Merck KGaA

EMA's CHMP Issues Positive Opinion for Avelumab for the Treatment of Metastatic Merkel Cell Carcinoma

Darmstadt, Germany and New York (ots/PRNewswire) - Not intended for US, Canadian and UK-based media

- If approved, avelumab could be the first immunotherapy treatment 
  indicated for this rare and aggressive skin cancer in the EU  
- Decision by  the  EC is expected in the third quarter of 2017 

Merck and Pfizer Inc. (NYSE: PFE) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the approval of avelumab* (BAVENCIO®) as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. The European Commission (EC) will now review the CHMP's recommendation, with a decision expected in the third quarter of 2017.

"We welcome the CHMP's recommendation, as there are currently no approved treatments in Europe for this type of skin cancer, which can be devastating for patients and their families," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck. "This is an important step towards making avelumab available to patients and we look forward to the European Commission's decision later this year."

"Metastatic Merkel cell carcinoma is a devastating disease and patients in Europe currently have very few treatment options," said Chris Boshoff, M.D., PhD, Senior Vice President and Head of Immuno-Oncology, Early Development, Translational Oncology, Pfizer Global Product Development. "This milestone further demonstrates our commitment to tackle hard-to-treat cancers as we continue to explore the potential of avelumab in other tumors."

The CHMP positive opinion is based on data from JAVELIN Merkel 200, an international, multicenter, single-arm, open-label, Phase II study split into two parts:

- Part A included 88 patients with mMCC whose disease had progressed 
  after at least one chemotherapy treatment, with 59% of patients 
  reported to have had one prior anti-cancer therapy for mMCC and 41%
  had two or more prior therapies. Data submitted included a minimum 
  of 18 months of follow-up.
- Part B, at the time of the data cut-off, included 39 patients with 
  histologically confirmed mMCC who were treatment-naïve to systemic 
  therapy in the metastatic setting, 29 of whom had at least 13 weeks
  of follow-up. Enrolment in Part B of the study is ongoing and is 
  planned to include 112 treatment-naïve patients. 

The human anti-PD-L1 antibody, avelumab, previously received Orphan Drug Designation (ODD) from the EC for MCC. To qualify for ODD in the EU, a medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating, and has a prevalence in the EU of not more than 5 in 10,000 people.

The US Food and Drug Administration (FDA) granted accelerated approval for avelumab in March 2017 for the treatment of mMCC in adults and pediatric patients 12 years and older; and in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy therapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[1] These indications were granted under accelerated approval based on tumor response rate and duration of response data/criteria. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 6,000 patients evaluated across more than 15 different tumor types. In addition to mMCC, these cancers include breast, gastric/gastro-esophageal junction, head and neck, Hodgkin's lymphoma, melanoma, mesothelioma, non-small cell lung, ovarian, renal cell carcinoma and urothelial carcinoma.

* Avelumab is not approved for any indication in any market outside the US. BAVENCIO® is the proprietary name submitted to EMA for the investigational medicine avelumab.

About Metastatic Merkel Cell Carcinoma

Metastatic MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings.[2],[3] MCC, which is also known as neuroendocrine carcinoma of the skin or trabecular cancer, often starts in those areas of skin that are most often exposed to the sun, including the head and neck, and arms.[2],[4] Risk factors for MCC include sun exposure and infection with Merkel cell polyomavirus. Caucasian males older than 50 are at increased risk.[2],[4] MCC is a highly immunogenic cancer, meaning that those with a weak immune system (i.e., solid organ transplant recipients, people with HIV/AIDS and people with other cancers, such as chronic lymphocytic leukemia) are also at a higher risk.[2],[4] MCC is often misdiagnosed for other skin cancers and grows at an exponential rate on chronically sun-damaged skin.[4]-[6] Current treatment options for MCC in Europe include surgery, radiation and chemotherapy.[3] Treatment for metastatic or Stage IV MCC is generally palliative.[3]

About JAVELIN Merkel 200

The efficacy and safety of avelumab was demonstrated in the JAVELIN Merkel 200 trial, an international, multicenter, single-arm, open-label, Phase II study split into two parts:

- Part A was conducted in 88 patients with histologically confirmed 
  mMCC whose disease had progressed on or after chemotherapy 
  administered for distant metastatic disease, with life expectancy 
  of more than 3 months. Overall in Part A, 59% of patients were 
  reported to have had one prior anti-cancer therapy for mMCC and 41%
  had two or more prior therapies. Data submitted included a minimum 
  of 18 months follow-up. The major efficacy outcome measures for 
  Part A were confirmed best overall response (BOR) and duration of 
  response (DOR), according to Response Evaluation Criteria in Solid 
  Tumors (RECIST) v1.1, as assessed by a blinded independent endpoint
  review committee (IERC); secondary efficacy outcome measures 
  included duration of response (DOR), and progression-free survival 
  (PFS).
- Part B, at the time of the data cut-off, included 39 patients with 
  histologically confirmed mMCC who were treatment-naïve to systemic 
  therapy in the metastatic setting, 29 of whom had at least 13 weeks
  of follow-up. Enrolment in Part B of the study is ongoing and is 
  planned to include 112 treatment-naïve patients. The major efficacy
  outcome measure is durable response, defined as objective response 
  (complete response [CR] or partial response [PR]) with a duration 
  of at least 6 months; secondary outcome measures include BOR, DOR, 
  progression-free survival (PFS) and overall survival (OS). 

The trial excluded patients with active or a history of central nervous system (CNS) metastasis, active or a history of autoimmune disease, a history of other malignancies within the last 5 years, organ transplant, and conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C. Patients received avelumab 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

About Avelumab

Avelumab is a human antibody specific for a protein called PD-L1, or programmed death ligand-1. Avelumab is designed to potentially engage both the adaptive and innate immune systems. By binding to PD-L1, avelumab is thought to prevent tumor cells from using PD-L1 for protection against white blood cells, such as T cells, exposing them to anti-tumor responses. Avelumab has been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Indications

The US Food and Drug Administration (FDA) granted accelerated approval for avelumab (BAVENCIO®) for the treatment of (i) mMCC in adults and pediatric patients 12 years and older and (ii) patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications were approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

The warnings and precautions for avelumab (BAVENCIO®) include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions), infusion-related reactions and embryo-fetal toxicity.

Common adverse reactions (reported in at least 20% of patients) in patients treated with avelumab for mMCC and patients with locally advanced or metastatic UC include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash.

About Merck-Pfizer Alliance

Immuno-oncology is a top priority for Merck and Pfizer. The global strategic alliance between Merck and Pfizer enables the companies to benefit from each other's strengths and capabilities and further explore the therapeutic potential of avelumab, an investigational anti-PD-L1 antibody initially discovered and developed by Merck. The immuno-oncology alliance will jointly develop and commercialize avelumab and advance Pfizer's PD-1 antibody. The alliance is focused on developing high-priority international clinical programs to investigate avelumab, as a monotherapy, as well as combination regimens, and is striving to find new ways to treat cancer.

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About Merck

Merck is a leading science and technology company in healthcare, life science and performance materials. Around 50,000 employees work to further develop technologies that improve and enhance life - from biopharmaceutical therapies to treat cancer or multiple sclerosis, cutting-edge systems for scientific research and production, to liquid crystals for smartphones and LCD televisions. In 2016, Merck generated sales of EUR 15.0 billion in 66 countries.

Founded in 1668, Merck is the world's oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck, Darmstadt, Germany holds the global rights to the "Merck" name and brand except in the United States and Canada, where the company operates as EMD Serono, MilliporeSigma and EMD Performance Materials.

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Pfizer Disclosure Notice

The information contained in this release is as of July 21, 2017. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about BAVENCIO (avelumab), including a potential indication in the EU as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (the "potential indication"), the Merck-Pfizer Alliance involving anti-PD-L1 and anti-PD-1 therapies, and clinical development plans, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of BAVENCIO; the uncertainties inherent in research and development, including the ability to meet anticipated clinical study commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable study results, including unfavorable new clinical data and additional analyses of existing clinical data; risks associated with interim data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether and when any other drug applications may be filed in any jurisdictions for potential indications for BAVENCIO, combination therapies or other product candidates; whether and when the European Commission may approve the pending marketing authorization application for the potential indication and whether and when regulatory authorities in any other jurisdictions where applications are pending or may be submitted for BAVENCIO, combination therapies or other product candidates may approve any such applications, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted; decisions by regulatory authorities regarding labeling and other matters that could affect the availability or commercial potential of BAVENCIO, combination therapies or other product candidates; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2016, and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors That May Affect Future Results", as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at http://www.sec.gov and http://www.pfizer.com.

References

1. BAVENCIO Prescribing Information. Rockland, MA: EMD Serono Inc.; 
   2017.
2. Schadendorf D et al. Merkel cell carcinoma: epidemiology, 
   prognosis, therapy and unmet medical needs. European Journal of 
   Cancer 2017;71;53-69
3. American Cancer Society. What is Merkel cell carcinoma? http://www
   .cancer.org/cancer/skincancer-merkelcell/detailedguide/skin-cancer
   -merkel-cell-carcinoma-what-is-merkel-cell-carcinoma. Last 
   accessed June 2017.
4. Nghiem P. Systematic literature review of efficacy, safety and 
   tolerability outcomes of chemotherapy regimens in patients with 
   metastatic Merkel cell carcinoma. Future Oncology 
   2017;13(14):1263-1279.
5. Heath M, Jaimes N and Lemos B. Clinical characteristics of Merkel 
   cell carcinoma at diagnosis in 195 patients: the AEIOU features. 
   Journal of the American Academy of Dermatology 2008;58:375-81. 
http://www.pnlab.org/clinical/documents/ClinCharacteristics.pdf. 
   Last accessed June 2017.
6. NCCN Merkel Cell Carcinoma Guidelines version I. 2017. 
http://www.nccn.org/professionals/physician_gls/PDF/mcc.pdf. Last 
   accessed June 2017. 
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