FDA Approves One Endothelin Antagonist for PAH, Nixes Another

FDA Approves One Endothelin Antagonist for PAH, Nixes Another  CME

News Author: Steve Stiles
CME Author: Yael Waknine
DisclosuresRelease Date: July 6, 2007; Valid for credit through July 6, 2008 Credits AvailablePhysicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™ for physicians;
Family Physicians - up to 0.25 AAFP Prescribed credit(s) for physicians

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

July 6, 2007 — The US Food and Drug Administration (FDA) has given the thumbs-up to one endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH) and a provisional thumbs-down to another.

Ambrisentan (Letairis, Gilead Sciences) was approved on the strength of two phase 3 trials that suggested it significantly improves six-minute-walk test results and delays worsening of PAH, the agency announced on June 15, 2007.

On the same day, Encysive Pharmaceuticals, the maker of another drug in the same class, sitaxsentan (Thelin) announced that the FDA has for the third time rejected its application to market the drug for the same indication. But the FDA signaled its willingness to consider the results of an additional study designed to show whether the drug could improve exercise capacity, according to the company.

Ambrisentan is classified as an orphan drug, which has qualified Gilead Sciences for tax credits and marketing incentives, the FDA notes. The drug joins several other available treatments for PAH, including bosentan (Tracleer, Actelion Pharmaceuticals), another endothelin antagonist, and sildenafil (Revatio, Pfizer), the phosphodiesterase inhibitor famously available, in different packaging, for the treatment of erectile dysfunction (Viagra, Pfizer).

In its own statement, Gilead Sciences notes that ambrisentan's approval is for patients with PAH who are in World Health Organization (WHO) symptom class 2 or 3. Bosentan is indicated for patients with somewhat more severe disease, WHO class 3 or 4. The company claims that its drug may be preferable to bosentan for patients who have experienced transient, asymptomatic liver enzyme elevations on bosentan, citing supporting evidence from an uncontrolled, 36-patient open-label study.

In its story on the ambrisentan approval, the New York Times notes that the "once-a-day pill will cost $3940 a month, about the same as Tracleer." Gilead Sciences, notes Times medical reporter Andrew Pollack, said it is "establishing programs to help uninsured or underinsured patients obtain the drug."

Encysive Pharmaceuticals. FDA issues third approvable letter for Thelin (sitaxsentan sodium) [press release]. June 15, 2007. Available at: http://www.encysive.com/news_20070615.html.

Gilead Sciences. US Food and Drug Administration approves Gilead's Letairis, (ambrisentan) 5 mg and 10 mg tablets for the once-daily treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO functional class II or III symptoms [press release]. June 15, 2007. Available at: http://www.gilead.com/wt/sec/pr_1016053.

Pollack A. Gilead's drug is approved to treat a rare disease. New York Times, June 16, 2007. Available at: http://www.nytimes.com/2007/06/16/business/16gilead.html?_r=1&ref=health&oref=slogin.

http://www.fda.gov/cder/foi/label/2007/022081s000lbl.pdf

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Study Highlights

Ambrisentan tablets 5- and 10-mg have been approved for the treatment of PAH (WHO group 1) in patients with WHO class 2 or 3 symptoms to improve exercise capacity and delay clinical worsening.Treatment should be initiated at 5 mg once daily with/without food; uptitration to 10-mg dose should be considered as tolerated.Approval was based on data from two 12-week, double-blind, placebo-controlled, phase 3 clinical trials (ARIES-1 and ARIES-2; n = 393) showing treatment with ambrisentan significantly increased exercise capacity, as evaluated by changes in walk distance relative to baseline.ARIES-1 study results revealed placebo-adjusted mean and median changes from baseline of 31 and 27 m, respectively, for 5-mg dose (P = .008); corresponding changes for 10-mg dose were 51 and 39 m (P < .001).In ARIES-2, placebo-adjusted mean and median changes from baseline of 59 and 45 m were observed for 5-mg dose (P < .001).Treatment with ambrisentan also significantly delayed time to clinical worsening of PAH, as defined by first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal resulting from addition of other PAH therapeutic agents, or study withdrawal resulting from progressive disease.Data from long-term follow-up of ARIES ambrisentan-treated patients and an open-label extension study (n = 383) showed 95% of subjects were still alive at 1 year and 94% continued using ambrisentan monotherapy. FDA notes these uncontrolled observations do not allow comparison with patients receiving placebo and cannot be used to determine drug's long-term effect.Most commonly reported adverse events in patients receiving 2.5-, 5-, or 10-mg doses of ambrisentan vs placebo in ARIES-1 and -2 included peripheral edema (17% vs 11%), nasal congestion (6% vs 2%), sinusitis (3% vs 0%), flushing (4% vs 1%), and palpitations (5% vs 2%). Most adverse drug reactions were mild to moderate, and only nasal congestion was dose dependent.The FDA warned ambrisentan can cause elevation of liver aminotransferase levels to at least 3 times the upper limit of normal. Observed incidence was 0.8% in the 12-week trials and 2.8% in long-term open-label studies. Because these changes may indicate potentially serious liver injury, serum aminotransferase levels (and bilirubin, if aminotransferase levels are elevated) should be measured prior to treatment initiation and monthly thereafter.However, findings from an uncontrolled open-label study of 36 patients who had previously discontinued using endothelin receptor antagonists because of aminotransferase level elevations 3 times the upper limit of normal or greater suggest ambrisentan therapy may be option for patients who have had asymptomatic aminotransferase level elevations while taking other endothelin receptor antagonists after aminotransferase levels have returned to normal.Results showed at a median follow-up period of 13 months with 50% of patients receiving 10 mg/day of ambrisentan that no patients discontinued use because of aminotransferase level elevations. Most common adverse events observed were peripheral edema, headache, dyspnea, and flushing.Caution is advised with coadministration of cyclosporine A because of risk for increased ambrisentan exposure; similar care should be taken when considering concomitant therapy with strong cytochrome P 450 isoenzyme 3A and 2C19 (CYP3A and CYP2C19) inhibitors.Monthly pregnancy tests are required for women of childbearing age.Because of risks for liver injury and birth defects (pregnancy category X), ambrisentan is available only via a special restricted distribution program.

Pearls for Practice

The FDA has approved 5- and 10-mg ambrisentan tablets for the treatment of PAH (WHO group 1) in patients with WHO class 2 or 3 symptoms to improve exercise capacity and delay clinical worsening.Treatment should be initiated at a dosage of 5-mg once daily with/without food; uptitration to a 10-mg dose should be considered as tolerated.

1. Which of the following statements is not correct regarding the potential benefits of ambrisentan therapy in patients with PAH (WHO group 1) and WHO class 2 or 3 symptoms?  (Required for credit)  Ambrisentan can delay the time to clinical worsening of PAH The 20-mg dose is more effective vs the 10-mg dose for improving exercise capacity In a long-term, open-label, follow-up study, 95% of patients were alive at 1 year Ambrisentan significantly increased exercise capacity

2. Which of the following statements is correct regarding the appropriate use of ambrisentan for the treatment of PAH?  (Required for credit)  Treatment should be initiated with 5 mg of ambrisentan twice daily The risk for peripheral edema is dose dependent Monthly pregnancy tests are required for most women of childbearing age Serum aminotransferase levels should be measured every 6 weeks

Medscape Medical News 2007. ©2007 Medscape

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