FDA Approves Merck’s DELSTRIGO™ (doravirine / lamivudine / tenofovir disoproxil fumarate), a Once-Daily Fixed-Dose Combination Tablet as a Complete Regimen and PIFELTRO™ (doravirine), an NNRTI, Both for the Treatment of HIV-1 in Appropriate Patients

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August 30, 2018 3:05 pm ET

Approvals Based on Findings from the Pivotal Phase 3 DRIVE-AHEAD and DRIVE-FORWARD Trials Evaluating the Efficacy and Safety of DELSTRIGO and PIFELTRO

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved two new HIV-1 medicines: DELSTRIGO™, a once-daily
fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC,
300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg); and PIFELTRO™
(doravirine, 100 mg), a new non-nucleoside reverse transcriptase
inhibitor (NNRTI) 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. DELSTRIGO contains a boxed warning regarding
post-treatment acute exacerbation of hepatitis B (HBV) infection.
DELSTRIGO and PIFELTRO do not cure HIV-1 infection or AIDS.

DELSTRIGO and PIFELTRO are contraindicated when co-administered with
drugs that are strong cytochrome P450 (CYP)3A enzyme inducers 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 3TC. For more information, see “Selected
Safety Information” below.

“As part of Merck’s 30-year commitment to the care of people with HIV,
we are pleased to now bring forward these two new antiretroviral
treatment options, DELSTRIGO and PIFELTRO, which we believe offer a
compelling clinical profile for clinicians and people living with HIV,”
said Dr. George Hanna, vice president and therapeutic area head of
infectious diseases, Global Clinical Development, Merck Research
Laboratories. “We are thankful to the researchers as well as those
living with HIV and their communities for the collaboration that made
today’s approval possible.”

Immune reconstitution syndrome can occur, including the occurrence of
autoimmune disorders with variable time to onset, which may necessitate
further evaluation and treatment. 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 non-steroidal anti-inflammatory drugs (NSAIDs)
have been reported in patients with risk factors for renal dysfunction
who appeared stable on TDF.

Data Supporting the Approvals of DELSTRIGO (doravirine 100 mg/3TC 300
mg/TDF 300 mg) and PIFELTRO (doravirine)

The FDA approvals of
DELSTRIGO, the once-daily fixed-dose combination tablet as a complete
regimen, and PIFELTRO, a new NNRTI, are based on findings from the
pivotal, randomized, multicenter, double-blind, active controlled Phase
3 trials, DRIVE-AHEAD and DRIVE-FORWARD, evaluating the efficacy and
safety of DELSTRIGO and PIFELTRO, respectively, in participants infected
with HIV-1 with no antiretroviral treatment history.

The DRIVE-AHEAD Clinical Trial

In DRIVE-AHEAD, 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. DELSTRIGO demonstrated sustained viral
suppression through 48 weeks, meeting its primary endpoint of
non-inferior efficacy compared to EFV/FTC/TDF (84% in the DELSTRIGO
group achieved viral suppression of HIV-1 RNA <50 copies/mL vs. 81% in
the EFV/FTC/TDF group; treatment difference: 3.5%, [95% CI:] -2.0%,
9.0%). Of the 21 percent of study participants with a high viral load at
baseline (HIV-1 RNA >100,000 copies/mL), 77 percent in the DELSTRIGO
group and 72 percent in the EFV/FTC/TDF group achieved HIV-1 RNA <50
copies/mL at Week 48.

At Week 48, DELSTRIGO-treated participants showed statistically
significant superior lipid profiles as measured by changes from baseline
in LDL-cholesterol and non-HDL-cholesterol (LDL-C: -2.1 mg/dL in the
DELSTRIGO group vs. 8.3 mg/dL in the EFV/FTC/TDF group; treatment
difference: -10.2 mg/dL, [95% CI:] -13.8, -6.7, p<0.0001; non-HDL-C:
-4.1 mg/dL in the DELSTRIGO group vs. 12.7 mg/dL in EFV/FTC/TDF;
treatment difference: -16.9 mg/dL, [95% CI:] -20.8, -13.0, p<0.0001).
However, the clinical benefit of these findings has not been
demonstrated. In addition, a statistically significant lower proportion
of DELSTRIGO-treated participants compared to EFV/FTC/TDF-treated
participants reported neuropsychiatric adverse events in the three
pre-specified categories of dizziness (9% vs. 37%; treatment difference:
-28.3%, [95% CI:] -34.0, -22.5, p <0.001), sleep disorders and
disturbances (12% vs. 26%; treatment difference: -13.5%, [95% CI:]
-19.1, -7.9, p <0.001), and altered sensorium (4% vs. 8%; treatment
difference: -3.8%, [95% CI:] -7.6, -0.3, p=0.033).

The rate of discontinuation of treatment due to adverse events was lower
in the DELSTRIGO treatment group than in the EFV/FTC/TDF treatment
group (3% and 6%, respectively). Clinical adverse reactions of all
grades occurring in ≥5 percent of participants in the DELSTRIGO
treatment group included dizziness (7%), nausea (5%) and abnormal dreams
(5%). No adverse reactions of Grade 2 or higher (moderate or severe)
occurred in ≥2 percent of participants treated with DELSTRIGO.

The DRIVE-FORWARD Clinical Trial

In DRIVE-FORWARD, 766
participants with no antiretroviral treatment history were randomized
and received at least one dose of either PIFELTRO once daily or
darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily, each in
combination with emtricitabine (FTC)/TDF or abacavir (ABC)/3TC selected
by the investigator. PIFELTRO demonstrated sustained viral suppression
through 48 weeks, meeting its primary endpoint of non-inferior efficacy
compared to DRV+r, each in combination with FTC/TDF or ABC/3TC (84% in
the PIFELTRO group achieved viral suppression of HIV-1 RNA <50 copies/mL
vs. 80% in the DRV+r group; treatment difference: 3.9%, [95% CI:] -1.6%,
9.4%). Of the 20 percent of study participants with a high viral load at
baseline (HIV-1 RNA >100,000 copies/mL), 77 percent in the PIFELTRO
group and 74 percent in the DRV+r group achieved HIV-1 RNA <50 copies/mL
at Week 48.

At Week 48, PIFELTRO-treated participants showed statistically
significant superior lipid profiles as measured by changes from baseline
in LDL-cholesterol and non-HDL-cholesterol (LDL-C: -4.6 mg/dL in the
PIFELTRO group vs. 9.5 mg/dL in the DRV+r group; treatment difference:
-14.4 mg/dL, [95% CI:] -18.0, -10.8, p<0.0001; non-HDL-C: -5.4 mg/DL in
the PIFELTRO group vs. 13.7 mg/dL in the DRV+r group, treatment
difference: -19.4 mg/dL, [95% CI:] -23.4, -15.4, p<0.0001). However, the
clinical benefit of these findings has not been demonstrated.

The rate of discontinuation of therapy due to adverse events in either
treatment group was low (2% in the PIFELTRO group and 3% in the DRV+r
group). Clinical adverse reactions of all grades occurring in ≥5 percent
of participants in the PIFELTRO treatment group included nausea (7%),
headache (6%), fatigue (6%), diarrhea (5%) and abdominal pain (5%). No
adverse reactions of Grade 2 or higher (moderate or severe) occurred in
≥2 percent of participants treated with PIFELTRO.

“As a result of the remarkable strides made in the fight against HIV,
clinicians and their patients have the opportunity to work together to
identify treatment regimens that may be best for each individual, taking
into account other aspects of that person’s health, including other
medicines they may be taking,” said Dr. David Wohl, professor, Division
of Infectious Diseases, University of North Carolina (UNC) Chapel Hill
School of Medicine and site leader, UNC AIDS Clinical Trials
Unit. “Today’s approvals of DELSTRIGO and PIFELTRO provide two new
options for the treatment of HIV-1 in appropriate treatment-naïve adult
patients.”

DELSTRIGO and PIFELTRO can be co-administered with a wide range of
non-antiretroviral agents, and PIFELTRO can be co-administered with a
wide range of antiretroviral agents. DELSTRIGO and PIFELTRO cannot be
co-administered with enzalutamide, carbamazepine, oxcarbazepine,
phenobarbital, phenytoin, rifampin, rifapentine, mitotane or St. John’s
wort. If DELSTRIGO is co-administered with rifabutin, patients should
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, patients need
to increase the PIFELTRO dosage to one tablet twice daily approximately
12 hours apart. Use of PIFELTRO with efavirenz, etravirine, or
nevirapine is not recommended.

No clinically significant changes in concentration have been observed
following the co-administration of doravirine and the following drugs:
dolutegravir, ritonavir, TDF, 3TC, elbasvir and grazoprevir, ledipasvir
and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium
hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an
oral contraceptive containing ethinyl estradiol and levonorgestrel,
metformin, methadone, and midazolam. For DELSTRIGO, no clinically
significant drug interactions have been observed in studies conducted in
healthy participants between TDF and the following medications:
entecavir, methadone, oral contraceptives, sofosbuvir or tacrolimus. If
DELSTRIGO is co-administered with ledipasvir/sofosbuvir or
sofosbuvir/velpatasvir, monitor for adverse reactions associated with
TDF. Co-administration of single doses of 3TC and sorbitol resulted in a
sorbitol dose-dependent reduction in 3TC exposures. When possible, avoid
use of sorbitol-containing medicines with 3TC-containing medicines, such
as DELSTRIGO.

Overall Viral Resistance Profile

In the DELSTRIGO and
PIFELTRO treatment arms of the DRIVE-AHEAD and DRIVE-FORWARD trials
(n=747), a total of 11 participants showed the emergence of
doravirine-associated resistance substitutions, among the 28
participants in the resistance analysis subset (participants with HIV-1
RNA >400 copies per mL at virologic failure or early study
discontinuation and having resistance data). Of these 11 participants,
seven showed both genotypic and phenotypic resistance to doravirine,
with at least a 100-fold reduction in susceptibility to doravirine. The
other four participants had substitutions that were associated with less
than twofold reduction in susceptibility to doravirine.

In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), 12
participants showed the emergence of efavirenz-associated resistance
substitutions among 20 participants in the resistance analysis subset.
In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no
participants showed the emergence of DRV+r associated resistance
substitutions among the nine participants with resistance data.

Cross-resistance has been observed among NNRTIs, including doravirine.
Treatment-emergent doravirine resistance-associated substitutions can
confer cross-resistance to efavirenz, rilpivirine, nevirapine and
etravirine. No significant cross-resistance has been demonstrated
between doravirine-resistant HIV-1 variants and 3TC, FTC or tenofovir or
between 3TC or tenofovir-resistant variants and doravirine.

“Today, with the right access and care, people living with HIV are
better able to manage this chronic condition,” said Kathie Hiers, chief
executive officer, AIDS Alabama. “We are thankful for Merck’s unwavering
commitment to help address unmet needs through the development of new
treatment options, and the provision of community support and
educational resources for people living with HIV.”

DELSTRIGO (doravirine/3TC/TDF) and PIFELTRO (doravirine) Availability
and Access

The approvals of DELSTRIGO and PIFELTRO come ahead
of the original FDA target action date of Oct. 23, 2018. Merck
anticipates that PIFELTRO and DELSTRIGO will be stocked through
wholesalers within one month. Merck is working to obtain access for
patients in government-sponsored programs, including Medicare Part D,
Medicaid and AIDS Drug Assistance Programs. Upon approval, DELSTRIGO and
PIFELTRO will be covered products under the Merck Patient Assistance
Program and will be available to eligible patients when the medicines
are available. Doravirine is also under regulatory review by the
European Medicines Agency (EMA).

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 lamivudine 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. 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, 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.

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
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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
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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