While Encysive Pharmaceuticals Inc. received a third approvable letter for Thelin (sitaxsentan sodium) on Friday, Gilead Sciences Inc. got approval for Letairis (ambrisentan), a competing endothelin A receptor antagonist for pulmonary arterial hypertension (PAH). (See Encysive story this issue).

Most investors had anticipated the approval, and shares of Foster City, Calif.-based Gilead dipped 32 cents to close at $80.51 on Monday.

Gilead plans to launch Letairis this week. It will compete against PAH drugs such as the PDE-5 inhibitor Revatio (sildenafil, Pfizer Inc.) and prostacyclins like Flolan (epoprostenol sodium, GlaxoSmithKline plc), Ventavis (iloprost, Actelion) and Remodulin (treprostinil, United Therapeutics Inc.). But Letairis' biggest competition will come from Tracleer (bosentan, Actelion Ltd.), the only endothelin receptor antagonist approved for PAH until now, which raked in sales of CHF898.7 million (US$722.1 million) in 2006.

Joel Sendek, analyst with Lazard Capital Markets, said in a report that Letairis' label may set the drug "on course to be best in class." He cited Letairis' once-daily administration vs. Tracleer's twice-daily administration as well as a potentially "superior efficacy profile" according to the six-minute walking test.

In two randomized, double-blind Phase III trials, the 5-mg dose of Letairis significantly increased the distance covered during a six-minute walk by a placebo-adjusted mean value of 31 meters (p=0.008) in one trial and 59 meters (p<0.001) in the other.

For the 10-mg dose, which was tested only in one trial, the placebo-adjusted mean increase was 51 meters (p<0.001). In the Tracleer Phase III program, the 125-mg dose increased walking distance by a placebo-adjusted mean value of 35 meters (p=0.01) in one trial and 76 meters (p=0.02) in the other.

Both drugs delayed time to clinical worsening of PAH in their Phase III trials. Letairis is indicated for PAH patients with WHO functional class II or III symptoms, while Tracleer is approved for PAH patients with WHO class III or IV symptoms. Both drugs have black box warnings for potential liver toxicity, although an uncontrolled, open-label trial of Letairis in patients who had discontinued Tracleer or investigational endothelin receptor antagonists due to aminotransferase elevations showed that no Letairis patients were discontinued for aminotransferase elevations.

Eun Yang, analyst at Jefferies & Co. Inc., also referenced Letairis' best-in-class profile in a report, specifically noting the dosing flexibility allowed by the drug's 5-mg and 10-mg tablets compared to Tracleer's 125-mg recommended dose. Yang also said the "lack of drug interactions positions Letairis well for combination therapy for PAH."

On a conference call late Friday, Gilead disclosed that its pricing for Letairis will be $3,940 for a monthly supply of either the 5-mg or 10-mg dose, which is similar to the cost of Tracleer. Sendek predicted Letairis 2007 sales of $20.1 million, building steadily to 2010 sales of $405.5 million.

Yang predicted Letairis will cross the $500 million mark in U.S. sales by 2012.

A regulatory application for Letairis is under review in Europe, where the drug would be marketed by GlaxoSmithKline plc. The big pharma picked up ex-U.S. marketing rights to Letairis in a potential $100 million deal with Myogen Inc. prior to Myogen's $2.5 billion acquisition by Gilead. (See BioWorld Today, March 8, 2006, and Oct. 3, 2006.)

In the U.S., Gilead plans to market the drug to large PAH centers, cardiologists, pulmonologists and rheumatologists. Because only about 35 percent to 40 percent of the 100,000 PAH patients in the U.S. are diagnosed, Gilead also will deploy a team of field-based medical scientists to educate doctors on the diagnosis.

Letairis will be distributed exclusively through eight specialty pharmacies according to the Letairis Education and Access Program (LEAP) restricted distribution program designed to monitor and provide education about the risks of liver injury and birth defects.

Gilead also is planning Phase IV trials of the drug, which Kevin Young, executive vice president of commercial operations, said will focus on combination therapies, long-term safety and efficacy, product differentiation and drug-drug interactions.

Concurrent with the announcement of Letairis' FDA approval, Gilead unveiled a program to help patients navigate reimbursement for the drug.

The program will focus on assisting with the out-of-pocket expenses for privately insured patients who have high monthly co-payments.

It also will provide reimbursement counseling to uninsured or underinsured patients, as Gilead has done to support access to its marketed HIV drugs Atripla (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), Truvada (emtricitabine and tenofovir disoproxil fumarate), Viread (tenofovir disoproxil fumarate) and Emtriva (emtricitabine), as well as its hepatitis B drug Hepsera (adefovir dipivoxil).