Gilead Presents New Findings on Profile of Descovy® for Potential Use as HIV Pre-exposure Prophylaxis Compared With Truvada®

Gilead Sciences, Inc. (NASDAQ: GILD) today presented additional results from the DISCOVER trial evaluating an investigational use of Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets; F/TAF) for HIV pre-exposure prophylaxis (PrEP). In a sub-analysis of the DISCOVER trial, Descovy reached intracellular drug concentration levels above the estimated protective threshold significantly more quickly than Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg tablets; F/TDF), and additional pharmacokinetic data confirm that these drug concentration levels persist longer than Truvada. The results were presented at the 10^th International AIDS Society Conference on HIV Science (IAS 2019) being held in Mexico City.

"Gilead is committed to driving advances in HIV prevention and supporting broader public health initiatives that are designed to reduce HIV infections," said Diana Brainard, MD, Senior Vice President, HIV and Emerging Viruses, Gilead Sciences. "These results presented at IAS provide further evidence supporting the potential for Descovy for PrEPtm to offer an important new prevention option for people at risk of acquiring HIV."

In April, Gilead submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for once-daily Descovy for PrEP. A Priority Review voucher was submitted with the filing, leading to an anticipated review time of six months. Descovy was approved in the United States in 2016 for the treatment of HIV-1 infection in combination with other antiretroviral agents, and the use of Descovy for a PrEP indication is investigational. Descovy and Truvada have a Boxed Warning in their U.S. product label regarding the risk of post-treatment acute exacerbation of hepatitis B; Truvada for PrEP also includes a Boxed Warning regarding the risk of drug resistance with use of Truvada for PrEP in undiagnosed early HIV infection. See below for Indications and Important Safety Information.

These results were based on a sub-analysis of the DISCOVER trial, a two-year Phase 3 randomized, controlled, double-blind study evaluating the safety and efficacy of the investigational use of once-daily Descovy for PrEP compared with Truvada for PrEP. The study enrolled adult men and transgender women who have sex with men who were both at substantial and sustained risk for sexually acquired HIV infection. DISCOVER trial sites included STI clinics, LGBTQ health centers, and other clinical practices that are located in areas with high background rates of HIV and that serve populations with among the highest risk of HIV infection.

The primary endpoint of the DISCOVER trial was the incidence of documented HIV infection per 100 person-years, with a minimum follow-up of 48 weeks and at least 50 percent of participants having 96 weeks of follow-up. Descovy met the primary endpoint of non-inferiority. The most common treatment-emergent adverse events (?25 percent; all grades) were bacterial sexually transmitted infections, including anal chlamydia infection, oropharyngeal gonococcal infection and rectal gonorrhea. Common study drug-related side effects (? 1 percent; all grades) included diarrhea, nausea, headache and fatigue.

There were no differences in HIV risk factors, acquired STIs or adherence between the two study drug arms in DISCOVER. Overall, study participants randomized to Descovy for PrEP had a significantly reduced time to achieve a 90 percent effective concentration (EC90) of tenofovir diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs), as compared with participants taking Truvada. At Week 4, levels of TFV-DP in PBMCs were 6.3-fold higher with Descovy compared with Truvada, resulting in 98 percent of participants receiving Descovy had drug levels above the EC90 compared with 68 percent of participants taking Truvada. Pharmacokinetic data from separate PK studies demonstrate that after using drugs for 14-28 days, F/TAF users who stop drug still maintain TFV-DP concentrations above the EC90 for at least 60 percent longer than F/TDF users.

"Low tenofovir diphosphate concentrations in PBMCs were associated with an increased risk of HIV acquisition," said Christoph Spinner, School of Medicine at Technical University of Munich and lead study author. "These results provide valuable new information about the profile of Descovy for its potential use as PrEP."

Additionally, at IAS, Gilead presented data assessing renal adverse events in people at risk for HIV acquisition taking Truvada for PrEP. These results of an analysis of multi-national Truvada for PrEP utilization data in MSM are summarized in Poster #TUPEC393.

The use of Descovy for the prevention of HIV is investigational and has not been determined to be safe or efficacious and is not approved anywhere globally.

IMPORTANT U.S. SAFETY INFORMATION AND INDICATION FOR THE USE OF DESCOVY FOR HIV TREATMENT

BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

• Descovy is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Descovy have not been established in patients coinfected with HIV-1 and HBV. 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 Descovy. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Descovy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Warnings and precautions

• Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.
• New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir prodrugs. In clinical trials of FTC and tenofovir alafenamide with elvitegravir and cobicistat, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Do not initiate Descovy in patients with estimated creatinine clearance (CrCl) <30 mL/min. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue Descovy in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
  Renal monitoring: In all patients, monitor CrCl, urine glucose, and urine protein prior to initiating and during therapy. In patients with chronic kidney disease, additionally monitor 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 Descovy 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 reaction (incidence ?10%; all grades) in clinical studies was nausea (10%).

Drug interactions

• Prescribing information: Consult the full prescribing information for Descovy for more information on potentially significant drug interactions, including clinical comments.
• Metabolism: Drugs that inhibit P-gp can increase the concentrations of components of Descovy. Drugs that induce P-gp can decrease the concentrations of components of Descovy, which may lead to loss of efficacy and development of resistance.
• Drugs affecting renal function: Coadministration of Descovy with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and tenofovir and the risk of adverse reactions.

Dosage and administration

• Dosage: Patients who weigh ?25 kg: 1 tablet taken orally once daily with or without food.
• Renal impairment: Not recommended in patients with CrCl <30 mL/min.
• Testing prior to initiation: Test patients for HBV infection and assess CrCl, urine glucose and urine protein.
• Pediatrics: The safety and effectiveness of Descovy coadministered with an HIV-1 protease inhibitor that is administered with either ritonavir or cobicistat have not been established in pediatric subjects weighing less than 35 kg.

Pregnancy and lactation

• Pregnancy: There is insufficient human data on the use of Descovy during pregnancy. An Antiretroviral Pregnancy Registry (APR) has been established; available data from the APR for FTC shows no difference in the rates of birth defects compared with a U.S. reference population.
• Lactation: Women infected with HIV-1 should be instructed not to breastfeed, due to the potential for HIV-1 transmission.

INDICATION

Descovy is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in patients weighing at least 35 kg.

Descovy is also indicated, in combination with other antiretroviral agents other than protease inhibitors that require a CYP3A inhibitor, for the treatment of HIV-1 infection in pediatric patients weighing at least 25 kg and less than 35 kg.

Limitations of Use:

Descovy is not indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of acquiring HIV-1 infection.

IMPORTANT U.S. SAFETY INFORMATION AND INDICATION FOR TRUVADA FOR PREP

BOXED WARNING: RISK OF DRUG RESISTANCE WITH USE OF TRUVADA FOR PrEP IN UNDIAGNOSED EARLY HIV-1 INFECTION and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

• Truvada for PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiation and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of Truvada for PrEP following undetected acute HIV-1 infection. Do not initiate if signs or symptoms of acute HIV-1 infection are present unless HIV-negative status is confirmed

• Severe acute exacerbations of hepatitis B have been reported in HBV-infected patients who discontinued Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients with HBV after discontinuing Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted

Contraindications

• Do not use Truvada for PrEP in individuals with unknown or positive HIV status

Warnings and precautions: Comprehensive risk reduction strategies

• Reduce HIV-1 risk: Truvada for PrEP is not always effective in preventing HIV-1. Use only as part of a comprehensive prevention strategy that includes safer sex practices, regular testing for HIV-1 and other STIs, and counseling on reducing sexual risk behaviors
• Reduce potential for drug resistance: Truvada for PrEP should only be used in individuals confirmed to be HIV-negative immediately prior to initiation, at least every 3 months while taking Truvada, and upon an STI diagnosis. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only Truvada. Truvada alone is not a complete regimen for treating HIV-1
  • HIV antibody tests may not detect acute HIV infection. If recent exposures are suspected or symptoms of acute HIV infection are present (e.g., fever, fatigue, myalgia, skin rash), delay initiating (?1 month) or discontinue use and confirm HIV-negative status with a test approved by U.S. Food and Drug Administration (FDA) for the diagnosis of acute HIV infection
  • If a screening test indicates possible HIV-1 infection, convert the HIV-1 PrEP regimen to an HIV treatment regimen until HIV-negative status is confirmed.
• Counsel on adherence: Counsel individuals to strictly adhere to their dosing schedule, as efficacy is strongly correlated with adherence. Some individuals, such as adolescents, may benefit from more frequent visits and counseling.

Warnings and precautions

• New onset or worsening renal impairment: Cases of acute renal impairment and Fanconi syndrome have been reported with the use of tenofovir disoproxil fumarate (TDF). Truvada is not recommended in individuals with estimated creatinine clearance (CrCl) <60 mL/min. Avoid concurrent or recent use with a nephrotoxic agent. Acute renal failure has been reported after initiation of high dose or multiple NSAIDs in patients at risk for renal dysfunction; consider alternatives to NSAIDs in these patients. Monitor renal function in all patients ? See Dosage and Administration
• Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia associated with proximal renal tubulopathy, have been reported with the use of TDF Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss
• Lactic acidosis and severe hepatomegaly with steatosis: Fatal cases have been reported with the use of nucleoside analogs, including Truvada. Discontinue use if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations
• Drug interactions: See Drug Interactions section. Consider the potential for drug interactions prior to and during use of Truvada and monitor for adverse reactions

Adverse reactions

• Common adverse reactions (>2% and more frequently than placebo) of Truvada for PrEP in clinical trials were headache, abdominal pain, and weight loss

Drug interactions

• Prescribing information: Consult the full Prescribing Information for Truvada for more information, warnings, and potentially significant drug interactions, including clinical comments
• Hepatitis C antivirals: Coadministration with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir increases TDF exposure; monitor for adverse reactions
• Drugs affecting renal function: Coadministration of Truvada with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and/or tenofovir

Pregnancy and lactation

• Pregnancy: An Antiretroviral Pregnancy Registry (APR) has been established. Available data from observational studies and the APR show no increase in the rate of major birth defects for Truvada compared with a US reference population. Consider HIV prevention methods, including Truvada for PrEP in at-risk women due to the potential increased risk of HIV-1 infection during pregnancy and mother to child transmission during acute HIV-1 infection
• Lactation: Emtricitabine and tenofovir have been detected in human milk. Evaluate the benefits and risks of Truvada for PrEP in breastfeeding women, including the risk of HIV-1 acquisition due to nonadherence, and subsequent mother to child transmission. Health benefits of breastfeeding should be considered along with potential adverse effects of Truvada on the child, which are unknown

Dosage and administration

• Dosage: One tablet once daily with or without food
• HIV screening: Test for HIV-1 infection prior to initiating and at least every 3 months during treatment
• HBV screening: Test for HBV infection prior to or when initiating treatment
• Renal impairment and monitoring: Not recommended in individuals with CrCl <60 mL/min. In all patients, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein on a clinically appropriate schedule. In patients with chronic kidney disease, also assess serum phosphorus

INDICATION

Truvada for PrEP (pre-exposure prophylaxis) is indicated to reduce the risk of sexually acquired HIV-1 in adults and adolescents (?35 kg) who are at risk for HIV, when used in combination with safer sex practices. HIV-negative status must be confirmed immediately prior to initiation

• If clinical symptoms of acute HIV-1 infection are present and recent exposures (<1 month) are suspected, delay initiation for at least 1 month until HIV-negative status is reconfirmed. Alternatively, confirm HIV-negative status with a test cleared by FDA to aid in the diagnosis of acute HIV-1 infection

Individuals at risk for sexually acquired HIV-1 may include those:

• With HIV-1 infected partner(s), or
• Who engage in sexual activity in a high prevalence area or social network and have additional risk factors, such as: inconsistent or no condom use, diagnosis of sexually transmitted infections (STIs), exchange of sex for commodities, use of illicit drugs or alcohol dependence, incarceration, or sexual partners of unknown HIV status with any of these risk factors

About Gilead Sciences

Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California.

For nearly 30 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention, testing and linkage to care, and cure research. Today, it's estimated that more than 12 million people living with HIV globally receive antiretroviral therapy provided by Gilead or one of the company's manufacturing partners.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com.

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 FDA and other regulatory agencies may not approve Descovy for PrEP in the currently anticipated timelines or at all, and any marketing approvals, if granted, may have significant limitations on its use. As a result, Descovy for PrEP may never be successfully commercialized. There is also the possibility of unfavorable results from additional studies involving Descovy and Truvada for PrEP. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. 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, 2019, 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 for Descovy and Truvada, including BOXED WARNINGS, is available at www.gilead.com

Descovy, Descovy for PrEP, Truvada, Truvada for PrEP and Gilead are trademarks of Gilead Sciences, Inc. or 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.