg).

Patients were first treated with PTI-808 or a placebo for seven days, followed by a 14-day triple combination treatment period, and then a seven-day washout period where no therapy was given.

Patients who received the therapy combo with high-dose PTI-801 experienced significant improvement in lung function, with a 5% increase in mean absolute ppFEV1 (percent predicted forced expiratory volume in one second; a measure of lung function) at 14 days compared with before the treatment. These patients also showed significant reductions in sweat chloride levels, with a decrease of 19 millimoles at 14 days compared with before treatment, and 24 millimoles compared with placebo.

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Positive effects were also reported in patients who were predisposed to rapid pulmonary decline, and would not be included in other CFTR modulator combination studies. When treated with the combo regimen with 600 mg of PTI-801, these patients had an improvement in ppFEVof 6% compared with before treatment, and 8% compared with placebo.

Results showed that ppFEV1 improvements did not reach a maximum stable response over the 14 days of treatment, suggesting that patients could benefit from longer treatment periods with the triple combo therapy.

“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,” said Meenu Chhabra, president and CEO of Proteostasis.

In general the different modulators were well-tolerated, and no serious adverse reactions were reported during the trial, with most being mild to moderate in severity.

The company is currently recruiting participants for an additional study group who will be treated with 400 mg of PTI-801 and 300 mg of PTI-808. More information on locations and contacts is available here.

A broad analysis of all data collected from double and triple combination 14-day clinical trials revealed a strong relationship between sweat chloride and ppFEVimprovements with the treatment doses. Data suggests that the best doublet combination backbone might be 600 mg of PTI-801 and 300 mg of PTI-808.

Proteostasis plans to further study these identified doses of the CFTR modulators, with and without PTI-428, in three new Phase 2 trials. These studies will enroll CF patients with at least one F508del mutation who will receive either placebo, triple or double CFTR modulator combinations for 28 days. These trials are expected to complete enrollment by the end of 2019.

The company also anticipates starting Phase 3 trials for its CFTR modulators by mid-2020.

“We look forward to understanding the full potential of these molecules in longer duration studies,” Taylor-Cousar said.

Proteostasis’ CFTR modulators as add-on therapy

The company is currently exploring the role of PTI-801 and PTI-428 in combination with other CF therapies, including Vertex’s Symdeko (tezacaftor/ivacaftor), in two other studies: a Phase 1 trial with PTI-801 (NCT03140527) and a Phase 2 trial with PTI-428 (NCT03591094).

These studies have enrolled 18 CF patients who received either PTI-801 (400 mg) or placebo for 14 days, and 38 patients who were treated with PTI-428 (10 or 30 mg) or a placebo for 28 days.

Analysis of patients’ clinical records while taking Symdeko alone revealed that they had experienced an average decline in ppFEV1 of three points. About a third of these patients also had at least three pulmonary exacerbations during the previous year.

Although these patients were, to some extent, considered CFTR modulator non-responders, they had an average sweat chloride reduction of 20 millimoles, compared with before treatment, when treated with Symdeko plus PTI-801. But no significant changes in ppFEV1 after 14 days of treatment were reported.

Consistent with the mode of action of PTI-428, patients treated with both tested doses (10 mg and 30 mg) had about a 50% increase in the amount of CFTR protein during the 28 days of treatment. But similar to PTI-801 add-on results, PTI-428-treated patients did not show statistically significant improvements in ppFEV1 at the end of the treatment.