Dofetilide

– New Data Showcase Safety Profile of Twice-Yearly Lenacapavir for Pre-Exposure Prophylaxis (PrEP) with Other Medications and Recruitment Strategies for PURPOSE 5 – – Five-Year BICSTaR Results Offer Insights into Long-Term Treatment with Biktarvy®, Helping Inform the Future of Coordinated, Person-Centered HIV Care – – Latest Results on Novel Long-Acting Combination Regimens, Including Once-Weekly and Twice-Yearly Treatment Options – FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced its upcoming participation in the 20th European AIDS Conference (EACS) to be held in Paris, France from October 15-18. As the leader in HIV innovation, Gilead will provide an update on its strategic initiatives, key collaborations, and share new scientific data from its HIV research and development programs. The research that will be presented at EACS 2025, along with the Gilead-led symposia and supported community forums, reflect the company’s person-centered approach to advancing scientific discovery and underscores its focus on community partnership to help end the HIV epidemic. “It is fitting that thousands of scientists and community stakeholders will gather in Paris for EACS 2025,” said Jared Baeten, MD, PhD, Senior Vice President, Clinical Development, Virology Therapeutic Area Head, Gilead Sciences. “The first Declaration on Fast-Track Cities to end the HIV epidemic was signed in Paris on World AIDS Day in 2014. Fueled by Gilead’s longstanding commitment to develop and deliver HIV prevention and treatment options tailored to the individual’s needs, my colleagues and I continue to strive for a future without HIV, in Europe and around the world.” Gilead’s EACS 2025 program highlights include: HIV Prevention Research Expanding reach to populations in Europe not currently using PrEP: Researchers will present the strategies that supported the recruitment of people in high-priority populations across France and the UK for the Phase 2 PURPOSE 5 trial (N06513CT312), which is evaluating the persistence of twice-yearly lenacapavir among people who need or want PrEP but who have not previously engaged with existing HIV prevention options. Through collaboration with community advisory groups, thoughtful site selection and targeted recruitment goals for understudied populations, the study team achieved its enrollment goals and established a model for future HIV prevention studies. Safety data build understanding around concomitant use of lenacapavir: Further data from the PURPOSE 2 trial examined the concomitant use of lenacapavir by people also taking statins administered to lower cholesterol and PDE-5 inhibitors to treat erectile dysfunction. Lenacapavir is a moderate inhibitor of the enzyme CYP3A4 and could potentially increase levels of these classes of drugs. The accumulated data suggests that lenacapavir, like other moderate CYP3A4 inhibitors, can be co-administered with statins and PDE5 inhibitors with appropriate monitoring and dose adjustment. HIV Treatment Research Five-year outcomes from the BICSTaR (NCT03580668) Study: Long-term, real-world data were analyzed from individuals with HIV who were enrolled in Canada, France and Germany. The five-year outcomes are consistent with the results observed from multiple Phase 3 clinical trials evaluating the treatment responses of people with HIV on Biktarvy (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablets, B/F/TAF). In the group of BICSTaR study participants with 5 years of real-world follow-up, Biktarvy continued to demonstrate sustained viral suppression, a favorable safety and tolerability profile, and a high barrier to resistance. These benefits were seen in both treatment-naïve and treatment-experienced people with HIV who have a high burden of co-morbidities. The results underscore the importance of patient-reported outcomes as a person-centered approach to HIV research and can help us to better understand the impact on health-related quality of life and specifically, mental health status of people with HIV. This could help inform treatment strategies for these groups. Demographic profile of ARTISTRY-1 participants: Baseline characteristics from the Phase 3 portion of an ongoing study (NCT05502341) investigating the efficacy and safety of switching from a complex stable baseline regimen to an investigational once-daily oral regimen of bictegravir and lenacapavir. The results contextualize the unmet need for people living with HIV on complex regimens who may benefit from a single-tablet regimen. In September, the last patient completed their Week 48 visit in the Phase 3 portion of ARTISTRY-1. A topline data readout for the primary endpoint is anticipated to be announced before the end of the year. Late-breaking: Week 96 outcomes of an oral combination of Islatravir and Lenacapavir: Data from an ongoing, randomized, open-label Phase 2 study (NCT05052996) demonstrate that switching to an investigational once-weekly combination regimen of islatravir and lenacapavir enabled people living with HIV to maintain viral suppression to two years. At 96 weeks, based on the Missing = Failure and Missing = Excluded analyses, respectively, 88.5% (46/52) and 100% (n=46/46) of adults treated with the novel investigation combination maintained an undetectable viral load (HIV-1 RNA <50 copies/mL) demonstrating the potential of the combination, which could become the first weekly oral HIV treatment option. Two Phase 3 studies - ISLEND-1 and ISLEND-2 are ongoing. Week 52 results of twice-yearly regimen of Lenacapavir and broadly neutralizing antibodies (bNAbs): The Phase 2 (NCT05729568) open-label study from Gilead’s long-acting treatment pipeline demonstrated that twice-yearly lenacapavir in combination with bNAbs (teropavimab [GS-5423, TAB] and zinlirvimab [GS-2872, ZAB]) maintained viral suppression in people with HIV with susceptible viruses out to 52 weeks and was generally well tolerated. The investigational combination has the potential to be the first twice-yearly complete regimen. The novel treatment combination is now progressing to Phase 3 clinical development. Gilead’s symposia at EACS are focused on exploring the treatment needs of women with HIV throughout life, plus long-acting PrEP options and opportunities to address unmet HIV prevention needs: Overview of Scientific Presentations HIV PREVENTION RESEARCH Recruitment of Disproportionately Affected Populations in the PURPOSE 5 Study Evaluating Lenacapavir for PrEP in France and the UK Analysis of Barriers to Testing for HIV Prevention and Linkage to Care Among Migrants in Europe Commonly Prescribed Concomitant Medications and Clinical Safety Findings with Lenacapavir for PrEP in PURPOSE 2 Annual Persistence to Twice-Yearly Lenacapavir vs Daily Oral F/TDF for PrEP in the PURPOSE 2 Trial HIV TREATMENT RESEARCH Efficacy and Safety of a Twice-Yearly Regimen of Lenacapavir, Teropavimab, and Zinlirvimab: Phase 2 Week 52 Results Oral Weekly ISL/LEN in VS PWH: 96 Week Outcomes from a Phase 2 Study Five-Year Extended Follow-Up of the Observational BICSTaR Cohort: Final Analysis in PWH Receiving B/F/TAF in Routine Clinical Practice Demographics and Clinical Characteristics of Phase 3 Participants in ARTISTRY-1, An Open- Label Study Comparing a BIC/LEN STR With Complex ART Regimens For more information about Gilead at EACS 2025, including a complete list of abstracts and their corresponding oral and poster sessions, please visit: https://eacs-conference.com Lenacapavir for PrEP is not approved by any regulatory authority outside of the U.S. and the EU. Bictegravir and lenacapavir in combination are investigational and not approved anywhere globally. Their safety and efficacy have not been established in combination. The combination of islatravir and lenacapavir is investigational. Use in combination for the treatment of HIV has not been approved by any regulatory authority. Teropavimab and zinlirvimab are investigational compounds. The use of these compounds in combination with lenacapavir are investigational, are not approved by any regulatory authority, and their safety and efficacy has not been established. The use of lenacapavir in virologically suppressed people with HIV is investigational and the safety and efficacy of this use have not been established. There is currently no cure for HIV or AIDS. Please see below for U.S. and E.U. Indications and Important Safety Information, including Boxed Warning, for Yeztugo and Yeytuo. Please see below for U.S. Indications and Important Safety Information, including Boxed Warning, for Biktarvy. About Lenacapavir Lenacapavir is approved in multiple countries as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV in adults and adolescents who are at risk of HIV acquisition. Lenacapavir is also approved in multiple countries for the treatment of multi-drug-resistant HIV in adults, in combination with other antiretrovirals. The multi-stage mechanism of action of lenacapavir is distinguishable from other currently approved classes of antiviral agents. While most antivirals act on just one stage of viral replication, lenacapavir is designed to inhibit HIV at multiple stages of its lifecycle and has no known cross resistance exhibited in vitro to other existing drug classes. Lenacapavir is being evaluated as a long-acting option in multiple ongoing and planned early and late-stage clinical studies in Gilead’s HIV prevention and treatment research program. Lenacapavir is being developed as a foundation for potential future HIV therapies with the goal of offering both long-acting oral and injectable options with several dosing frequencies, in combination or as a mono agent, that help address individual needs and preferences of people and communities affected by HIV. The journal Science named lenacapavir its 2024 “Breakthrough of the Year.” EU Indication for Yeytuo® Yeytuo® injection is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents with increased HIV-1 acquisition risk weighing at least 35kg. U.S. Indication for Yeztugo® Yeztugo® (lenacapavir) injection, 463.5 mg/1.5 mL, is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents (≥35kg) who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating Yeztugo. U.S. Important Safety Information for Yeztugo BOXED WARNING: RISK OF DRUG RESISTANCE WITH USE OF YEZTUGO IN UNDIAGNOSED HIV-1 INFECTION Individuals must be tested for HIV-1 infection prior to initiating Yeztugo, and with each subsequent injection of Yeztugo, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of Yeztugo by individuals with undiagnosed HIV-1 infection. Do not initiate Yeztugo unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving Yeztugo must transition to a complete HIV-1 treatment regimen. Contraindications Yeztugo is contraindicated in individuals with unknown or positive HIV-1 status. Warnings and precautions Comprehensive risk management: Use Yeztugo to reduce the risk of HIV-1 acquisition as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). HIV-1 acquisition risk includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or present STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high-prevalence area or network. Counsel individuals on the use of other prevention methods to help reduce their risk. Use Yeztugo only in individuals confirmed to be HIV-1 negative. Evaluate for current or recent signs or symptoms consistent with HIV-1 infection. Confirm HIV-1 negative status prior to initiating, prior to each subsequent injection, and as clinically appropriate. Potential risk of resistance: There is a potential risk of developing resistance to Yeztugo if an individual acquires HIV-1 before or when receiving Yeztugo, or following discontinuation. HIV- 1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection taking only Yeztugo, because Yeztugo alone is not a complete regimen for HIV-1 treatment. To minimize this risk, it is essential to test before each injection and additionally as clinically appropriate. Individuals confirmed to have HIV-1 must immediately begin a complete HIV-1 treatment regimen. Alternative forms of PrEP should be considered after discontinuation of Yeztugo for those who are at continuing risk of HIV-1 acquisition and should be initiated within 28 weeks of the last Yeztugo injection. Long-acting properties and potential associated risks: Residual concentrations of Yeztugo may remain in systemic circulation for up to 12 months or longer after the last injection. Select individuals who agree to the required injection dosing schedule because nonadherence or missed doses could lead to HIV-1 acquisition and development of resistance. Serious injection site reactions: Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer. Only administer Yeztugo subcutaneously. Use Yeztugo to reduce the risk of HIV-1 acquisition as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). HIV-1 acquisition risk includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or present STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high-prevalence area or network. Counsel individuals on the use of other prevention methods to help reduce their risk. Use Yeztugo only in individuals confirmed to be HIV-1 negative. Evaluate for current or recent signs or symptoms consistent with HIV-1 infection. Confirm HIV-1 negative status prior to initiating, prior to each subsequent injection, and as clinically appropriate. There is a potential risk of developing resistance to Yeztugo if an individual acquires HIV-1 before or when receiving Yeztugo, or following discontinuation. HIV- 1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection taking only Yeztugo, because Yeztugo alone is not a complete regimen for HIV-1 treatment. To minimize this risk, it is essential to test before each injection and additionally as clinically appropriate. Individuals confirmed to have HIV-1 must immediately begin a complete HIV-1 treatment regimen. Alternative forms of PrEP should be considered after discontinuation of Yeztugo for those who are at continuing risk of HIV-1 acquisition and should be initiated within 28 weeks of the last Yeztugo injection. Residual concentrations of Yeztugo may remain in systemic circulation for up to 12 months or longer after the last injection. Select individuals who agree to the required injection dosing schedule because nonadherence or missed doses could lead to HIV-1 acquisition and development of resistance. Adverse reactions Most common adverse reactions(≥5%) in Yeztugo clinical trials were injection site reactions, headache, and nausea. Drug interactions Strong or moderate CYP3A inducers may significantly decrease Yeztugo concentrations. Dosage modifications are recommended when initiating these inducers. It is not recommended to use Yeztugo with combined P-gp, UGT1A1, and strong CYP3A inhibitors. Coadministration of Yeztugo with sensitive substrates of CYP3A or P-gp may increase their concentrations and result in the increased risk of their adverse events. Yeztugo may increase the exposure of drugs primarily metabolized by CYP3A initiated within 9 months after the last injection of Yeztugo. Dosage and administration HIV screening: Test for HIV-1 infection prior to initiating, prior to each subsequent injection, and as clinically appropriate using an approved or cleared test for the diagnosis of acute or primary HIV-1 infection. Dosage: Initiation dosing (injections and tablets) followed by once-every-6-months continuation injection dosing. Tablets may be taken with or without food. Initiation: Day 1: 927 mg by subcutaneous injection (2 x 1.5-mL injections) and 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally. Continuation: 927 mg by subcutaneous injection every 6 months (26 weeks) from date of last injection ±2 weeks. Anticipated delayed injections: If scheduled 6-month injection is anticipated to be delayed by more than 2 weeks, Yeztugo tablets may be taken on an interim basis (for up to 6 months) until injections resume. Dosage is 300 mg orally (1 x 300-mg tablet) once every 7 days. Resume continuation injections within 7 days of the last oral dose. Missed injections: If more than 28 weeks have elapsed since the last injection and Yeztugo tablets have not been taken, restart with initiation dosing if clinically appropriate. Dosage modifications of Yeztugo are recommended when initiating with strong or moderate CYP3A inducers. Consult the full Prescribing Information for recommendations. Initiation: Day 1: 927 mg by subcutaneous injection (2 x 1.5-mL injections) and 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally. Continuation: 927 mg by subcutaneous injection every 6 months (26 weeks) from date of last injection ±2 weeks. About Biktarvy Biktarvy is a complete HIV treatment that combines three powerful medicines to form the smallest 3-drug, integrase strand transfer inhibitor (INSTI)-based single-tablet regimen (STR) available, offering simple once-daily dosing with or without food, with a limited drug interaction potential and a high barrier to resistance. Biktarvy combines the novel, unboosted INSTI bictegravir with the F/TAF backbone. Biktarvy is a complete STR and should not be taken with other HIV medicines. U.S. Indication for Biktarvy Biktarvy is indicated as a complete regimen for the treatment of HIV-1 infection in adult and pediatric patients weighing ≥14 kg with no antiretroviral treatment history; or with an ARV treatment history and not virologically suppressed, with no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir; or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ARV regimen with no known or suspected substitutions associated with resistance to bictegravir or tenofovir. U.S. Important Safety Information for Biktarvy BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of BIKTARVY. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue BIKTARVY. If appropriate, anti-hepatitis B therapy may be warranted. Contraindications Coadministration: Do not use BIKTARVY with dofetilide or rifampin. Warnings and precautions Drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during BIKTARVY therapy and monitor for adverse reactions. Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported. New onset or worsening renal impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)–containing products. Do not initiate BIKTARVY in patients with estimated creatinine clearance (CrCl) <30 mL/min except in virologically suppressed adults <15 mL/min who are receiving chronic hemodialysis. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue BIKTARVY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Renal monitoring: Prior to or when initiating BIKTARVY and during therapy, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, assess serum phosphorus. Lactic acidosis and severe hepatomegaly with steatosis: Fatal cases have been reported with the use of nucleoside analogs, including FTC and TDF. Discontinue BIKTARVY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse reactions Most common adverse reactions (incidence ≥5%; all grades) in clinical studies through week 144 were diarrhea (6%), nausea (6%), and headache (5%). Drug interactions Prescribing information: Consult the full prescribing information for BIKTARVY for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments. Enzymes/transporters: Drugs that induce P-gp or induce both CYP3A and UGT1A1 can substantially decrease the concentration of components of BIKTARVY. Drugs that inhibit P-gp, BCRP, or inhibit both CYP3A and UGT1A1 may significantly increase the concentrations of components of BIKTARVY. BIKTARVY can increase the concentration of drugs that are substrates of OCT2 or MATE1. Drugs affecting renal function: Coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC and tenofovir and the risk of adverse reactions. Dosage and administration Dosage: Adult and pediatric patients weighing ≥25 kg: 1 tablet containing 50 mg bictegravir (BIC), 200 mg emtricitabine (FTC), and 25 mg tenofovir alafenamide (TAF) taken once daily with or without food. Pediatric patients weighing ≥14 kg to <25 kg: 1 tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food. For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes. Renal impairment: For patients weighing ≥25 kg, not recommended in patients with CrCl 15 to <30 mL/min, or <15 mL/min who are not receiving chronic hemodialysis, or <15 mL/min who are receiving chronic hemodialysis and have no antiretroviral treatment history. For patients weighing ≥14 kg to <25 kg, not recommended in patients with CrCl <30 mL/min. Hepatic impairment: Not recommended in patients with severe hepatic impairment. Prior to or when initiating: Test patients for HBV infection. Prior to or when initiating, and during treatment: As clinically appropriate, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, assess serum phosphorus. Pregnancy and lactation Pregnancy: BIKTARVY is recommended in pregnant individuals who are virologically suppressed on a stable ARV regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY. Lower plasma exposures of BIKTARVY were observed during pregnancy; therefore, viral load should be monitored closely during pregnancy. An Antiretroviral Pregnancy Registry (APR) has been established. Available data from the APR for BIC, FTC, or TAF show no difference in the rates of birth defects compared with a US reference population. Lactation: Individuals infected with HIV-1 should be informed of the potential risks of breastfeeding. About Gilead HIV For more than 35 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention and cure research. Gilead researchers have developed 13 HIV medications, including the first single-tablet regimen to treat HIV, the first antiretroviral for pre-exposure prophylaxis (PrEP) to help reduce new HIV infections, and the first long-acting injectable HIV treatment medication administered twice-yearly. Our advances in medical research have helped to transform HIV into a treatable, preventable, chronic condition for millions of people. Gilead is committed to continued scientific innovation to provide solutions for the evolving needs of people affected by HIV around the world. Through partnerships, collaborations and charitable giving, the company also aims to improve education, expand access and address barriers to care, with the goal of ending the HIV epidemic worldwide. Gilead has been repeatedly recognized as one of the top two leading philanthropic funders of HIV-related programs in a report released by Funders Concerned About AIDS. Discover more about Gilead’s unique collaborations worldwide and the work to help end the HIV epidemic. 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, COVID-19, cancer and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California. 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 and complete clinical trials in the anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials, including those involving Biktarvy, lenacapavir, teropavimab and zinlirvimab (such as ARTISTRY-1, BICsTaR, EMPOWER, PURPOSE 2 and PURPOSE 5); uncertainties relating to regulatory applications and related filing and approval timelines, including regulatory applications for lenacapavir for PrEP, and the risk that any regulatory approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of the programs for the indications currently under evaluation and, as a result, the programs may never be successfully commercialized for such indications; Gilead’s ability to effectively manage its global health equity access strategy; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2025, 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. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is 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 Truvada, Yeztugo, and Biktarvy including Boxed Warning, are available at www.gilead.com. Truvada, Truvada for PrEP, Yeztugo, Yeytuo, Biktarvy, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at www.gilead.com, follow Gilead on X (@Gilead Sciences) and LinkedIn, or contact Gilead Public Affairs. Blair Baumwell, Media public_affairs@gilead.com Jacquie Ross, Investors Investor_relations@gilead.com

Over-the-Counter Drug Research Evaluation of Sunscreen Active Ingredients DARS has conducted two randomized clinical trials which demonstrated systemic exposure of multiple commonly used sunscreen active ingredients under single and maximal use conditions. Additionally, DARS is evaluating in vitro metabolism and transporter-based drug interactions with sunscreen active ingredients. The clinical effect of these findings is unknown and continued use of sunscreen is encouraged. Publications Abbasi J. FDA Trials Find Sunscreen Ingredients in Blood, but Risk Is Uncertain. JAMA 2020, 323(15):1431–1432 . FDA Spotlight on CDER Science: New FDA Study Shines Light on Sunscreen Absorption. July 2019 . FDA Voices: Shedding More Light on Sunscreen Absorption. January 2020 . Matta et al. Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA 2019, 321(21):2082-91 . Matta et al. Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA 2020, 323(3):256-67 . Pre-Market Research Comprehensive in vitro Proarrhythmia Assay (CiPA) DARS is working with an international consortium on the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, which is developing an in vitro (cellular models) and in silico (computational) paradigm for cardiac safety evaluation of new drugs. CiPA involves four components: (1) in vitro assessment of drug effects on multiple cardiac ion channels; (2) integration of the multi-ion channel effects in an in silico computer model of the human ventricular cardiomyocyte (heart cells) to output a proarrhythmic (abnormal heart rhythm) risk score; (3) assessment for unanticipated effects in vitro using human-induced pluripotent stem cell-derived cardiomyocytes; and (4) phase 1 clinical studies with exposure-response analysis. DARS is leading applied research across all four components to develop and validate this novel regulatory paradigm. Integrated Cellular Systems DARS is currently evaluating liver, heart, and connected liver and heart microphysiological systems to determine if they are suitable for drug development, including prediction of adverse events and metabolism. Additionally, both hepatocytes and cardiomyocytes are currently being engineered from stem cells. The cardiomyocytes are microengineered at the single-cell and tissue levels so they are more similar to mature cardiomyocytes compared to more traditional methods. The hepatocytes are being evaluated in both planar and spheroid form to determine how their function and reaction to toxicity compares to primary human hepatocytes. Publications Blinova et al. Clinical Trial in a Dish: Personalized Stem Cell-Derived Cardiomyocyte Assay Compared With Clinical Trial Results for Two QT-Prolonging Drugs. Clin Trans Sci 2019, 12(6):687-97. FDA Impact Story: Improved Assessment of Cardiotoxic Risk in Drug Candidates: The Comprehensive in vitro Proarrhythmia Assay. March 2020. Indapurkar et al. Simultaneous UHPLC-MS/MS method of estradiol metabolites to support the evaluation of Phase-2 metabolic activity of induced pluripotent stem cell derived hepatocytes. J Chromatogr B Analyt Technol Biomed Life Sci 2019, 1126-27:121765. Li et al. Quantitative Systems Pharmacology Models for a New International Cardiac Safety Regulatory Paradigm: An Overview of the Comprehensive In Vitro Proarrhythmia Assay In Silico Modeling Approach. CPT Pharmacometrics Syst Pharmacol 2019, 8(6):371-9. Li et al. General Principles for the Validation of the Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy. Clin Pharmacol Ther 2020, 107(1):102-11. Matta et al. Novel High-Throughput Quantitation of Potent hERG Blocker Dofetilide in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry: Application in a Phase 1 ECG Biomarker Validation Study. J Anal Toxicol 2019, Epub . Ribeiro et al. Liver Microphysiological Systems for Predicting and Evaluating Drug Effects. Clin Pharmacol Ther 2019, 106(1):139-47 . Ribeiro et al. Considerations for an In Vitro, Cell-Based Testing Platform for Detection of Drug-Induced Inotropic Effects in Early Drug Development. Part 2: Designing and Fabricating Microsystems for Assaying Cardiac Contractility With Physiological Relevance Using Human iPSC-Cardiomyocytes. Front Pharmacol 2019, 10:934 . Wu et al. Drug potency on inhibiting late Na+ current is sensitive to gating modifier and current region where drug effects were measured. J Pharmacol Toxicol Methods 2019, 100:106605 . Biosimilar and Generic Drug Research Pharmacodynamic Biomarkers for Biosimilar Approval To ensure US patients realize the public health benefit of a robust, competitive market for biosimilar products, FDA is focused on improving the efficiency of biosimilar development. DARS is conducting research to inform FDA’s thinking on critical aspects of the use of pharmacodynamic biomarkers to demonstrate biosimilarity, which can either streamline or negate the need for comparative clinical studies. This project will result in an evidentiary framework and methodology for identifying, characterizing and applying biomarkers to serve as primary clinical assessment for biosimilar approval. Three clinical studies are being performed to characterize biomarkers for biosimilar development. Biologics/Biosimilars and Complex Generics Safety, Quality, and Availability Studies DARS is utilizing a wide range of studies, including in vitro and in vivo methodologies, to evaluate the safety, quality, and availability of biologics, biosimilars, and generics. Humanized mouse models are being utilized to evaluate immune-mediated response to biologic products and peptide generic drugs. Additionally, in vitro methods are being used to evaluate the suitability of multiple bioassays for PEGylated products to better address the challenges associated with determining biosimilarity. Finally, an in vivo model to evaluate a dexamethasone intravitreal implant will determine if systemic dexamethasone exposure may serve as a surrogate biomarker to assess bioequivalence of generic implant products. Publications Li et al. Advancing Biosimilar Development Using Pharmacodynamic Biomarkers in Clinical Pharmacology Studies. Clin Pharmacol Ther 2020; 107:40-42 . Semple et al. Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20-Specific Cytotoxicity Induced by Ofatumumab. Clin Transl Sci 2019, 12(3):283-90 . Weaver et al. BLT-Immune Humanized Mice as a Model for Nicolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains. Toxicol Sci 2019, 169(1):194-208 . Yan et al. Bone marrow-liver-thymus (BLT) immune humanized mice as a model to predict cytokine release syndrome. Transl Res 2019, 210:43-56 . Yan et al. Evaluation of a TGN1412 analogue using in vitro assays and two immune humanized mouse models. Toxicol Appl Pharmacol 2019, 372:57-69 . Drugs with Abuse Potential Research Clinical Study on the Combination of Psychotropic Drugs and Opioids on Respiratory Depression FDA recently added black box warning to drug labels for opioids and benzodiazepines to not co-administer due to risk for respiratory depression; it is unclear whether other psychotropic drugs can have a similar effect when co-administered with opioids. The primary objective of this project is to study whether two psychotropic drugs increase opioid-induced respiratory depression when co-administered. Computational Models and in vitro Studies DARS uses multiple computational and in vitro methodologies to predict the risk to public safety of newly-identified compounds. For example, a quantitative structure-activity relationship model was recently created to predict if a chemical will cross the blood-brain barrier, therefore potentially leading to neurotoxic effects. Additionally, a model is currently under development to predict the dose of naloxone needed to overcome opioid-induced respiratory depression. Finally, an in vitro study is evaluating if opioids can block cardiac ion channels and how that affects QTc prolongation. Publications Xu et al. Developing an animal model to detect drug-drug interactions impacting drug-induced respiratory depression. Toxicol Rep 2020, 7:188-97 . Post-Market Research Assessing Drug Combination Strategies to Reduce Antimicrobial Resistance DARS has developed an in vitro method to quantitate the rate at which antibiotic resistance appears. The system uses a hollow fiber bioreactor system to deliver single drugs or combinations of drugs using human pharmacokinetic profiles. Additionally, next-generation sequencing is used to investigate the genetic and epigenetic biomarkers of antibiotic resistance, and genomics and bioinformatics are utilized to investigate the effects of oral antibiotics on in vitro bacterial genomes and in vivo gut microbiome. Publications Chockalingam et al. Evaluation of Immunocompetent Urinary Tract Infected Balb/C Mouse Model for the Study of Antibiotic Resistance Development Using Escherichia Coli CFT073 Infection. Antibiotics (Basel) 2019, 8(4):E170 . Gandhi et al. Combining LC-MS/MS and hollow-fiber infection model for real-time quantitation of ampicillin to antimicrobial resistance. Future Sci OA 2018. 5(1):FSO349 . (Quantitative) Structure Activity Relationship Consult Service DARS chemical informatics projects (using computational techniques to solve chemistry problems) are focused on endpoints of regulatory interest, linked through chemical structure. Research activities include (1) database development for model training and validation; (2) development of web-based applications to enable direct structure-based searching by CDER staff; and (3) (Q)SAR model development (models using physical and chemical properties to predict the behavior of new drugs) to support drug safety review. Databases and models are used to respond to regulatory review consultation requests. Publications Amberg, et al. Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity? Mutagenesis 2019, 34(1):67-82 . FDA Impact Story: CDER Assessment of Drug Impurity Mutagenicity by Quantitative Structure-Activity Relationship Modeling. May 2020 . Hasselgren, et al. Genetic toxicology in silico protocol. Regul Toxicol Pharmacol 2019, 107:104403 . Landry et al. Transitioning to composite bacterial mutagenicity models in ICH M7 (Q)SAR analyses. 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