Merck Announces Week 96 Data from Pivotal Phase 3 DRIVE-AHEAD Study Evaluating DELSTRIGO™ (doravirine / lamivudine / tenofovir disoproxil fumarate) for the Treatment of HIV-1 in Treatment-Naïve Patients

October 4, 2018 5:45 am ET

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced new results from the Phase 3 DRIVE-AHEAD clinical trial
evaluating the efficacy and safety of DELSTRIGO™, a once-daily
fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC,
300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg) in
treatment-naïve adults with HIV-1 infection. The efficacy findings at
Week 96 in DRIVE-AHEAD were consistent with the findings at Week 48 in
which DELSTRIGO demonstrated non-inferior efficacy in comparison to a
fixed-dose combination of efavirenz (EFV, 600 mg), emtricitabine (FTC,
200 mg) and TDF (300 mg). The pivotal Phase 3, Week 48 data were
previously presented at the 9^th IAS Conference on HIV Science
/ IAS
2017.

The new Week 96 findings will be presented today as a late-breaking oral
presentation at
IDWeek
2018
taking place Oct. 3-7, 2018, in San Francisco.

“Long-term data from this pivotal clinical trial further confirm the
efficacy and safety of DELSTRIGO in treatment-naïve patients,” said Dr.
Jean-Michel Molina, Professor of Infectious Diseases, University of
Paris, and Head of the Infectious Diseases Department at Saint-Louis
Hospital in Paris, France. “The data position this fixed-dose
combination as a new treatment option that can address the needs of
people living with HIV today.”

Data from DRIVE-AHEAD

In DRIVE-AHEAD, 728 participants with no antiretroviral treatment
history were randomized and received at least one dose of either
DELSTRIGO or EFV/FTC/TDF once daily. In this trial, after 96 weeks of
treatment, the proportion of participants achieving plasma HIV-1 RNA
levels less than 50 copies/mL was 77.5 percent in the group treated with
DELSTRIGO (doravirine/3TC/TDF) and 73.6 percent in the group treated
with EFV/FTC/TDF (treatment difference: 3.8%, 95% confidence interval:
-2.4, 10.0).

No additional viral drug resistance to doravirine was observed in study
participants between Week 48 and Week 96, while two study participants
in the EFV/FTC/TDF group developed viral drug resistance to EFV.

At Week 96, the rate of discontinuation of therapy due to adverse events
was 3.0 percent (11/364) in the DELSTRIGO group and 7.0 percent (27/364)
in the EFV/FTC/TDF group. In addition, the three pre-specified
neuropsychiatric endpoints of dizziness, sleep disorders/disturbances
and altered sensorium were significantly less frequent in the DELSTRIGO
group than in the EFV/FTC/TDF group: dizziness (10.2% vs. 38.2%,
treatment difference: -28%, 95% confidence interval: -33.9, -22.1),
sleep disorders and disturbances (14.0% vs. 27.5%, treatment difference:
-13.5%, 95% confidence interval: -19.3, -7.6) and altered sensorium
(4.9% vs. 8.5%, treatment difference: -3.6%, 95% confidence interval:
-7.4, 0.1).

The study also reported lower mean changes from baseline in the levels
of fasting lipids in the DELSTRIGO group compared with the EFV/FTC/TDF
group at Week 96, including LDL-C (-0.6 mg/dL vs. 10.8 mg/dL, treatment
difference: -11.1, 95% confidence interval: -14.8, -7.4) and non-HDL-C
(-2.1 mg/dL vs. 15.0 mg/dL, treatment difference: -17.0, 95% confidence
interval: -21.1, -13.0).

“At Merck, we are committed to continued scientific innovation as we
look for new ways to help improve how HIV is treated. The recent U.S.
Food and Drug Administration approval of DELSTRIGO represents this
ongoing commitment,” said Dr. George Hanna, vice president and
therapeutic area head of infectious diseases, global clinical
development, Merck Research Laboratories. “We are pleased to see the
efficacy results for DELSTRIGO at 96 weeks, which support the initial
findings seen in the 48 week data.”

On Aug. 30, 2018, DELSTRIGO and PIFELTRO (doravirine) were approved by
the U.S. Food and Drug Administration (FDA). DELSTRIGO was approved as a
once-daily fixed-dose combination tablet of doravirine (100 mg), 3TC
(300 mg) and TDF (300 mg); and PIFELTRO (100 mg), a new non-nucleoside
reverse transcriptase inhibitor (NNRTI), was approved to be administered
in combination with other antiretroviral medicines. Both DELSTRIGO and
PIFELTRO are indicated for the treatment of HIV-1 infection in adult
patients with no prior antiretroviral treatment experience, and are
administered orally once daily with or without food. In the U.S.,
DELSTRIGO contains a boxed warning regarding post-treatment acute
exacerbation of hepatitis B (HBV) infection. DELSTRIGO
(doravirine/3TC/TDF) does not cure HIV-1 infection or AIDS. On Sept. 20,
2018, the Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) adopted a positive opinion recommending
granting of marketing authorization for DELSTRIGO (doravirine/3TC/TDF)
and PIFELTRO (doravirine).

About DRIVE-AHEAD

DRIVE-AHEAD is a Phase 3 multicenter, double-blind, randomized clinical
trial in which 728 participants with no antiretroviral treatment history
were randomized and received at least one dose of either DELSTRIGO or
efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC
200 mg/TDF 300 mg) once daily. The primary endpoint of the clinical
trial was the proportion of participants with HIV-1 RNA copies of less
than 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 (altered sensorium). The trial consists of a 96-week
double-blind treatment period (base study) and an open label extension
after participants complete the base study. Secondary endpoints include
efficacy at Week 96, an evaluation of the effects of DELSTRIGO and
EFV/FTC/TDF on fasting serum lipids, change from baseline in CD4+ T-cell
count and evaluation of safety and tolerability. For further information
regarding DRIVE-AHEAD please visit www.clinicaltrials.gov
clinical trial registry number NCT02403674.

Selected Safety Information about DELSTRIGO (doravirine/3TC/TDF)

Warning: Post treatment Acute Exacerbation of Hepatitis B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before
initiating antiretroviral therapy. Severe acute exacerbations of HBV
have been reported in patients who are coinfected with HIV-1 and HBV and
have discontinued products containing 3TC or 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.

DELSTRIGO is 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 (doravirine/3TC/TDF).
DELSTRIGO is contraindicated in patients with a previous
hypersensitivity reaction to 3TC.

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, as 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.

Consult the full Prescribing Information prior to and during treatment
for important potential drug-drug interactions.

If 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. The most common adverse reactions
with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%),
nausea (5%) and abnormal dreams (5%).

There is a pregnancy exposure registry that monitors pregnancy outcomes
in individuals exposed to DELSTRIGO during pregnancy. Healthcare
providers are encouraged to register patients by calling the
Antiretroviral Pregnancy Registry at 1-800-258-4263. Mothers infected
with HIV-1 should be instructed not to breastfeed if they are receiving
DELSTRIGO due to the potential for HIV-1 transmission. Because DELSTRIGO
is a fixed-dose combination tablet and the components cannot be altered,
it is not recommended in patients with estimated creatinine clearance
less than 50 mL/min.

Selected Safety Information about PIFELTRO (doravirine)

PIFELTRO is 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 PIFELTRO plasma concentrations
may occur, which may decrease the effectiveness of PIFELTRO. Immune
reconstitution syndrome can occur, including the occurrence of
autoimmune disorders with variable time to onset, which may necessitate
further evaluation and treatment. Co-administration of PIFELTRO with
efavirenz, etravirine or nevirapine is not recommended. If
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 important potential drug-drug interactions. The safety of PIFELTRO
is based on two studies, DRIVE-FORWARD and DRIVE-AHEAD. In
DRIVE-FORWARD, the most common adverse reactions (incidence ≥5%, all
intensities) were nausea (7%), headache (6%), fatigue (6%), diarrhea
(5%) and abdominal pain (5%). In DRIVE-AHEAD, the most common adverse
reactions (incidence ≥5%, all intensities) were dizziness (7%), abnormal
dreams (5%) and nausea (5%).

There is a pregnancy exposure registry that monitors pregnancy outcomes
in individuals exposed to PIFELTRO during pregnancy. Healthcare
providers are encouraged to register patients by calling the
Antiretroviral Pregnancy Registry at 1-800-258-4263. Mothers infected
with HIV-1 should be instructed not to breastfeed if they are receiving
PIFELTRO due to the potential for HIV 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 to continuing progress.

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
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Please see Prescribing Information for DELSTRIGO (doravirine/3TC/TDF)
at:

https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf

Patient
Information for DELSTRIGO (doravirine/3TC/TDF) at:

https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf

Please
see Prescribing Information for PIFELTRO (doravirine) at:

https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf

Patient
Information for PIFELTRO (doravirine) at:

https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ppi.pdf