Merck Announces Positive Data from Phase 3 Trials that Show the Investigational, Once-Daily, Oral, Two-Drug Regimen of Doravirine/Islatravir (DOR/ISL) Maintained HIV-1 Viral Suppression at Week 48
Merck (NYSE: MRK) announced positive results from two Phase 3 trials of its investigational once-daily oral two-drug regimen doravirine/islatravir (DOR/ISL) for HIV-1 treatment. The trials demonstrated non-inferiority to existing therapies in maintaining viral suppression at Week 48.
Key findings from the trials:
- In MK-8591A-052 trial: 1.5% of DOR/ISL patients had viral load ≥50 copies/mL vs 0.6% on BIC/FTC/TAF, with 91.5% maintaining viral suppression
- In MK-8591A-051 trial: 1.4% of DOR/ISL patients had viral load ≥50 copies/mL vs 4.9% on baseline antiretroviral therapy, with 95.6% maintaining viral suppression
The safety profile was comparable to existing treatments, with no treatment-emergent resistance observed. Merck plans to submit applications for marketing authorization by mid-2025.
Merck (NYSE: MRK) ha annunciato risultati positivi da due studi di Fase 3 del suo regime orale investigativo a due farmaci da assumere una volta al giorno, doravirina/islatravir (DOR/ISL) per il trattamento dell'HIV-1. Gli studi hanno dimostrato non inferiorità rispetto alle terapie esistenti nel mantenimento della soppressione virale alla settimana 48.
Risultati chiave degli studi:
- Nello studio MK-8591A-052: il 1,5% dei pazienti trattati con DOR/ISL aveva una carica virale ≥50 copie/mL rispetto allo 0,6% con BIC/FTC/TAF, con il 91,5% che manteneva la soppressione virale
- Nello studio MK-8591A-051: il 1,4% dei pazienti trattati con DOR/ISL aveva una carica virale ≥50 copie/mL rispetto al 4,9% con la terapia antiretrovirale di base, con il 95,6% che manteneva la soppressione virale
Il profilo di sicurezza era comparabile a quello dei trattamenti esistenti, senza resistenza emergente al trattamento osservata. Merck prevede di presentare domande per l'autorizzazione alla commercializzazione entro la metà del 2025.
Merck (NYSE: MRK) anunció resultados positivos de dos ensayos de Fase 3 de su régimen oral investigacional de dos fármacos, doravirina/islatravir (DOR/ISL), para el tratamiento del VIH-1. Los ensayos demostraron no inferioridad frente a las terapias existentes en el mantenimiento de la supresión viral a la semana 48.
Hallazgos clave de los ensayos:
- En el ensayo MK-8591A-052: el 1,5% de los pacientes con DOR/ISL presentaron carga viral ≥50 copias/mL frente al 0,6% con BIC/FTC/TAF, con un 91,5% manteniendo la supresión viral
- En el ensayo MK-8591A-051: el 1,4% de los pacientes con DOR/ISL presentaron carga viral ≥50 copias/mL frente al 4,9% con la terapia antirretroviral de base, con un 95,6% manteniendo la supresión viral
El perfil de seguridad fue comparable al de los tratamientos existentes, sin resistencia emergente al tratamiento observada. Merck planea presentar solicitudes para la autorización de comercialización a mediados de 2025.
머크 (NYSE: MRK)는 HIV-1 치료를 위한 하루 한 번 복용하는 두 약물 병용 요법인 도라비린/이스라트라비르(DOR/ISL)의 3상 시험 두 건에서 긍정적인 결과를 발표했습니다. 이 시험들은 48주 차에 기존 치료법에 비해 바이러스 억제 유지에서 비열등성을 입증했습니다.
시험의 주요 발견:
- MK-8591A-052 시험에서: DOR/ISL 환자의 1.5%가 바이러스 부하 ≥50 복사본/mL를 나타냈고, BIC/FTC/TAF에서는 0.6%였으며, 91.5%가 바이러스 억제를 유지했습니다.
- MK-8591A-051 시험에서: DOR/ISL 환자의 1.4%가 바이러스 부하 ≥50 복사본/mL를 나타냈고, 기초 항레트로바이러스 요법에서는 4.9%였으며, 95.6%가 바이러스 억제를 유지했습니다.
안전성 프로필은 기존 치료와 유사했으며, 치료에서의 내성 발생은 관찰되지 않았습니다. 머크는 2025년 중반까지 마케팅 허가 신청을 제출할 계획입니다.
Merck (NYSE: MRK) a annoncé des résultats positifs de deux essais de Phase 3 de son schéma thérapeutique oral à deux médicaments à prendre une fois par jour, doravirine/islatravir (DOR/ISL), pour le traitement du VIH-1. Les essais ont démontré une non-infériorité par rapport aux thérapies existantes en maintenant la suppression virale à la semaine 48.
Résultats clés des essais :
- Dans l'essai MK-8591A-052 : 1,5 % des patients sous DOR/ISL avaient une charge virale ≥50 copies/mL contre 0,6 % avec BIC/FTC/TAF, avec 91,5 % maintenant la suppression virale.
- Dans l'essai MK-8591A-051 : 1,4 % des patients sous DOR/ISL avaient une charge virale ≥50 copies/mL contre 4,9 % avec le traitement antirétroviral de référence, avec 95,6 % maintenant la suppression virale.
Le profil de sécurité était comparable à celui des traitements existants, sans résistance émergente observée. Merck prévoit de soumettre des demandes d'autorisation de mise sur le marché d'ici mi-2025.
Merck (NYSE: MRK) hat positive Ergebnisse aus zwei Phase-3-Studien zu ihrem investigativen, einmal täglich einzunehmenden oralen Zwei-Medikamenten-Regime Doravirin/Islatravir (DOR/ISL) zur Behandlung von HIV-1 bekannt gegeben. Die Studien zeigten eine Nichtunterlegenheit gegenüber bestehenden Therapien bei der Aufrechterhaltung der viralen Suppression nach 48 Wochen.
Wichtige Ergebnisse der Studien:
- Im MK-8591A-052-Studie: 1,5% der DOR/ISL-Patienten hatten eine Viruslast ≥50 Kopien/mL im Vergleich zu 0,6% bei BIC/FTC/TAF, wobei 91,5% die virale Suppression aufrechterhielten.
- Im MK-8591A-051-Studie: 1,4% der DOR/ISL-Patienten hatten eine Viruslast ≥50 Kopien/mL im Vergleich zu 4,9% bei der Basis-Antiretroviralen Therapie, wobei 95,6% die virale Suppression aufrechterhielten.
Das Sicherheitsprofil war mit bestehenden Behandlungen vergleichbar, ohne beobachtete behandlungsbedingte Resistenzen. Merck plant, bis Mitte 2025 Anträge auf Marktzulassung einzureichen.
- Demonstrated non-inferiority to existing HIV treatments in Phase 3 trials
- High viral suppression rates of 91.5-95.6% at Week 48
- First two-drug regimen without integrase inhibitor showing comparable efficacy
- No treatment-emergent resistance observed
- Regulatory submission timeline established for mid-2025
- Slightly lower viral suppression rate vs BIC/FTC/TAF (91.5% vs 94.2%) in one trial
- Marketing authorization still pending, delaying potential commercialization to post-2025
Insights
Merck's Phase 3 trial results represent a significant advancement in HIV treatment options. The investigational once-daily oral two-drug regimen of doravirine/islatravir (DOR/ISL) successfully demonstrated non-inferiority to current standard-of-care treatments in maintaining viral suppression at 48 weeks. The two pivotal trials showed DOR/ISL met primary efficacy and safety objectives with viral suppression rates of 91.5% compared to 94.2% for BIC/FTC/TAF in one trial, and 95.6% versus 91.9% for baseline antiretroviral therapy in the second trial.
What differentiates this development is that DOR/ISL represents the first two-drug regimen without an integrase inhibitor demonstrating comparable efficacy to three-drug regimens. This innovation addresses evolving patient needs, particularly as HIV patients age and manage comorbidities where simplified treatment regimens may offer advantages. The absence of treatment-emergent resistance to both components further strengthens its clinical profile.
With regulatory submissions planned by mid-2025, Merck is advancing this treatment toward commercialization. While still several quarters from potential revenue generation, this development strengthens Merck's infectious disease portfolio and demonstrates continued innovation in a therapeutic area where the company has historic research strength. The successful trials also validate Merck's investment in islatravir's novel mechanism of action as a nucleoside reverse transcriptase translocation inhibitor.
These positive Phase 3 results strengthen Merck's position in the valuable HIV therapeutics market and advance a potential new revenue driver in their pipeline. The success of DOR/ISL in meeting non-inferiority endpoints against both BIC/FTC/TAF and other antiretroviral therapies provides a clear path toward regulatory submissions by mid-2025.
The strategic significance extends beyond this specific product. DOR/ISL validates Merck's innovative nucleoside reverse transcriptase translocation inhibitor (NRTTI) technology platform, which blocks HIV replication through multiple mechanisms. This scientific achievement potentially creates a foundation for additional pipeline assets and treatment approaches.
From a competitive standpoint, Merck's development of a two-drug regimen that matches three-drug efficacy could provide market differentiation in a mature therapeutic area. As HIV treatment shifts toward addressing long-term patient needs, including aging populations with comorbidities, simplified regimens that maintain efficacy represent meaningful clinical and commercial advantages.
While revenue impact remains several quarters away pending regulatory review, these results reduce clinical risk in Merck's pipeline. The company has explicitly stated their continued commitment to HIV research, including longer-acting islatravir-based therapies, indicating a broader strategic investment beyond this single product. This positions Merck to potentially expand their infectious disease portfolio with multiple HIV treatment options addressing different patient needs and preferences.
DOR/ISL demonstrated non-inferiority and a similar safety profile to comparator antiretroviral therapies in adults with virologically suppressed HIV-1
In the double-blind trial MK-8591A-052 (Abstract #204A), results for the primary endpoint (HIV-1 RNA ≥50 copies/mL) showed that
In the open-label trial MK-8591A-051 (Abstract #204B), results for the primary endpoint (HIV-1 RNA ≥50 copies/mL) showed that
Across both trials, the safety profile of DOR/ISL was generally comparable to the comparator antiretroviral regimens, including
“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
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,
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
Results for the primary efficacy endpoint showed that five participants (
At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and
Drug-related adverse events (AEs) and discontinuations due to drug-related AEs were similar between groups (n=35,
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
Results for the primary efficacy endpoint showed that five participants (
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;
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,
Indications and usage for PIFELTRO® (doravirine) and DELSTRIGO® (doravirine, lamivudine, and tenofovir disoproxil fumarate) in the
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 ≥
By week 96 in DRIVE-FORWARD,
By week 96 in DRIVE-AHEAD,
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
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,
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
Forward-Looking Statement of Merck & Co., Inc.,
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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 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/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf and Patient Information for PIFELTRO at: https://www.merck.com/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/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf and Patient Information for DELSTRIGO at: https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf
ibictegravir/emtricitabine/tenofovir alafenamide (BIKTARVY) is a registered trademark of Gilead Sciences, Inc.
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FAQ
What are the efficacy results of Merck's DOR/ISL HIV treatment in Phase 3 trials?
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