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Merck's Investigational NNRTI, Doravirine, Meets Primary Efficacy Endpoint of Non-Inferiority to Efavirenz, Both in Combination with Other Antiretroviral Agents, in Pivotal Phase 3 Trial for Treatment of HIV-1 Infection
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Merck Plans to Submit New Drug Applications with the U.S. FDA in Q4 2017
Tuesday, July 25, 2017 8:35 am EDT
KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of results from the DRIVE-AHEAD study, the second of two pivotal Phase 3 clinical trials evaluating the efficacy and safety of doravirine, the company's investigational, non-nucleoside reverse transcriptase inhibitor (NNRTI), for the treatment of HIV-1 infection. At 48 weeks, the study showed that a once-daily single tablet, fixed-dose combination of doravirine (DOR), lamivudine (3TC), and tenofovir disoproxil fumarate (TDF) met its primary efficacy endpoint of non-inferiority based on the proportion of participants achieving levels of HIV-1 RNA less than 50 copies/mL at 48 weeks of treatment, compared to a fixed-dose combination of efavirenz (EFV), emtricitabine (FTC), and TDF, in treatment-naïve adults infected with HIV-1.
In addition, through 48 weeks, statistically significantly fewer patients taking DOR/3TC/TDF reported pre-specified categories of neuropsychiatric events (dizziness, sleep disorders and disturbances, and inability to think clearly or concentrate) than patients receiving the EFV/FTC/TDF regimen. Treatment with DOR/3TC/TDF also showed a statistically significant lower change from baseline in fasting low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) compared to EFV/FTC/TDF at Week 48. Findings from the ongoing DRIVE-AHEAD Phase 3 trial were featured as part of a late-breaking oral presentation session at the 9th International Conference on HIV Science (IAS 2017) taking place in Paris, France, from July 23-26, 2017.
"Data from DRIVE-AHEAD at 48 weeks show that a fixed-dose combination tablet containing doravirine achieved viral suppression in HIV-1 infected treatment-naïve adults, comparable to a fixed-dose combination containing efavirenz," said Dr. Kathleen Squires, professor and director of infectious diseases, Thomas Jefferson University, Philadelphia, PA, a study investigator. "The results for doravirine are encouraging, as it may offer appropriate patients a new single-tablet treatment option."
After 48 weeks of treatment, 84 percent of the 364 treatment-naïve patients taking once-daily DOR/3TC/TDF achieved levels of HIV-1 RNA <50 copies/mL compared to 81 percent of the 364 patients taking once-daily EFV/FTC/TDF, with an estimated treatment difference of 3.5 percent (95 percent confidence interval; -2.0, 9.0). Increases in mean CD4+ T-cell counts from baseline for the DOR/3TC/TDF and EFV/FTC/TDF groups were 198 and 188 cells/mm3, respectively, with an estimated treatment difference of 10.1 (95 percent confidence interval; -16.1, 36.3). In addition, comparable efficacy was observed across both treatment groups among individuals with high viral load (HIV-1 RNA >100,000 copies/mL) at baseline, which consisted of 69 patients in the DOR/3TC/TDF group and 73 patients in the EFV/FTC/TDF group (Observed Failure approach). Of those patients with a high viral load (HIV-1 RNA >100,000 copies/mL) at baseline, 81 percent in the DOR/3TC/TDF group and 81 percent in the EFV/FTC/TDF group achieved the study's primary endpoint of <50 copies/mL of HIV-1 RNA, with a treatment difference of 1.0 percent (95 percent confidence interval; -12.4, 14.3).
The study also met its primary safety endpoint, showing that treatment with DOR/3TC/TDF resulted in fewer patients reporting events of several pre-specified neuropsychiatric adverse events compared to EFV/FTC/TDF by Week 48, including dizziness (8.8 percent versus 37.1 percent); sleep disorders and disturbances (12.1 percent versus 25.5 percent); and inability to think clearly or concentrate (4.4 percent versus 8.2 percent). The 2-sided p-values for treatment differences with respect to these three pre-specified categories were p<0.001, p<0.001, and p=0.033, respectively.
Furthermore, the reported rates of drug-related adverse events were lower in the group taking DOR/3TC/TDF (31 percent; 113/364) versus the group taking EFV/FTC/TDF (63 percent; 229/364), representing a -31.9 percent treatment difference (95 percent confidence
interval, -38.6, -24.8). Treatment discontinuations due to adverse events for DOR/3TC/TDF and EFV/FTC/TDF were 3 percent (11/364) and 7 percent (24/364), respectively.
The most commonly reported adverse events occurring in ≥10 percent of patients in the DOR/3TC/TDF group compared to the EFV/FTC/TDF group were: headache (13 percent vs. 12 percent); diarrhea (11 percent vs. 14 percent); nasopharyngitis (11 percent vs. 9 percent); dizziness (9 percent vs. 37 percent); nausea (8 percent vs. 11 percent); abnormal dreams (5 percent vs. 12 percent) and, rash (5 percent vs. 12 percent), respectively.
Treatment-emergent viral mutations leading to any drug-associated resistance was detected in 1.6 percent of patients in the group receiving DOR/3TC/TDF, and 3.3 percent of those in the EFV/FTC/TDF group, respectively, through Week 48.
An analysis of fasting lipid levels showed a statistically significant treatment difference in mean changes from baseline in fasting LDL-C and non-HDL-C between the two treatment groups (p<0.0001 for both cholesterol types). The mean changes from baseline in levels of fasting LDL-C and non-HDL-C among the group taking DOR/3TC/TDF was -1.6 mg/dL and -3.8 mg/dL, respectively; compared to the group taking EFV/FTC/TDF which was +8.7 mg/dL and +13.3 mg/dL, respectively.
"For more than 30 years, Merck has been at the forefront of HIV research and the development of new treatments that make a difference for people living with HIV," said Dr. George Hanna, associate vice president, clinical research, Merck Research Laboratories. "The development of doravirine is the result of a decade of Merck research. Based on our encouraging Phase 3 study findings, we plan to file regulatory applications in Q4 2017."
About DRIVE-AHEAD
DRIVE-AHEAD is an ongoing Phase 3 multicenter, double-blind, randomized, active comparator-controlled clinical trial evaluating the safety and efficacy of a once-daily, single-tablet, fixed-dose combination containing doravirine 100 mg, lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg versus a once-daily, single-tablet, fixed-dose combination containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg in treatment-naïve HIV-1 infected adults. The primary endpoint of the clinical trial was the proportion of participants with levels of HIV-1 RNA <50 copies/mL at Week 48. The primary safety endpoint was the proportion of participants with neuropsychiatric adverse events through Week 48 in the following pre-specified categories: dizziness, sleep disorders and disturbances, and the inability to think clearly or concentrate. The trial consists of a 96-week double-blind treatment period (base study) and an open label extension after participants complete the base study.
For further information regarding DRIVE-AHEAD please visit www.clinicaltrials.gov clinical trial registry number NCT02403674.
About Doravirine
Doravirine (MK1439) is an investigational NNRTI being evaluated by Merck for the treatment of HIV-1 infection. Doravirine is being evaluated in several ongoing clinical trials as a once-daily fixed dose combination with 3TC and TDF or individually for use in combination with other antiretroviral agents. Phase 3 trials include DRIVE-AHEAD, a trial comparing DOR/3TC/TDF to EFV/FTC/TDF in treatment-naïve adults; DRIVE-FORWARD, a trial comparing DOR to once-daily ritonavir-boosted darunavir (DRV+r), each administered in combination with FTC/TDF or abacavir (ABC)/3TC, in treatment-naïve adults; and DRIVE-SHIFT, a trial evaluating a switch to DOR/3TC/TDF in HIV-1 infected adults who are currently virologically suppressed on another antiretroviral regimen. Other ongoing Phase 2 clinical trials include an evaluation of DOR/3TC/TDF in treatment-naïve adults with transmitted resistance to NNRTIs and in individuals switching from efavirenz due to intolerability.
About Merck
For more than a century, Merck, a leading global biopharmaceutical company 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. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer's disease and infectious diseases including HIV and Ebola. 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 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 2016 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 (www.sec.gov).
Contact:
Merck
Media:Doris Li, 908-246-5701
Carmen de Gourville,
267-664-0146
Investor:
Teri Loxam,
908-740-1986
Amy Klug, 908-740-1898
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