First-Line Combination of Ambrisentan and Tadalafil Reduces Risk of Clinical Failure Compared to Monotherapy in Pulmonary Arterial Hypertension Outcomes Study

-- AMBITION Study of Ambrisentan/Tadalafil Combination Therapy Versus Monotherapy Achieves Primary Endpoint of Time to First Clinical Failure Event --

-- Data Presented at the ERS International Congress 2014 --

MUNICH--(BUSINESS WIRE)--Sep. 8, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced results from the AMBITION study (a randomized, double-blind, multicenter study of first-line combination therapy with AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION), which was conducted in collaboration with GlaxoSmithKline (GSK). In AMBITION, first-line treatment of pulmonary arterial hypertension (PAH) with the combination of ambrisentan 10 mg and tadalafil 40 mg reduced the risk of clinical failure by 50 percent compared to the pooled ambrisentan and tadalafil monotherapy arm (hazard ratio = 0.502; 95 percent CI: 0.348, 0.724; p=0.0002). The combination was also statistically significant versus the individual ambrisentan and tadalafil monotherapy groups for the primary endpoint (pERS International Congress 2014, the annual meeting of the European Respiratory Society.

Gilead plans to submit the AMBITION data in a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration by the end of this year. Combination use with ambrisentan and tadalafil is currently not approved.

Ambrisentan, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE5 inhibitor, are each approved in the United States, the European Union (EU) and other countries as once-daily treatments for PAH (WHO Group 1), in patients with WHO/NYHA functional class II and III symptoms. Ambrisentan is indicated in the U.S. to improve exercise ability and delay clinical worsening and in the EU to improve exercise capacity. Tadalafil 40 mg is indicated in the U.S. and the EU to improve exercise ability and capacity, respectively. Preclinical data have suggested these therapies may have synergistic effects.

“The pulmonary hypertension medical community has long been interested in determining whether newly diagnosed PAH patients would have improved outcomes with upfront combination therapy versus monotherapy,” said Lewis J. Rubin, MD, Emeritus Professor, University of California, San Diego and Co-Chair of the AMBITION Steering Committee. “The majority of combination studies to date have evaluated add-on combination treatment approaches with mixed results. Thus, having demonstrated a 50 percent reduction in risk of clinical failure, the AMBITION results using ambrisentan and tadalafil together as upfront combination therapy potentially establish a new treatment paradigm in PAH.”

AMBITION was a randomized, double-blind study designed to compare the safety and efficacy of investigational first-line combination therapy (ambrisentan and tadalafil) to first-line monotherapy (ambrisentan or tadalafil) in patients with WHO/NYHA functional class II and III PAH. In the study, 500 patients were randomized (2:1:1) to receive ambrisentan and tadalafil (n=253) or monotherapy with ambrisentan (n=126) or tadalafil (n=121) (titrated from 5 mg to 10 mg once-daily and from 20 mg to 40 mg once-daily for ambrisentan and tadalafil, respectively). The primary endpoint was time to first clinical failure event, defined as time from randomization to the first occurrence of death (all-cause), hospitalization for worsening PAH, disease progression or unsatisfactory long-term clinical response (events adjudicated by an independent, blinded committee).

The treatment effect observed with the primary endpoint was mainly driven by a reduction in hospitalizations. Time to first hospitalization was delayed by 63 percent (hazard ratio = 0.372; 95 percent CI: 0.217, 0.639; p=0.0002).

Statistically significant improvements were also observed with the following secondary endpoints versus the pooled monotherapy arm: change from baseline at week 24 in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (-67.4 percent vs. -49.7 percent; p

No new safety signals were detected with the combination of ambrisentan and tadalafil. Adverse events occurring more frequently in the combination arm than in each monotherapy arm were peripheral edema (Combination: 45 percent; ambrisentan: 33 percent; tadalafil: 28 percent), headache (Combination: 42 percent; ambrisentan: 33 percent; tadalafil: 35 percent), nasal congestion (Combination: 21 percent; ambrisentan: 15 percent; tadalafil: 12 percent) and anemia (Combination: 15 percent; ambrisentan: 6 percent; tadalafil: 12 percent).

The AMBITION study was cosponsored by Gilead and GSK. Eli Lilly and Company also provided funding and tadalafil drug supply for the trial. Gilead commercializes ambrisentan under the tradename Letairis^® in the U.S. and GSK commercializes ambrisentan under the tradename Volibris^® in territories outside of the United States.

“The AMBITION study is a reflection of Gilead’s ongoing commitment to PAH,” said Norbert Bischofberger, PhD, Gilead’s Executive Vice President of Research and Development and Chief Scientific Officer. “We are pleased that the combination of ambrisentan and tadalafil has resulted in a clinically meaningful benefit for PAH patients, and we extend our thanks to the patients, investigators and other research collaborators who participated in the study.”

In the U.S., Letairis has a labeled BOXED WARNING and an associated Risk Evaluation and Mitigation Strategy (REMS) program regarding the risk of embryo-fetal toxicity; see below for Letairis Important Safety Information.

About Pulmonary Arterial Hypertension (WHO Group 1)

PAH is a debilitating disease characterized by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide.

Important U.S. Safety Information for Letairis

BOXED WARNING: EMBRYO-FETAL TOXICITY

Do not administer Letairis to a pregnant female because it may cause fetal harm.Letairis is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is administered to animals.

Exclude pregnancy before the initiation of treatment with Letairis. Females of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after discontinuation of treatment.

Because of the risk of embryo-fetal toxicity birth defects, females can only receive Letairis through a restricted program called the Letairis REMS program.

Contraindications

• Do not administer Letairis to a pregnant woman because it can cause fetal harm.
• Letairis is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3).

Warnings and precautions

• Embryo-fetal Toxicity: Letairis may cause fetal harm when administered during pregnancy.
• Letairis REMS Program: For all females, Letairis is only available through a restricted program called Letairis REMS. Some requirements of the Letairis REMS Program include:
  • Prescribers must be certified with the program by enrolling and completing training.
  • All females, regardless of reproductive potential, must enroll in the Letairis REMS Program prior to initiating Letairis. Male patients are not enrolled in the REMS.
  • Pharmacies that dispense Letairis must be certified with the program and must dispense to female patients who are authorized to receive Letairis.

  Further information is available at www.letairisrems.com or 1-866-664-5327.

• Mild to moderate peripheral edema: Peripheral edema occurred more frequently in elderly patients (age ≥65 years) receiving Letairis (29 percent; 16/56) compared to placebo (4 percent; 1/28). Peripheral edema is a known class effect of endothelin receptor antagonists. In addition, there have been postmarketing reports of fluid retention occurring within weeks after starting Letairis that required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.

• Pulmonary Edema with PVOD: If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Letairis, pulmonary veno-occlusive disease should be considered, and if confirmed, Letairis should be discontinued.
• Decreases in sperm count have been observed in patients taking endothelin receptor antagonists and in animal fertility studies with ambrisentan. Counsel patients about potential effects on fertility.
• Hematologic changes: Decreases in hemoglobin have been observed within the first few weeks of treatment with Letairis, and may persist during treatment. There have been postmarketing reports of anemia requiring transfusion. Measure hemoglobin prior to initiation, at 1 month, and periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically significant anemia.

Adverse reactions

• During 12-week controlled clinical trials, the incidence of liver aminotransferase (AST, ALT) elevations >3x ULN was 0 percent for Letairis and 2.3 percent for placebo.
• In postmarketing experience, elevations of aminotransferases have been reported with Letairis use; in most cases alternative causes of liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). In practice, cases of hepatic injury should be carefully evaluated for cause.
• Other ERAs have been associated with aminotransferase elevations, hepatotoxicity, and cases of liver failure.
• Discontinue Letairis if aminotransferase elevations are >5x ULN or if elevations are accompanied by bilirubin >2x ULN or by signs or symptoms of liver dysfunction, and other causes are excluded.

Drug interactions

• Multiple-dose co-administration of Letairis and cyclosporine resulted in an approximately two-fold increase in Letairis exposure in healthy volunteers. Limit the dose of Letairis to 5 mg once daily when co-administered with cyclosporine.

Dosage and administration

Adult Dosage:Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated. Tablets may be taken with or without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH).

Pregnancy Testing in Females of Reproductive Potential:Initiate treatment with, Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment.

Not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Letairis in patients with mild hepatic impairment; however, exposure to Letairis may be increased in these patients.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including Gilead’s ability to submit its sNDA in the currently anticipated timeline. In addition, regulatory authorities may not approve the sNDA and any marketing approvals may have significant limitations on use. Further, even if approved, physicians may not see the benefit of combining Letairis with tadalafil. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information including BOXED WARNING for Letairis is available at www.gilead.com.

Letairis and Volibris are registered trademarks of Gilead Sciences, Inc. or one of its related companies.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.Investors:Patrick O’Brien, 650-522-1936Media:Nathan Kaiser, 650-522-1853