\nMerck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced topline results from the pivotal double-blind Phase 3 trial of the investigational, once-daily, oral, two-drug, single-tablet regimen of doravirine\/islatravir [DOR\/ISL (100 mg\/0.25 mg)] in adults with HIV-1 infection who had not previously received antiretroviral treatment (treatment-na\u00efve) (MK-8591A-053<\/a>). The success criterion for the primary efficacy hypothesis, as measured by the percentage of participants with HIV-1 RNA levels <50 copies\/mL at Week 48, was met, with DOR\/ISL demonstrating non-inferiority to once-daily oral bictegravir\/emtricitabine\/tenofovir alafenamidei<\/sup> [BIC\/FTC\/TAF (50 mg\/200 mg\/25 mg)]. The primary safety objective of the trial was also met, with the safety profile of DOR\/ISL being comparable to BIC\/FTC\/TAF.<\/p>\n
\nThe company is planning to present detailed findings from this trial at a future scientific congress and to submit applications including these data to health authorities. The U.S. Food and Drug Administration (FDA) accepted<\/a> the New Drug Application (NDA) for DOR\/ISL for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically-suppressed on a stable antiretroviral regimen and has set a target action date of April 28, 2026, for the application under the Prescription Drug User Fee Act (PDUFA). In the U.S., doravirine is approved for the treatment of adults with HIV-1 in combination with other antiretrovirals as a single agent (PIFELTRO) and a component of a single-tablet regimen [DELSTRIGO; doravirine, lamivudine, and tenofovir disoproxil fumarate (DOR\/3TC\/TDF)].<\/p>\n \n\u201cWe are encouraged by the results from this Phase 3 trial with DOR\/ISL, evaluating the regimen in adults with HIV who have not previously taken antiretroviral treatments. DOR\/ISL is the first two-drug regimen without an integrase inhibitor showing non-inferior efficacy and safety when compared to the three-drug INSTI-based regimen BIC\/FTC\/TAF in this population,\u201d said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. \u201cThese data support the potential for this regimen to be a meaningful treatment option for virally suppressed people living with HIV who are looking to switch to a new regimen or people who have not previously been on antiretroviral therapy to start treatment.”<\/p>\n About MK-8591A-053 (<\/b>NCT05705349<\/b><\/a>)<\/b><\/p>\n \nMK-8591A-053 is a Phase 3, randomized, active-controlled, double-blind, clinical trial designed to evaluate the antiretroviral activity, safety, and tolerability of once-daily DOR\/ISL (100 mg\/0.25 mg) in treatment-na\u00efve adults with HIV-1 infection compared to the once-daily 3-drug combination of BIC\/FTC\/TAF. Participants (n=537) were randomized 1:1 to either investigational DOR\/ISL or BIC\/FTC\/TAF regimen through Week 48. Participants will continue in the double blinded study through Week 144, with a readout planned at Week 96. After Week 144, eligible participants will be given an option to continue in an open label extension and receive DOR\/ISL until Week 240 or when DOR\/ISL becomes commercially accessible (whichever comes first). The primary efficacy (percentage of participants with HIV-1 RNA levels <50 copies\/mL) and safety (number of participants experiencing adverse events (AEs) and discontinuing trial intervention due to AEs) endpoints were assessed at Week 48.<\/p>\n About Islatravir (MK-8591) and Merck\u2019s HIV Research<\/b><\/p>\n \nIslatravir (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. 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.<\/p>\n \nIn addition to the MK-8591A-053 trial, the MK-8591A-051 and MK-8591A-052 Phase 3 trials are evaluating a switch to DOR\/ISL in adults with HIV-1 infection that is virologically suppressed on baseline antiretroviral therapy (NCT05631093<\/a>) or BIC\/FTC\/TAF (NCT05630755<\/a>). MK-8591A-054 (NCT05766501<\/a>) is an open label study evaluating 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 (NCT05052996<\/a>), and islatravir in combination with our company\u2019s investigational non-nucleoside reverse transcriptase inhibitor (NNRTI) ulonivirine (MK-8507) is in Phase 2b development (MK-8591B-060, NCT06891066<\/a>) as an oral once-weekly treatment.<\/p>\n \nMerck\u2019s commitment to researching NRTTIs includes MK-8527, an investigational, novel oral, once-monthly NRTTI that is in Phase 3 development<\/a> for HIV-1 pre-exposure prophylaxis (PrEP). The EXPrESSIVE-11 (MK-8527-011, NCT07044297<\/a>) trial is evaluating the safety and efficacy of MK-8527 among people with greater likelihood of HIV-1 exposure in 16 countries, and in collaboration with the Gates Foundation, the EXPrESSIVE-10 (MK-8527-010, NCT07071623<\/a>) trial is evaluating the safety and efficacy of MK-8527 in women and adolescent girls in sub-Saharan Africa; both trials are now enrolling.<\/p>\n \nFor an overview of Merck\u2019s HIV treatment and prevention clinical development program, please click here<\/a>.<\/p>\n Indications and usage for PIFELTRO\u00ae<\/sup> (doravirine) and DELSTRIGO\u00ae<\/sup> (doravirine, lamivudine, and tenofovir disoproxil fumarate) in the U.S.<\/b><\/p>\n \nPIFELTRO 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 \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<\/b><\/p>\n 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 Contraindications<\/b><\/p>\n \nPIFELTRO 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 \nDELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.<\/p>\n Warnings and Precautions<\/b><\/p>\n Severe Skin Reactions<\/b><\/p>\n \nSevere 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 New or Worsening Renal Impairment<\/b><\/p>\n \nRenal 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 \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<\/b><\/p>\n \nIn 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 Immune Reconstitution Syndrome<\/b><\/p>\n \nImmune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.<\/p>\n Drug Interactions<\/b><\/p>\n \nBecause DELSTRIGO is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.<\/p>\n \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<\/b><\/p>\n Renal Impairment<\/b><\/p>\n \nBecause 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 Adverse Reactions<\/b><\/p>\n \nThe 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 \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<\/b><\/p>\n \nThere 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 \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 Merck\u2019s Commitment to HIV<\/b><\/p>\n \nFor 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 About Merck<\/b><\/p>\n \nAt 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 Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA<\/b><\/p>\n \nThis 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 \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 i<\/sup> bictegravir\/emtricitabine\/tenofovir alafenamide (BIKTARVY) is a registered trademark of Gilead Sciences, Inc.<\/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 Patient Information for PIFELTRO (doravirine) 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 Patient Information for DELSTRIGO (doravirine, lamivudine, and tenofovir disoproxil fumarate) <\/b>https:\/\/www.merck.com\/product\/usa\/pi_circulars\/d\/delstrigo\/delstrigo_ppi.pdf<\/b><\/a><\/p>\n<\/p>\n
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