Zydelig® in Combination With Ofatumumab Improves Progression-Free Survival in Previously-Treated Patients With Chronic Lymphocytic Leukemia

Gilead Sciences, Inc. (Nasdaq:GILD) today announced results from the Phase 3 clinical Study 119 of an investigational use of Zydelig^® (idelalisib) in combination with ofatumumab in previously-treated patients with chronic lymphocytic leukemia (CLL). In Study 119, there was a 73 percent reduction in the risk of disease progression or death in patients receiving Zydelig in combination with ofatumumab compared to ofatumumab alone (hazard ratio (HR) = 0.27; 95 percent CI: 0.19, 0.39; p<0.0001). Detailed results will be presented today during a poster session at the 51^st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (Abstract #7023).

“The data reported today reinforce prior results showing that idelalisib, here in combination with the anti-CD20 monoclonal antibody ofatumumab, not only significantly improved overall and lymph node response rates, but more importantly progression-free survival in patients with previously treated CLL,” said Jeffrey A. Jones, MD, MPH, Associate Professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). “Importantly, these improvements were also observed in patients with genetic features typically associated with poor prognosis.”

Study 119 was a randomized, controlled, open-label Phase 3 study evaluating the efficacy and safety of Zydelig in combination with ofatumumab. The study enrolled 261 adult patients with previously treated CLL whose disease had progressed less than 24 months following completion of prior therapy, and had not previously been refractory to ofatumumab. Eligible patients were randomized 2:1 to receive an ofatumumab 1,000 mg dosing regimen (12 infusions, first infusion 300mg) over 24 weeks plus Zydelig (150 mg) twice daily (n=174) continuously until disease progression or unacceptable toxicity or an ofatumumab 2,000 mg dosing regimen (12 infusions, first infusion 300mg) over 24 weeks (n=87).

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to definitive disease progression or death assessed by an independent review committee. Median PFS in the Zydelig/ofatumumab arm was 16.3 months, compared to 8.0 months in the ofatumumab monotherapy arm. Statistically significant improvements were also observed for overall response rate (75 percent vs. 18 percent; odds ratio (OR) = 15.9, p<0.0001) and lymph node response rate (93.3 percent vs. 4.9 percent; OR=486.96, p<0.0001). Median PFS in the approximately 40 percent of patients with 17p deletion or TP53 mutation was 13.7 months vs. 5.8 months (HR=0.32, p<0.0001). A statistically significant difference was not achieved in median overall survival (20.9 months vs. 19.4 months; HR=0.74, p=0.27).

The safety profile of Zydelig was similar to prior studies in previously-treated patients with CLL. Grade ≥3 adverse events occurring in the Zydelig plus ofatumumab arm included diarrhea/colitis (20.2 percent), pneumonia (12.7 percent) and febrile neutropenia (11.6 percent).

Based on the Study 119 trial results, Gilead has filed a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration to include data from this study in the U.S. label. Gilead plans to submit a supplemental filing to the European Medicines Agency later this year.

“Zydelig has now demonstrated strong efficacy in two randomized Phase 3 studies among previously treated CLL patients,” said Norbert Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer. “We continue to explore the clinical profile of Zydelig in combination with both standard and novel treatment regimens, including seven ongoing or completed Phase 3 clinical trials for B-cell malignancies.”

The Zydelig U.S. Prescribing Information includes a BOXED WARNING regarding fatal and serious toxicities of hepatotoxicity, severe diarrhea/colitis, pneumonitis, and intestinal perforation; see below for Important Safety Information.

The use of Zydelig in combination with ofatumumab is investigational and the safety and efficacy of this combination has not yet been established.

Dr. Jones is an uncompensated advisory board member to Gilead and receives research grant support to support this Phase 3 trial at The OSUCCC – James.

About Zydelig (idelalisib)

Zydelig is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system. PI3K delta signaling is active in many B-cell leukemias and lymphomas, and by inhibiting the protein, Zydelig blocks several cellular signaling pathways that drive B-cell viability.

On July 23, 2014, Zydelig received accelerated approval from the U.S. Food and Drug Administration as monotherapy for patients with relapsed follicular lymphoma (FL) or small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies, and full approval in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities. On September 19, 2014, the European Commission granted marketing authorization for Zydelig as monotherapy in FL patients who are refractory to two prior lines of treatment, and in combination with rituximab for CLL patients who have received at least one prior therapy, or in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemoimmunotherapy.

Additional information about clinical studies of Zydelig and Gilead’s investigational cancer agents can be found at www.clinicaltrials.gov.

Important U.S. Safety Information

BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 14 percent of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14 percent of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig for intestinal perforation.

Contraindications

• History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN).

Warnings and Precautions

• Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x ULN, withhold Zydelig and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue Zydelig for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs.
• Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.
• Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5 percent
• Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting.
• Severe cutaneous reactions: One case of TEN occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig if a reaction occurs.
• Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue Zydelig permanently and institute appropriate supportive measures if a reaction occurs.
• Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31 percent of Zydelig-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly.
• Embryo-fetal toxicity: Zydelig may cause fetal harm. Women who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Zydelig and to use effective contraception during and at least 1 month after treatment with Zydelig.

Adverse Reactions

• Most common adverse reactions (incidence ≥10 percent and ≥2 percent than rituximab alone, all grades) were pyrexia, nausea, pneumonia, diarrhea, chills, rash, vomiting and headache.
• Most frequent serious adverse reactions (SAR) were pneumonia (17 percent), pyrexia (9 percent), sepsis (8 percent), febrile neutropenia (5 percent) and diarrhea (5 percent); SAR were reported in 49 percent of patients and 10 percent of patients discontinued due to adverse reactions.
• Most common lab abnormalities (incidence ≥30 percent and ≥5 percent than rituximab alone; all grades) were neutrophils decreased, hypertriglyceridemia, hyperglycemia and ALT elevation.

Drug Interactions

• CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
• CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for Zydelig toxicity.
• CYP3A substrates: Avoid coadministration with CYP3A substrates.

Dosage and Administration

• Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown.
• Dose modification: Consult the Zydelig full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations, bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold Zydelig until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, Zydelig should be permanently discontinued.

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. 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 risk that Gilead may be unable to submit a supplemental filing for the use of Zydelig in combination with ofatumumab to the EMA in the currently anticipated timelines. In addition, the regulatory filings may not be approved by the FDA, EMA and other regulatory agencies and marketing approvals, if granted, may have significant limitations on their use. As a result, Zydelig in combination with ofatumumab may never be successfully commercialized. Further, there is the possibility of unfavorable results from other clinical trials involving idelalisib. 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 March 31, 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 Zydelig is available at  www.gilead.com .

Zydelig is a registered trademark of Gilead Sciences, Inc.

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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