Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has placed clinical holds on the investigational new drug applications (INDs) for the oral and implant formulations of islatravir (MK-8591) for HIV-1 pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for HIV-1 treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) HIV-1 once-daily treatment. The FDA’s clinical hold is based on previously announced observations of decreases in total lymphocyte and CD4+ T-cell counts in some participants receiving islatravir in clinical studies. As previously announced, Merck has stopped dosing in the Phase 2 IMAGINE-DR clinical trial of islatravir in combination with MK-8507 (MK-8591-013) and paused enrollment in the once-monthly Phase 3 PrEP studies, (MK-8591-022 and MK-8591-024) (see announcements here and here). With the FDA’s clinical hold, no new studies may be initiated. Participants who are currently receiving islatravir as part of the studies for PrEP, including oral and implant formulations, as well as injectable islatravir for treatment and prophylaxis, will no longer receive the study drug; CD4+ T-cell and total lymphocyte counts will be monitored for recovery (full clinical hold). Participants in the PrEP studies will be offered approved, once-daily, oral PrEP. Additionally, participants in studies of DOR/ISL who were started on treatment will continue to receive study medication (partial clinical hold). No new participants will be screened or randomized in DOR/ISL studies for treatment during the partial clinical hold. Investigators have been informed of these actions.

“We are grateful to the participants and the study investigators for their ongoing contributions to this research,” said Dr. Joan Butterton, vice president, infectious diseases, Global Clinical Development, Merck Research Laboratories. “Merck continues to investigate the potential of islatravir and nucleoside reverse transcriptase translocation inhibitors and remains committed to helping to address unmet needs in HIV treatment and prevention.”

The following studies have been placed on full clinical hold:

• MK-8591-016 – A Phase 2a PrEP study evaluating the safety and pharmacokinetics of oral islatravir once-monthly in participants at low risk of HIV-1 infection
• MK-8591-022 (IMPOWER 22) – A Phase 3 PrEP study evaluating oral islatravir once-monthly in cisgender women at high risk for HIV-1 infection
• MK-8591-024 (IMPOWER 24) – A Phase 3 PrEP study evaluating oral islatravir once-monthly in cisgender men and transgender women who have sex with men, and are at high risk for HIV-1 infection
• MK-8591-034 – A Phase 1 study evaluating injectable islatravir (dosing complete)
• MK-8591-035 – A Phase 2 PrEP study evaluating once-monthly oral islatravir in trans and gender diverse individuals (study had not yet opened enrollment)
• MK-8591-043 – A Phase 2a PrEP study evaluating islatravir implant once-yearly in individuals at low risk for HIV-1 infection (study had not yet opened enrollment)

The following studies have been placed on partial clinical hold:

• MK-8591-011 – A Phase 2 dose ranging study of oral DOR/ISL once-daily and lamivudine (3TC) in treatment-naïve adult participants with HIV-1 infection (fully enrolled)
• MK-8591A-017 (ILLUMINATE SWITCH A) – A Phase 3 oral once-daily, open label study evaluating a switch from antiretroviral therapy (ART) to DOR/ISL in adults with HIV-1 who are virologically suppressed (fully enrolled)
• MK-8591A-018 (ILLUMINATE SWITCH B) – A Phase 3 oral once-daily study evaluating a switch from bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) to DOR/ISL in adults with HIV-1 who are virologically suppressed (fully enrolled)
• MK-8591A-019 (ILLUMINATE HTE) – A Phase 3 study evaluating oral islatravir and DOR/ISL once-daily in heavily treatment-experienced (HTE) participants with HIV-1 infection
• MK-8591A-020 (ILLUMINATE NAIVE) – A Phase 3 study evaluating oral islatravir and DOR/ISL once-daily in treatment-naïve participants with HIV-1 infection
• MK-8591A-028 (ILLUMINATE YOUTH) – A Phase 2 open label study evaluating oral DOR/ISL once-daily for the treatment of HIV-1 infection in pediatric participants who are virologically suppressed on ART for ≥3 months or are treatment-naive
• MK-8591A-033 – A Phase 3 open label follow up of adult and pediatric participants with HIV-1 who were treated with oral DOR/ISL once-daily in earlier clinical studies

Additionally, Gilead and Merck have made the decision to stop all dosing of participants in the Phase 2 clinical study (NCT05052996) evaluating an oral-weekly combination treatment regimen of Merck’s investigational islatravir and Gilead’s investigational lenacapavir in people living with HIV who are virologically suppressed on antiretroviral therapy. This decision follows the joint announcement on November 23 of a temporary hold on further enrollment and screening in the study, which commenced in October 2021. Following this decision to stop dosing in the study, participants in both treatment groups will stop taking study drug and restart their prior antiretroviral regimen, as the two companies assess whether a different dosing of islatravir in combination with lenacapavir may provide a once-weekly oral therapy option for people living with HIV. Gilead and Merck remain committed to the collaboration, which aims to develop long-acting new treatment options to address the unmet needs for people living with HIV.

About IMPOWER 22 (MK-8591-022) and IMPOWER 24 (MK-8591-024)

The IMPOWER 22 clinical trial is a Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the efficacy and safety of oral islatravir once-monthly compared to once-daily emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as pre-exposure prophylaxis (PrEP) in cisgender women at high risk for HIV-1 Infection.

The IMPOWER 24 clinical trial is a Phase 3, randomized, active-controlled, double-blind clinical study to evaluate the efficacy and safety of oral islatravir once-monthly as PrEP compared to once-daily FTC/TDF or emtricitabine/tenofovir alafenamide (FTC/TAF) in cisgender men and transgender women who have sex with men, and are at high risk for HIV-1 infection.

About IMAGINE-DR

The IMAGINE-DR clinical trial was a Phase 2, randomized, controlled, double-blind, dose-ranging study, designed to evaluate a switch to MK-8507 and ISL in combination as a once-weekly oral treatment in adults with HIV-1 who have been virologically suppressed for greater than or equal to six months on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once-daily. The study had been fully enrolled with 161 participants and was ongoing.

About ILLUMINATE SWITCH A (MK-8591A-017) and ILLUMINATE SWITCH B

The ILLUMINATE SWITCH A clinical trial is a Phase 3, randomized, active-controlled, open-label clinical trial to evaluate a switch from ART to DOR/ISL, in adults with HIV-1 who are virologically suppressed.

The ILLUMINATE SWITCH B clinical trial is a Phase 3, randomized, double-blind clinical trial to evaluate a switch from BIC/FTC/TAF to DOR/ISL in adults with HIV-1 who are virologically suppressed.

About Islatravir (MK-8591)

Islatravir (MK-8591) is Merck’s investigational nucleoside reverse transcriptase translocation inhibitor under evaluation for the treatment and prevention of HIV-1.

About PIFELTRO™ and DELSTRIGO™

PIFELTRO ™ (doravirine, 100 mg) 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™ (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) 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. DELSTRIGO contains a boxed warning regarding post-treatment acute exacerbations of hepatitis B (HBV) infection. See Selected Safety Information below.

Selected Safety Information about PIFELTRO and DELSTRIGO

Warning: Posttreatment Acute Exacerbation of Hepatitis B (HBV)

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 patients who are coinfected with HIV-1 and HBV and 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.

PIFELTRO and DELSTRIGO are contraindicated when co-administered 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.

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 patients 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.

In clinical trials in HIV-1 infected adults, 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.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Because DELSTRIGO is a complete regimen, co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Co-administration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

If DELSTRIGO is co-administered 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 co-administered 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.

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.

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 subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

By Week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the EFV/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-cholesterol (LDL-C) and non-HDL-cholesterol (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 48 in LDL-cholesterol (LDL-C) and non-HDL-cholesterol (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 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 subjects 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 subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

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.

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

Our Commitment to HIV

For more than 35 years, Merck has been committed to scientific research and discovery (R&D) in 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 remain committed to working hand-in-hand with our partners in the global HIV community to address the complex challenges that impede progress toward ending the epidemic.

About Merck

For over 130 years, Merck, known as MSD outside the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

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