Treprostinil Palmitil for Pulmonary Arterial Hypertension

No longer recruiting at 115 trial locations

Overseen By Insmed Medical Information

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Insmed Incorporated

Must be taking: Endothelin antagonists, PDE5 inhibitors

Disqualifiers: Heart disease, Liver disease, HIV, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new inhalation powder treatment, treprostinil palmitil, designed to reduce resistance in the blood vessels of the lungs. It targets individuals with pulmonary arterial hypertension (PAH), characterized by high blood pressure in the lung arteries. Participants will receive either the trial treatment or a placebo to assess effectiveness. Suitable candidates have had a PAH diagnosis for at least three months and are on stable medication for the condition. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important early-stage findings.

Do I have to stop taking my current medications?

The trial requires participants to stay on their current pulmonary hypertension medications, which can include up to two drugs from specific classes like endothelin receptor antagonists, phosphoesterase type 5 inhibitors, or guanylate cyclase stimulators. There should be no change in these medications or their dosages for at least 30 days before the screening.

Is there any evidence suggesting that treprostinil palmitil is likely to be safe for humans?

Research shows that treprostinil palmitil, used as an inhalation powder, is generally well-tolerated by people with pulmonary arterial hypertension (PAH). This medication helps widen blood vessels. Studies have found that the inhaled form is designed to remain in the lungs longer, potentially reducing the drug's spread to the rest of the body. This could result in fewer side effects compared to other forms of the medication.

In earlier studies, patients using the inhaled powder reported few serious side effects. Most experienced mild issues, such as throat irritation or cough, which are common with inhaled treatments. The treatment has been used in other situations, providing additional safety information. Overall, current evidence suggests that treprostinil palmitil inhalation powder is a safe option for managing PAH, with manageable side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pulmonary arterial hypertension?

Unlike the standard treatments for pulmonary arterial hypertension, which often involve oral medications or intravenous infusions, Treprostinil Palmitil is administered as an inhalation powder. This unique delivery method allows the medication to be absorbed directly through the lungs, potentially offering faster relief with fewer systemic side effects. Researchers are excited about Treprostinil Palmitil because it could improve patient convenience and adherence by reducing the frequency and complexity of dosing. Additionally, the ability to up-titrate the dose to a patient's highest tolerated level might allow for more personalized treatment, optimizing therapeutic outcomes.

What evidence suggests that treprostinil palmitil might be an effective treatment for pulmonary arterial hypertension?

Research has shown that Treprostinil Palmitil Inhalation Powder (TPIP), which participants in this trial may receive, can effectively treat pulmonary arterial hypertension (PAH). One study found that TPIP significantly lowered resistance in lung blood vessels, a major issue in PAH. Specifically, resistance decreased to an average of 0.63 compared to 0.97 with a placebo after 16 weeks. This reduction helps the heart pump blood more easily through the lungs. Additionally, some patients experienced improvements in symptoms and overall function. These findings suggest that TPIP could be a beneficial treatment for people with PAH. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

Adults aged 18-75 with Pulmonary Arterial Hypertension (PAH) who are on stable PH therapy can join this trial. They must not smoke, have a history of certain heart diseases or infections, and women should use effective contraception. Participants need to be able to perform physical tests like walking.

Inclusion Criteria

I have been diagnosed with pulmonary arterial hypertension for over 3 months.

I've been on the same pulmonary hypertension medication for at least 30 days.

I am following the required guidelines for contraception, sterilization, or am post-menopausal.

Exclusion Criteria

I have a history of blood clots, liver disease, HIV, hepatitis B or C, or symptomatic COVID-19.

I am allergic or sensitive to certain medications.

I have a history of pulmonary hypertension, but not the specified types.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treprostinil palmitil inhalation powder or placebo once per day, with up-titration over the first 3 weeks to the highest tolerated dose, for a total of 16 weeks

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Treprostinil Palmitil

Trial Overview

The study is testing Treprostinil Palmitil inhalation powder against a placebo to see if it improves blood flow resistance in the lungs for PAH patients. The participants will either receive the actual drug or a placebo without knowing which one they're getting.

How Is the Trial Designed?

Group I: Treprostinil Palmitil Inhalation Powder Experimental Treatment 1 Intervention

Participants will be administered TPIP once per day at a starting dose of 80 micrograms (μg). Participants will be up-titrated to the highest tolerated dose for each individual participant of between 80 μg and 640 μg during the initial 3 weeks of treatment. The overall treatment period will be 16 weeks.

Group II: Placebo Placebo Group 1 Intervention

Participants will be administered a placebo matching TPIP once per day for 16 weeks.

Treprostinil Palmitil is already approved in United States, European Union for the following indications:

Approved in United States as Treprostinil palmitil for:

• Pulmonary arterial hypertension

Approved in European Union as Treprostinil palmitil for:

• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

Insmed Incorporated

Lead Sponsor

Trials

44

Recruited

7,600+

Published Research Related to This Trial

In a study using male Sprague-Dawley rats, inhaled treprostinil palmitil (TPIS) demonstrated sustained efficacy in inhibiting hypoxia-induced increases in right ventricular pulse pressure over 32 days, without evidence of tachyphylaxis, unlike continuous intravenous treprostinil (TRE) infusion which lost effectiveness after 16 days.

The lack of tachyphylaxis with TPIS is attributed to its local action in the lungs and lower plasma concentrations of TRE, suggesting that TPIS may provide a more consistent therapeutic effect for pulmonary vasodilation compared to traditional delivery methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treprostinil palmitil, an inhaled long-acting pulmonary vasodilator, does not show tachyphylaxis with daily dosing in rats. Chapman, RW., Li, Z., Chun, D., et al.[2021]

Treprostinil palmitil (TP) has been successfully reformulated into a metered-dose inhaler (MDI) that maintains the pharmacokinetic and efficacy profile of the previously used nebulized formulation, making it a more convenient option for patients.

The optimized MDI formulation, TPIA-W, shows effective drug delivery and a prolonged efficacy lasting at least 12 hours, along with a higher cough threshold compared to the original treprostinil, indicating improved tolerability and potential for once-daily use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension. Plaunt, AJ., Islam, S., Macaluso, T., et al.[2021]

Treprostinil palmitil (TP), a long-acting prodrug of treprostinil, shows promise as a nebulized inhalation treatment for pulmonary arterial hypertension (PAH), maintaining effective drug levels in the lungs while minimizing systemic side effects compared to traditional treprostinil.

In preclinical studies, TP demonstrated superior efficacy in inhibiting pulmonary vasoconstriction and showed fewer respiratory-related side effects in humans, suggesting it could be a safer and more effective alternative to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of the biology of a long-acting inhaled treprostinil prodrug. Chapman, RW., Corboz, MR., Malinin, VS., et al.[2021]

In a study of 187 patients with erectile dysfunction, both alprostadil and a combination of vasoactive intestinal polypeptide (VIP) and phentolamine were effective, with 83% of alprostadil users achieving a suitable erection compared to 73% for VIP/phentolamine.

Patients significantly preferred the VIP/phentolamine combination due to its lower incidence of pain (3% vs. 28% for alprostadil), despite both treatments being similarly effective in producing erections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Injection therapy for the treatment of erectile dysfunction: a comparison between alprostadil and a combination of vasoactive intestinal polypeptide and phentolamine mesilate. Shah, PJ., Dinsmore, W., Oakes, RA., et al.[2013]

Treprostinil palmitil inhalation powder (TPIP) was found to be well tolerated in healthy adults, with a high completion rate of 97.6% in the study, and most treatment-emergent adverse events (TEAEs) were mild, indicating a favorable safety profile for potential use in patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD).

The pharmacokinetics of TPIP showed linearity and supported a once-daily dosing regimen, with no severe or serious TEAEs reported, suggesting that TPIP could allow for higher tolerated doses compared to existing treprostinil formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder for Pulmonary Hypertension: A Phase 1, Randomized, Double-Blind, Single- and Multiple-Dose Study. Ismat, FA., Usansky, HH., Villa, R., et al.[2023]

In a study of 55 patients with erectile dysfunction due to atherosclerosis, both sildenafil and alprostadil improved penile rigidity, but only alprostadil and sildenafil significantly increased arterial penile inflow (PSV) in patients with vasculogenic impotency.

The findings suggest that alprostadil and sildenafil should be considered first-line treatments for men with vasculogenic impotency, while alprostadil is not recommended as the initial treatment for those with nonvasculogenic impotency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil citrate vs intracavernous alprostadil for patients with arteriogenic erectile dysfunction: a randomised placebo controlled study. Mancini, M., Raina, R., Agarwal, A., et al.[2016]

In a study of 115 men with erectile dysfunction, only 30% achieved sufficient erections for intercourse using the Medicated Urethral System for Erection (MUSE) at the highest dose of 1,000 microg, indicating limited efficacy compared to expectations from previous studies.

The treatment was associated with significant discomfort and adverse events, including pain and orthostatic hypotension, leading to over 80% of participants discontinuing use at home due to these side effects and the cost of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disappointing initial results with transurethral alprostadil for erectile dysfunction in a urology practice setting. Fulgham, PF., Cochran, JS., Denman, JL., et al.[2019]

In a study of 44 men aged 41 to 74 with erectile dysfunction who did not respond to sildenafil citrate, 29.5% experienced successful improvement in erectile function using intraurethral alprostadil, indicating its potential as an alternative treatment.

Among men who had previously undergone radical retropubic prostatectomy, 50% reported success with intraurethral alprostadil, suggesting it may be particularly effective for this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of intraurethral alprostadil in patients not responding to sildenafil citrate. Jaffe, JS., Antell, MR., Greenstein, M., et al.[2015]

Treprostinil palmitil (TP) inhalation powder (TPIP) shows consistent aerosol performance across various inhalation profiles, indicating its reliability for patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD).

The emitted dose of TP from the TPIP capsules remains high (79-89%) at a 60 LPM inspiratory flow rate, suggesting effective delivery to the lungs, even with reduced inspiratory volumes and varying inhalation acceleration rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Inhalation Profile on Delivery of Treprostinil Palmitil Inhalation Powder. Gauani, H., Baker, T., Li, Z., et al.[2023]

Treprostinil palmitil (TP), a long-acting inhaled pulmonary vasodilator, showed superior efficacy in reducing harmful changes in lung and heart function in a rat model of pulmonary arterial hypertension compared to inhaled and intravenous treprostinil and oral selexipag.

In a study involving male Sprague-Dawley rats subjected to a Sugen5416/hypoxia challenge, TPIP (117 μg/kg, once daily) provided greater overall benefits in inhibiting increases in pulmonary arterial pressure and other pathophysiological changes than the other treatments tested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Inhaled Treprostinil Palmitil, Inhaled and Intravenous Treprostinil, and Oral Selexipag in a Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension. Corboz, MR., Plaunt, AJ., Malinin, VS., et al.[2022]

Intraurethral alprostadil is an effective treatment for erectile dysfunction (ED) that can be used when oral PDE5 inhibitors are unsuitable, showing a fast onset of action and a good safety profile without serious side effects like priapism or fibrosis.

It is recommended to start with a 500 μg dose of intraurethral alprostadil for better efficacy, and patients generally prefer this method over intracavernosal injections due to its ease of use and positive impact on quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraurethral alprostadil for erectile dysfunction: a review of the literature. Costa, P., Potempa, AJ.[2021]

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