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A Phase 2b, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension

A Randomized, Double-Blind, Placebo-Controlled Study of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Arterial Hypertension

102

Across the two treatment groups, the majority of participants were female [84 (82.4%)]. Overall, participant's ages ranged from 19 to 74 years, with a mean (standard deviation) age of 47.7 (15.0) years. The majority of participants were White [62 (60.8%)]. Demographic and Baseline characteristics were generally similar between treatment groups.

A total of 165 participants were screened for this study. Of which, 102 participants were randomized (69 in the Treprostinil Palmitil Inhalation Powder group and 33 in the Placebo group) and received either of the treatments, and 95 participants completed the study. A total of 7 participants from the Treprostinil Palmitil Inhalation Powder group discontinued the study.

Of the 102 participants who were randomized and received at least one dose of TPIP or placebo, 61 (88.41%) participants in the TPIP group and 25 (75.76%) participants in the placebo group experienced at least one treatment-emergent adverse event (TEAE). Serious TEAEs were reported in 5 participants (7.25%) in the TPIP group and 1 participant (3.03%) in the placebo group. The serious adverse events (SAEs) reported were tachyarrhythmia, increased transaminases, rhabdomyolysis, transient ischaemic attack, and chronic bronchitis in TPIP group and right ventricular failure in placebo group. No deaths occurred during the study. The most commonly reported TEAEs (occurring in greater than or equal to 5% participants in either group) and at a higher incidence in the TPIP group were cough, headache, fatigue, chest discomfort, flushing, upper respiratory tract infection, and non-cardiac chest pain.

Primary Endpoints Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 The mean (standard deviation [SD]) for baseline visit was 9.588 (5.0072) wood units (WU) in TPIP group and 11.069 (5.9400) WU in placebo group. The mean (SD) change from baseline at Week 16 was -3.386 (4.1230) WU in TPIP group and -1.050 (4.2161) WU in placebo group. Comparison was tested at a two-sided 0.05-level of significance. There was a statistically significant placebo-adjusted 35% reduction in PVR in the TPIP group compared with the placebo group at Week 16, with a placebo-adjusted LS mean ratio to Baseline of 0.65 (95% CI; 0.54, 0.79, p less than 0.001). Analysis was performed using an ANCOVA model, adjusting for treatment group, baseline PVR, and randomization stratification factors. The model was applied to log-transformed PVR values, which were then back-transformed to the original scale. Secondary Endpoints Change from Baseline in 6-Minute Walk Test (6MWT) Distance at Week 5, Week 10 and Week 16 The mean (SD) for baseline visit was 348.48 (79.791) meters (m) in TPIP group and 371.06 (60.571) m in placebo group. The mean (SD) change from baseline in 6MWD in TPIP and placebo groups, respectively, was 36.37 (47.628) m and 12.28 (48.292) m at Week 5, 39.95 (59.279) m and 22.70 (50.076) m at Week 10, and 49.71 (66.197) m and 11.55 (65.167) m at Week 16. Change From Baseline in the Concentration of N-Terminal-Pro Hormone Brain Natriuretic Peptide (NT-proBNP) Levels at Week 5, Week 10 and Week 16 The mean (SD) for baseline visit was 785.58 (1172.386) picogram per millilitre (pg/mL) in TPIP group and 798.91 (1010.052) pg/mL in placebo group. The mean (SD) change from baseline in NT-proBNP levels for the TPIP and placebo groups, respectively, was -354.43 (763.012) pg/mL and -64.64 (444.935) pg/mL at Week 5; -457.71 (910.590) pg/mL and 282.88 (1666.108) pg/mL at Week 10; and -432.52 (867.538) pg/mL and 381.23 (1867.584) pg/mL at Week 16. Percentage of Participants Who Experienced Atleast one Treatment-emergent Adverse Event (TEAEs) At least one TEAE was reported in 88.4% of participants in the TPIP group and 75.8% of participants in the placebo group. Pharmacokinetics of TPIP and treprostinil (TRE) On Day 1, following a single dose of 80 micrograms TPIP, median Tmax of treprostinil palmitil (TP) was achieved in 0.98 hours. The geometric mean (geometric coefficient of variation [CV%]) of Cmax and AUClast were 13.98 (20.8%) pg/mL and 11.91 (118.4%) picograms*hours per millilitre (pg*h/mL), with no participants analyzed in higher-dose groups. At Week 10, following 160 micrograms to 640 micrograms TPIP, the median Tmax was reached between 0.47 to 5.53 hours. The geometric mean (geometric CV%) of Cmax and AUClast were observed to range from 11.50 (NA%) to 39.96 (68.2%) pg/mL and 36.69 (NA%) to 139.0 (66.7%) (pg*h/mL) respectively. Geometric CV% was not estimable in dose groups with a single participant. On Day 1, following a single dose of 80 micrograms TPIP, median Tmax of TRE was achieved in 2.00 hours. The geometric mean (geometric CV%) of Cmax and AUClast were 64.84 (67.8%) pg/mL and 187.1 (66.3%) (pg*h/mL), with no participants analyzed in higher-dose groups. At Week 10, following 80 micrograms to 640 micrograms TPIP, the median Tmax was reached between 0.98 h to 2.07 hours. The geometric mean (geometric CV%) of Cmax and AUClast were observed to range from 64.90 (NA%) to 1070 (NA%) pg/mL and 75.45 (NA%) to 2686 (66.0%) (pg*h/mL) respectively. Geometric CV% was not estimable in dose groups with a single participant.

TPIP was generally safe & well tolerated in participants with PAH over treatment period. No additional/new safety concerns were identified in connection with use of inhaled TPIP in participants with PAH. It showed statistically significant placebo-adjusted 35% reduction from baseline in PVR at Week 16. Hemodynamic improvements were reflected by an early & meaningful reduction in NT-pro-BNP. Importantly, there was clinically meaningful 35.49 m placebo-adjusted improvement in 6MWD from Baseline at Week 16.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071220033

F Ismat

Insmed Incorporated

700 US Highway 202/206 Bridgewater, NJ 08807-1704

medicalinformation@insmed.com

Medical Information Center

Insmed Godo Kaisha

13th Floor, 2-10-3 Nagata-cho, Chiyoda-ku Tokyo

+81-120-118808

medicalinformation@insmed.com

Complete

Aug. 02, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Participants must be greater than or equal to 18 to less than or equal to 75 years at the time of signing the informed consent form (ICF).
2. Participants must have a diagnosis of World Health Organization (WHO) Group 1 Pulmonary Hypertension (PH) [pulmonary arterial hypertension (PAH)] in any of the following subtypes idiopathic, heritable, drug or toxin-induced or connective tissue disease (CTD) associated pulmonary arterial hypertension (PAH), Congenital heart disease-related with simple systemic-to-pulmonary shunt at least 1 year following repair.
3. PAH diagnosis for at least 3 months.
4. Participants must be on stable pulmonary hypertension (PH) therapy consisting of up to 2 medications from the following classes
- Endothelin receptor antagonists (eg. ambrisentan, bosentan, macitentan)
- Phosphodiesterase type 5 inhibitors (eg. sildenafil, tadalafil)
- Guanylate cyclase stimulator (eg. riociguat)
5. No change in PH medications (eg. ambrisentan, bosentan, macitentan, sildenafil, tadalafil, riociguat) or dosage for at least 30 days prior to Screening.
6. No change in long-term diuretic use or dosage for at least 30 days prior to Screening.
7. Body mass index (BMI) within the range of 18.0-37.0 kg per meter square (inclusive).
8. Male participants who are not sterile, and have female partners of childbearing potential, must be using effective contraception from Day 1 to at least 90 days after the last dose of study drug.
9. Women must be postmenopausal (defined as no menses for 12 months without an alternative medical cause), surgically sterile, (ie, post-tubal ligation for at least 12 months) or using highly effective contraception methods (ie, methods that alone or in combination achieve less than 1 percent unintended pregnancy rates per year when used consistently and correctly) from Day 1 to at least 90 days after the last dose of study drug.
10. Male participants: Male participants with pregnant or non-pregnant woman of childbearing potential partner must use a condom in order to avoid potential exposure to embryo or fetus.
11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

1. History of PH other than idiopathic, hereditary, drug/toxin-induced, repaired simple congenital heart disease, or CTD-associated PAH (eg, complex, congenital heart disease-associated PAH, portal hypertension-associated PAH, PH belonging to Groups 2 through 5).
2. Allergy, or documented hypersensitivity or contraindication, to TPIP or Treprostinil (TRE) or mannitol (an excipient of the TPIP formulation).
3. Any known ventricular or supraventricular tachyarrhythmia except for paroxysmal atrial fibrillation and any symptomatic bradycardia.
4. History of heart disease including left ventricular ejection fraction (LVEF) less than or equal to 40% or clinically significant valvular, constrictive, or symptomatic atherosclerotic heart disease (eg, stable angina, myocardial infarction, etc).
5. Participation in a cardio-pulmonary rehabilitation program within 1 month of Screening Visit.
6. Evidence of thromboembolic disease as assessed by ventilation-perfusion (VQ) scan, pulmonary angiography, or pulmonary computerized tomography (CT) scan.
7. Active liver disease or hepatic dysfunction.
8. History of HIV infection.
9. Established diagnosis of hepatitis B viral infection, or positive for hepatitis B surface antigen (HBsAg) at the time of Screening.
10. Established diagnosis of hepatitis C viral infection at the time of screening.
11. Active and current symptomatic coronavirus disease 2019 (COVID-19) or previous severe disease and/or hospitalization due to COVID-19.
12. Use of live attenuated vaccines within 30 days of the Screening Visit.
13. Participants with Down Syndrome.
14. History of abnormal bleeding or bruising.
15. History of solid organ transplantation.
16. Known or suspected immunodeficiency disorder, including history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged infections suggesting an immune-compromised status, as judged by the Investigator.
17. History of alcohol or drug abuse within 6 months prior to Screening.
18. Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6-mintute walk test (eg, angina pectoris, claudication, musculoskeletal disorder, need for walking aids).
19. Participants with current or recent (past 30 days) lower respiratory tract infection.
20. History of malignancy in the past 5 years, with exception of completely treated in situ carcinoma of the cervix and completely treated non-metastatic squamous or basal cell
carcinoma of the skin.
21. Change in PH medication (endothelin receptor agonists, phosphoesterase type 5 inhibitors, and guanylate cyclase stimulators or diuretics) between Screening and Baseline.
22. Have participated in any other interventional clinical studies within 30 days prior to Screening.
23. Current use of cigarettes (as defined by Centers for Disease Control [CDC]) or e-cigarettes.
24. Participants who currently inhale marijuana (recreational or medical).
25. Pregnant or breastfeeding.

Both

Pulmonary Arterial Hypertension

Experimental: Treprostinil Palmitil Inhalational Powder
Participants will be administered TPIP once per day at a starting dose of 80 micrograms. Participants will be titrated to the highest tolerated dose for each individual participant of between 80 micrograms and 640 micrograms during the initial 3 weeks of treatment. The overall treatment period will be 16 weeks.

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

Change from Baseline in Pulmonary Vascular Resistance at Week 16

1. Change from Baseline in 6-Minute Walk Test Distance at Week 5, Week 10 and Week 16
2. Percent Change from Baseline in 6-Minute Walk Test Distance at Week 5, Week 10 and Week 16
3. Number of Participants Who Experience a Treatment-emergent Adverse Event (AE) from Day 1 up to Week 20
4. Number of Participants Who Experience a Clinically Significant Change from Baseline in Clinical Laboratory Evaluations, Vital Sign Measurements, Electrocardiogram (ECG) Measurements, Physical Examinations Over the 16-Week Treatment Period
5. Maximum Plasma Concentration (Cmax) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10, and 16: Predose and 0.5, 1, 2, 4 and 6 hours post-dose
6. Maximum Plasma Concentration (Cmax) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10, and 16: Predose and 0.5, 1, 2, 4 and 6 hours post-dose
7. Time to Maximum Plasma Concentration (Tmax) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
8. Time to Maximum Plasma Concentration (Tmax) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
9. Area Under the Concentration-time Curve from Time 0 to 24 Hours Post-Dose (AUC24) of Treprostinil Palmitil on Day 1 at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
10. Area Under the Concentration-time Curve from Time 0 to 24 Hours Post-Dose (AUC24) of Treprostinil on Day 1 at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
11. Area Under the Concentration-time Curve from Time 0 to Infinity (AUC infinity) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
12. Area Under the Concentration-time Curve from Time 0 to Infinity (AUC infinity) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
13. Area Under the Concentration-time Curve from Time 0 to Last Measurable Concentration (AUClast) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
14. Area Under the Concentration-time Curve from Time 0 to Last Measurable Concentration (AUClast) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
15. Apparent Total Clearance (CL/F) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5,10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
16. Apparent Total Clearance (CL/F) of Treprostinil on Day 1, at Weeks 2, 3, 5,10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
17. Apparent Volume of Distribution After Non-Intravenous Administration (Vd/F) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
18. Apparent Volume of Distribution After Non-Intravenous Administration (Vd/F) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
19. Elimination Half-Life (t1/2) of Treprostinil Palmitil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
20. Elimination Half-Life (t1/2) of Treprostinil on Day 1, at Weeks 2, 3, 5, 10 and 16: Predose and 0.5, 1, 2, 4, and 6 hours post-dose
21. Change from Baseline in the Concentration of N-Terminal-Pro Hormone Brain Natriuretic Peptide (NT-proBNP) Levels at Week 5, Week 10, and Week 16 or end of study.

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