First New Front-Line Treatment Option for HCC Approved in Japan in Nearly 10 Years

First Approval Under Global Strategic Collaboration Between Eisai Co., Ltd. and Merck

TOKYO, Japan & KENILWORTH, NJ, USA I March 23, 2018 I Eisai Co., Ltd. and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the multiple receptor tyrosine kinase inhibitor LENVIMA® (lenvatinib mesylate) has been approved in Japan for unresectable hepatocellular carcinoma (HCC). This is the first approval worldwide for LENVIMA for the indication of unresectable HCC and the first new systemic therapy to be approved in Japan for the front line treatment of HCC in approximately 10 years. Additionally, this is the first regulatory approval for LENVIMA under the global strategic collaboration agreement executed in March 2018 between Eisai and Merck for the co-development and co-commercialization of LENVIMA.

This approval was based on a phase 3 clinical study (Study 304/REFLECT study) conducted by Eisai investigating LENVIMA as a first-line treatment in patients with unresectable HCC. In this study, LENVIMA demonstrated statistically significant non-inferiority of overall survival (OS) (13.6 months) compared to sorafenib (12.3 months) (hazard ratio [HR] 0.92, 95% confidence interval [CI]=0.79-1.06). Additionally, LENVIMA showed highly statistically significant and clinically meaningful improvements as compared to sorafenib in the secondary endpoints of progression-free survival (PFS) (HR 0.66, 95% CI=0.57-0.77, p<0.00001), time to progression (TTP) (HR 0.63, 95% CI=0.53-0.73, p<0.00001), and objective response rate (ORR) (LENVIMA 24% versus sorafenib 9%, p<0.00001). Furthermore, LENVIMA helped to delay deterioration in several quality of life (QOL) and symptom domains (pre-specified secondary endpoint), including in areas such as pain and diarrhea, compared to sorafenib (nominal p-value<0.05).

In this study, the five most common adverse events observed in the LENVIMA arm were hypertension (42%), diarrhea (39%), decreased appetite (34%), weight loss (31%) and fatigue (30%), which is consistent with the known safety profile of LENVIMA.

Liver cancer is the second leading cause of cancer-related deaths, with approximately 750,000 deaths per year estimated globally. Additionally, approximately 780,000 cases are newly diagnosed each year, about 80 percent of which occur in Asia, including Japan and China. HCC accounts as the primary reason for 85 percent to 90 percent of liver cancer cases. It is estimated that there are approximately 42,000 HCC patients in Japan, with approximately 26,000 deaths every year. To date, treatment options for unresectable HCC have been limited, and the prognosis is very poor, emphasizing that this is an area of high unmet medical need.

“With the approval of this additional indication of unresectable HCC for LENVIMA, we are proud to be able to deliver the first new front-line systemic therapy treatment option for HCC in Japan in approximately 10 years, and expect this will contribute to HCC treatment,” said Dr. Takashi Owa, Eisai Oncology Business Group Chief Medicine Creation Officer. “Eisai will continue with its efforts in oncology research and development in order to deliver hopes for a potential cure for cancer to patients and their families.”

“Today’s approval is an important first for LENVIMA and a significant first regulatory event under our collaboration with Eisai,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “We congratulate Eisai on the approval of this new indication and look forward to working together to bring this important treatment option to patients.”

Having received approval of this indication, Eisai will receive a development milestone payment from Merck. There are no changes to Eisai’s consolidated financial results forecasts for the fiscal year ending March 31, 2018 based on the receipt of this milestone payment.

LENVIMA Product Details in Japan (underlined parts have been added)

1) Product name

LENVIMA® Capsule 4 mg

2) Generic name

Lenvatinib mesylate

3) Indication

Unresectable thyroid cancer, unresectable hepatocellular carcinoma

4) Dosage and Administration

Unresectable thyroid cancer

The usual adult dose is 24 mg as lenvatinib administered orally once a day. The dose may be reduced depending on the condition of the individual patient.

Unresectable hepatocellular carcinoma

The usual adult dose is an amount of lenvatinib in accordance with body weight administered orally once a day. For adults weighing 60 kg and over, the dose should be 12 mg. For adults weighing less than 60 kg, the dose should be 8 mg. The dose may be reduced depending on the condition of the individual patient.

About LENVIMA® (lenvatinib mesylate) capsules, 10 mg and 4 mg

Discovered by Eisai, LENVIMA is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET) involved in tumor angiogenesis, tumor progression and modification of tumor immunity.

Currently, LENVIMA is approved as a treatment for refractory thyroid cancer in over 50 countries, including the United States, Japan, in Europe and Asia. Additionally, Eisai has obtained approval for the agent in combination with everolimus as a treatment for renal cell carcinoma (second-line) in over 40 countries, including the United States and in Europe. In Europe, the agent was launched under the brand name Kisplyx® for renal cell carcinoma.

Outside of Japan, Eisai has submitted applications for an indication covering hepatocellular carcinoma in the United States and Europe (July 2017), China (October 2017), Taiwan (December 2017) and other countries.

About the Eisai and Merck Strategic Collaboration

In March 2018, Eisai and Merck entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will develop and commercialize LENVIMA jointly, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab). In addition to ongoing clinical studies of the combination, the companies will jointly initiate new clinical studies evaluating the LENVIMA/KEYTRUDA combination to support 11 potential indications in six types of cancer (endometrial cancer, non-small cell lung cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer and melanoma), as well as a basket trial targeting multiple cancer types.

About the REFLECT Study (Study 304)

The REFLECT study is a multicenter, open-label, randomized, global phase 3 study comparing the efficacy and safety of LENVIMA versus sorafenib, a standard treatment for advanced HCC, as a first-line treatment for patients with unresectable HCC. In the study, 954 patients were randomized in a 1:1 ratio to receive LENVIMA 12 mg (≥60 kg) or 8 mg (<60 kg) once a day, depending on baseline body weight (n=478), or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoint of the study was OS, with the goal of demonstrating non-inferiority. Other factors including PFS, TTP, ORR and QOL were assessed as secondary endpoints. According to the results of the study, LENVIMA met the statistical criteria for non-inferiority in the primary endpoint of median OS (13.6 months) compared to sorafenib (12.3 months) (HR 0.92, 95% CI=0.79-1.06).

Additionally, LENVIMA showed statistically significant improvements in the three secondary efficacy endpoints (investigator assessment), doubling sorafenib’s median values and ratios: median PFS (LENVIMA 7.4 months versus sorafenib 3.7 months [HR 0.66, 95% CI=0.57-0.77, p<0.00001]), median TTP (LENVIMA 8.9 months versus sorafenib 3.7 months [HR 0.63, 95% CI=0.53-0.73, p<0.00001]) and ORR (LENVIMA 24% versus sorafenib 9%, [p<0.00001]).

Eisai’s Focus on Cancer

Eisai regards oncology as a key therapeutic area and is aiming to discover revolutionary new medicines with the potential to cure cancer by leveraging drug creation base technologies cultivated through the discovery of LENVIMA and Halaven, as well as technologies associated with organic synthetic chemistry and drug discovery science. Eisai’s research groups in Japan and the United States are working on drug discovery activities using drug discovery platforms mainly for the cancer microenvironment, driver gene mutation and aberrant splicing in cancer cells, that are Eisai’s strengths.

About Eisai Co., Ltd.

Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as “giving first thought to patients and their families and to increasing the benefits health care provides,” which we call our human health care (hhc) philosophy. With approximately 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realize our hhc philosophy by delivering innovative products in various therapeutic areas with high unmet medical needs, including Oncology and Neurology.

As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries.

For more information about Eisai Co., Ltd., please visit www.eisai.com.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

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.

SOURCE: Merck