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By Cormac Sheridan
BioWorld International Correspondent
With positive data from a Phase IIa trial in hand, Actelion AG plans to move directly into a Phase III morbidity/mortality trial of its first-in-class oral prostacyclin (PGI2) receptor agonist in pulmonary arterial hypertension (PAH) before year-end.
Allschwil, Switzerland-based Actelion gained worldwide rights to the vasodilatory compound, excluding Japan, when it entered an alliance last year with Kyoto, Japan-based Nippon Shinyaku Co. Ltd., which originally discovered the compound. The two companies are jointly developing and commercializing the drug for the Japanese market.
Nippon Shinyaku had initiated the 43-patient, Phase IIa trial in Europe in December 2007, but Actelion, which has long experience of the PAH indication, took charge of the study when the agreement was signed in April 2008.
The company last week reported that the compound achieved the primary endpoint of change from baseline in pulmonary vascular resistance with a high level of statistical significance (p < 0.01). Patients were randomized to receive drug or placebo on a 3:1 basis in the study.
An oral drug acting via the prostacyclin pathway has eluded the pharmaceutical industry for several decades, according to Actelion. Existing prostacyclin analogues are available, but they are costly and require either continuous intravenous infusion or inhalation.
"Prostacyclin works. It has been a key feature of prostacyclin therapy that patients could not be given the drug orally," Roland Haefeli, head of investor relations at Actelion, told BioWorld International.
Patients are dosed individually and are up-titrated to a maximum-tolerable dose. "We already reached efficacious levels without going all the way," Haefeli said. "We can still go higher."
The company will complete discussions with the FDA before finalizing its trial design. The study will take several years to complete. But the required endpoint is already obvious. "The morbidity/mortality [endpoint] is related to the fact that in pulmonary arterial hypertension you have massive change over the last few years," Haefeli said.
Actelion already has one other compound undergoing a Phase III morbidity/mortality study, a potent, tissue-targeting endothelin receptor antagonist (ERA) called macitentan.
The company introduced the first ERA for PAH in 2001, Tracleer (bosentan), when improvement on a six-minute walk test represented a sufficient measure of efficacy. Several others in the same class have followed, including Letairis (ambrisentan), marketed by Gilead Sciences Inc., and Thelin (sitaxsentan sodium), which is undergoing Phase III trials at New York-based Pfizer Inc.
More recently, phosphodiesterase 5 (PDE5) inhibitors, originally associated with treating - at lower doses - erectile dysfunction, also gained approval in PAH.
United Therapeutics, of Silver Spring, Md., in-licensed rights to tadalafil in PAH from Eli Lilly and Co., of Indianapolis, and markets the drug as Adcirca. Pfizer is marketing sildenafil in PAH as Revatio.
Despite the broadening of the therapeutic options available, competition acts within rather than across drug classes. The efficacy reported in the recent trial of the PGI2 receptor agonist was additional to what is already available from current therapies - patients were receiving concomitant ERAs and/or PDE5 inhibitors. "The treatment goal today is, if you have a patient diagnosed with PAH, you would like to go after all the involved pathways to arrest the disease," Haefeli said.
In that context, Actelion yesterday posted strong first half revenue figures for Tracleer, with sales of CHF739.3 million (US$693.7 million), vs. CHF605.2 million for the first half of 2008. It reported net profit of CHF218.4 million - or CHF1.79 in diluted earnings per share - on total revenues of CHF855.2 million. The company has CHF1.2 billion in cash.
It accordingly increased its guidance for the full year. It is forecasting revenue growth - in local currencies - in the range of 16 percent to 19 percent, up from 12 percent to 15 percent forcasted in February. It is forecasting growth in earnings before interest and taxes in the range of 16 percent to 19 percent also, up from growth of 10 percent to 12 percent in February. The stock (Zurich:ATLN) closed Tuesday at CHF58.10, up 1 percent. | 
