European Commission 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

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the European Commission has approved DELSTRIGO™ and
PIFELTRO™ for the treatment of HIV-1 infection. DELSTRIGO is a new
once-daily fixed-dose combination tablet of doravirine (100 mg),
lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg[1]).
It is indicated in the European Union for the treatment of adults with
HIV-1 infection without past or present evidence of resistance to the
non-nucleoside reverse transcriptase inhibitor (NNRTI) class of
antiviral agents, lamivudine or tenofovir. PIFELTRO (doravirine,
100 mg) is a new, once-daily NNRTI indicated (in the EU) in combination
with other antiretroviral medicines for the treatment of adults with
HIV-1 infection without past or present evidence of resistance to the
NNRTI class.

In the United States, both DELSTRIGO and PIFELTRO are indicated for the
treatment of HIV-1 infection in adults 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 exacerbations of hepatitis B (HBV) infection.
DELSTRIGO and PIFELTRO do not cure HIV-1 infection or AIDS.

We are very pleased that the European Commission has approved DELSTRIGO
and PIFELTRO, as this approval marks another important milestone in
Merck’s unwavering commitment to the global HIV community,” said Dr.
George Hanna, vice president and therapeutic area head of infectious
diseases, Global Clinical Development, Merck Research Laboratories.
These medicines bring new treatment options with demonstrated efficacy
that could potentially address unmet needs for people in Europe living
with HIV.”

The approval allows for marketing of DELSTRIGO and PIFELTRO in all 28
European Union member states, plus Iceland, Lichtenstein and Norway, and
follows a positive opinion from the Committee for Medicinal Products for
Human Use of the European Medicines Agency announced on Sept. 20, 2018.
Marketing authorization applications for DELSTRIGO and PIFELTRO are also
under review in other countries, including Australia and Switzerland.
The U.S. Food and Drug Administration approved DELSTRIGO and PIFELTRO on
Aug. 30, 2018. Health Canada approved PIFELTRO on Oct. 12, 2018 and
DELSTRIGO on Nov. 9, 2018. Availability for DELSTRIGO and PIFELTRO in
the EU is anticipated to begin in the first half of 2019.

As a practitioner serving people living with HIV, I welcome new
medicines that can help us tailor HIV treatment regimens to the needs of
the individual,” said Dr. Esteban Martínez, senior consultant and
associate professor of medicine, infectious diseases, University of
Barcelona, Spain. “The approvals of DELSTRIGO and PIFELTRO bring
important new treatment options to market which have shown demonstrated
efficacy and low rates of discontinuation.”

Data Supporting the Approvals of DELSTRIGO and PIFELTRO in the
European Union

The approval from the European Commission was based on data from two
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 prior antiretroviral treatment history. Across both
of the studies, 25.4 percent of the participants were based in Europe
(379/1494).

In DRIVE-AHEAD, DELSTRIGO met its primary endpoint, demonstrating
non-inferior efficacy compared to efavirenz (EFV)/emtricitabine
(FTC)/tenofovir disoproxil fumarate (TDF) at 48 weeks (84% in the
DELSTRIGO group achieved viral suppression of HIV-1 RNA 40 copies/mL
vs. 80% in the EFV/FTC/TDF group; treatment difference: 4.1%, 95%
confidence interval: -1.5, 9.7). The Week 96 data were supportive of the
Week 48 findings. At Week 96, 76% in the DELSTRIGO group achieved viral
suppression of HIV-1 RNA 40 copies/mL vs. 73% in the EFV/FTC/TDF group;
treatment difference: 3.3%, 95% confidence interval: -3.1, 9.6. 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 6.6% respectively. Clinical adverse reactions of all grades
occurring in ≥5 percent of participants in the DELSTRIGO treatment group
included nausea (6%) and headache (5%).

In DRIVE-FORWARD, PIFELTRO met its primary endpoint, demonstrating
non-inferior efficacy compared to darunavir + ritonavir (DRV+r), each in
combination with FTC/TDF or abacavir (ABC)/3TC at 48 weeks (83% in the
PIFELTRO group achieved viral suppression of HIV-1 RNA 40 copies/mL vs.
79% in the DRV+r group; treatment difference: 4.2%, 95% confidence
interval: -1.4, 9.7). The Week 96 data were supportive of the Week 48
findings. At week 96, 72% in the PIFELTRO group achieved viral
suppression of HIV-1 RNA 40 copies/mL vs. 64% in the DRV+r group;
treatment difference: 7.6%, 95% confidence interval: 1.0, 14.2. In a
pooled analysis combining data from two clinical trials of
treatment-naïve participants (P007 and P021/DRIVE-AHEAD), fewer
participants in the combined doravirine (100 mg) treatment groups (2.8%)
discontinued due to an adverse event by week 48 compared with the
combined EFV treatment group (6.1%) (treatment difference -3.4%,
p=0.012). Clinical adverse reactions of all grades occurring in ≥5
percent of participants in the PIFELTRO treatment group included nausea
(6%) and headache (5%).

Selected Safety Information about DELSTRIGO (doravirine/3TC/TDF) in
the U.S.

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) in the U.S.

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 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 TwitterFacebookInstagram,
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
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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
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Risks and uncertainties include but are not limited to, general industry
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The company undertakes no obligation to publicly update any
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statements can be found in the company’s 2017 Annual Report on Form 10-K
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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
and 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
and Patient Information for PIFELTRO (doravirine) at:
https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ppi.pdf

[1] Equivalent to 245 mg of tenofovir disoproxil

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