New Medicines

OrenitramPulmonary arterial hypertension (PAH) - oral modified-release formulation


New formulation
United Therapeutics Limited

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Nov 20United Therapeutics enters into an exclusive agreement with Ferrer to distribute Orenitram throughout the territories where it also has distribution rights for Remodulin (includes Europe plus UK). Ferrer plans to seek marketing authorisation approval in certain of these territories after conducting several registration-enabling pediatric studies of Orenitram, which are expected to be completed in 2023 [21].
Feb 20Orenitram is currently only approved in the US, but United Therapeutics is evaluating whether the FREEDOM-EV results could support marketing applications in other countries [20].
Oct 19Label amendment approved in US based on data from the PIII FREEDOM-EV trial. The new approved indication is treatment of PAH [WHO Group 1] to delay disease progression and to improve exercise capacity (previously treatment of PAH [WHO Group 1] to improve exercise capacity) [17,18].
Feb 19In its latest 10k annual report, United Therapeutics does not describe any plans to develop this product for EU markets [19].

Mar 15: The PIII FREEDOM-Ev trial is expected to be complete by end of 2016; the company aims to obtain approval for oral treprostinil in the EU following completion of the trial and no later than 2017 [12].

May 14: Treprostinil extended-release tablets launched in the US for treatment of pulmonary arterial hypertension [12].

Dec 13: The FDA has approved Orenitram (treprostinil) extended-release tablets for the treatment of PAH in WHO Group I patients to improve exercise capacity [11].

Sep 13: Refiled in the US, with a decision on approval expect Feb 14 [10].

Mar 13: The FDA has issued a second complete response letter [8]

Feb 13: US FDA has acknowledged the resubmission of the new drug application (NDA) for treprostinil diolamine for the treatment of pulmonary arterial hypertension. The FDA classified the resubmission as a complete, class 1 response to FDA´s October 23, 2012 complete response letter and the FDA set a user fee goal date of March 31, 2013. [7]

Oct 12: The FDA issued a complete response letter. The letter questioned the clinical importance of the 6 Minute Walk Distance (6MWD) effect size shown in the FREEDOM-M study, the inability to demonstrate an improvement in time to clinical worsening in all three PIII studies, and the inability to demonstrate a statistically significant effect on 6MWD in the two FREEDOM-C studies as reasons for being unable to approve the NDA in its current form. The FDA noted that it was unsure whether an additional clinical study could alter these impressions, but if an additional study was undertaken it should use a fixed dose design and more frequent dosing [6].

Jan 12: Filed in the US on 27/12/11 [4].

Aug 11: Company intend to file in US 1H 2012 for treatment-naïve patients [2].

Jul 05: granted orphan drug status in the EU [1].


Prostacyclin agonist in a modified-release tablet formulation
In its pure idiopathic form pulmonary hypertension is a rare disease with an approximate annual incidence of about 1–3 cases per million population. There is a higher incidence of cases associated with connective tissue disease – about 10% of sufferers of CREST/scleroderma syndromes have the condition. [5]
Pulmonary arterial hypertension (PAH) - oral modified-release formulation

Trial or other data

Aug 18FREEDOM-EV study (now described as phase IV) meets its primary endpoint of delayed time to first clinical worsening event. In particular, the preliminary results showed that Orenitram, when taken with an oral PAH background therapy, decreased the risk of a clinical worsening event versus placebo by 25 percent (p=0.0391), driven by a 61 percent decrease in the risk of disease progression for patients taking Orenitram, when compared to placebo (p=0.0002) [20].

Nov 17: The PIII FREEDOM-Ev trial is still recruiting subjects, with an estimated primary completion dateofJuly 2018. [15].

Nov 16. The PIII FREEDOM-Ev trial is still recruiting subjects [14]

Sep 15. The PIII FREEDOM-Ev trial is still recruiting subjects [13]

Mar 13: An event-driven PIII trial to compare the time to first clinical worsening in patients with PAH receiving sustained-release oral treprostinil twice-daily in combination with a PDE5 inhibitor or an endothelin receptor antagonist (ERA), compared with a PDE5 inhibitor or ERA alone (FREEDOM-Ev; NCT01560624). The randomised, double-blind trial will enrol 858 patients, and will be followed by a long-term, open-label extension trial (NCT01560637). Study start date is July 2012 and estimated completion date is August 2016 [9].

Aug 11: In a preliminary analysis the FREEDOM-C2 PIII trial did not achieve statistical significance for the primary endpoint, six-minute walk distance (6MWD) at Week 16. The RCT involved 310 patients with PAH who were optimized on an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, or both. Patients were administered oral treprostinil or placebo twice daily with the dose titrated over 16-weeks. 73% of patients were classified as WHO Class III. Mean baseline walk distance was ~ 333 metres. The placebo-corrected median change in 6MWD at Week 16 was 10 metres (p=0.089, Hodges-Lehmann estimate and non-parametric analysis of covariance). 84% vs 90% of patients on oral treprostinil and placebo, respectively, completed Week 16 with an average dose of 3mg in the oral treprostinil group. Discontinuations due to adverse events were 11vs 3%. Outcomes of secondary efficacy measures, including time to clinical worsening, change in combined 6MWD and Borg Dyspnea Score rating (shortness of breath test) and Dyspnea-Fatigue index, WHO functional class, and PAH signs and symptoms, did not differ significantly between oral treprostinil and placebo (p>0.05) [2].

NCT01027949: An open-label extension study which started in May 06 is recruiting 900 patients from the Freedom studies. The study will assess long term safety and exercise capacity after one year of treatment. The study is due to complete Dec 12 [3].

Two multinational PIII placebo-controlled studies started in Oct 06: FREEDOM-C (NCT00325442) was a 16-week study of patients on approved background therapy using a PDE-5 inhibitor or an endothelin receptor antagonist, or both, and FREEDOM-M (NCT00325403) is a 12-week study in patients not on any background therapy. Both trials started using a 1mg tablet but there were problems with tolerability and a 0.25mg tablet was introduced in Apr 08. The FREEDOM-C trial reported in Apr 08 and did not meet statistical significance for its primary endpoint. Analysis suggested that the inability to dose titrate was a limiting factor that suppressed the overall treatment effect. A protocol amendment was submitted to the FDA in Feb 09 to add patients to the ongoing FREEDOM-M trial using the new strength tablet. A 2nd PIII trial, FREEDOM-C2 (NCT00887978) in PAH patients on an approved background therapy started Jun 09 [1].