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Gilead Statement on Zydelig® U.S. Indication for Follicular Lymphoma and Small Lymphocytic Leukemia

Foster City, Calif., January 14, 2022 – In 2014, Zydelig® (idelalisib) received accelerated approval from the U.S. Food and Drug Administration (FDA) to treat relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL). Approval was based on a Phase 2 study in indolent non-Hodgkin lymphoma showing that 54% of those with FL and 58% of those with SLL had an objective response as assessed by an Independent Review Committee.

Continued approval for these indications was contingent upon providing evidence supporting confirmation of clinical benefit in FL and SLL. As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge. As a result, Gilead Sciences, Inc. (Nasdaq: GILD) formally notified the FDA of its decision to voluntarily withdraw these indications from the U.S. market.

Zydelig was also approved in 2014 to treat relapsed chronic lymphocytic leukemia (CLL) in the U.S. Additionally, Zydelig has marketing authorization to treat CLL and FL in the EU, UK, Canada, Australia, New Zealand and Switzerland. None of these approvals are affected by the proposed withdrawal. Thus, Zydelig will remain on the market in the U.S. for CLL and for CLL and FL in the EU, UK, Canada, Australia, New Zealand, and Switzerland.

Gilead continues to work collaboratively with the FDA to complete the withdrawal of the FL and SLL indications in the U.S. and with healthcare professionals to support those currently being treated with Zydelig. People receiving Zydelig for relapsed FL or SLL in the U.S. should discuss their treatment options with their healthcare provider.

About Zydelig
Zydelig® (idelalisib) is approved in the U.S. for the treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities. Currently, Zydelig is also approved under the accelerated approval pathway for relapsed FL and SLL in patients who have received at least two prior systemic therapies. Accelerated approval was granted for FL and SLL based on overall response rate since an improvement in patient survival or disease-related symptoms has not been established. Zydelig is not indicated or recommended for first-line treatment for any use or in combination with bendamustine and/or rituximab for the treatment of FL. The Zydelig U.S. Prescribing Information has a Boxed Warning for the risks of fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation; see below for Important Safety Information.

U.S. Important Safety Information for Zydelig
BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

  • Fatal and/or serious hepatotoxicity occurred in 16% to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig.
  • Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig.
  • Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig.
  • Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
  • Fatal and serious intestinal perforation can occur in Zydelig-treated patients. Discontinue Zydelig if intestinal perforation is suspected.

Contraindications

  • History of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis (TEN) with any drug.

Warnings and Precautions

  • Hepatotoxicity: Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. 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: Severe diarrhea or colitis (Grade ≥3) occurred in 14% of patients treated with Zydelig monotherapy and 20% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea.
  • Pneumonitis: Fatal and serious pneumonitis occurred in 4% of patients treated with Zydelig compared to 1% on the comparator arms in randomized clinical trials of combination therapies. Time to onset of pneumonitis ranged from <1 to 15 months. Clinical manifestations included interstitial infiltrates and organizing pneumonia. Monitor patients on Zydelig for pulmonary symptoms. In patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5%, interrupt Zydelig until the etiology has been determined. If symptomatic pneumonitis or organizing pneumonia is diagnosed, initiate appropriate treatment with corticosteroids and permanently discontinue Zydelig.
  • Infections: Fatal and/or serious infections occurred in 21% of patients treated with Zydelig monotherapy and 48% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. The most common infections were pneumonia, sepsis, and febrile neutropenia. Treat infections prior to initiation of Zydelig therapy and interrupt Zydelig for Grade 3 or higher infection. Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in <1% of patients treated with Zydelig. Provide PJP prophylaxis during treatment with ZYDELIG. Interrupt Zydelig in patients with suspected PJP infection of any grade, and permanently discontinue Zydelig if PJP infection of any grade is confirmed. Regular clinical and laboratory monitoring for CMV infection is recommended in patients with a history of CMV infection or positive CMV serology at the start of treatment with Zydelig. Interrupt Zydelig in the setting of positive CMV PCR or antigen test until the viremia has resolved. If Zydelig is subsequently resumed, patients should be monitored (by PCR or antigen test) for CMV reactivation at least monthly.
  • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Zydelig permanently in patients who experience intestinal perforation.
  • Severe cutaneous reactions: Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with Zydelig. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also occurred. If suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS or TEN, or DRESS is confirmed, permanently discontinue Zydelig. Other severe or life-threatening (Grade ≥3) cutaneous reactions have been reported. Monitor patients for the development of severe cutaneous reactions and permanently discontinue Zydelig.
  • Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients on Zydelig. Zydelig is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis. Permanently discontinue Zydelig and institute appropriate supportive measures if a reaction occurs.
  • Neutropenia: Grade 3-4 neutropenia occurred in 25% of patients treated with monotherapy and 58% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Monitor blood counts at least every 2 weeks for the first 6 months, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L. Interrupt Zydelig until resolution and resume at reduced dose.
  • Embryo-fetal toxicity: Zydelig may cause fetal harm. Females who are or become pregnant while taking Zydelig should be apprised of the potential hazard to the fetus. Advise females of reproductive potential 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 in patients treated with Zydelig in combination trials (incidence ≥30%, all grades) were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea; and in the monotherapy trial (incidence ≥20%, all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash.
  • Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (23%), diarrhea (10%), pyrexia (9%), sepsis (8%) and febrile neutropenia (5%); SAR were reported in 59% of patients, and 17% discontinued therapy due to adverse reactions. Most frequent SAR in clinical studies when used alone were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients, and 53% discontinued due to adverse reactions.
  • Most common lab abnormalitiesinclude neutropenia, ALT elevations, and AST elevations.

Drug Interactions

  • CYP3A inducers: Avoid coadministration with strong CYP3A inducers.
  • CYP3A inhibitors: Avoid coadministration with strong CYP3A inhibitors. If unable to use alternative drugs, monitor patients more frequently for Zydelig adverse reactions.
  • CYP3A substrates: Avoid coadministration with sensitive CYP3A substrates.

Dosage and Administration

  • Recommended Dosage: 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: ALT/AST elevations, bilirubin elevations, diarrhea, pneumonitis, infections, intestinal perforation, severe cutaneous reactions, hypersensitivity reactions, neutropenia, and thrombocytopenia. For other severe or life-threatening adverse reactions, withhold Zydelig until resolution. If resuming Zydelig after interruption for other severe or life-threatening toxicities, reduce the dosage to 100 mg twice daily. Permanently discontinue Zydelig for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.

About Gilead Sciences
Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Gilead Forward-Looking Statements
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 initiate, progress or complete clinical trials within currently anticipated timelines or at all, including those involving Zydelig; the possibility of unfavorable results from ongoing or additional trials, including those involving Zydelig; Gilead’s ability to receive regulatory approvals in a timely manner or at all, including additional regulatory approvals of Zydelig, and the risk that any such approvals may be subject to significant limitations on use; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2021, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Investors are cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and are cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements.

U.S. full Prescribing Information for Zydelig, including Boxed Warning, is available at www.gilead.com.

Zydelig, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies.