Pulmonary Arterial Hypertension

September 14, 2015

Gilead Sciences issued results of a phase III/IV study of first-line combination therapy Letairis and tadalafil to monotherapy (Letairis or tadalafil) in patients with WHO/ NYHA functional class II and III pulmonary arterial hypertension (PAH). The multicenter, randomized, double-blind study enrolled 500 patients randomized (2:1:1) to receive Letairis and tadalafil (n=253) or monotherapy with Letairis (n=126) or tadalafil (n=121) (titrated from 5mg to 10mg once-daily and from 20mg to 40mg once-daily for Letairis and tadalafil, respectively). The treatment effect for the composite primary endpoint of time to clinical failure was driven mainly by a reduced number of hospitalizations due to PAH, with a reduced risk of hospitalization due to PAH of 63% (hazard ratio=0.37; 95% CI: 0.22, 0.64; p<0.001). Consistently favorable reductions in clinical failure events were observed based on etiology, WHO functional class, age, geographical area and gender. The predefined subgroup analysis of the primary endpoint suggested that patients with WHO functional class II (n=155; hazard ratio=0.21; 95% CI: 0.07, 0.63); p=0.005) responded even more positively than patients with WHO functional class III (n=345; hazard ratio=0.58; 95% CI: 0.39, 0.86; p=0.006). Statistically significant improvements also were observed with the following secondary endpoints v. the pooled monotherapy arm: change from baseline at week 24 in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (-67% v. -50%; p<0.001), percentage of patients with satisfactory clinical response at week 24 (39% v. 29%; odds ratio 1.56; p=0.03) and median change from baseline to week 24 in six-minute walk distance (6MWD) (49 meters v. 24 meters; p<0.001). There was no difference between treatment groups in the change from baseline to week 24 for WHO functional class. Letairis is indicated in the U.S. to improve exercise ability and delay clinical worsening and in the E.U. under the tradename Volibris to improve exercise capacity. Tadalafil 40mg is indicated in the U.S. and the E.U. to improve exercise ability and capacity, respectively.

September 15, 2014

Mast Therapeutics reported results from a phase II study of AIR001 (sodium nitrite) inhalation solution for pulmonary arterial hypertension (PAH). The multi-center, open-label, randomized, parallel-dose study randomized subjects into one of three treatment arms and treated with AIR001 for 16 weeks: 80mg once daily after a two-week “run-in” period of 46mg once daily; 46mg four times daily after a two-week run-in period of 46mg four times daily; or 80mg four times daily after a two-week run-in period of 46mg four times daily. The study enrolled 29 patients. All doses showed improvement in median pulmonary vascular resistance (PVR). In the secondary efficacy analysis, all doses showed improvements in the median distances obtained in the six-minute walk test, including clinically meaningful improvements at the highest dose level. AIR001 was well-tolerated, with no treatment-related serious adverse events. In particular, methemoglobin levels remained normal (<1.5%), which distinguishes AIR001 from safety concerns associated with intravenously administered nitrite. AIR001 has been granted Orphan Drug status by the FDA and the EMA for the treatment of PAH. The company will proceed with phase IIa studies and anticipates reporting preliminary study results as early as the second half of 2015.

October 29, 2012

Bayer HealthCare released data from a phase III trial of riociguat for pulmonary arterial hypertension (PAH). This randomized, double-blind, placebo-controlled, multinational study enrolled 445 patients with symptomatic PAH. Subjects received titrated doses of riociguat three times daily in increments of 0.5mg, with doses as low as 1.0mg and as high as 2.5mg, over eight weeks, followed by a four-week follow-up period. The study met its primary endpoint by demonstrating a statistically significant improvement in the six-minute walk distance (6MWD) with patients treated with riociguat showing an improvement of 36 meters 95%-CI [20-52 meters] (p<0.0001) after 12 weeks compared with placebo. Results also showed a statistically significant improvement in 6MWD, both in the treatment-naive patient group (38 meters after 12 weeks compared with placebo [95%-CI 15-62 meters]) and the pre-treated patient group (36 meters after 12 weeks compared with placebo [95%-CI 15-56 meters]). The drug was well tolerated.

May 7, 2012

Actelion Pharmaceuticals reported results from a long-term phase III trial of macitentan, a novel dual endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension. This multinational, multi-center, event-driven study, SERAPHIN, enrolled 742 patients. Subjects received macitentan 3mg, 10mg or placebo for up to three and a half years. The trial met a primary endpoint of decreasing the risk of a morbidity/mortality event over the treatment period, with the 3mg dose reducing risk by 30% (p≡0.0108) and the 10mg dose reducing risk by 45% (p<0.0001). The drug was well tolerated. The most frequent adverse events were elevations in liver alanine or aspartate aminotransferases and a decrease in hemoglobin. Based on these data, Actelion plans to submit the registration dossier to Health Authorities world-wide in the fourth quarter of 2012.

June 13, 2011

United Therapeutics released results from a phase III study of treprostinil for pulmonary arterial hypertension (PAH). This 12-week, multi-center, international, double-blind, randomized, placebo-controlled study, FREEDOM-M, enrolled 349 subjects not receiving any other approved PAH therapy. The subjects received oral treprostinil (0.25 mg) or placebo twice daily, with the doses titrated to effect over the course of the 12-week trial. The primary endpoint of the trial was change in six-minute walk distance at Week 12. These results are from 228 evaluable subjects. The subjects receiving oral treprostinil improved their median 6MWD by approximately 23 meters as compared to subjects receiving placebo (p≡0.0125). The median change from baseline was 25 meters for oral treprostinil and -5 meters for placebo at week 12.

June 1, 2009

Gilead released positive results from a phase III trial of ambrisentan for the treatment of pulmonary hypertension. This open-label, single-arm study, dubbed ARIES-3, enrolled 224 subjects with pulmonary hypertension due to a variety of etiologies. The subjects received ambrisentan at a dose of 5 mg once daily for 24 weeks. The primary endpoint was the change from baseline in six-minute walk distance (6MWD) at Week 24. In the overall study population, subjects experienced a mean 6MWD improvement of 21 meters (11.8 to 29.3; p<0.001) from baseline at 24 weeks. At the end of treatment, 97% of subjects were still alive. The probability of no clinical worsening at 24 weeks across the population was 90%. Treatment was generally well tolerated.

November 12, 2007

United Therapeutics and Lung Rx released positive results from a phase III trial of Viveta for the treatment of pulmonary arterial hypertension (PAH). This randomized, double-blind, placebo-controlled study, dubbed TRIUMPH-1 (TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension), enrolled 235 subjects who were optimized on an approved oral therapy for PAH, either bosentan or sildenafi. In addition to one of these therapies, the subjects received placebo or Viveta, inhaled four times a day, with a maximum dose of 45 micrograms per session over the course of the twelve-week trial. The primary efficacy endpoint was the change in the six-minute walk test (6MW) at twelve weeks measured at peak exposure, defined as ten to sixty minutes after inhalation of Viveta, over baseline. Results showed that the subjects receiving Viveta demonstrated an improvement in median 6MW distance by approximately 20 meters (p<0.0006) over placebo. The trough exposure, defined as a minimum of four hours after inhalation of Viveta, for treatment change in 6MW distance at week twelve relative to baseline was also significantly improved, with an increase in median 6MW distance of approximately 14 meters (p<0.01). In addition, the 6MW distance at week six relative to baseline was significantly improved, with an increase in median 6MW distance of approximately 18 meters (p<0.0005). Analysis of other secondary data, including change in Borg Dyspnea Scale rating scale, NYHA functional class, time to clinical worsening and the 6MW distance at treatment day one, did not differ significantly between the Viveta and placebo groups (p>0.05). Treatment was determined to be safe and well tolerated. Based on the results, the companies plan to file for regulatory approval.

August 13, 2007

Epix announced positive results from a phase IIa trial of PRX-08066 for the treatment of pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD). This randomized, double-blind, placebo-controlled trial enrolled 71 subjects who received 200 mg of PRX-08066 once-daily; 400 mg of PRX-08066 once-daily or placebo. This two week double-blind phase was followed by an open-label extension phase in which 10 subjects received 200 mg of PRX-08066 daily for six weeks. A statistically significant dose response was observed in the decrease of 4mmHg or more in post-exercise systolic pulmonary artery pressure (SPAP) (p=0.036). In the 400 mg dose group, 45% of the subjects had a reduction in post-exercise SPAP of 4mmHg or more versus 14% on placebo (p=0.043). The median reductions were 1.1 mmHg and 3.37 mmHg in the 200 mg and 400 mg dose groups, respectively, compared with no change on placebo (p=0.08 for high dose versus placebo). Treatment was well tolerated and no effect on systemic blood pressure was observed. Based on the results Epix plans to advance PRX-08066 into further trials.

June 25, 2007

Cytos released positive top-line results from a phase I/IIa trial of CYT-006 for the treatment of hypertension, at the 17th European Meeting on Hypertension. This randomized, double-blind and placebo-controlled trial enrolled 72 subjects with mild to moderate hypertension. Subjects were randomized into two arms to receive one of two doses of the vaccine or placebo administered via 3 subcutaneous injections at week 0, 4 and 12. Efficacy on systolic and diastolic blood pressure was assessed by 24-hour ambulatory blood pressure monitoring at baseline and post-treatment. All subjects who received the vaccine showed a strong antibody response on the first injection which was boosted by the subsequent injections. CYT-006 showed strong efficacy in the early morning hours. The early morning rise of blood pressure starting at 5 am was suppressed by the vaccine, leading at 8 am to a change from baseline of the blood pressure of - 25 / - 13 mm Hg compared to placebo (SBP / DBP, p<0.0001 / p=0.0035). This suppression of early morning rise blood pressure was associated with an exceptionally low increase in plasma renin concentration (PRC) from a mean renin concentration of 5.1 pg/ml at baseline to 6.3 pg/ml at week 14 (p=0.02). The induced anti-angiotensin antibody levels were significantly higher at the 300 microgram than at the 100 microgram dose (p=0.0098). Blood pressure reduction was much larger and only significant at the 300 microgram dose (p=0.0498). Based on the results Cytos plans to move forward with the development of CYT-006.

April 24, 2006

Predix reported positive preliminary results of a phase Ib trial of PRX-08066, for the treatment of hypoxia-induced pulmonary hypertension. Results from the study yielded preliminary evidence of efficacy, with PRX-08066 administration yielding reductions in systolic pulmonary blood pressure during both resting and exercise hypoxia conditions; this corresponded to a statistically significant 40% relative reduction in hypoxia-induced increase in pulmonary blood pressure compared to placebo. This randomized, double-blind, three-period crossover study enrolled 15 healthy adult subjects, who received oral doses of 200 mg of the drug or placebo twice daily for 3 days per treatment period, with a 2 week washout between cycles.

September 19, 2005

Encysive Pharmaceuticals issued preliminary results of their phase III STRIDE-2X trial, investigating Thelin (sitaxsentan) for the treatment of pulmonary arterial hypertension (PAH). Top-line data yielded several indications of efficacy: mean exposure time was higher in patients receiving Thelin than bosentan (45 vs. 43 weeks; p<0.01), due to a higher discontinuation rate for bosentan (21% vs. 37%; p<0.01);median six minute walk distance for Thelin demonstrated non-inferiority (p>0.8); fewer patients receiving Thelin experienced clinical worsening at 12 months (20% vs. 30%; p=0.03); time to WHO-functional class improvement was also non- inferior (p>0.01); and liver function abnormalities occurred in significantly fewer Thelin patients than with bosentan (4% vs. 14%; p=0.01). This open-label extension study enrolled 229 PAH patients, who received 100 mg Thelin (n=145) or an approved dose of bosentan (n=84) for 12 months.

October 28, 2002

ICOS-Texas Biotechnology reported some favorable results from a phase IIa/III clinical trial investigating sitaxsentan, an endothelin receptor. The 12-week, double blind, placebo-controlled trial was designed to assess the safety and efficacy of sitaxsentan in subjects with pulmonary arterial hypertension (PAH). The study utilized 178 subjects who were randomized to sitaxsentan 100 mg, sitaxsentan 300 mg, or placebo treatment once a day. The primary endpoint, a change in percent of predicted peak VO2 from baseline to week 12 was shown to be statistically significant for improvement in the 300 mg group compared to placebo. The primary end point was not shown to be statistically significant for the 100 mg dose group. Two other secondary endpoints, a greater six-minute walk distance and a NYHA class improvement were found to be statistically significant in both treatment groups. Incidences of liver abnormalities in this trial, combined with an extension study, were shown to be 5% for the sitaxsentan 100 mg dose group and 21% for the 300 mg dose group. The most frequent adverse events that occurred in subjects receiving sitaxsentan were headache, peripheral edema, nausea, nasal congestion and prolonged clotting time, and were more common than in placebo-treated subjects.