Once-daily inhaled PAH treatment shows long-term benefits in study
Developer now recruiting patients in US for large, late-stage trial
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Once-daily use of Insmed‘s experimental inhaled treatment TPIP — fully, treprostinil palmitil inhalation powder — showed a range of benefits over one year in people with pulmonary arterial hypertension (PAH), a rare condition in which the blood vessels supplying the lungs become narrowed.
That’s according to new 12-month results from an ongoing open-label extension (OLE) study evaluating the therapy’s long-term safety, tolerability, and effectiveness. The PAH treatment candidate was found to improve exercise capacity and heart function among patients, while easing their disease severity.
The positive findings from the OLE study (NCT05649748), which involved people with PAH who had completed earlier TPIP clinical trials, support both the therapy’s continued development and the recent launch of a late-stage trial now recruiting in two U.S. states, Insmed said in a company press release providing program updates.
“These data from our ongoing OLE study with TPIP represent an important milestone in our efforts to fully harness the potential of treprostinil and provide meaningful benefit to patients with pulmonary arterial hypertension,” said Gene Sullivan, MD, chief product strategy officer of Insmed. “In this analysis, TPIP demonstrated sustained improvement across all efficacy endpoints [goals] and was well tolerated with no newly identified safety signals.”
The new Phase 3 trial, dubbed PALM-PAH (NCT07481981), will evaluate the daily therapy versus a placebo in more than 300 adults with PAH. It’s now recruiting participants ages 18 to 75 at sites in California and South Carolina.
According to Sullivan, the new OLE data, “coupled with the statistically significant and clinically meaningful results from our [earlier] randomized study, demonstrate TPIP’s potential to become the prostanoid of choice for PAH patients, and we remain excited to be advancing our Phase 3 PALM-PAH study.”
In PAH, narrowed blood vessels force the heart to work harder to pump blood. Over time, this can lead to worsening of symptoms such as shortness of breath, fatigue, and reduced exercise capacity, and eventually result in heart failure.
TPIP, formerly known as INS1009, is an investigational dry-powder formulation of treprostinil palmitil, an inactive precursor of the vasodilator treprostinil. After inhalation, treprostinil palmitil is converted into treprostinil in the lungs, where it relaxes blood vessels and helps lower blood pressure. Unlike other treprostinil-based medications — such as Orenitram (oral treprostinil) and Tyvaso (inhaled treprostinil) — that require multiple doses each day, TPIP allows once-daily dosing.
The OLE is testing TPIP over 24 months, or two years, in individuals who took part in earlier trials, including a Phase 2b study (NCT05147805). Importantly, according to Sullivan, “patients who switched from [the] placebo to TPIP in the OLE study achieved similar clinical benefit.”
TPIP shown to improve heart function, exercise capacity
Clinical improvements had previously been seen among participants given TPIP versus a placebo in the Phase 2b study, which involved 102 adults with PAH.
Top-line results from that 16-week trial showed reduced pulmonary vascular resistance (PVR) — a measure of how hard it is for blood to flow through the lungs — by 35% for participants receiving the treatment compared with those on the placebo. With those findings, the trial met its main goal, or endpoint, the developer noted.
The therapy also improved exercise capacity, increasing six-minute walking distance by a mean of 35.5 meters (116.5 feet), and reduced NT-proBNP, a marker of heart stress, by 60%. It was also generally well tolerated. These findings paved the way for the ongoing Phase 3 PALM-PAH trial, according to Insmed.
Nearly all patients (95%) who completed the Phase 2b trial enrolled in the ongoing OLE study.
After 12 months, participants who received TPIP throughout the earlier studies improved the distance they could walk in six minutes by a mean of 55.7 meters (182.7 feet). Those who switched from the placebo to TPIP walked a mean of 54.1 meters (177.5 feet) farther since the start of the OLE study.
NT-proBNP levels were reduced by approximately 60% in both groups. By 12 months, 78% of participants who had received TPIP throughout the earlier studies and 81% of those who switched from the placebo had reached World Health Organization (WHO) functional class I or II, indicating no or only mild limitations in physical activity, according to the developer.
Sustained improvements of this magnitude, alongside gains in exercise capacity and Functional Class, provide a strong clinical rationale to advance this therapy into Phase 3 development.
Mean REVEAL Lite 2.0 scores, which are used to estimate the risk of death or clinical worsening in PAH, improved by two points in participants who received TPIP throughout the earlier studies and by 1.4 points in those who switched from the placebo. Overall, about 65% of patients achieved Refined Low Risk status, which is associated with an estimated risk of death lower than 5% at three years and about a 7% risk of clinical worsening within one year.
Once-daily TPIP continued to be generally well tolerated, with no new safety signals identified. The most commonly reported side effects were headache, cough, and inflammation of the nose and throat (nasopharyngitis). Four patients died during the study, but according to Insmed, none of the deaths were related to TPIP.
“Pulmonary arterial hypertension is one of the most devastating diseases we face as clinicians, and these results from the ongoing TPIP OLE study give us genuine reason for optimism,” said Raymond Benza, MD, a member of the Phase 2b study’s steering committee, and academic chair of cardiology at Sentara Health.
“Sustained improvements of this magnitude, alongside gains in exercise capacity and Functional Class, provide a strong clinical rationale to advance this therapy into Phase 3 development,” Benza added.
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