Gilead Sciences Inc., of Foster City, Calif., has terminated a Phase II trial of cicletanine for pulmonary arterial hypertension (PAH) due to a failure of the trial to meet its primary endpoint of improvement in exercise capacity.

Gilead acquired cicletanine from Navitas Assets LLC in 2008 for a $10.9 million up-front payment and milestones. The drug is approved in some European countries for hypertension.

The randomized, double-blind, placebo-controlled dose-ranging study was divided into three phases: a screening period, a 12-week placebo-controlled treatment period and a long-term, blinded extension study.

The primary outcome measure was change in the six-minute walk distance after 12 weeks. Secondary outcomes included change from baseline in Beck Depression Inventory, World Health Organization functional class, brain natriuretic peptide, cardiac hemodynamics and SF-36 functional scale.

The trial was also designed to track time to clinical worsening.

Inclusion criteria for the trial were extensive. Participants were between 16 and 70 years of age, and more than 40 kg in weight, with a current diagnosis of idiopathic pulmonary arterial hypertension, familial pulmonary arterial hypertension or pulmonary hypertension due to connective tissue disease, congenital heart defects, drug use or HIV infection.

In addition to meeting lab test criteria, some participants were receiving treatment with an approved endothelial receptor antagonist, phosphodiesterase type 5 (PDE5) inhibitor and/or parenteral prostanoid prior to enrollment.

Pulmonary arterial hypertension is a condition of increased pressure in the pulmonary artery that causes shortness of breath or dizziness, and can lead to heart failure. The disorder is commonly treated with endothelin receptor antagonists (ERA) such as Tracleer (bosentan, Actelion Ltd.) and Gilead's Letairis (ambrisentan).

Approved PDE5 inhibitors include Revatio (sildenafil, Pfizer Inc.) and Adcirca (tadalafil, United Therapeutics Corp.).

Even with the best quality existing therapies, life expectancy following a diagnosis of PAH is four to five years. The unmet need opportunity includes improved survival and delayed progression, as well improved function and fewer hospital admissions.

Cicletanine was invented and developed by Ipsen SA, of Paris, which licensed it to Navitas Assets in 2005.

The mechanism of cicletanine's action is believed to be enhanced coupling of endothelial nitric oxide synthase (eNOS). Endothelial dysfunction is implicated in PAH and may be related to a deficiency of vascular nitric oxide caused by decoupling of eNOS.

The trial's failure comes as a surprise, as previous clinical trials in Europe, and use in more than 10,000 patients supported claims for efficacy of cicletanine in PAH. The FDA granted orphan drug status to cicletanine for PAH.

The drug was to become part of Gilead's pipeline of therapies for PAH and other serious cardiovascular diseases. That pipeline includes approved products Letairis, Lexiscan (regadenoson) and Ranexa (ranolazine). Its investigational pipeline for cardiovascular disease features additional indications for ranolazine and a ranolazine/dronedarone fixed-dose combination for paroxysmal atrial fibrillation.

The cicletanine trial termination leaves Gilead without a follow-on candidate for pulmonary arterial hypertension and lapped by competitor Actelion, which turned in powerful Phase III results for its dual ERA antagonist, macitentan, for PAH earlier this year. (See BioWorld Today, May 9, 2012.)

In that large trial in 1,700 patients, morbidity and mortality was reduced by 30 percent in the lowest dose group (3 mg) and by 45 percent in the higher dose group (10 mg).

The trial outcome gives Actelion a strong chance of approval for macitentan and potential access to the $3.8 billion global PAH market.

Gilead isn't the only company to flame out recently in the PAH indication. Novartis AG withdrew its new drug application for imatinib for PAH after the FDA requested additional data to support approval. Imatinib is marketed as Gleevec in the U.S. in several cancer indications. (See BioWorld Today, Aug. 22, 2012.)

For a smaller, single-drug company, a trial termination for a drug like cicletanine could have been a death knell. For Gilead, it's barely even a blip. Gilead's stock (NASDAQ:GILD) ticked down 34 cents to close at $56.48.

The firm is busy making history with its HIV Quad regimen, which comes up for decision by the FDA on Aug. 27. Approval is widely anticipated for the four-drug, single-tablet regimen, which combines the ingredients of Truvada plus elvitegravir and cobicistat, following a 13-1 vote in favor of approval from the Antiviral Drugs Advisory Committee. (See BioWorld Today, Aug. 21, 2012.)

With the looming launch of a franchise that could bring in $4 billion per year, the investment community is unconcerned about the potential loss of Gilead's $10.9 million wager on cicletanine.