Merck Announces New Analyses for Investigational Islatravir in Combination with Doravirine

- July 6th, 2020

Merck announced new analyses from the Phase 2b trial (NCT03272347) evaluating the safety and efficacy of islatravir, the company’s investigational oral nucleoside reverse transcriptase translocation inhibitor, in combination with doravirine (PIFELTRO), in adults with HIV-1 infection who had not previously received antiretroviral treatment.

Analyses Add Support for Further Investigation of Islatravir in Combination with Doravirine for Certain Patients

Post-hoc Weight Analyses from DRIVE-SHIFT Trial of DELSTRIGO™ (doravirine/lamivudine/tenofovir disoproxil fumarate) Also Announced

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced new analyses from the Phase 2b trial (NCT03272347) evaluating the safety and efficacy of islatravir, the company’s investigational oral nucleoside reverse transcriptase translocation inhibitor (NRTTI), in combination with doravirine (PIFELTRO™), in adults with HIV-1 infection who had not previously received antiretroviral treatment. The first sub-analysis further characterized the tolerability and safety profile of islatravir in combination with doravirine (100 mg) through Week 48 across the three dose levels studied (0.25, 0.75, 2.25 mg). The second sub-analysis demonstrated that participants who initiated treatment with islatravir and doravirine in combination with 3TC and switched to islatravir and doravirine maintained antiviral activity at Week 48 as measured by HIV-1 RNA <50 copies/mL similar to DELSTRIGO, with low rates of protocol defined virologic failure (PDVF). These latest findings will be made available this week in two oral presentations during the 23rd International AIDS Conference (AIDS 2020: Virtual). The primary endpoints and full study design of the Phase 2b Week 48 trial results were originally presented at IAS 2019.

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/3TC 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.

“These Week 48 analyses reinforce the potential for islatravir in combination with doravirine as a two-drug regimen for people living with HIV,” said Dr. Jean-Michel Molina, Professor of Infectious Diseases at Paris University and Head of the Infectious Diseases Department, Saint-Louis and Lariboisière Hospitals, Paris, and the study’s lead investigator. “I am encouraged by the results seen in this study and look forward to learning more about the potential of this investigational regimen for the treatment of HIV-1.”

“These findings add to the growing body of evidence supporting the potential of islatravir and doravirine for the treatment of people living with HIV. We look forward to learning more about this treatment combination from the ongoing Phase 3 clinical development program,” said Dr. Joan Butterton, vice president, infectious diseases, Global Clinical Development, Merck Research Laboratories. “Merck’s steadfast commitment to innovation persists, with the ultimate goal of tackling unmet needs across diverse populations and for those disproportionately affected by HIV.”

Week 48 Safety Sub-Analysis and Protocol Defined Virologic Failure Results from Phase 2b Study of Investigational 2-Drug Regimen of Islatravir with Doravirine

In this international, multicenter clinical trial, treatment-naïve adult participants with HIV-1 infection were randomly assigned (1:1:1:1) to one of four once-daily oral treatment groups: islatravir 0.25 mg (n=29), 0.75 mg (n=30) or 2.25 mg (n=31) in combination with doravirine (100 mg) and 3TC (300 mg) compared to DELSTRIGO (n=31). After a minimum of 24 weeks of treatment, participants in the islatravir treatment groups with HIV-1 RNA less than 50 copies/mL who had not met protocol defined virologic failure (PDVF) criteria were transitioned to a two-drug regimen consisting of the same dose of islatravir plus doravirine (100 mg), without 3TC.

Through Week 48, a lower rate of drug-related adverse events (AE) occurred in the islatravir groups (7.8%) compared with the DELSTRIGO group (19.4%). From Week 0-48, similar rates of drug-related adverse events were observed across all islatravir groups (0.25 mg – 0.0%; 0.75 mg – 10.0%; 2.25 mg – 12.9%), with no dose-dependent difference in the safety profile of islatravir. Drug-related adverse events were generally more frequent in the first 24 weeks (0.0% in the 0.25 mg islatravir group; 10.0% in the 0.75 mg islatravir group; 6.5% in the 2.25 mg islatravir group; 19.4% in the DELSTRIGO group) versus the second 24-week period of the trial (0.0% in the 0.25 mg islatravir group; 3.3% in the 0.75 mg islatravir group; 7.4% in the 2.25 mg islatravir group; 3.6% in the DELSTRIGO group) for all treatment arms. The most common reported adverse events (reported by >10% participants) in the DELSTRIGO-treated group were diarrhea (16.1%), bronchitis (12.9%) and syphilis (12.9%). The most common reported adverse events (reported by >10% participants) in the islatravir-treated groups were: 0.25 mg (sinusitis, pain in extremity, headache – 10.3%, 10.3% and 13.8%, respectively); 0.75 mg (diarrhea, nausea, bronchitis, nasopharyngitis, syphilis, vitamin D deficiency -13.3%, 13.3%, 13.3%, 13.3%, 10.0%, 13.3%, respectively); 2.25 mg (arthralgia, headache – 12.9%, 12.9%, respectively). The majority of all adverse events were mild and did not result in study discontinuation. Two participants in the islatravir-treated dose groups (both 2.25 mg) discontinued due to an AE. One participant in the DELSTRIGO group discontinued due to a serious AE considered to be drug related.

In the study, PDVF was defined as viral rebound (HIV-1 RNA ≥50 copies/mL after initial response at any time during the study or confirmed HIV-1 RNA >1 log increase from the lowest HIV-1 RNA level after a >1 log decrease in HIV-1 RNA from baseline, at any time during the study) or non-response (≥200 copies/mL at any time from Week 24 through Week 48 and confirmed HIV-1 RNA ≥50 copies/mL at Week 48); PDVF had to be confirmed by an additional HIV-1 RNA measurement within two weeks. At Week 48, rates of PDVF were low and all participants who discontinued due to PDVF had levels of HIV-1 RNA below the clinically significant level of 200 copies/mL. The observed low-level viremia was comparable to levels detected in other studies of previously untreated patients. At Week 48, 89.7% (26/29), 90.0% (27/30) and 77.4% (24/31) of randomized participants achieved HIV-1 RNA <50 copies/mL in the 0.25, 0.75 and 2.25 mg islatravir groups, respectively, compared to 83.9% (26/31) with the DELSTRIGO group. Six participants met the criteria for PDVF: two rebounders each in the 0.25 and 0.75 mg islatravir groups, one non-responder in the 2.25 mg islatravir group, and one rebounder in the DELSTRIGO group. All confirmatory HIV-1 RNA levels were <80 copies/mL and none met criteria for resistance testing (>400 copies/mL). Despite changing to new regimens, three of six participants (one each from the 0.25 and 0.75 mg islatravir groups and one from the DELSTRIGO group) continued to have low-level viremia with HIV-1 RNA<200 copies/mL during the 42-day post-discontinuation assessment.

Analyses of Weight Changes in Phase 3 DRIVE-SHIFT Trial

Separately, new findings from a post-hoc analysis of the Phase 3 DRIVE-SHIFT trial evaluating a switch to DELSTRIGO show that weight changes among participants switching to DELSTRIGO were similar to the average change observed in HIV negative adults in the U.S.1,2 Weight gains after switch to DELSTRIGO were 1.4 kg (95% confidence interval [CI]; 0.8, 1.9) in the Immediate Switch Group and 1.2 kg (95% CI: 0.4, 2.0) in the Delayed Switch Group after 2 years (144 weeks) on doravirine/3TC/TDF. The DRIVE-SHIFT trial results were first presented at IDWeek 2018.

“The initiation of some types of antiretroviral therapy in people living with HIV has been associated with weight gain,” said Dr. Princy Kumar, Chief, Division of Infectious Diseases and Tropical Medicine at MedStar Georgetown University Hospital and Professor of Medicine and Microbiology, Georgetown University School of Medicine, Washington, D.C. “Our post-hoc analysis of weight changes from the Phase 3 DRIVE-SHIFT trial showed weight changes with DELSTRIGO comparable to the average annual weight gain observed in the general adult population.”

About Islatravir (MK-8591)

Islatravir (formerly MK-8591) is Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently being evaluated in clinical trials for the treatment of HIV-1 infection in combination with other antiretrovirals, as well as for pre-exposure prophylaxis (PrEP) of HIV-1 infection as a single investigational agent, across a variety of formulations.

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.

Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and 16% of subjects 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 subjects 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 subjects in the delayed switch group experienced ALT and AST elevations of greater than 1.25 X ULN through 24 weeks on their baseline regimen.

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 30 years, Merck has been committed to scientific research and discovery in HIV, and we continue to be driven by the conviction that more medical advances are still to come. Our focus is on pursuing research that addresses unmet medical needs and helps people living with HIV and their communities. We remain committed to working hand-in-hand with our partners in the global HIV community to address the complex challenges that hinder continued progress.

Our Commitment to Infectious Diseases

For more than 100 years, Merck has contributed to the discovery and development of novel medicines and vaccines to combat infectious diseases. In addition to a combined portfolio of vaccines and antibacterial, antiviral and antifungal medicines, Merck has multiple programs that span discovery through late-stage development. To learn more about Merck’s infectious diseases pipeline, visit www.merck.com.

About Merck

For more than 125 years, Merck, known as MSD outside of 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.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, 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 products that the products 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 the recent global outbreak of novel coronavirus disease (COVID-19); 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 2019 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (https://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 (doravirine) at: https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ppi.pdf

Please see Prescribing Information for DELSTRIGO (doravirine/3TC/TDF) at: https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf and Patient Information for DELSTRIGO (doravirine/3TC/TDF) at: https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf

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1 Williamson DF. Descriptive epidemiology of body weight and weight change in U.S. adults. Ann Intern Med. 1993;119(7 Pt 2):646–9.

2 Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here?. Science. 2003;299(5608):853-855. doi:10.1126/science.1079857

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July 6, 2020 – 3:45 AM PDT
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