Merck Plans to Submit New Drug Applications
with the U.S. FDA in Q4 2017
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.
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Kenilworth, N.J., USA
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USA (the “company”) includes “forward-looking statements” within
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