20 • MED AD NEWS FEBRUARY 2018
pany’s continued launches with new indications
globally. EvaluatePharma analysis has the blockbuster medicine reaching $6.1 billion in global
sales during 2018, with its potential $2.28+ billion
year-over-year growth representing the largest increase of any prescription drug this year.
Merck has the industry’s largest immuno-oncology clinical research program, consisting of more
than 650 studies exploring Keytruda (
pembroli-zumab) across a wide range of cancers and treatment settings. The Keytruda clinical program seeks
to understand the role of the medicine across cancers and the factors that may predict a patient’s
likelihood of bene;ting from its treatment, including exploring several di;erent biomarkers.
The anti-PD-1 therapy works by increasing the
ability of the body’s immune system to help detect
and ;ght tumor cells. The humanized monoclonal
antibody Keytruda blocks the interaction between
PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may a;ect tumor cells
and healthy cells.
Merck continues to expand the company’s
focus in oncology by further advancing the development program for Keytruda as well as the
poly (ADP-ribose) polymerase inhibitor Lynparza
(olaparib), which is co-developed and co-com-mercialized with AstraZeneca.
In January 2018, Merck announced the pivotal
Phase 3 KEYNOTE-189 study exploring Keytruda in
combination with pemetrexed (branded as Alim-ta) and cisplatin or carboplatin, for the ;rst-line
treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), met its
dual primary endpoints of overall survival (OS) and
progression-free survival (PFS). Based on an interim analysis performed by the independent Data
Monitoring Committee, treatment with Keytruda
in combination with pemetrexed plus platinum
chemotherapy led to signi;cantly longer OS and
PFS than pemetrexed plus platinum chemotherapy alone. Keytruda, in combination with pemetrexed and platinum chemotherapy, is the ;rst
immuno-oncology combination to demonstrate
improved OS for the ;rst-line treatment of patients
with metastatic non-squamous NSCLC.
The FDA accepted for priority review the sBLA
for Keytruda for treating adult and pediatric patients with refractory primary mediastinal B-cell
lymphoma, or who have relapsed after two or
more prior lines of therapy. FDA set a PDUFA date
of April 3, 2018, and granted Breakthrough Therapy Designation for this indication in January 2017.
During January 2018, U.S. regulators issued
Breakthrough Therapy Designation for Keytru-
da in combination with Eisai’s multiple receptor
tyrosine kinase inhibitor Lenvima (lenvatinib) for
the potential treatment of advanced and/or met-
astatic renal cell carcinoma. The combo product
is jointly developed as part of a Merck and Eisai
collaboration. This marked the 12th Breakthrough
Therapy Designation awarded to Keytruda.
The Japanese Ministry of Health, Labour and Welfare granted approval in early January for Keytruda
for treating patients with radically unresectable
urothelial carcinoma who progressed after cancer
chemotherapy. This approval marked the ;rst an-
ti-PD-1 therapy cleared in Japan for previously treated urothelial carcinoma, a form of bladder cancer.
The European Organization for Research and
Treatment of Cancer (EORTC) announced on Jan.
8 the Phase 3 EORTC1325/KEYNOTE-054 study
exploring Keytruda as monotherapy for surgically resected high-risk melanoma met the primary
endpoint of recurrence-free survival. Based on an
interim analysis and following review by the Independent Data Monitoring Committee, Keytruda’s
performance resulted in signi;cantly longer recurrence-free survival than placebo.
The FDA gave the green light to Lynparza in
January 2018 for a new indication: for use in patients with germline BRCA-mutated, HER2-nega-
tive metastatic breast cancer who have been previously treated with chemotherapy either in the
neoadjuvant, adjuvant or metastatic settings. Lynparza represents the ;rst PARP inhibitor approved
for breast cancer. A supplemental New Drug Application was ;led to Japan’s Pharmaceuticals and
Medical Devices Agency for the same usage.
Lynparza is the ;rst targeted treatment to potentially exploit DNA damage response (DDR)
pathway de;ciencies, including BRCA mutations,
to preferentially kill cancer cells. Speci;cally, in
vitro studies have demonstrated that Lynpar-za-induced cytotoxicity may involve inhibition of
PARP enzymatic activity and increased formation
of PARP-DNA complexes, leading to DNA damage
and cancer cell death.
The Japanese Ministry of Health, Labour and
Welfare during January granted approval to Lynparza for use as a maintenance therapy for patients with platinum-sensitive relapsed ovarian
cancer, regardless of their BRCA mutation status,
who responded to their last platinum-based chemotherapy. Lynparza is the ;rst PARP inhibitor to
win marketing approval in Japan.
AstraZeneca and Merck announced during July
2017 a worldwide strategic oncology collabora-
tion to jointly develop and commercialize Lynpar-
za and the potential new medicine selumetinib, a
MEK inhibitor, for multiple cancer types. The col-
laboration is based on increasing evidence that
PARP and MEK inhibitors can be combined with
PD-L1/PD-1 inhibitors for various tumor types. The
companies will jointly develop Lynparza and selu-
metinib in combination with other potential new
medicines and as a monotherapy. Independently,
Merck and AstraZeneca will develop Lynparza and
selumetinib in combination with their respective
PD-L1 and PD-1 medicines.
FDA approval was granted in December to
Merck and P;zer for the oral sodium-glucose
cotransporter 2 inhibitor Steglatro (
ertugli;ozin) tablet, the ;xed-dose combination Steglujan
(ertugli;ozin and sitagliptin) and the ;xed-dose
combination Segluromet (ertugli;ozin and metformin hydrochloride) to help improve glycemic
control in adults with type 2 diabetes. In addition,
the Committee for Medicinal Products for Human
Use of the European Medicines Agency adopted a
positive opinion for these products.
The FDA approvals are supported by seven
Phase 3 trials of 4,800 patients. Steglatro was
studied as monotherapy and in combination with
metformin and/or sitagliptin, as well as with insulin and a sulfonylurea, in adult patients with type 2
diabetes and moderate renal impairment.
The FDA and European Commission granted
approval in November to Prevymis (letermovir),
once-daily tablets for oral use and injection for
intravenous infusion, for the prevention of cytomegalovirus (CMV) infection and disease in adult
CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant. Prevymis represents the ;rst new medicine FDA-approved for
CMV infection in 15 years.
Prevymis belongs to a new class of non-nucleoside CMV inhibitors ( 3, 4 dihydro-quinazolines) and
inhibits viral replication by speci;cally targeting
the viral terminase complex. Letermovir has been
granted orphan designation for the prevention of
CMV disease in at-risk populations in the United
States, EU and Japan. The product is undergoing
accelerated review in the EU and Japan.
Two NDAs were accepted for U.S. regulatory
review during January for Merck’s investigational non-nucleoside reverse transcriptase inhibitor
doravirine as a treatment for HIV-1 infection in
adults. The NDAs include data for doravirine as a
once-daily tablet for use in combination with other antiretroviral agents, and for use of doravirine
with lamivudine and tenofovir disoproxil fumarate
in a once-daily ;xed-dose combo single tablet as
a complete regimen. The PDUFA action date for
each application is scheduled for Oct. 23, 2018.
Doravirine (MK-1439, DOR) is being studied
in several Phase III clinical trials as a once-daily
single-entity tablet in combination with other
antiretroviral agents in a tailored regimen, and as
a once-daily ;xed-dose combination (DOR/3TC/
TDF) in a complete single tablet regimen.
The U.S. regulatory agency during November
issued marketing approval to Isentress (raltegravir)
for use in combination with other antiretroviral
agents for treating HIV-1 in newborn patients from
birth to 4 weeks of age weighing at least 2 kg. Isentress is the only integrase inhibitor approved in
the United States for this indication. The medicine
was initially cleared for U.S. marketing during 2007
as the ;rst integrase inhibitor for the treatment of
Denmark’s Novo Nordisk in December re- ceived U.S. regulatory approval for sema- glutide, a once-weekly diabetes drug
that industry analysts have been excited about for
quite some time. Approved under the trade name
Ozempic, the product is indicated as an adjunct
to diet and exercise to improve glycemic control
in adults with type 2 diabetes mellitus. The gluca-gon-like peptide 1 (GLP-1) receptor agonist was
approved for use in two therapeutic dosages – 0.5
mg and 1 mg – and was launched in the Ozempic
Pen, the latest generation of Novo Nordisk pre-;lled devices.
The FDA review of Ozempic was based on SUSTAIN, a global clinical development program consisting of eight phase 3a trials encompassing more
than 8,000 adults with type 2 diabetes. The phase
3a program involves a wide array of people with
type 2 diabetes, including some with high cardiovascular risk pro;les and individuals with and
without renal disease.
In August 2017, Novo Nordisk demonstrated that the GLP-1 semaglutide was superior to
once-weekly dulaglutide on glucose control and
weight loss in people with type 2 diabetes in the
SUSTAIN 7 study. Dulaglutide is marketed by Eli
Lilly as Trulicity, a blockbuster medicine that captured FDA approval in September2014.
A positive 16-0 recommendation was issued
by an FDA advisory committee meeting on Oct.
18, 2017. In people with type 2 diabetes, Ozempic
produced clinically meaningful and statistically
signi;cant reductions in HbA1c versus placebo,
sitagliptin, exenatide extended-release and insu-
lin glargine U100. In the clinical trials, treatment
with Ozempic led to statistically signi;cant reduc-
tions in body weight. Ozempic showed a safe and
well-tolerated pro;le across the SUSTAIN program.
As part of the post-approval requirements,
Novo Nordisk is conducting a pediatric study in
adolescents younger than 18 years old and will
add Ozempic to the 15-year MTC (medullary thy-
roid carcinoma) registry that is being conducted
for all other long-acting GLP-1 products.
Ozempic is undergoing review by several other
regulatory agencies, including the European Med-
icines Agency and the Japanese Pharmaceuticals
We have established an internal oncology pipeline focused
on agents that could further enhance KEYTRUDA activity
GI TR (MK-1248)
IL- 10 (MK-1966)
LAG- 3 (MK-4280)
GI TR (MK-4166)
Clinical Programs Preclinical Programs
CDK 1, 2, 5, 9 (MK-7965)
Ozempic® approved in the US and launch is planned for Q1 2018
Competitive US label for Ozempic®
Investor presentation US approval of Ozempic®
• Statistically significant reduction in HbA1c compared with placebo, sitagliptin, exenatide extended-release
and insulin glargine U100
• Statistically significant reduction in body weight confirmed in all trials against all comparators
• To be launched in the Ozempic® Pen, the latest generation of Novo Nordisk prefilled devices
• Once-weekly subcutaneous injections
• Ozempic® is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with
type 2 diabetes
• Ozempic® is approved for use in two therapeutic dosages, 0.5 mg and 1 mg
• Ozempic® demonstrated a safe and well-tolerated profile across the SUSTAIN programme
• In SUSTAIN 6, there were 108 MACE events with Ozempic® compared to 146 events with placebo,
equivalent to an event rate of 6.6% with Ozempic® and 8.9% with placebo
MACE: Major adverse cardiovascular event