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Actelion Jumps as PAH Drug Macitentan Aces Pivotal Trial

By Cormac Sheridan
Staff Writer

Shares in Actelion Ltd. rose 13 percent Monday on news that macitentan, its dual endothelin receptor antagonist (ERA), hit the primary endpoint in a pivotal Phase III trial in pulmonary arterial hypertension (PAH), raising the prospect that the company will be able to revitalize its aging PAH franchise with a safer, more potent drug.

Both the low (3 mg once daily) and the high doses (10 mg once daily) of macitentan lowered the risk of a morbidity/mortality event vs. placebo over the 3.5 year study period, with reductions of 30 percent (p = 0.0108) and 45 percent (p < 0.0001), respectively.

"With over 20 years in this field, I have rarely seen such an effect," Jean Paul Clozel, CEO and co-founder of Allschwil, Switzerland-based Actelion, said on a conference call.

Guy Braunstein, Actelion's head of global clinical development, echoed that enthusiasm, saying the treatment effect was "quite exceptional" for such a study.

The company plans to file for approval globally by the fourth quarter. If approved – and if it obtains an attractive label – the drug could bring new life to Actelion's core business. Its first-in-class ERA antagonist Tracleer (bosentan) brought in CHF1.5 billion (US$1.65 billion) in sales last year, but it is facing competitive headwinds, particularly in the U.S., and generic competition in 2015.

In a research note, Peter Welford, analyst at Jefferies International, wrote that he was retaining a peak sales forecast of CHF800 million for now, although "a 45 percent reduced risk of morbidity/mortality with the 10-mg dose should certainly be sufficient to shift the PAH treatment paradigm, in our view, which could drive significant upside to our sales."

Brett Holley, analyst at Oppenheimer & Co. Inc., was also impressed.

"We believe these results are compelling and note these are the first robust clinical outcome results for a PAH therapy," he wrote in a research note. However, he added that macitentan's impact would be mainly limited to the ERA market segment and would have little impact on United Therapeutics Corp., which markets phosphodiesterase 5 inhibitor Adcirca (tadalafil) in PAH.

Gilead Sciences Inc., of Foster City, Calif., which markets ERA Letairis (ambrisentan), could "face pressure as macitentan ramps," Holley added, though the impact to the big biotech's valuation "is minor."

The macitentan trial, dubbed SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve clinical outcome), was, according to Actelion, the most thorough study ever conducted in PAH patients.

It recruited 742 subjects who received treatment for an average of either 85.3 weeks (placebo group), 99.5 weeks (3-mg group) or 103.9 weeks (10-mg group). "We believe this is a quantum leap in drug development in PAH," Braunstein said.

All four previously approved PAH drugs, including Tracleer, Letairis, Revatio (sildenafil, Pfizer Inc.) and Adcirca, received approval mainly based on improvements in the six-minute walk test in trials that recruited between 32 and 405 patients, and whose durations ranged from just 12 weeks to 24 weeks.

The primary endpoint in SERAPHIN was a composite endpoint, based on five distinct events: death, atrial septostomy, lung transplant, initiation of prostanoid therapy or worsening of PAH. All, Braunstein noted, are clinically meaningful, and the composite endpoint is a far more "robust" measure of drug effect than the six-minute walk test used historically in PAH trials.

Once patients experienced an event, they were invited to enroll in an open-label macitentan extension study. Those who did not experience an event by the end of the study period also were invited onto the open-label extension. Patients were permitted to use concomitant medication, apart from ERAs, if they were stable on therapy for three months prior to randomization. About half of them did so, Braunstein said.

Macitentan also demonstrated statistical significance on several secondary endpoints, including the six-minute walk test, and the high dose of the drug demonstrated a trend toward efficacy on all-cause mortality, an outcome that was "probably 'best case' given [that] statistical significance would be challenging with relatively few deaths during the study," Welford wrote.

For a member of the ERA drug class, macitentan appears to exhibit a highly differentiated safety profile, with none of the liver toxicity problems associated with other ERAs. Elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal were seen in 4.5 percent of patients receiving placebo, in 3.6 percent of patients on 3 mg of macitentan and in 3.4 percent of patients on 10 mg of macitentan, Actelion said. In addition, no difference was observed between macitentan and placebo on edema or fluid retention.

Macitentan did result in a greater reduction in levels of hemoglobin in some patients. "The hemoglobin [reduction] is in keeping with what we expect from this class of drug," Clozel said. There was, however, no overall difference in treatment discontinuations or in adverse events between the control arm and either of the two study arms.

Actelion has another shot on PAH with selexipag, a first-in-class oral prostacyclin receptor agonist, which it in-licensed from Kyoto, Japan-based Nippon Shinyaku Co. Ltd. and which is now undergoing Phase III testing in a trial that has recruited about 700 of an anticipated 1,100 patients. Interim data are expected next year.

In the midst of near-universal offers of congratulations from the analysts assembled on the call came a bizarre intervention from a caller identifying himself as being from Basel, Switzerland-based Novartis AG, who asked Actelion officials about "rumors" of deaths on the trial. Actelion head of investor relations Roland Haefeli swiftly moved to the next question, emphasizing that the call was focusing on clinical data, not rumors.

Shares in Actelion (Zurich:ATLN) peaked at CHF41.55 during early trading Monday but settled back to close at CHF38.40, up CHF4.60.