U.S. Food and Drug Administration Approves New Treatment Combination of Gilead’s Letairis® with Tadalafil for Pulmonary Arterial Hypertension (WHO Group 1)

Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved the use of Letairis^® (ambrisentan) in combination with tadalafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Letairis is an endothelin receptor antagonist that was first approved in 2007 in the U.S. as monotherapy for PAH to improve exercise ability and delay clinical worsening. Tadalafil is a PDE5 inhibitor that was initially approved for PAH in the U.S. in 2009 to improve exercise ability.

“The evidence to support the use of ambrisentan and tadalafil in PAH is well-established, however an outstanding question has been whether combining these two medications up front may further delay the progression of this disease over the long term for patients who are newly starting PAH therapy,” said Ronald J. Oudiz, MD, Professor of Medicine, David Geffen School of Medicine at UCLA and Director, Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. “Based on the data supporting today’s approval, we now know that patients receiving ambrisentan and tadalafil up front are less likely to experience disease progression or be hospitalized, and have more improvement in exercise ability than patients receiving either effective therapy alone. As such, this combination represents a new treatment strategy for patients living with this debilitating and life-threatening disease.”

The new labeling is supported by data 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). In AMBITION, 605 patients with WHO Functional Class II or III PAH were randomized (2:1:1) to receive once-daily Letairis plus tadalafil (n=302) or to Letairis (n=152) or tadalafil (n=151) alone. Treatment was initiated with Letairis 5 mg and tadalafil at 20 mg. If tolerated, tadalafil was increased to 40 mg at four weeks and Letairis was increased to 10 mg at eight weeks. The primary endpoint was time to first occurrence of death, hospitalization for worsening PAH, greater than 15 percent decrease from baseline in six-minute walk distance (6MWD) combined with WHO Functional Class III or IV symptoms sustained over 14 days (short-term clinical worsening) or reduction in 6MWD sustained over 14 days combined with WHO Functional Class III or IV symptoms sustained over 6 months (inadequate long-term clinical response).

In the study, combination therapy with Letairis and tadalafil demonstrated superiority in reducing the risk of the composite primary endpoint by 49 percent and 45 percent, respectively, versus monotherapy with Letairis (hazard ratio = 0.51; 95 percent CI: 0.35, 0.73; p=0.0002) or tadalafil (hazard ratio = 0.55; 95 percent CI: 0.37, 0.81; p=0.002). Overall, 20 percent of patients receiving combination therapy experienced a primary endpoint event compared to 35 percent and 30 percent, respectively, in patients receiving Letairis or tadalafil.

Combination therapy also demonstrated a reduced risk of hospitalization for worsening PAH of 67 percent and 56 percent, respectively, compared to Letairis (hazard ratio = 0.33; 95 percent CI: 0.19, 0.55) or tadalafil (hazard ratio = 0.44; 95 percent CI: 0.25, 0.79). Overall, 8 percent of patients receiving combination therapy were hospitalized for worsening PAH compared to 22 percent and 15 percent, respectively, in patients receiving Letairis or tadalafil.

Patients receiving Letairis plus tadalafil also experienced statistically significant improvements from baseline in 6MWD versus individual monotherapy, with a median difference of 24 meters and 20 meters, respectively, from Letairis (95 percent CI: 11, 37; p=0.0004) or tadalafil (95 percent CI: 8, 32; p=0.0016) at Week 24.

When Letairis is used in combination with tadalafil, the common adverse reactions (>5 percent than on either monotherapy) were peripheral edema (Combination: 45 percent; Letairis: 38 percent; tadalafil: 28 percent), headache (Combination: 41 percent; Letairis: 34 percent; tadalafil: 35 percent), nasal congestion (Combination: 19 percent; Letairis: 16 percent; tadalafil: 11 percent), cough (Combination: 18 percent; Letairis: 13 percent; tadalafil: 16 percent), anemia (Combination: 15 percent; Letairis: 7 percent; tadalafil: 11 percent), dyspepsia (Combination: 11 percent; Letairis: 3 percent; tadalafil: 12 percent) and bronchitis (Combination: 10 percent; Letairis: 4 percent; tadalafil: 9 percent). 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 Important U.S. Safety Information for Letairis.

Data from AMBITION were published in The New England Journal of Medicine and Letairis plus tadalafil was the only recommended initial combination therapy option for PAH in the “2015 European Society of Cardiology / European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension” published in the European Heart Journal in August 2015.

AMBITION was cosponsored by Gilead and GlaxoSmithKline (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 U.S.

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.

About Letairis

Letairis is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening; and in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (60 percent) or PAH associated with connective tissue diseases (34 percent).

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

• Pregnancy: Letairis can cause fetal harm
• Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3)

Warnings and Precautions

• Embryo-fetal toxicity and Letairis REMS Program requirements:
  • Prescribers must be certified with the program by enrolling in and completing training
  • All female patients, regardless of reproductive potential, must enroll in the Letairis REMS Program
  • Male patients are not enrolled in the program
  • Pharmacies 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.

• Peripheral edema: Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. Further evaluate patients who develop clinically significant fluid retention to determine the cause and possible need for edema treatment or to discontinue Letairis. In clinical studies, peripheral edema was more common with Letairis than with placebo (most edema was mild to moderate in severity); and with Letairis plus tadalafil than with either drug alone. There have also been postmarketing reports of fluid retention occurring within weeks after starting Letairis that required a diuretic, fluid management, or hospitalization for decompensating heart failure.

• Pulmonary edema with pulmonary veno-occlusive disease (PVOD): Consider PVOD in patients who develop acute pulmonary edema during Letairis initiation and discontinue Letairis if PVOD is confirmed.
• Decreased sperm counts 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: Measure hemoglobin prior to initiation of Letairis, at 1 month, and periodically thereafter. Letairis initiation is not recommended for patients with clinically significant anemia. Consider discontinuing Letairis if clinically significant decreases in hemoglobin occur and other causes have been excluded. Decreases in hemoglobin and hematocrit have been observed within the first few weeks of Letairis treatment, which may persist during treatment. There have also been postmarketing reports of anemia requiring transfusion.

Adverse Reactions

• Most common adverse reactions when used as monotherapy compared to placebo were peripheral edema (17% vs 11%), nasal congestion (6% vs 2%), sinusitis (3% vs 0%) and flushing (4% vs 1%).
• Most common adverse reactions in combination with tadalafil compared to Letairis or tadalafil monotherapy were peripheral edema (45% vs 38% or 28%), headache (41% vs 34% or 35%), nasal congestion (19% vs 16% or 11%), cough (18% vs 13% or 16%), anemia (15% vs 7% or 11%), dyspepsia (11% vs 3% or 12%) and bronchitis (10% vs 4% or 9%).

Drug Interactions

• Cyclosporine increases ambrisentan exposure by 2-fold; limit Letairis to 5 mg once daily

Use in Specific Populations

• Breastfeeding: Choose Letairis or breastfeeding.
• Hepatic impairment: Letairis is not recommended in patients with moderate or severe hepatic impairment. Fully investigate cause of liver injury in patients who develop hepatic impairment; discontinue Letairis if liver aminotransferases 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.

Dosage and Administration

• Adult dosage: Initiate Letairis 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, consider either increasing to Letairis 10 mg or tadalafil 40 mg. Do not split, crush, or chew tablets.
• Pregnancy testing: Initiate Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment.

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. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

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 the possibility that physicians may not see the benefit of combination therapy with Letairis and 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, 2015, 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.

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