Proximal tubulopathy

– New findings to be presented at the 2025 European Association for the Study of the Liver (EASL) Congress continue to demonstrate the effectiveness of Livdelzi (seladelpar) in reducing pruritus in people with primary biliary cholangitis (PBC) – – Additional presentations will showcase the potential for maintained virologic response following treatment with investigational bulevirtide in people with hepatitis delta virus (HDV) – – Presentations in hepatitis B virus (HBV) and hepatitis C virus (HCV) will underscore Gilead’s commitment to advancing scientific research and our understanding of viral hepatitis in the real-world setting – FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced new research to be presented at the European Association for the Study of the Liver (EASL) Congress, May 7-10, 2025, Amsterdam, furthering Gilead’s commitment to transform the lives of people living with liver disease. New data to be presented at EASL will include a subgroup analysis from ASSURE, an ongoing open-label study, and an analysis of the Phase 3 RESPONSE trial and the open-label extension. Data will reinforce the effectiveness of Livdelzi® (seladelpar), known as Lyvdelzi® in the European Union, in reducing pruritus (chronic itch), a debilitating common symptom of primary biliary cholangitis (PBC). Moreover, the results will highlight seladelpar’s ability to deliver a sustained biochemical response regardless of prior treatment history, and as an option for a broad range of people with PBC. “Our focus remains on addressing the areas of greatest unmet need across liver diseases,” said Dietmar Berger, MD, PhD, Chief Medical Officer, Gilead Sciences. “Our deep expertise in treating liver disease has delivered the first and only treatment for hepatitis delta and the first treatment for primary biliary cholangitis that has demonstrated statistically significant improvements across both chronic itch and markers of disease progression. Our studies continue to deliver transformational insights and therapies to help foster healthier futures for the millions of people who live with viral hepatitis and those who live with less prevalent liver conditions with remaining high unmet needs.” Key findings from 29 accepted abstracts will include two oral presentations showcasing new data on the critical goal of maintained virologic response following treatment with 2 mg and 10 mg bulevirtide in people living with hepatitis delta virus (HDV). These findings build on the wealth of long-term data for the treatment of chronic HDV. A late breaker presentation on the final results from the pivotal MYR301 Phase 3 study evaluating the efficacy and safety of 2 mg and 10 mg bulevirtide as monotherapy will reveal long-term response rates, including the proportion of participants with undetectable virus levels two years after treatment cessation. In hepatitis B (HBV), Gilead will present initial results from a Phase 1a study of a novel investigational therapeutic vaccine that shows early promise towards the goal of achieving a functional cure for HBV infection. A separate analysis of real-world data showed that individuals with low-level HBV viremia still have a risk of negative events. Additionally, a retrospective analysis of participants enrolled in two Phase 3 studies evaluating Vemlidy® (tenofovir alafenamide) using a risk score for liver cancer highlights the importance of treatment to help reduce liver cancer risk. Gilead will also showcase real-world data on hepatitis C (HCV), demonstrating the effects of direct-acting antivirals (DAA) against all genotypes of the virus across diverse geographical regions, supporting the global applicability of HCV treatment guidelines. In addition, new real-world insights will show that the choice of DAA for people living with HCV taking other medicines, such as antipsychotics, was associated with reducing the problem of drug-drug interactions. To help raise awareness about HCV and encourage people to get screened for the disease, Gilead will again support EASL’s “Love Your Liver” Campaign at the congress. At the EASL Congress, Gilead, in collaboration with the PBC Foundation and Friends of the PBC Foundation, will also launch “All the Feelings with PBC,” a campaign highlighting the experiences of people living with PBC and emphasizing the importance of listening to and addressing their needs in clinical practice and research. The campaign will feature paintings by Berlin-based artist, Nour Khwies, based on the physical and emotional experiences of people living with PBC: Dilek from Germany, Angela from Scotland, Joana from Portugal, and L. Marie from the United States, whose painting will be painted live at EASL. Key Abstracts at EASL 2025: ID Abstract Title PBC THU-291 Clinical meaningful change of pruritus numeric rating scale in adults with primary biliary cholangitis with moderate-to-severe pruritus THU-286 Seladelpar treatment of patients with primary biliary cholangitis improves the GLOBE score and predicts improved transplant-free survival THU-294 Change in pruritus in patients with primary biliary cholangitis and moderate-to-severe pruritus: A pooled analysis from the RESPONSE and ENHANCE studies THU-274 Efficacy and safety of seladelpar in patients previously treated with fibrates or OCA FRI-318 Evaluation of the potential impact of seladelpar on the pharmacokinetics of midazolam, tolbutamide, simvastatin, rosuvastatin, and atorvastatin HDV OS-066 Predictors of undetectable hepatitis delta virus RNA at 48 weeks after end of treatment with bulevirtide monotherapy in the MYR 301 study OS-070 Achieving undetectable hepatitis delta virus RNA at end of therapy with bulevirtide 10 mg/day with or without pegIFN is strongly associated with post-treatment virologic response in chronic hepatitis delta LBO-004 Final results of MYR301: A randomised Phase 3 study evaluating the efficacy and safety of up to 144 weeks of bulevirtide monotherapy for chronic hepatitis delta and 96 weeks of posttreatment follow-up HCV WED-276 The SVR10K Hepatitis C study: Final results show 98.9% SVR in 7,000 patients treated with SOF/VEL in Asia, Latin America, Middle East, Nordics, and Southern Europe WED-031 Healthcare resource use (HCRU) and cost impact of potential drug-drug interactions (DDIs) among HCV patients receiving Direct-Acting Antivirals (DAAs) concomitantly with antipsychotic drugs in the US HBV THU-246 Safety, tolerability and immunogenicity of GS-2829 and GS-6779, a novel arenaviral vectored therapeutic hepatitis B vaccine: results from a phase 1a study in healthy participants SAT-009 Risk of advanced liver disease among individuals with hepatitis B virus infection with low level viremia compared to individuals with no evidence of hepatitis B virus infection WED-296 Impact of long-term tenofovir-based treatment on hepatocellular carcinoma risk in patients with chronic hepatitis B using the reREACH-B score For more information on the EASL Congress 2025 and Gilead’s presentations, please visit the congress website. About Gilead Sciences in Liver Disease For decades, Gilead has pioneered the way forward to improve the lives of people living with liver disease around the world. The company has helped to transform hepatitis C from a chronic condition into a curable condition. For individuals living with hepatitis B or hepatitis delta, Gilead's focus on advancing medicines drives hope that today’s research will turn into tomorrow’s cures. Beyond viral hepatitis, Gilead is working to deliver advanced treatments for people living with PBC. The commitment of Gilead does not stop there. Through ground-breaking science and collaborative partnerships, the company strives to create healthier futures for everyone living with liver disease. Gilead remains devoted to a future without liver disease. Marketing Authorization In July 2023, the European Commission (EC) granted full Marketing Authorization (MA) for Hepcludex® (bulevirtide) 2 mg for the treatment of adults with chronic HDV and compensated liver disease. Bulevirtide was initially granted a conditional MA from the EC in July 2020 to provide people living with HDV urgent access to treatment. Bulevirtide’s conditional MA license in the UK was converted to a full MA in August 2023, and a full MA was granted in Switzerland in February 2024. In regions where bulevirtide is not approved, including the U.S., bulevirtide 2 mg is an investigational product. In these regions, health authorities have not established the safety and efficacy of bulevirtide. Bulevirtide 10 mg is an investigational product and is not approved anywhere globally. In February 2025, the European Commission (EC) granted conditional marketing authorization for Lyvdelzi® (seladelpar) for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA alone, or as monotherapy in those unable to tolerate UDCA. Lyvdelzi provides an important treatment option for people living with PBC in the European Economic Area (EEA). Gilead is working with health authorities across Europe to ensure people living with PBC who are eligible for Lyvdelzi have access as soon as possible. Continued approval of Lyvdelzi for the approved indication will be contingent on verification and description of clinical benefit in confirmatory trial(s). Lyvdelzi has Priority Medicine (PRIME) designation in the EU, assigned to optimize the development of novel medicines that target conditions with an unmet medical need for which no treatment options exist or where they can offer a major therapeutic advantage over existing treatments, as well as well as Orphan Drug Designation for the treatment of people living with PBC. Livdelzi® received conditional approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) in January 2025. In the U.S., Livdelzi® obtained accelerated approval for the treatment of PBC by the U.S. Food and Drug Administration (FDA) in August 2024. Livdelzi received Breakthrough Therapy Designation, as well as Orphan Drug Designation for the treatment of people living with PBC. As part of the FDA accelerated approval, Gilead has committed to AFFIRM, a long-term outcomes study, which has begun in people with compensated cirrhosis. Continued U.S. approval may be contingent upon verification of clinical benefit in confirmatory trial(s). Regulatory review for Livdelzi is underway in Canada, Australia, and Switzerland. U.S. Indication for Livdelzi® Livdelzi is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have had an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. The FDA approved this indication under accelerated approval based on a reduction of alkaline phosphatase (ALP). Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use: Use of Livdelzi is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). U.S. Important Safety Information for Livdelzi Warnings and Precautions Fractures: Fractures occurred in 4% of Livdelzi-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with Livdelzi and monitor bone health according to current standards of care. Liver Test Abnormalities: Livdelzi has been associated with dose-related increases in serum transaminase (AST and ALT) levels > 3 x ULN in patients receiving 50 mg and 200 mg once daily (5x and 20x higher than the recommended dosage of 10 mg once daily). Perform baseline clinical and laboratory testing when starting Livdelzi® and monitor thereafter according to routine patient management. Interrupt treatment if the liver tests (ALT, AST, total bilirubin, and/or ALP) worsen, or if the patient develops signs and symptoms of clinical hepatitis (eg, jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting Livdelzi. Biliary Obstruction: Avoid use of Livdelzi in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt Livdelzi and treat as clinically indicated. Adverse Reactions The most common adverse reactions (≥5%) with Livdelzi were headache (8%), abdominal pain (7%), nausea (6%), abdominal distension (6%), and dizziness (5%). Drug Interactions OAT3 Inhibitors and Strong CYP2C9 Inhibitors: Avoid co-administration with L due to increased Livdelzi exposure. Rifampin: Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during Livdelzi treatment. Coadministration may result in delayed or suboptimal biochemical response of Livdelzi. Dual Moderate CYP2C9 and Moderate-to-Strong CYP3A4 Inhibitors and BCRP Inhibitors (e.g., cyclosporine): Monitor closely for adverse effects. Concomitant administration with Livdelzi may increase Livdelzi exposure. CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors: Monitor more frequently for adverse reactions as concomitant use of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9 poor metabolizers may increase Livdelzi exposure and risk of LIVDELZI adverse reactions. Bile Acid Sequestrants: Administer Livdelzi at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible. Pregnancy and Lactation Pregnancy: There is insufficient data from human pregnancies exposed to Livdelzi to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Gilead Sciences, Inc., at 1-800-445-3235. Lactation: There is no data on the presence of Livdelzi in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Livdelzi and any potential adverse effects on the breastfed infant from Livdelzi. U.S. Indication for Vemlidy® VEMLIDY is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients six years of age and older and weighing at least 25 kg with compensated liver disease. U.S. Important Safety Information for and Indication for the Use of Vemlidy BOXED WARNING: POSTTREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted. Warnings and Precautions Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected Patients:Due to this risk, VEMLIDY alone should not be used for the treatment of HIV-1 infection. Safety and efficacy of VEMLIDY have not been established in HBV/HIV-1 coinfected patients. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and if positive, an appropriate antiretroviral combination regimen that is recommended for HBV/HIV-1 coinfected patients should be used. 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 TAF-containing products. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Monitor renal function in all patients – See Dosage and Administration. Lactic Acidosis and Severe Hepatomegaly with Steatosis:Fatal cases have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (TDF). Discontinue VEMLIDY 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 events in the week 96 pediatric population reported in ≥5% were: nasopharyngitis, headache, COVID-19, pyrexia, diarrhea, upper respiratory tract infection, cough, respiratory tract infection viral, abdominal pain upper. Overall, abdominal pain upper and metabolic nephropathy were the only study drug–related adverse events, which occurred in > 1 participant, reported in 2.3% (2/88 participants) each. Drug Interactions Coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and the risk of adverse reactions. Coadministration of VEMLIDY is not recommended with the following: oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John’s wort. Such coadministration is expected to decrease the concentration of tenofovir alafenamide, reducing the therapeutic effect of VEMLIDY. Drugs that strongly affect P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) activity may lead to changes in VEMLIDY absorption. Coadministration of VEMLIDY with carbamazepine, the tenofovir alafenamide dose should be increased to two tablets once daily. Consult the full prescribing information for VEMLIDY for more information on potentially significant drug interactions, including clinical comments. Dosage and Administration Testing Prior to Initiation:HIV infection. Prior to or When Initiating, and During Treatment:On a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Dosage:1 tablet taken once daily with food. Renal Impairment:Not recommended in patients with end-stage renal disease (ESRD; eCrCl <15 mL/min) who are not receiving chronic hemodialysis; in patients on chronic hemodialysis, on hemodialysis days, administer VEMLIDY after completion of hemodialysis treatment. No data are available to make dose recommendations in pediatric patients with renal impairment. Hepatic Impairment:Not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment. 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 or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials, including those involving Lyvdelzi®/Livdelzi® (seladelpar), Vemlidy®, bulevirtide, sofosbuvir, velpatasvir, GS-2829 and GS-6779 (such as the ASSURE, MYR301, RESPONSE, SVR10K and any confirmatory studies); uncertainties relating to regulatory applications and related filing and approval timelines, including additional pending and potential applications for seladelpar; 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; uncertainties regarding Gilead’s ability to coordinate access to seladelpar in a timely manner or at all; the risk that physicians may not see the benefits of prescribing seladelpar for treatment of PBC; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2024, 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. Hepcludex, Lyvdelzi, Livdelzi, Vemlidy, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. Full Prescribing Information for Livdelzi® and Vemlidy® are available at www.gilead.com . For more information about Gilead, please visit the company’s website at www.gilead.com , follow Gilead on X/Twitter (@Gilead Sciences) and LinkedIn (@Gilead-Sciences). Blair Baumwell, Media public_affairs@gilead.com Jacquie Ross, Investors investor_relations@gilead.com

MNV-201 is Minovia’s second generation mitochondrial cell therapy product composed of autologous hematopoietic stem cells enriched with allogeneic mitochondria Rare Pediatric Designation granted MNV-201 is also being studied in a Phase Ib for low-risk Myelodysplastic Syndrome; Preliminary clinical data demonstrate safety and efficacy HAIFA, Israel, April 03, 2025 (GLOBE NEWSWIRE) -- Minovia Therapeutics Ltd, a clinical stage biopharmaceutical company advancing mitochondrial therapies for primary and secondary mitochondrial diseases, today announced that the U.S. Food and Drug Administration (FDA) has cleared its second Investigational New Drug (IND) application for MNV-201, an autologous hematopoietic stem cell product augmented with allogeneic mitochondria. The IND supports the initiation of a Phase II clinical trial of MNV-201 in pediatric patients with Pearson Syndrome, a primary mitochondrial disease. Based on previous clinical experience from the 1st generation product, MNV-101 (autologous hematopoietic stem cell product augmented with syngeneic maternal mitochondria), Minovia designed this phase II study with change in growth (height SDS) as primary endpoint. According to the natural history study recently published by Dr. Rebecca Ganetzky from CHOP, all patients with Pearson Syndrome suffer from failure to thrive and do not respond to growth hormone. Natural history shows an annual reduction of 0.5 units in height SDS, while MNV-101 treated patients showed stabilization or improvement, with no decline of height SDS at the 6 and 12 month follow up time points in a comparable subset of patients. This change in growth correlated with an improved International Pediatric Mitochondrial Disease Scale (IPMDS), which measures how the patient feels and functions (R2=0.9; p=0.0036). Linear growth was also suggested as an objective and clinically meaningful endpoint for a pivotal trial in Pearson by the FDA in early interactions. “The FDA’s clearance of our IND marks an important achievement for Minovia, allowing us to clinically evaluate our allogeneic mitochondrial cell therapy approach and proceed with the Phase II clinical program for this first-in-class allogeneic mitochondrial therapy for Pearson Syndrome patients,” said Natalie Yivgi Ohana, PhD, CEO of Minovia. “We are pleased to have safely dosed three Pearson patients enrolled in an ongoing study under the Israeli Ministry of Health. We look forward to treating additional patients under this IND, as well as to learning about the potential of MNV-201 to improve growth in this patient population.” “We are pleased that our cumulative interactions with the FDA enabled alignment on requirements for the entire MNV-201 program, including preclinical, CMC, and clinical aspects,” said Noa Sher, PhD, CSO of Minovia. “Early clinical and regulatory experience with MNV-101 shaped the current program and enabled a successful IND submission.” The Phase II clinical trial is an open-label, single dose study to evaluate the safety and efficacy of MNV-201 in pediatric subjects diagnosed with Pearson Syndrome. The trial will also enable assessment of efficacy in improving growth and quality of life. The study is expected to enroll three additional patients up to a total of 6 patients. For more information visit clinicaltirals.gov About MNV-201MNV-201 is an autologous hematopoietic stem cell product enriched with allogeneic mitochondria. MNV-201 aims to restore mitochondrial function in patient hematopoietic stem cells, resulting in improved differentiation and function. Preclinical research suggests the potential for safe dosing with low immunogenicity risk and scalable manufacturing to address the significant number of patients who are potentially eligible for MNV-201 therapy. About Pearson SyndromePearson Syndrome is a multisystem progressive pediatric mitochondrial disease caused by single large-scale mitochondrial deletions (SLSMDS) of mitochondrial DNA (mtDNA), with consequent defects in the mitochondrial respiratory chain function. Pearson Syndrome classically presents in the first year of life with bone marrow failure and exocrine pancreatic dysfunction. Patients have macrocytic sideroblastic anemia that is frequently transfusion-dependent and may be accompanied by thrombocytopenia and neutropenia. Pancreatic dysfunction occurs secondary to fibrosis and leads to chronic diarrhea, malabsorption, and failure to thrive. Pearson Syndrome is marked by accumulating organ system involvement and worsening disease: variable other organ involvement can occur, including renal tubulopathy, liver cholestasis and/or fibrosis, adrenal insufficiency, diabetes mellitus, cardiomegaly, and/or cardiac conduction defects. Pearson Syndrome is universally fatal and since there is no effective therapy, the diagnosis of Pearson Syndrome is one of the worst diagnoses that a caregiver must deliver to parents of an affected infant. MNV-201 aims to reduce disease-associated symptoms and the risk of disease progression and death, thereby improving both lifespan and quality of life. About Minovia TherapeuticsMinovia Therapeutics Ltd. is a clinical stage biotechnology company advancing mitochondrial therapies for primary-genetic and age-related mitochondrial diseases. Minovia's clinical stage product candidate, MNV-201, is composed of mobilized peripheral blood, autologous CD34+ cells enriched with allogeneic, cryopreserved placental derived mitochondria, produced by Minovia's proprietary Mitochondrial Augmentation Technology (MAT). The enrichment of hematopoietic stem cells with healthy and functional mitochondria aims to restore stem cells function of patients suffering mitochondrial dysfunction, caused both by mtDNA mutations or deletions in pediatric patients suffering from primary mitochondrial diseases, or in adults with age-related diseases. MNV-201 is currently in clinical studies for pediatric patients with single-large scale mtDNA deletion syndromes (Pearson Syndrome and Kearn Sayre Syndrome) with five patients successfully dosed; and in Low Risk Myelodysplastic Syndrome. For more information, please visit www.minoviatx.com or follow the Company LinkedIn. Contact Information: Natalie Yivgi Ohana, Co-Founder and CEO Phone: +972-74-7039954 Email: info@minoviatx.com

March 12, 2025 11:26 am ET DOR/ISL demonstrated non-inferiority and a similar safety profile to comparator antiretroviral therapies in adults with virologically suppressed HIV-1 RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the presentation of positive results from two pivotal Phase 3 trials of the investigational, once-daily, oral, two-drug regimen of doravirine/islatravir [DOR/ISL (100mg/0.25mg)] in adults with HIV-1 infection that is virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamidei [BIC/FTC/TAF (50mg/200mg/25mg)] in trial MK-8591A-052 ) or antiretroviral therapy [baseline antiretroviral therapy (bART)] in trial MK-8591A-051. In both trials, DOR/ISL met the primary efficacy success criterion for non-inferiority to comparator antiretroviral therapies and primary safety objectives at Week 48. The findings will be shared in late-breaking oral presentations at the 32nd Conference on Retroviruses and Opportunistic Infections (CROI) being held in San Francisco and were featured in a CROI press conference. Merck plans to begin submitting applications for marketing authorization to regulatory agencies by mid-2025. In the double-blind trial MK-8591A-052 (Abstract #204A), results for the primary endpoint (HIV-1 RNA ≥50 copies/mL) showed that 1.5% of participants who switched to DOR/ISL had a viral load of ≥50 copies/mL at Week 48, compared to 0.6% on BIC/FTC/TAF (treatment difference 0.9%, 95% CI -1.9, 2.9). At Week 48, 91.5% of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) compared to 94.2% of participants who continued receiving BIC/FTC/TAF (treatment difference -2.6%, 95% CI -7.1, 2.6; secondary endpoint). In the open-label trial MK-8591A-051 (Abstract #204B), results for the primary endpoint (HIV-1 RNA ≥50 copies/mL) showed that 1.4% of participants who received DOR/ISL had a viral load of ≥50 copies/mL at Week 48, compared to 4.9% on bART (treatment difference -3.6%, 95% CI -7.8, -0.8. At Week 48, 95.6% of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) compared to 91.9% of participants who continued on bART (treatment difference 3.7%, 95% CI -0.3, 8.9; secondary endpoint). Across both trials, the safety profile of DOR/ISL was generally comparable to the comparator antiretroviral regimens, including BIC/FTC/TAF in MK-8591A-052. At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and comparator regimens. No treatment-emergent resistance to DOR or ISL was observed in either trial. “Despite the availability of multiple daily antiretroviral therapies, the needs of people living with HIV are evolving. Many people living with HIV are older and also managing comorbidities, making it important to have daily treatment options that can help meet each person’s unique health needs,” said Professor Chloe Orkin, Dean for Healthcare Transformation, Queen Mary University of London, United Kingdom. “I’m excited to see that DOR/ISL has potential as a new daily treatment option for people living with HIV who may benefit from this two-drug regimen.” Islatravir, Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), blocks HIV-1 replication by multiple mechanisms including inhibition of reverse transcriptase translocation resulting in immediate chain termination and delayed chain termination from structural changes induced in the viral DNA. “We are excited that DOR/ISL is the first two-drug regimen without an integrase inhibitor to demonstrate comparable efficacy and safety to the three-drug InSTI-based regimen, BIC/FTC/TAF, in a Phase 3 pivotal trial,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “Merck has been a research pioneer in HIV for decades. These data and our work on the longer-acting islatravir-based therapies in our pipeline show our continued commitment to help find new options that address the evolving needs of people living with HIV.” About the Phase 3 data from MK-8591A-052 MK-8591A-052 is a Phase 3, double-blind randomized, active-controlled, clinical trial to evaluate the efficacy and safety of a switch to investigational, oral, once-daily DOR/ISL (100mg/0.25mg) in adults with HIV-1 infection that has been virologically suppressed on BIC/FTC/TAF (50mg/200mg/25mg). The primary efficacy endpoint was the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (non-inferiority margin 4%). In this trial, 513 adults with HIV-1 who had virologic suppression for three months or more on BIC/FTC/TAF, no history of treatment failure and no known resistance to DOR were randomized (2:1) and switched to DOR/ISL (n= 342) or continued treatment with BIC/FTC/TAF (n=171). The median age of participants was 47 years; 21.4% were assigned female sex at birth, 30.8% were Black or African American, and 22.8% were Hispanic or Latine. The median duration of BIC/FTC/TAF treatment prior to trial enrollment was 3.4 years (IQR 2.0-5.0). Results for the primary efficacy endpoint showed that five participants (1.5%) treated with DOR/ISL and one participant (0.6%) in the BIC/FTC/TAF group had a viral load of ≥50 copies/mL at Week 48, demonstrating non-inferiority of DOR/ISL to BIC/FTC/TAF (treatment difference 0.9%, 95% CI -1.9, 2.9). The superiority criteria were not met. Results for a secondary endpoint, the proportion of individuals with HIV-1 RNA <50 copies/mL at Week 48, showed that participants who switched to treatment with DOR/ISL or continued BIC/FTC/TAF maintained comparable rates of viral suppression at Week 48 (91.5% on DOR/ISL vs. 94.2% on BIC/FTC/TAF (treatment difference -2.6%, 95% CI -7.1, 2.6). No treatment-emergent resistance to DOR or ISL was observed. At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and BIC/FTC/TAF. There were identical rates of discontinuation for protocol-specified decreases in total lymphocyte and/or CD4 counts (two participants (0.6%) in the DOR/ISL group and one participant (0.6%) in the BIC/FTC/TAF group). Drug-related adverse events (AEs) and discontinuations due to drug-related AEs were similar between groups (n=35, 10.2% for DOR/ISL and n=16, 9.4% for BIC/FTC/TAF; n=4, 1.2% for DOR/ISL and n=2, 1.2% for BIC/FTC/TAF, respectively). Rates of toxicity grade 3 or 4 AEs and serious AEs were similar for DOR/ISL and BIC/FTC/TAF (n=25, 7.3% for DOR/ISL and n=13, 7.6% for BIC/FTC/TAF; n=15, 4.4% for DOR/ISL and n=11, 6.4% for BIC/FTC/TAF, respectively). Mean change in weight from baseline to Week 48 was minimal (-0.03 kg for DOR/ISL versus 0.28 kg for BIC/FTC/TAF; difference -0.30 kg, 95% CI -1.13, 0.53). The most common AEs (>6% in either study arm) were arthralgia, COVID-19, nasopharyngitis, and fatigue. One participant on DOR/ISL discontinued due to a drug-related serious AE (immune thrombocytopenia). There were two cases of low-level hepatitis B (HBV) viremia (HBV DNA <50 IU/mL) with no antigenemia or elevated transaminases in the DOR/ISL group and no cases in the BIC/FTC/TAF group; there were no cases of clinical HBV reactivation. About the Phase 3 data from MK-8591A-051 MK-8591A-051 is a Phase 3, open-label randomized, active-controlled, clinical trial evaluating the efficacy and safety of a switch to investigational, oral, once-daily DOR/ISL (100mg/0.25mg) in adults with HIV-1 infection that has been virologically suppressed using ART. The primary efficacy endpoint was percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (non-inferiority margin 4%). In this trial, 551 adults with HIV-1 RNA <50 copies/mL for three months or more on oral 2- or 3-drug ART, with no history of treatment failure and no known virologic resistance to DOR were randomized 2:1 and switched to DOR/ISL (n=366) or continued baseline antiretroviral therapy (bART) (n=185), stratified by bART regimen. The median age of participants was 51 years; 39.7% were assigned female sex at birth, 45.4% Black or African American and 14.5% Hispanic or Latine. At baseline, 64.2% were treated with an InSTI-based regimen, 30.3% with an NNRTI-based regimen, and 5.4% with a protease inhibitor (PI)-based regimen, with median duration on current ART of 3.8 years (IQR 2.0-6.3). Results for the primary efficacy endpoint showed that five participants (1.4%) in the DOR/ISL group and nine participants (4.9%) in the bART group had a viral load of ≥50 copies/mL at Week 48, demonstrating non-inferiority of DOR/ISL to bART (treatment difference -3.6%, 95% CI -7.8, -0.8). Results for a secondary endpoint, the proportion of individuals with HIV-1 RNA <50 copies/mL at Week 48, showed that participants who switched to treatment with DOR/ISL or continued bART maintained comparable rates of viral suppression at Week 48 (95.6% on DOR/ISL vs. 91.9% on bART; treatment difference 3.7%, 95% CI -0.3, 8.9). No treatment-emergent resistance to DOR or ISL was observed. Two participants discontinued DOR/ISL early after virologic failure at Week 4 with multiple resistance-associated mutations that were also present in baseline proviral DNA. These two participants were later found to be not eligible for the trial due to history of prior virologic failure and exclusionary DOR resistance. At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and bART. No participants discontinued treatment due to decrease in total lymphocyte and/or CD4 counts. In this open-label study, drug-related AEs were more commonly reported with DOR/ISL (n=44; 12.0%) than bART (n=9; 4.9%). Rates of toxicity grade 3 or 4 AEs and serious AEs were similar for DOR/ISL and bART (n=39, 10.7% for DOR/ISL and n=18, 9.7% for bART and n=23, 6.3% for DOR/ISL and n=9, 4.9% for bART, respectively). There were no drug-related serious AEs and there were no discontinuations due to serious AEs in the DOR/ISL group; there was one drug-related serious AE and two discontinuations due to serious AEs in the bART group. The most common drug-related AEs were diarrhea (DOR/ISL 3.3%, bART 0%), fatigue (1.9%, 0.5%), dizziness (1.9%, 0.5%), abdominal distention (1.6%, 0%), weight increased (1.6%, 0%), and headache (1.6%, 1.1%). Change in lipid parameters from baseline were similar between treatment groups for all bART strata. Mean change in weight from baseline to Week 48 was 0.94 kg for DOR/ISL and -0.18 kg for bART (difference -1.13 kg, 95% CI 0.31, 1.94). For baseline regimens without EFV or TDF, the difference in weight between DOR/ISL and bART was 0.82 kg (95% CI -0.22, 1.87). There was one case of low-level HBV viremia with no antigenemia or elevated transaminases in the DOR/ISL group and no cases in the bART group; there were no cases of clinical HBV reactivation. Indications and usage for PIFELTRO® (doravirine) and DELSTRIGO® (doravirine, lamivudine, and tenofovir disoproxil fumarate) in the U.S. PIFELTRO is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine. DELSTRIGO is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO. Selected Safety Information Warning: Posttreatment Acute Exacerbation of Hepatitis B Virus (HBV) for DELSTRIGO All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in people with concomitant HIV-1 and HBV who have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted. Contraindications PIFELTRO and DELSTRIGO are contraindicated when coadministered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO. DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine. Warnings and Precautions Severe Skin Reactions Severe skin reactions, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), have been reported during the postmarketing experience with doravirine-containing regimens. Discontinue PIFELTRO or DELSTRIGO, and other medications known to be associated with severe skin reactions, immediately if a painful rash with mucosal involvement or a progressive severe rash develops. Clinical status should be closely monitored, and appropriate therapy should be initiated. New or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in people living with HIV with risk factors for renal dysfunction who appeared stable on TDF. Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min. Bone Loss and Mineralization Defects In clinical trials in adults living with HIV, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults are unknown. Immune Reconstitution Syndrome Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment. Drug Interactions Because DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Coadministration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended. If DELSTRIGO is coadministered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO. If PIFELTRO is coadministered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart). Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions. Dosage and Administration/Specific Populations Renal Impairment Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min. Adverse Reactions The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%). By week 96 in DRIVE-FORWARD, 2% of adult participants in the PIFELTRO group and 3% in the darunavir+ritonavir (DRV+r) group had adverse events leading to discontinuation of study medication. By week 96 in DRIVE-AHEAD, 3% of adult participants in the DELSTRIGO group and 7% in the efavirenz (EFV)/emtricitabine (FTC)/TDF group had adverse events leading to discontinuation of study medication. In DRIVE-FORWARD, mean changes from baseline at week 48 in LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated. In DRIVE-AHEAD, mean changes from baseline at week 48 in LDL-C and non-HDL-C were pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated. In DRIVE-SHIFT, mean changes from baseline at week 24 in LDL-C and non-HDL-C were pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated. In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult participants in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium. The safety of DELSTRIGO in virologically-suppressed adults was based on week 48 data from participants in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult participants was similar to that in participants with no ARV treatment history. Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of participants in the immediate switch group experienced ALT and AST elevations greater than 1.25 X ULN, respectively, through 48 weeks on DELSTRIGO. For these ALT and AST elevations, no apparent patterns with regard to time to onset relative to switch were observed. One percent of participants had ALT or AST elevations greater than 5 X ULN through 48 weeks on DELSTRIGO. The ALT and AST elevations were generally asymptomatic, and not associated with bilirubin elevations. In comparison, 4% and 4% of participants in the delayed switch group experienced ALT and AST elevations of greater than 1.25 X ULN through 24 weeks on their baseline regimen. Pregnancy/Breastfeeding There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Inform individuals with HIV-1 infection of the potential risks of breastfeeding, including: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults. About Islatravir (MK-8591) and Merck’s HIV Research Islatravir (MK-8591) is Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) under evaluation in multiple ongoing early and late-stage clinical trials in combination with other antiretrovirals for the treatment of HIV-1. Trials with islatravir are designed to offer different dosing options as potential daily and once-weekly treatments. In addition to the MK-8591A-051 and MK-8591A-052 trials, ongoing Phase 3 trials of daily DOR/ISL (100mg /0.25mg) include MK-8591A-053 in people with HIV who had not previously received treatment (treatment-naïve), and MK-8591A-054 evaluating open-label DOR/ISL (100 mg/0.25 mg) in individuals who participated in earlier Phase 3 trials of DOR/ISL (100 mg/0.75 mg). For an overview of Merck’s HIV treatment and prevention clinical development program, please click here. Merck’s Commitment to HIV For more than 35 years, Merck has been committed to scientific research and discovery in HIV leading to scientific breakthroughs that have helped change HIV treatment. Our work has been pioneering in the development of new options across multiple drug classes to help those impacted by HIV. Today, we are developing a series of antiviral options designed to help people manage HIV and protect people from HIV, with the goal of reducing the growing burden of infection worldwide. We want to ensure people are not defined by HIV and our work focuses on transformational innovations, collaborations with others in the global HIV community, and access initiatives aimed at the goal of helping to end the HIV epidemic for everyone. About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn. Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov). Please see Prescribing Information for PIFELTRO (doravirine) at: https://www-merck-com.libproxy1.nus.edu.sg/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf and Patient Information for PIFELTRO at: https://www-merck-com.libproxy1.nus.edu.sg/product/usa/pi_circulars/p/pifeltro/pifeltro_ppi.pdf Please see Prescribing Information for DELSTRIGO (doravirine, lamivudine, and tenofovir disoproxil fumarate) at: https://www-merck-com.libproxy1.nus.edu.sg/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf and Patient Information for DELSTRIGO at: https://www-merck-com.libproxy1.nus.edu.sg/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf i bictegravir/emtricitabine/tenofovir alafenamide (BIKTARVY) is a registered trademark of Gilead Sciences, Inc. Media Contacts: Julie Cunningham (617) 519-6264 Deb Wambold (215) 779-2234 Investor Contacts: Peter Dannenbaum (732) 594-1579 Ayn Wisler (732) 594-0482