\nMerck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for doravirine\/islatravir (DOR\/ISL), an investigational, once-daily, oral, two-drug regimen for adults with HIV-1 infection that is virologically suppressed on antiretroviral therapy. The FDA has set a target action date of April 28, 2026, for the application under the Prescription Drug User Fee Act (PDUFA).<\/p>\n
\n\u201cMerck has been at the forefront of HIV research for more than 35 years and we are pleased to continue our work to innovate and deliver new options that aim to meet the needs of the HIV community,\u201d said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. \u201cThe health needs of people living with HIV often change over time \u2013 whether it\u2019s managing comorbidities or navigating complex medication regimens. We believe DOR\/ISL, if approved, will represent an important new complete regimen option designed to help meet their diverse needs.\u201d<\/p>\n
\nThe NDA is based on findings at Week 48 of two pivotal Phase 3 clinical trials (MK-8591A-051<\/a> and MK-8591A-052<\/a>) where DOR\/ISL was demonstrated to be non-inferior to baseline antiretroviral therapy (bART) in the open-label trial MK-8591A-051 and non-inferior to bictegravir\/emtrictabine\/tenofovir alafenamidei<\/sup> [BIC\/FTC\/TAF (50mg\/200mg\/25mg)] in the double-blind trial MK-8591A-052. Across both trials, the safety profile of DOR\/ISL was generally comparable to comparator baseline antiretroviral regimens in trial MK-8591A-051 and BIC\/FTC\/TAF in trial MK-8591A-052. Data from these trials were presented<\/a> during the 2025 Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.<\/p>\n About the Phase 3 Trial MK-8591A-051 About the Phase 3 Trial MK-8591A-052 About Islatravir (MK-8591) and Merck\u2019s HIV Research \nMerck\u2019s commitment to researching NRTTIs includes MK-8527, an investigational, novel oral, once-monthly NRTTI candidate that is in Phase 2 development for HIV-1 pre-exposure prophylaxis (PrEP). For an overview of Merck\u2019s HIV treatment and prevention clinical development program, please click here<\/a>.<\/p>\n Merck\u2019s Commitment to HIV Indications and usage for PIFELTRO\u00ae<\/sup> (doravirine) and DELSTRIGO\u00ae<\/sup> (doravirine, lamivudine, and tenofovir disoproxil fumarate) in the U.S. \nDELSTRIGO 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.<\/p>\n Selected Safety Information<\/b><\/p>\n Warning: Posttreatment Acute Exacerbation of Hepatitis B Virus (HBV) for DELSTRIGO Contraindications \nDELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.<\/p>\n Warnings and Precautions New or Worsening Renal Impairment \nPrior 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.<\/p>\n Bone Loss and Mineralization Defects Immune Reconstitution Syndrome Drug Interactions \nCoadministration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.<\/p>\n \nIf 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.<\/p>\n \nIf PIFELTRO is coadministered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart).<\/p>\n \nConsult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions.<\/p>\n Dosage and Administration\/Specific Populations Adverse Reactions \nBy 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.<\/p>\n \nBy 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.<\/p>\n \nIn 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.<\/p>\n \nIn 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.<\/p>\n \nIn 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.<\/p>\n \nIn 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.<\/p>\n \nThe 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.<\/p>\n Serum ALT and AST Elevations:<\/i> 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.<\/p>\n Pregnancy\/Breastfeeding \nInform individuals with HIV-1 infection of the potential risks of breastfeeding, including: (1) HIV-1 transmission (in HIV-1\u2013negative infants), (2) developing viral resistance (in HIV-1\u2013positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults.<\/p>\n About Merck Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA \nRisks 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\u2019s 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\u2019s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and\/or regulatory actions.<\/p>\n \nThe 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\u2019s Annual Report on Form 10-K for the year ended December 31, 2024 and the company\u2019s other filings with the Securities and Exchange Commission (SEC) available at the SEC\u2019s Internet site (www.sec.gov<\/a>).<\/p>\n Please see Prescribing Information for PIFELTRO (doravirine) at: <\/b>https:\/\/www.merck.com\/product\/usa\/pi_circulars\/p\/pifeltro\/pifeltro_pi.pdf<\/b><\/a> and <\/b>Patient Information for PIFELTRO at: <\/b>https:\/\/www.merck.com\/product\/usa\/pi_circulars\/p\/pifeltro\/pifeltro_ppi.pdf<\/b><\/a><\/p>\n Please see Prescribing Information for DELSTRIGO (doravirine, lamivudine, and tenofovir disoproxil fumarate) at: <\/b>https:\/\/www.merck.com\/product\/usa\/pi_circulars\/d\/delstrigo\/delstrigo_pi.pdf<\/b><\/a> and <\/b>Patient Information for DELSTRIGO at: <\/b>https:\/\/www.merck.<\/b><\/a><\/p>\n i<\/sup> bictegravir\/emtricitabine\/tenofovir alafenamide (BIKTARVY) is a registered trademark of Gilead Sciences, Inc.<\/p>\n<\/td>\n<\/tr>\n<\/table>\n \n\u00a0<\/p>\n
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<\/b>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 the percentage of participants with HIV-1 RNA \u226550 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 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% were Black or African American, and 14.5% were 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).<\/p>\n
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<\/b>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 \u226550 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).<\/p>\n
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<\/b>Islatravir (MK-8591), Merck\u2019s 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 induction of structural changes in the viral DNA, resulting in delayed chain termination. Islatravir is under evaluation in multiple ongoing early and late-stage clinical trials in combination with other antiretrovirals for potential daily and once-weekly treatments for HIV-1, with islatravir serving as the anchor medicine in the treatment regimens based on its potency and resistance profile. 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<\/a> in people with HIV who had not previously received treatment (treatment-na\u00efve), and MK-8591A-054<\/a> 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). Islatravir in combination with Gilead\u2019s lenacapavir is in Phase 3 development as a novel oral once-weekly treatment for HIV-1, and islatravir in combination with our company\u2019s investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) ulonivirine (MK-8507) is in Phase 2 development as an oral once-weekly treatment.<\/p>\n
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<\/b>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 helped pioneer 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 their HIV and to help prevent 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 helping to end the HIV epidemic for everyone.<\/p>\n
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<\/b>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.<\/p>\n
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<\/b>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.<\/b><\/p>\n
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<\/b>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\u2019s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.<\/p>\n
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<\/b>Severe Skin Reactions
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<\/b>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.<\/p>\n
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<\/b>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.<\/p>\n
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<\/b>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.<\/p>\n
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<\/b>Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.<\/p>\n
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<\/b>Because DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.<\/p>\n
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<\/b>Renal Impairment
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<\/b>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.<\/p>\n
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<\/b>The most common adverse reactions with DELSTRIGO (incidence \u22655%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence \u22655%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).<\/p>\n
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<\/b>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.<\/p>\n
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<\/b>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 \u2013 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<\/a> and connect with us on X (formerly Twitter)<\/a>, Facebook<\/a>, Instagram<\/a>, YouTube<\/a> and LinkedIn<\/a>.<\/p>\n
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<\/b>This news release of Merck & Co., Inc., Rahway, N.J., USA (the \u201ccompany\u201d) includes \u201cforward-looking statements\u201d 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\u2019s 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.<\/p>\n\n
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