Insmed's TPIP Shows Durable PAH Benefits in 12-Month Study

Key Points

• Insmed said 12-month data from its TPIP open-label extension in pulmonary arterial hypertension showed sustained improvements in key efficacy measures, including six-minute walk distance, NT-proBNP, functional class and REVEAL Lite 2.0 risk scores.
• The study suggested TPIP was generally well tolerated, with no new safety signals; most adverse events were mild or moderate, and patients titrated to higher doses did not appear to face major additional safety issues.
• Management said the results support TPIP’s potential as a once-daily prostacyclin option, while Phase III trials in PAH and other lung diseases continue to advance, with more long-term data expected next year.

Insmed NASDAQ: INSM reported 12-month results from an ongoing open-label extension study of TPIP in patients with pulmonary arterial hypertension, saying the data showed sustained efficacy measures and a generally favorable safety profile over longer-term use.

TPIP is an inhaled prodrug of treprostinil being developed for PAH and other pulmonary conditions. Will Lewis, Insmed’s chair and chief executive officer, said the results “continue to validate” the company’s view of TPIP’s potential in PAH. He said TPIP was designed to address efficacy, safety and convenience challenges in prostacyclin therapy, including once-daily dosing and slow conversion to active drug in the lung.

Open-Label Extension Followed Phase IIb Study

Gene Sullivan, Insmed’s chief product strategy officer, said the open-label extension is a 24-month study that allowed patients who previously received TPIP to continue therapy and patients who previously received placebo to cross over to TPIP. Investigators were permitted to titrate patients up to 1,280 micrograms, double the maximum dose allowed in the prior Phase II study.

Sullivan said the primary endpoint of the extension study is safety and tolerability during long-term use. Secondary efficacy endpoints include change from baseline in six-minute walk distance, NT-proBNP, WHO functional class and REVEAL Lite 2.0 score, a validated measure associated with morbidity and mortality risk in PAH patients.

The open-label extension enrolled 91 patients, including patients from a randomized Phase IIb placebo-controlled trial and one patient from a separate single-dose PVR monitoring study. Sullivan said 83 patients, or 91%, completed at least 12 months of treatment in the extension. Eight patients discontinued: four due to death, none considered study drug-related; three due to an adverse event; and one who was lost to follow-up.

Company Reports Sustained Functional and Biomarker Improvements

Lewis said patients who had received TPIP in the prior randomized trial sustained improvements in six-minute walk distance and NT-proBNP through 12 months of the extension. Patients who crossed over from placebo to TPIP showed improvements in six-minute walk distance, NT-proBNP, functional class and REVEAL Lite 2.0 risk scores that “caught up” with the continued TPIP group by month 12, according to the company.

Sullivan said both groups showed roughly a 55-meter improvement in six-minute walk distance from baseline by month 12. He also said both groups showed approximately 60% reductions from baseline in NT-proBNP at months six and 12.

On WHO functional class, Sullivan said all patients were in functional class 2 or 3 at baseline. By month 12 of the extension, more than 25% of patients in both groups had achieved functional class 1 status, and 80% of patients in both groups reached either functional class 1 or 2. He said 50% of patients in the continued TPIP group and 42% of patients in the placebo crossover group had at least a one-category improvement in functional class by month 12.

Risk Scores Declined During Treatment

Sullivan said both the continued TPIP and placebo crossover groups began the randomized trial with average REVEAL Lite 2.0 scores in the intermediate-risk range. By six months in the open-label extension, the mean score in both groups had dropped below 4, which Sullivan described as the refined low-risk category.

He said patients in the continued TPIP group had an average improvement of about 2 points in REVEAL Lite 2.0 score, while patients in the placebo crossover group improved by about 1.4 points. Sullivan also said 65% of patients in both groups reached the refined low-risk category by month 12 of the extension.

Raymond Benza, the George M. and Linda H. Kaufman Academic Chair of Cardiology at Sentara Health, said the results gave “genuine reason for optimism” in PAH. He said the reductions in pulmonary vascular resistance and improvements in six-minute walk distance seen in the prior Phase IIb study were within ranges clinicians consider meaningful, and he called the REVEAL risk score reductions notable. Benza also said that if TPIP is approved and the data are reproduced, the drug could change his clinical practice.

Safety Profile and Higher-Dose Use

Sullivan said TPIP was generally safe and well tolerated, with no new safety signals identified. He said 89% of patients experienced a treatment-emergent adverse event, most of which were mild or moderate. Serious adverse events occurred in 19% of patients, with one serious adverse event considered related to study drug: a case of orthostatic hypotension that did not lead to discontinuation or dose reduction.

The most common events in the extension were headache, cough, nasopharyngitis and diarrhea. Sullivan said all treatment-emergent adverse events of cough were mild or moderate, with more than 85% classified as mild.

Among patients titrated to doses greater than 640 micrograms, Sullivan said there were no deaths or treatment-emergent adverse events leading to discontinuation. He said 10.5% of those patients experienced a serious adverse event, compared with 18.7% overall, and one patient experienced mild cough. During the question-and-answer session, Martina Flammer, Insmed’s chief medical officer, said three participants reached 1,280 micrograms before month 12 and none required a dose reduction.

Phase III Program Continues

Lewis said Insmed’s Phase III study in pulmonary hypertension associated with interstitial lung disease began in December and is progressing. He said the Phase III PAH study opened its first trial site in April and sites are now screening patients. The company also plans a Phase III study in progressive pulmonary fibrosis later this year and expects a Phase III study in idiopathic pulmonary fibrosis to begin in the first half of next year.

Lewis said the current open-label extension remains ongoing, with 24-month data expected “around this time next year.” During the Q&A session, he said PAH Phase III enrollment was ahead of schedule and that the company had not changed its Phase III assumptions based on the 12-month extension results.

Sullivan cautioned that comparisons across trials require care because of differences in patient populations, trial designs and endpoint timing. However, he said the totality of TPIP’s data to date supports the company’s view that it could become a significant prostanoid option if future clinical and regulatory milestones are successful.

About Insmed NASDAQ: INSM

Insmed Incorporated is a biopharmaceutical company focused on developing and commercializing therapies for patients with rare and serious diseases, with a particular emphasis on difficult-to-treat pulmonary infections. Headquartered in Bridgewater, New Jersey, the company concentrates its research and development efforts on targeted drug delivery technologies and novel formulations intended to improve clinical outcomes for patients who have limited treatment options.

The company's principal marketed product is ARIKAYCE (amikacin liposome inhalation suspension), an inhaled liposomal formulation of the antibiotic amikacin that is approved by the U.S.

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