United Therapeutics’ oral Remodulin falls short of breath before FDA approval

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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United Therapeutics’ (NASDAQ:UTHR) oral Remodulin (treprostinil) reported mixed results in late-stage development, leading physicians to question the drug’s use in pulmonary arterial hypertension (PAH), if approved, according to experts interviewed by BioPharm Insight.

Despite a recent failure in the pivotal Phase III Freedom-C2 study, the company plans to file for FDA approval as a new oral therapy in PAH. The failed study evaluated oral Remodulin in combination with other therapies, which is how the drug would most likely be used in the real-world setting, physicians noted.

While the company has not disclosed its correspondence with the FDA and the exact NDA filing requirements for oral Remodulin, experts told this news service they expect the FDA to require two positive trials for the drug’s approval. Most physicians added they would be surprised if the drug received approval by the FDA.

Pulmonary arterial hypertension (PAH) is a disease characterized by abnormally high blood pressure in the lungs, leading to shortness of breath, fatigue and fainting.

Positive results from another Phase III trial, Freedom-M, testing the drug as a single agent, reported a median six-minute-walk distance (6MWD) improvement of 23 meters. The C2 trial failed to reach statistical significance on its 6MWD primary endpoint with a median improvement of 10m. Both studies missed on secondary endpoints.

The 6MWD is a standardized measure of submaximal exercise capacity, and is used as a frequent endpoint in pulmonary trials.

United Therapeutics is anticipated to file an NDA in 1H12 for oral Remodulin, according to a company press release. The positive Freedom-M study should support the application in treatment-naïve patients.

Treprostinil, the active ingredient, is already-approved in subcutaneous, intravenous and inhaled form, which should also support the filing, the company press release stated.

A previous combination trial (Freedom-C) evaluating oral Remodulin in combination with other first line PAH therapies failed due to side-effects which caused a high patient drop-out rate. The company then revised the dosing for its monotherapy trial (Freedom-M) and started a new combination trial (Freedom-C2).

United Therapeutics declined to comment.

Dr Harrison Farber, Director of the Pulmonary Hypertension Center at Boston University, said the results of the C2 trial were “totally underwhelming.” He added he was surprised the company was going ahead with the FDA filing, despite the results. Although the monotherapy trial was statistically significant, the results were not very impressive and the efficacy was marginal at best, he added.

One C2 study investigator called the results of the study “unimpressive,” and although the Freedom-M trial was positive, the magnitude of change in the 6MWD was still “a little disappointing.” The only reason for approval would be leniency, as the molecule is already approved in other forms, such as IV, inhaled and sub-cutaneous mode of delivery.

Following the data release, there isn’t much enthusiasm about the drug, regardless of the outcome, added Dr Peter Engel, medical director of the Pulmonary Hypertension Program, Heart & Vascular Center at The Christ Hospital, Cincinnati. Even if approved, Farber said he doubted any experienced physician would use the drug in practice.

The data is not strong enough to even think about giving this drug to treatment-naïve patients as a first-line option, said Farber. The drug takes time to dose, and it is not worth wasting any time with the efficacy demonstrated in the trials as a result, Engel added.

Data inferior to current therapies

The oral Remodulin data is inferior to the data achieved by drugs already used as first line therapies, said Engel. Current standard first-line therapies include PDE5 inhibitors such as Pfizer’s (NYSE:PFE) Revatio and United Therapeutics’ Adcirca as well as endothelial receptor agonists (ERA) such as Actelion’s (VTX:ATLN) Tracleer and Gilead’s (NASDAQ:GILD) Leitaris.

In addition, Farber expressed concern that less experienced physicians, who may be swayed by the attractive route of delivery as a pill, may prescribe oral Remodulin. However, this would not be best practice, as IV Remodulin has established efficacy for more severe patients, he explained.

The safety of the drug was superior in the Freedom-C2 trial compared to the failed Freedom-C trial, said Engel, so the company appears to have worked out the dosing, he added. There was still a notable difference in side effects (headache, diarrhea, nausea) between study drug and placebo and patients who dropped out of the trial cannot tolerate it at all, said Farber. 11 percent of patients dropped out of the C2 study due to adverse events and considering this is just a 16-week trial, that is a high number for an incredibly short period of time, Farber added.

With the way PAH trials are conducted now, United’s trial design is somewhat inferior with an easier endpoint to hit and the drug still did not deliver attractive results, said Farber. The second investigator noted the 6MWD endpoint has been used for 15 years and a more modern morbidity/mortality endpoint in the form of an “event driven” trial, similar to Actelion’s ongoing trials for macitentan and selexipag, would have given more confidence on the drug’s efficacy.

Engel noted that if the drug was not able to show a benefit in the 6MWD trial, which is a lower bar, then this is discouraging regarding its success in an event-driven study. However the first investigator said a longer event-driven trial might be worthwhile, as the problem with oral Remodulin is escalating the dose up high enough to show efficacy -- which can be somewhat limited by shorter-duration trials.

While the drug did not show efficacy or statistical significance in C2, the company could still submit the C2 trial to show its improved safety, Farber said. Yet he questioned why a company would submit data to show that a compound did not work.

Experts noted that despite the drug’s improved safety profile in the C2 trial, the oral route of treprostinil was still accompanied by higher tolerability risks compared with other modes of delivery.

The disorder affects approximately 100,000 patients globally. Oral Remodulin has a peak sales estimate of USD 500m by 2015 if approved, according to BioPharm Insight data.

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