Actelion plans to enter Phase III trials by the end of the year with a novel treatment for chronic insomnia that has the potential to transform the company from its nearly singular focus on pulmonary arterial hypertension.

The investigational compound, ACT-078573, is an orexin receptor antagonist. Positive results from a Phase II proof-of-concept study were announced in February, and the results will likely be presented in September at the World Sleep Congress in Australia, Actelion Chief Financial Officer Andrew Oakley said during a June 13 presentation at the Goldman Sachs Healthcare Conference.

Internally developed ACT-078573 penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, OX1 and OX2, according to Actelion.

In the trial, the compound met its primary endpoint, an improvement in sleep efficiency measured by polysomnograph, the company reported. A per-protocol analysis of 39 patients receiving the starting dose was statistically significant (p<0.0001). treatment="" was="" well-tolerated,="" and="" there="" were="" no="" reports="" of="" serious="" adverse="" events="" and="" no="" emerging="" safety="" findings="" in="" the="" double-blind,="" randomized,="" placebo-controlled,="" two-way="" crossover,="" single-dose="">

Oakley said it is too early in development to discuss whether Actelion will partner the drug. "We don't know from the strategy point of view whether this is a drug that's going to be simply targeted toward high-price niche indications or whether it's the panacea of everyone's problems in sleep and, therefore, a very, very, very large product," he said.

Actelion, in Allschwil, Switzerland, is partnered with Merck on a Phase I renin inhibitor program and with Roche on a selective sphingosine-1-phosphate receptor program Oakley said is expected to enter Phase II trials in multiple sclerosis later this year.

The company also has an extensive clinical program in pulmonary arterial hypertension to support label extensions for its lead product Tracleer (bosentan), an endothelin receptor antagonist approved by FDA in 2003 for patients with moderate to severe PAH.

Actelion, which until recently owned the sole ERA approved for PAH, is now facing competition. Gilead Sciences, in Foster City, Calif., won FDA approval of its same-class product Letairis (ambrisentan) on June 15 after a priority review (see ¹ Also see "Gilead Letairis Will Be Available Through LEAP Restricted Distribution Program" - Pink Sheet, 15 June, 2007.).

As part of the agreement surrounding Gilead's $2.5 billion purchase of Myogen in October, GlaxoSmithKline has rights to ambrisentan outside of the U.S. and will be competing with Actelion in Europe (² Also see "Gilead Ramps Up For Ambrisentan; Calls For 75 To 100 Sales Reps" - Pink Sheet, 9 January, 2007.).

Houston-based Encysive Pharmaceuticals' PAH product Thelin (sitaxsentan) was approved for sale in Europe last August and had a June 15 action date in the U.S. after two "approvable" letters (³ Also see "Encysive Thelin Approval Could Come Days Ahead Of Gilead’s Ambrisentan" - Pink Sheet, 28 December, 2006.). FDA issued a third approvable decision June 15 (⁴ Also see "Thelin's Third "Approvable" Letter Recommends Additional Clinical Trial" - Pink Sheet, 15 June, 2007.).

At the Goldman Sachs conference, Oakley said Actelion would handle the competition through a combination of new indications, some additional geographic expansion and possibly through competitive pricing. He also said he thought Glaxo's sales efforts would be good for business.

"Having the Gilead sales force out there beating the bushes and beating the drums and Glaxo's sales force in Europe doing the same thing [will] increase awareness, increase diagnosis rate, and basically all of the participants in the market will benefit," the CFO said. Oakley estimated that Actelion has penetrated only about 20 percent of the PAH market.

"We're probably not at a point where we're saying there's massive amounts of geographic expansion left to do," Oakley said. "We still have some territories in Latin American we're starting to think about, and some ... Eastern European countries are still coming online." In the fourth quarter of 2006, Tracleer was launched in China and in South Korea, and "Japan will continue to grow," he added.

Oakley said Actelion expects to see the Tracleer label expanded this year to include data from the EARLY study in mildly symptomatic PAH patients. EARLY is the first and only study in that patient population, whose disease will worsen without treatment, Actelion said.

In addition, data from the BENEFIT study in chronic thromboembolic pulmonary hypertension, which will become available this year, should go into labeling, along with data on a new children's formulation, Oakley said.

With the acquisition of Brisbane, Calif.-based CoTherix in November, Actelion gained the only FDA-approved inhaled PAH therapy Ventavis (iloprost) (⁵ Also see "Actelion Acquires CoTherix For $420 mil." - Pink Sheet, 20 November, 2006.). Ventavis, a liquid prostacyclin, must be inhaled seven to nine times a day via nebulizer.

Oakley said that "longer term," Actelion wants to change Ventavis from its current role as what is effectively an IV-sparing regimen to more of a symptomatic relief role, "so that basically every PAH patient will carry a Ventavis inhaler and will use it as and when actually required."

Phase III studies of sildenafil (Pfizer's Revatio , marketed as Viagra under a different dosing scheme) in combination with bosentan, dubbed COMPASS, are ongoing, and it "might still be some time" before that data is finalized, Oakley said.

- Shirley Haley (s.haley@elsevier.com)

Actelion Will Take Novel Sleep Therapy Into Phase III This Year

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