Gilead's Zydelig® Combined with Bendamustine and Rituximab Shows Superior Efficacy to Bendamustine/Rituximab in Phase 3 Study of Patients with Relapsed Chronic Lymphocytic Leukemia
Following the recommendation by an independent Data Monitoring Committee (DMC), Gilead Sciences, Inc. (NASDAQ: GILD) today announced that its Phase 3 Study 115 evaluating Zydelig® (idelalisib) added to standard therapy in previously-treated chronic lymphocytic leukemia (CLL) patients will be unblinded early. The DMC recommendation is based upon a predefined interim analysis indicating a statistically significant benefit in efficacy for progression-free survival (PFS) and overall survival (OS) in patients receiving Zydelig plus bendamustine and rituximab, compared to those receiving only bendamustine and rituximab. The safety profile of Zydelig was consistent with prior studies. Detailed results from this study will be presented during a late-breaking abstracts session (#LBA-5) at the Annual Meeting of the American Society of Hematology (ASH) in Orlando, Florida taking place December 5-8.
Zydelig is approved in the United States in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to comorbidities.
"The clinical benefit observed in this Phase 3 study adds to the body of evidence demonstrating the potential of Zydelig-containing treatment regimens for patients with previously treated CLL," said Norbert W. Bischofberger, PhD, Gilead's Executive Vice President, Research and Development and Chief Scientific Officer. "We look forward to sharing the detailed scientific data with the hematology community at the upcoming ASH meeting."
Study 115 is a randomized, double-blind, placebo-controlled, Phase 3 study evaluating the efficacy and safety of Zydelig in combination with bendamustine and rituximab among 416 adult patients with previously treated CLL. Eligible patients were randomized (1:1) to receive six cycles of bendamustine and rituximab over 24 weeks combined with either Zydelig 150 mg or placebo taken orally twice daily continuously until disease progression or unacceptable toxicity. The primary endpoint is PFS.
Additional details contained in the Study 115 abstract are available at https://ash.confex.com/ash/2015/webprogram/start.html. Based on these results, Gilead plans to submit supplemental regulatory filings in the U.S. and Europe early next year.
The use of Zydelig in combination with bendamustine/rituximab is investigational and the safety and efficacy of this combination has not been established.
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.
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.
- 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.
- 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.
- 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 worldwide. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.
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 supplemental filings for the use of Zydelig in combination with bendamustine and rituximab in the U.S. and Europe in the currently anticipated timelines. In addition, the regulatory filings may not be approved by regulatory agencies and marketing approvals, if granted, may have significant limitations on their use. As a result, Zydelig in combination with bendamustine and rituximab may never be successfully commercialized. Further, there is the possibility of unfavorable results from other clinical trials involving Zydelig. 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 September 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 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.
Gilead Sciences, Inc.
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