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Merck and Pfizer Inc. (NYSE: PFE) today announced that the European Medicines Agency (EMA) has validated for review Merck's Marketing Authorization Application (MAA) for avelumab, for the proposed indication of metastatic Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, which impacts approximately 2,500 Europeans a year.[1],[2] Validation of the MAA confirms that submission is complete and begins the EMA's centralized review process.* If approved, avelumab, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, could be the first approved treatment indicated for metastatic MCC in the EU. Patients with metastatic MCC face a very poor prognosis, with less than 20 percent surviving beyond five years.[3]     (Logo: http://photos.prnewswire.com/prnh/20151207/293543LOGO ) "While early-stage Merkel cell carcinoma can be generally managed with surgery, there are significant unmet needs in metastatic disease, where treatment options are severely limited," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck. "We are pleased that the EMA is initiating its review of avelumab, as this means we are one step closer to bringing a much-needed new treatment option to European patients." "This is the first of what we hope will be many regulatory milestones for avelumab," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "We are committed to evaluating avelumab in a number of hard-to-treat cancers, and we believe it may have potential to be an important treatment option for patients with metastatic Merkel cell carcinoma." The avelumab metastatic MCC MAA submission is supported by data from JAVELIN Merkel 200, a multicenter, single-arm, open-label, Phase II study of 88 patients with metastatic MCC whose disease had progressed after at least one chemotherapy treatment.[1] The JAVELIN Merkel 200 study represents the largest data set of any anti-PD-L1/PD-1 antibody reported in this patient population. These data were recently published in the Lancet Oncology.[1] Avelumab received an Orphan Drug Designation (ODD) from the European Commission for MCC. To qualify for an 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; the prevalence of the condition in the EU must not be more than 5 in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development; and it must be for a disease where no satisfactory treatment is currently available.[4] The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and over 2,900 patients evaluated across more than 15 different tumor types. In addition to metastatic MCC, 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 (primarily bladder). *Avelumab is not approved for any indication in any market. This marks the first acceptance of an EU market authorization application to review the safety and efficacy results for the investigational product avelumab. Metastatic MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings.[1],[5] 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.[6] Risk factors for MCC include sun exposure and having 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 at higher risk). Caucasian males older than 50 are at increased risk.[5] MCC is often misdiagnosed for other skin cancers and grows at an exponential rate on chronically sun-damaged skin. [7]-[10] Current treatment options for MCC include surgery, radiation and chemotherapy.[8]Treatment for Metastatic or Stage IV MCC is generally palliative. Avelumab (also known as MSB0010718C) is an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab. In the JAVELIN Merkel 200 trial, treatment-related adverse events (AEs) occurred in 62 (70%) of 88 patients including fatigue and infusion-related reactions. Five grade 3 treatment-related AEs were reported in four of 88 patients and include two patients with lymphopenia and three patients with isolated laboratory abnormalities (elevated blood creatine phosphokinase, blood cholesterol, and hepatic aminotransferase).[1] There were no grade 4 treatment-related AEs or deaths related to treatment.[1] No patients in the trial discontinued treatment with avelumab permanently due to AEs; however, AEs leading to temporary treatment discontinuation of avelumab were anemia, diarrhea, and increased ALT in one patient each.[1] 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. All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service. For further details and press materials about Merck in oncology please visit www.merckgroup.com/en/media/media_center_oncology.html 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 2015, Merck generated sales of € 12.85 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. The only exceptions are the United States and Canada, where the company operates as EMD Serono, MilliporeSigma and EMD Performance Materials. Pfizer Inc.: Working together for a healthier world[® ] At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of healthcare products. Our global portfolio includes medicines and vaccines, as well as many of the world's best-known consumer healthcare products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. To learn more, please visit us at http://www.pfizer.com. In addition, to learn more, follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn   and like us on Facebook at Facebook.com/Pfizer. The information contained in this release is as of October 31, 2016. 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 avelumab (MSB0010718C), including a potential indication for avelumab for the treatment of metastatic Merkel cell carcinoma (the "Potential Indications"), Pfizer's and Merck's immuno-oncology 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, the uncertainties inherent in research and development, including the ability to meet anticipated clinical study commencement and completion dates as well as the possibility of unfavorable study results; 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 drug applications may be filed in other jurisdictions for the Potential Indication or whether and when drug applications may be filed in any jurisdictions for any other potential indications for avelumab, combination therapies or other product candidates; whether and when the MAA for the Potential Indication or any such applications may be approved by regulatory authorities, 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 avelumab, 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, 2015, 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.


DARMSTADT, Germany and NEW YORK, May 18, 2017 /PRNewswire/ -- Merck and Pfizer today announced that 13 avelumab* abstracts across seven challenging tumor types will be featured at the 53rd American Society of Clinical Oncology (ASCO) Annual Meeting held June 2-6, 2017 in Chicago, IL. Key presentations include data for avelumab in first-line metastatic Merkel cell carcinoma (mMCC) and in previously treated metastatic urothelial carcinoma (UC), as well as results from the Phase Ib trial investigating avelumab in combination with the tyrosine kinase inhibitor axitinib, in advanced renal cell carcinoma (RCC). "Our ASCO presence adds to what has already been a momentous year for the alliance, coming shortly after the US FDA granted two accelerated approvals for avelumab," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck, which in the US and Canada operates as EMD Serono. "We're particularly excited to share the latest avelumab data in both metastatic Merkel cell carcinoma in the first-line setting and previously treated metastatic urothelial carcinoma with the cancer community." "Our data at ASCO this year underscore the potential of avelumab as a monotherapy treatment, as well as part of combination regimens," said Chris Boshoff, M.D., PhD, Senior Vice President and Head of Immuno-Oncology, Early Development, Translational Oncology, Pfizer Global Product Development. "Now with accelerated approvals in two indications for avelumab in the US, we are entering the next chapter of our clinical development program to provide meaningful new treatment options for patients who need them most." Highlights of avelumab data at ASCO 2017 include the following: The alliance's rapidly accelerating JAVELIN clinical development program now involves at least 30 clinical programs, including nine Phase III trials, and more than 5,200 patients across more than 15 tumor types. Results from JAVELIN program trials have supported two FDA accelerated approvals in 2017. A list of accepted avelumab abstracts is included below. The abstracts are also available on the ASCO website. *Avelumab is under clinical investigation for treatment of NSCLC, RCC, DLBCL, SSCHN and mCRPC and has not been demonstrated to be safe and effective for these indications. There is no guarantee that avelumab will be approved for NSCLC, RCC, DLBCL, SSCHN and mCRPC by any health authority worldwide. 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) metastatic Merkel cell carcinoma (mMCC) in adults and pediatric patients 12 years and older and (ii) patients with locally advanced or metastatic urothelial carcinoma (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. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. Avelumab is not approved for any indication in any market outside the US. Important Safety Information   The warnings and precautions for 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 include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash. About the Merck-Pfizer Alliance  Immuno-oncology is a top priority for Merck and Pfizer Inc. 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 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 in combination regimens, and is striving to find new ways to treat cancer. All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to http://www.merckgroup.com/subscribe to register online, change your selection or discontinue this service. For further details and press materials about Merck in oncology please visit http://www.merckgroup.com/en/media/media_center_oncology.html 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 € 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. Pfizer Inc.: Working together for a healthier world®  At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at http://www.pfizer.com. In addition, to learn more, please visit us at http://www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn,  and like us on Facebook at Facebook.com/Pfizer. Pfizer Disclosure Notice  The information contained in this release is as of May 17, 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), 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 drug applications may be filed in any jurisdictions for potential indications for BAVENCIO, combination therapies or other product candidates; whether and when any such applications (including the pending application for BAVENCIO for metastatic Merkel cell carcinoma in the EU) may be approved by regulatory authorities, 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.


"Our ASCO presence adds to what has already been a momentous year for the alliance, coming shortly after the US FDA granted two accelerated approvals for avelumab," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "We're particularly excited to share the latest avelumab data in both metastatic Merkel cell carcinoma in the first-line setting and previously treated metastatic urothelial carcinoma with the cancer community." "Our data at ASCO this year underscore the potential of avelumab as a monotherapy treatment, as well as part of combination regimens," said Chris Boshoff, M.D., PhD, Senior Vice President and Head of Immuno-Oncology, Early Development, Translational Oncology, Pfizer Global Product Development. "Now with accelerated approvals in two indications for avelumab in the US, we are entering the next chapter of our clinical development program to provide meaningful new treatment options for patients who need them most." Highlights of avelumab data at ASCO 2017 include the following: The alliance's JAVELIN clinical development program now involves at least 30 clinical programs, including nine Phase III trials, and more than 5,200 patients across more than 15 tumor types. Results from JAVELIN program trials have supported two FDA accelerated approvals in 2017. A list of accepted avelumab abstracts is included below. The abstracts are also available on the ASCO website. *Avelumab is under clinical investigation for treatment of NSCLC, RCC, DLBCL, SSCHN and mCRPC and has not been demonstrated to be safe and effective for these indications. There is no guarantee that avelumab will be approved for NSCLC, RCC, DLBCL, SSCHN and mCRPC by any health authority worldwide. 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 KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab. The US Food and Drug Administration (FDA) granted accelerated approval for avelumab (BAVENCIO®) for the treatment of (i) metastatic Merkel cell carcinoma (mMCC) in adults and pediatric patients 12 years and older and (ii) patients with locally advanced or metastatic urothelial carcinoma (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. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials. Avelumab is not approved for any indication in any market outside the US. The warnings and precautions for 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 include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash. For full prescribing information and medication guide for BAVENCIO, please see http://www.BAVENCIO.com. Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer Inc. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US, enables the companies to benefit from each other's strengths and capabilities and further explore the therapeutic potential of avelumab, an anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. 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 in combination regimens, and is striving to find new ways to treat cancer. All Merck KGaA, Darmstadt, Germany Press Releases are distributed by e-mail at the same time they become available on the Merck KGaA, Darmstadt, Germany Website. Please go to http://www.emdgroup.com/subscribe to register online, change your selection or discontinue this service. Merck KGaA, Darmstadt, Germany, 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 KGaA, Darmstadt, Germany, generated sales of €15.0 billion in 66 countries. Founded in 1668, Merck KGaA, Darmstadt, Germany, is the world's oldest pharmaceutical and chemical company. The founding family remains the majority owner of the publicly listed corporate group. Merck KGaA, Darmstadt, Germany, operates as EMD Serono, MilliporeSigma and EMD Performance Materials in the United States and Canada. Pfizer Inc.: Working together for a healthier world® At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world's best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at http://www.pfizer.com . In addition, to learn more, please visit us at http://www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn,  and like us on Facebook at Facebook.com/Pfizer. The information contained in this release is as of May 17, 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), the alliance between Merck KGaA, Darmstadt, Germany, and Pfizer 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 drug applications may be filed in any jurisdictions for potential indications for BAVENCIO, combination therapies or other product candidates; whether and when any such applications (including the pending application for BAVENCIO for metastatic Merkel cell carcinoma in the EU) may be approved by regulatory authorities, 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.


Peng J.,Translational Oncology | Peterson D.,Translational Oncology | Yue P.,Genentech | Settleman J.,Genentech
Cancer Research | Year: 2014

Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced-stage disease. However, their clinical benefit is typically short-lived because of the relatively rapid acquisition of drug resistance following treatment response. Accumulating preclinical and clinical data point to a role for a heterogeneous response to treatment within a subpopulation of tumor cells that are intrinsically drug-resistant, such as cancer stem cells. We have previously described an epigenetically determined reversibly drug-tolerant subpopulation of cancer cells that share some properties with cancer stem cells. Here, we define a requirement for the previously established cancer stem cell marker ALDH (aldehyde dehydrogenase) in the maintenance of this drug-tolerant subpopulation. We find that ALDH protects the drug-tolerant subpopulation from the potentially toxic effects of elevated levels of reactive oxygen species (ROS) in these cells, and pharmacologic disruption of ALDH activity leads to accumulation of ROS to toxic levels, consequent DNA damage, and apoptosis specifically within the drug-tolerant subpopulation. Combining ALDH inhibition with other kinase-directed treatments delayed treatment relapse in vitro and in vivo, revealing a novel combination treatment strategy for cancers that might otherwise rapidly relapse following single-agent therapy. Cancer Res; 74(13); 3579-90. © 2014 American Association for Cancer Research.


News Article | February 23, 2017
Site: www.sciencenews.org

Like many living things, a cancer cell cannot survive without oxygen. When young and tiny, a malignancy nestles inside a bed of blood vessels that keep it fed. As the mass grows, however, its demand for oxygen outpaces supply. Pockets within the tumor become deprived and send emergency signals for new vessel growth, a process called angiogenesis. In the 1990s, a popular cancer-fighting theory proposed interfering with angiogenesis to starve tumors to death. One magazine writer in 2000 called the strategy “the most important single insight about cancer of the past 50 years.” It made such intuitive sense. Rakesh Jain viewed angiogenesis through a different lens. Trained as an engineer, not a biologist, Jain was studying tumor vasculature during the height of excitement about drugs that could impede vessel growth. He was bothered by the fact that capillaries that arise in the tumor aren’t normal; they’re gnarled and porous, incapable of effective blood flow in the same way a leaky pipe is lousy at delivering water. The expanding tumor squeezes smaller vessels, making them even less able to transport blood. “The mantra was, ‘Let’s starve tumors,’ ” recalls Jain, director of the Edwin L. Steele Laboratories for Tumor Biology at Harvard Medical School. “I said, ‘No, we need to do the opposite.’ ” In 2001, he published a commentary in Nature Medicine predicting that angiogenesis inhibitors would not entirely shrivel the tumor. Instead, he argued, starving tumors might make them harder to treat. “I was sticking my neck out and saying this is not a good thing to do,” he says. “I had tremendous resistance.” Time has proved him right. Once they came on the market, anti-angiogenesis drugs were not the boon doctors had hoped for. Most disturbing, some patients saw their tumors shrink, only to have the disease return with renewed vengeance. Today, more than a decade after the introduction of the first tumor-starving drug, researchers have a far greater understanding of the role of oxygen deprivation in cancer. Instead of slowing tumors, hypoxia appears to trigger a metabolic panic that can drive growth, drug resistance and metastasis. Rescue proteins called hypoxia-inducible factors, or HIFs, open a bag of tricks so tumors can adapt and outrun the body’s defenses. But there’s now reason for hope: Recent insights into the effects of oxygen deprivation in cancer are sparking new ideas and providing the blueprint for treatments that could short-circuit a cancer’s ability to survive and spread, and help make existing drugs more effective. While the idea of starving cancer made sense, the approach may have underestimated the strength and complexity of a tumor’s resilience. Since oxygen is essential for so much of life, nature equips cells with elaborate safeguards that kick in when the oxygen-rich blood supply dwindles — whether the cells are part of a tumor or part of a muscle straining for one last push of strength. When oxygen levels drop, newly minted proteins stampede throughout the cell, turning on a frenzy of chemical reactions that offer protection from the crisis. Cancer cells distort this natural coping mechanism for their own means. Growing new vessels is just one move in an elaborate strategy. Many changes accompany hypoxia, including: The malignant cells loosen from each other and become less adhesive, ready to break free; tendrils of collagen, a natural binding substance, form and start to reach out to nearby vessels; and proteins appear on the cell surface to pump out lactic acid, a product of the tumor’s switch from primarily aerobic to anaerobic respiration. Researchers now think stopping enough of these and other changes could cripple the cancer. Much of the research focuses on the proteins that are among the first to deploy when a cell senses a danger of asphyxiation. “At zero oxygen, the cell can’t survive,” says Daniele Gilkes of Johns Hopkins University School of Medicine. “Inside a tumor you will see these regions of necrosis,” or dead cells. But those cells that are low on oxygen but still alive will produce new proteins: Key among them are HIF-1 and HIF-2. Both are transcription factors — they help transcribe DNA instructions into RNA. Under normal conditions, the genes that make HIF proteins are mostly silent. Once HIF proteins are made, they turn on genes — Gilkes estimates there are hundreds — that enable cells to live when oxygen concentrations are low. Gilkes’ target of choice is HIF-1. It is not only a first responder, but the protein also appears to be key to cancer’s spread. Tumors with high levels of HIF-1, particularly when concentrated at the invasive outer edge of the mass, are more likely to become metastatic, invading other parts of the body. The reverse is also true: Human tumors transplanted into mice that genetically can’t produce HIF-1 are less likely to spread. The reasons are complicated, Gilkes says, but she considers one thing really interesting: HIF-1 is involved with a lot of enzymes in collagen formation. The collagen appears to provide a means of escape. Last year, in a review in the International Journal of Molecular Sciences, Gilkes described genes, found by her lab group and others, that breast tumors activate to degrade the surrounding environment. In turn, the tumor wraps itself in a stringy web of collagen. As the collagen forms, the strands stretch outward from the tumor and latch onto nearby vessels. “We think cancer cells will find this collagen and use it to migrate and glide.” She calls them “collagen highways.” Her laboratory captured video of human tumor cells migrating along a fibrous strand. “To see them move is really scary.” Once they’ve broken from their home tumor, many types of cancer, including prostate and breast cancers, commonly move into bones. This is no coincidence, Gilkes says. Bones lack the dense thickets of blood vessels that run through soft tissues. That means cancer cells migrating from a hypoxic environment, and therefore already trained for low oxygen, would find hospitable surroundings in the bone. Her lab group is now looking for ways to block collagen formation to close the travel lanes and perhaps keep the cancer from spreading. She and others are also working to find a way to inhibit HIF-1 directly, but so far those efforts have proved challenging. HIF-1’s accomplice, HIF-2, may be a more available target. HIF-2 is a molecule made of two parts that clamp onto DNA to trigger production of other proteins that make tumors tougher to kill. In 2009, structural biologists at University of Texas Southwestern Medical Center in Dallas discovered that the HIF-2 protein had a large cavity. “Usually proteins don’t have holes inside them,” says James Brugarolas, leader of UT Southwestern’s kidney cancer program. With the discovery, researchers began working on a way to use the gap as a foothold for drugs. Now in development, the experimental drug PT2399 slips inside HIF-2 and effectively breaks the molecule in two. Brugarolas and colleagues from six other institutions and the biotech company Peloton Therapeutics Inc. in Dallas published results of the first animal tests of the compound in Nature in November. In mice with implanted grafts of human kidney tumors, PT2399 split HIF-2 and slowed growth in 56 percent of tumors — better than a standard treatment. Brugarolas hypothesizes that the drug worked only about half the time because the other half of tumors relied more heavily on HIF-1. A similar HIF-2–busting drug is now in Phase I safety testing in humans, described in June in Chicago at the annual meeting of the American Society of Clinical Oncology. While Phase I studies are not designed to test whether the treatment works, the drug showed few side effects among 51 people with advanced kidney cancer who took the drug at ever-increasing doses. The patients had already been through multiple types of treatments, one as many as seven. After taking the drug, 16 patients experienced a slowing in disease progression, three more had a partial response and one a complete reversal. Given the dearth of treatments for advanced kidney cancer, Brugarolas says, “this is a big deal.” Still more molecules throw a lifeline to hypoxic tumors in ways that scientists are just beginning to understand. In 2008, pathologist David Cheresh and colleagues at the University of California, San Diego announced a curious discovery in Nature: Depriving cells of vascular endothelial growth factor, or VEGF — the key protein responsible for new vessel growth in a tumor and the main target of drugs that block angiogenesis — could actually make tumors more aggressive. His team went on to discover the same was true for another popular class of drugs, which work by depriving a tumor cell of nutrients in the same way anti-angiogenesis drugs limit oxygen. The drugs, called EGFR inhibitors, were capable of doing the opposite of what was expected: They could make tumors stronger. Cheresh believes that hypoxia — and other stresses of low blood supply, like nutrient deprivation — inflict a wound on the tumor. When normal tissues sustain an injury (like a cut), they immediately enter a period of healing and regeneration. The bleeding stops and the skin grows back. Low oxygen delivers a blow to tumor cells, sending them into a similar state of rejuvenation, he says. “They’re now prepared to survive not only the hypoxia, but everything else thrown at it.” In 2014, Cheresh published his take on why this occurs, at least in some cases, in Nature Cell Biology. He and his team described a molecule called avb3 found on the surface of drug-resistant tumors that appears to reprogram tumor cells into a stem cell–like state. As embers of the original tumor that are often impermeable to treatment, these stem cell–like cells can lie quietly for a time and then reignite. The discovery of avb3 has redefined how Cheresh thinks about resistance. He no longer believes that tumors defy chemotherapy in the way bacteria overcome antibiotics, with only the strongest cells surviving and then roaring back to become dominant. “The tumor cells are adapting, changing in real time,” Cheresh says. In short, his data suggest that when EGFR inhibitors deprive a cell of nutrients, some cells survive not because they are naturally tougher, but because the appearance of avb3 transforms them into drug-resistant stem cells. The good news is that laboratory tests suggest an experimental drug might block this reprogramming, and it may even prevent chemotherapy resistance. A clinical trial will soon begin that combines usual cancer treatment with this avb3-disabling drug, in a one-two punch aimed at reversing or delaying resistance so the treatment can do its job. There are still more ways tumors withstand low oxygen. They start eating leftovers. HIF-1 triggers a switch from oxygen-based aerobic respiration to anaerobic respiration using pyruvate, a product of glucose breaking down. The strategy works in the short term; it’s the reason your muscles keep pumping for a time, even when you’re gasping for air on the last few yards of a sprint. Problem is, anaerobic respiration leaves a trail of lactic acid. A lot of it. “Lactic acid buildup leads to a precipitous drop in pH inside of the tumor,” says Shoukat Dedhar of the BC Cancer Research Centre in Vancouver. To compensate, HIF-1 deploys a fleet of proteins that remove the acid so it won’t accumulate and burn up the cell. Dedhar’s laboratory didn’t start out studying hypoxia. “We had tumors that were readily metastatic and genetically related tumors that couldn’t metastasize,” he says. Those tumors that easily spread were producing HIF-1, along with products from other genes. Searching for the functions of those genes, his group and others found two proteins important in pH balance. The first, MCT-4, acts like a molecular sump pump, bailing out lactic acid. But it’s not enough to normalize the pH, Dedhar says. That job goes to the second protein, carbonic anhydrase 9, or CAIX. “Its job is simply to convert carbon dioxide to bicarbonate, which then neutralizes the acid,” he says. In March 2016, in a review in Frontiers in Cell and Developmental Biology, Dedhar and colleagues described how to improve cancer treatment by taking away some of the tools for hypoxia survival — that is, keeping the cell from neutralizing acid — while simultaneously giving drugs that boost the immune system. His team has developed new compounds that specifically block CAIX. Since CAIX is almost exclusively produced in tumor cells, CAIX inhibitors should theoretically have few side effects. A Phase I safety trial is testing possible drugs now. Harvard’s Jain is still making the case for bathing the tumors in oxygen, giving them more blood, not less. This could keep the tumor from becoming hypoxic and throwing up a new series of defenses, including a flood of angiogenesis-promoting proteins, which produce tormented circulation. When he proposed that concept in 2001, “I thought abnormal vessels were bad,” he says. “I now think they are worse.” His idea is to make tumor vasculature more normal, using the very drugs that he was concerned about almost two decades ago. His research suggests that giving anti-angiogenesis drugs in modest doses will keep the vessels from becoming abnormal, making them less tortured and more capable of normal blood flow (SN: 10/5/13, p. 20). He believes the restored oxygen not only shuts down the hypoxic response that gives the cancer a survival advantage, but also serves as a conduit for chemotherapy drugs and immune cells to penetrate deeper into the tumor. Oxygen is also necessary for radiation to work. His latest experiments take the concept of more oxygen, not less, even further. He combined two chemotherapy drugs with losartan, a generic medicine used to control blood pressure. The result, reported in Nature Communications in 2013, was a delay in pancreatic and breast tumor growth in mice. Another experiment from Jain and colleagues, published in 2016 in Translational Oncology, had similar results. “We are finding every therapy works better when we do this,” he says. A clinical trial is now under way at Massachusetts General Hospital testing whether giving losartan during radiation and chemotherapy will improve results for pancreatic cancer patients. The concept still remains unproven, but Jain has reason for optimism. And he is no longer in the scientific minority. Last May, he received the National Medal of Science from President Barack Obama, who commended Jain for “groundbreaking discoveries of principles leading to the development and novel use of drugs for treatment of cancer.” Jain hopes to see the day, not long in the future, when hypoxic tumors are defeated by giving them the very thing they need the most. This article appears in the March 4, 2017, issue of Science News with the headline, "Deflating cancer: New approaches to low oxygen may thwart tumors."


News Article | February 15, 2017
Site: www.eurekalert.org

Sandra Horning, MD, Chief Medical Officer and executive vice president of global development for Roche and Genentech, a member of the Roche Group, has been named the 2017 recipient of the Duane Roth Memorial Award, which will be presented February 16 at the annual Industry/Academia Translational Oncology Symposium at UC San Diego Moores Cancer Center. The award celebrates Duane Roth, who was Chief Executive Officer of Connect, a San Diego-based organization that promotes technology innovation and entrepreneurship. Roth died in 2013 from injuries suffered in a bicycling accident. Horning has had a long and distinguished career in cancer treatment and research, first as a practicing oncologist, investigator and professor at Stanford University for 25 years, then at the San Francisco-based biotech company Genentech, which merged with the Swiss firm Roche in 2009. Horning, a cancer survivor, has focused much of her work on developing new treatments for lymphoma, a cancer that affects the immune system, including leading clinical trials that eventually resulted in new, approved drug treatments. She was president of the American Society of Clinical Oncology in 2005-2006. "Throughout her impressive career, Sandra Horning has been an unwavering champion of personalized therapies and shifting the focus from treatment of cancer to a more holistic approach of treating the patient as an individual, mindful of his or her family and anticipating survivorship issues, such as fertility, secondary malignancies, cardiopulmonary and endocrine side-effects and more," said Ida Deichaite, PhD, director of UC San Diego Moores Cancer Center's Office of Industry Relations and an organizer of the symposium. "Her scientific achievements in oncology have been amazing and continue to give life, but it's her passion and commitment to promoting empathetic treatment plans that exemplify how establishing collaborations across disciplines can truly improve cancer treatment." The Roth award is bestowed upon leaders in health care whose work has overcome numerous scientific, financial, institutional, political and cultural obstacles to create new paradigms in research and treatment, said Deichaite. Past recipients include: Dennis Slamon, MD, PhD, UCLA Jonsson Comprehensive Cancer Center; Brian Druker, MD, Knight Institute at Oregon Health and Science University; and Laura Esserman, MD, UCSF Helen Diller Family Comprehensive Cancer Center. The symposium, now in its 13th year, is a day-long event at Moores Cancer Center, bringing together scientists, physicians and biopharma representatives to discuss innovations and new collaborations in cancer research and treatment.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the development of medicines to control the expression of disease-driving genes, today announced that its collaborator, Andrew Lowy, M.D., Professor of Surgery and Chief of the Division of Surgical Oncology at the University of California San Diego Moores Cancer Center, presented Syros’ drug discovery research in immuno-oncology at the Moores Cancer Center Industry/Academia Translational Oncology Symposium. As part of a research collaboration in pancreatic cancer with the Lowy laboratory at the Moores Cancer Center, Syros scientists discovered alterations in regulatory regions of the genome in tumor-associated macrophages in a subset of patient tissues. Because these alterations are unique to the immunosuppressive state, they could point to genes critical for driving immunosuppression in the tumor microenvironment, as well as potential drug targets to reactivate the immune system to fight cancer. “Syros’ gene control platform provides a unique lens for understanding how cancer can evade and manipulate the body’s immune system to fuel its growth and become resistant to existing therapies,” Dr. Lowy said. “Through investigation of the immune components within the tumor microenvironment, our hope is to develop medicines that can unleash our natural defenses against cancer.” Together with the Lowy laboratory, Syros used its proprietary gene control platform to isolate tumor-associated macrophages directly from pancreatic cancer patient tissues and analyze regulatory regions of DNA in these cells. Then, by comparing those regions in the tumor-associated macrophages to those from healthy donors, Syros scientists identified alterations unique to the immunosuppressive state. Tumor-associated macrophages are of significant interest in immuno-oncology because they play a key role in the body’s immune response to cancer, with M1 macrophages promoting immune-mediated tumor regression and M2 macrophages allowing tumors to grow unimpeded. “The inclusion of our research at this conference reflects the recognition among academic and industry leaders of the promise of Syros’ gene control platform to uncover important insights into the mechanisms employed by cancer cells to essentially shut down the immune response within the tumor and to create drugs that can increase killing of tumor cells by the immune system,” said Eric Olson, Ph.D., Chief Scientific Officer of Syros. “We believe our focus on the regulatory genome of immune and tumor cells isolated from primary tumors represents a distinct approach to immuno-oncology with the potential to provide a profound benefit for subsets of cancer patients.” Syros has a broader immuno-oncology drug discovery effort outside of the collaboration focused on identifying and drugging novel targets to control the function of immune cells within the tumor microenvironment. Using a similar approach to the one used in the Lowy collaboration, Syros has identified and validated a drug target that, when inhibited, re-activates tumor-associated macrophages to a pro-tumor killing state. Syros’ immuno-oncology research is focused on cancers in which the tumor microenvironment is known to play a key role in disease progression or drug resistance, including glioblastoma and pancreatic, triple negative breast and ovarian cancers. By analyzing immune and tumor cells directly in patient tumor tissues, Syros aims to better understand the heterogeneity of immune responses among patients and identify subsets of patients most likely to respond to specific immunotherapy strategies. About Syros Pharmaceuticals Syros Pharmaceuticals is pioneering the understanding of the non-coding region of the genome to advance a new wave of medicines that control expression of disease-driving genes. Syros has built a proprietary platform that is designed to systematically and efficiently analyze this unexploited region of DNA in human disease tissue to identify and drug novel targets linked to genomically defined patient populations. Because gene expression is fundamental to the function of all cells, Syros’ gene control platform has broad potential to create medicines that achieve profound and durable benefit across a range of diseases. Syros is currently focused on cancer and immune-mediated diseases and is advancing a growing pipeline of gene control medicines. Syros’ lead drug candidates are SY-1425, a selective RARα agonist in a Phase 2 clinical trial for genomically defined subsets of patients with acute myeloid leukemia and myelodysplastic syndrome, and SY-1365, a selective CDK7 inhibitor with potential in a range of solid tumors and blood cancers. Led by a team with deep experience in drug discovery, development and commercialization, Syros is located in Cambridge, Mass. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, including without limitation statements regarding the benefits of Syros’ gene control platform in the field of immuno-oncology. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘continue,’’ ‘‘could,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘potential,’’ ‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘should,’’ ‘‘would,’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: Syros’ ability to: advance the development of its programs; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; replicate scientific and non-clinical data in clinical trials;; obtain and maintain necessary regulatory approvals; identify, enter into and maintain collaboration agreements with third parties; manage competition; manage expenses; raise the substantial additional capital needed to achieve its business objectives; attract and retain qualified personnel; and successfully execute on its business strategies; risks described under the caption “Risk Factors” in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, which is on file with the Securities and Exchange Commission; and risks described in other filings that the company makes with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Syros expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.


News Article | December 21, 2016
Site: www.businesswire.com

SAN DIEGO--(BUSINESS WIRE)--Batu Biologics, a San Diego based immuno-oncology company focused on the development of its tumor angiogenesis targeting immune therapy, ValloVax™, announced today the formation of a Clinical Advisory Board to guide the company in the development of its lead program. “Members of the Batu Biologics Clinical Advisory Board have aligned their vision to assess the clinical feasibility of targeting the tumor vasculature as an effective treatment for solid tumors,” said Samuel C. Wagner, President and CEO of Batu Biologics. “Our goal is to streamline and optimize the clinical development plan for the ValloVax™ program in order to ensure the highest likelihood of patient response in the clinical setting.” “Making advances in a challenging and competitive environment requires a team of experts who can share experiences, information and innovative ideas,” said Dr. Santosh Kesari, Chairman of Batu’s Clinical Advisory Board and Professor at the Pacific Neuroscience Institute and John Wayne Cancer Institute at Providence Saint John’s Health Center. “We are excited to explore various strategies in the areas of predictive biomarkers, personalized therapy, and combination approaches with FDA-approved cancer therapeutics in an effort to ensure the best patient response to the ValloVax™ therapy.” The newly appointed members of the Batu Biologics Clinical Advisory Board are: Dr. Santosh Kesari is a Professor and Chair of Translational Neurosciences and Neurotherapeutics at Pacific Neuroscience Institute and John Wayne Cancer Institute at Providence Saint John’s Health Center. His research investigates the biology of gliomas and brain metastases with the aim of developing new therapeutics. He has a long-standing interest in neural development, cancer stem cells, and neuroimmunology and translational research in these areas to accelerate drug development; Mai is a strategic advisor for biotechnology companies with a focus in oncology and immunotherapy. Dr. Le has over 8 years of oncology drug development experience that includes small molecules, biologics, medical devices and companion diagnostics strategy. She previously served as a medical director at Calithera Biosciences, Plexxikon Inc., Onyx Pharmaceuticals and Proteolix, Inc (acquired by Onyx Pharmaceuticals), and most recently, as the Chief Medical Officer at OncoSec Medical, Inc. Dr. Le obtained a medical degree from the University of Rochester School of Medicine and Dentistry and trained in Laboratory Medicine at University of California, San Francisco; and Boris is currently the President of Clinical and Scientific Affairs at StemImmune Inc. and Adjunct Professor at the Moores UCSD Cancer Center. Dr. Minev previously worked as Director of Immunotherapy and Translational Oncology at Genelux Corporation and was heading the Laboratory of Tumor Immunology and Immunotherapy at the Moores UCSD Cancer Center. Dr. Minev has an extensive experience in Immuno-Oncology and cancer vaccine development, having worked closely on the development of the first tumor vaccine to be approved by a regulatory body (Melacine). Batu Biologics is an immuno-oncology company developing novel gene and cellular based therapies for the treatment of cancer. The Company has filed an IND application for its lead therapeutic, ValloVax™, a multivalent therapeutic vaccine for Non Small Cell Lung Cancer targeting several tumor-angiogenesis associated antigens. ValloVax™ has demonstrated strong inhibition of tumor growth in several histologically distinct tumor models, and the company is currently raising funds that will enable the completion of a Phase I clinical study.


Merck and Pfizer Inc.  today announced that the US Food and Drug Administration (FDA) has accepted for Priority Review the Biologics License Application (BLA) for avelumab*, as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC) with disease progression on or after platinum-based therapy. The BLA was submitted by EMD Serono, the biopharmaceutical business of Merck in the US and Canada. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of August 27, 2017, for avelumab in this indication. "Taken together with last year's filing for metastatic Merkel cell carcinoma, this BLA acceptance confirms our rapid and continued progress in the clinical development of avelumab," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck. "We continue to evaluate avelumab in cancers that have limited or suboptimal treatment choices, such as metastatic or locally advanced urothelial carcinoma, to hopefully be able to provide patients with new treatment options for fighting their disease." Despite advances in the treatment of UC, the prognosis for patients remains poor, particularly when the disease has metastasized. Bladder cancer makes up approximately 90% of urothelial cancers and is the sixth most common cancer in the US.[1],[2] "Advanced urothelial carcinoma remains a difficult-to-treat tumor, which is why we are developing a comprehensive clinical development program that involves Phase I and III trials designed to address this challenge," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "We're continuing to accelerate our urothelial carcinoma development program and look forward to continuing our dialogue with the FDA." Avelumab is an investigational, fully human anti-PD-L1 antibody. The FDA's Priority Review status reduces the review time from 10 months to a goal of six months from the day of filing acceptance and is given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. In November 2016, the FDA accepted, and granted Priority Review status to, the BLA for avelumab for the treatment of patients with metastatic Merkel cell carcinoma. The international clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs, including nine Phase III trials, and more than 4,000 patients evaluated across more than 15 tumor types. In December 2015, Merck and Pfizer announced the initiation of a Phase III study (JAVELIN Bladder 100) of avelumab in the first-line setting as a maintenance treatment in patients with locally advanced or metastatic UC. This trial is currently enrolling patients. *Avelumab is not approved for any indication in any market. This marks the second acceptance of an application by the FDA to review the investigational product, avelumab. Urothelial Carcinoma includes several tumors originating from the cells lining the bladder, renal pelvis and urethra. While cancers outside of the bladder are relatively uncommon, accounting for an estimated 10% of cases, bladder cancer represents 90% of urothelial cancers and is the ninth most common cancer globally.[1],[3] Worldwide, approximately 400,000 new cases of bladder cancer are diagnosed and 150,000 deaths are attributed to this disease each year.[3] The incidence and mortality of bladder cancer have remained unchanged over the past 25 years.[3] Avelumab is a fully human antibody specific for a protein found on tumor cells called PD-L1, or programmed death ligand-1. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab. Common adverse reactions include fatigue, musculoskeletal pain, diarrhea, nausea peripheral edema, decreased appetite, and rash.  Immune-mediated adverse reactions have also been reported. Immuno-oncology is a top priority for Merck and Pfizer Inc. 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 in combination regimens, and is striving to find new ways to treat cancer. EMD Serono is the biopharmaceutical business of Merck in the US and Canada - a leading science and technology company - focused exclusively on specialty care. For more than 40 years, the business has integrated cutting-edge science, innovative products and industry-leading patient support and access programs. EMD Serono has deep expertise in neurology, fertility and endocrinology, as well as a robust pipeline of potential therapies in oncology, immuno-oncology and immunology as R&D focus areas. Today, the business has 1,200 employees around the country with commercial, clinical and research operations based in the company's home state of Massachusetts. http://www.emdserono.com All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to http://www.merckgroup.com/subscribe to register online, change your selection or discontinue this service. For further details and press materials about Merck in oncology please visit 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 2015, Merck generated sales of € 12.85 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. The only exceptions are the United States and Canada, where the company operates as EMD Serono, MilliporeSigma and EMD Performance Materials. Pfizer Inc.: Working together for a healthier world® At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of healthcare products. Our global portfolio includes medicines and vaccines, as well as many of the world's best-known consumer healthcare products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. To learn more, please visit us at http://www.pfizer.com. In addition, to learn more, follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn  and like us on Facebook at Facebook.com/Pfizer. The information contained in this release is as of February 28, 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 avelumab (MSB0010718C), including a potential indication for avelumab for the treatment of metastatic urothelial carcinoma (the "Potential Indication"), Pfizer's and Merck's immuno-oncology 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, 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; 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 drug applications may be filed in other jurisdictions for the Potential Indication and whether and when drug applications may be filed in any jurisdictions for any other potential indications for avelumab, combination therapies or other product candidates; whether and when the BLA for the Potential Indication, the BLA and EU marketing authorization application for avelumab for the treatment of metastatic Merkel cell carcinoma or any such other applications may be approved by regulatory authorities, 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 avelumab, 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, 2015, 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.


Merck and Pfizer Inc. (NYSE: PFE) today announced that the US Food and Drug Administration (FDA) has accepted for Priority Review the Biologics License Application (BLA) for avelumab, which was submitted by EMD Serono, the biopharmaceutical business of Merck in the US and Canada. This review relates to avelumab's proposed use in patients with metastatic Merkel cell carcinoma (MCC), based on tumor response results from the JAVELIN Merkel 200 trial. Avelumab is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody and could be the first treatment indicated for metastatic MCC in the US, if approved.* MCC is a rare and aggressive skin cancer, which impacts approximately 2,500 Americans a year.[1],[2] "We are pleased the FDA has granted a Priority Review designation for avelumab," said Luciano Rossetti, M.D., Executive Vice President, Global Head of Research & Development at the biopharma business of Merck. "There are currently no approved treatment options for metastatic MCC, and we are committed to working with the FDA to potentially bring the first approved cancer immunotherapy to patients with this aggressive disease." The avelumab metastatic MCC BLA submission is supported by data from JAVELIN Merkel 200, a multicenter, single-arm, open-label, Phase II study of 88 patients with metastatic MCC, whose disease had progressed after at least one chemotherapy treatment.[1] The JAVELIN Merkel 200 study represents the largest data set of any anti-PD-L1/PD-1 antibody reported in this patient population. These data were presented in June 2016 at the Annual Meeting of the American Society of Clinical Oncology (ASCO) and published in the Lancet Oncology in October 2016.[1] "Metastatic Merkel cell carcinoma is an aggressive disease, and patients face a very poor prognosis, with less than 20 percent surviving beyond five years," said Chris Boshoff, M.D., Ph.D., Senior Vice President and Head of Immuno-oncology, Early Development and Translational Oncology, Pfizer Global Product Development. "We are encouraged by the results of our Phase II trial and believe avelumab may have potential to be an important treatment option for patients living with this hard-to-treat skin cancer." The FDA's Priority Review status reduces the review time from 10 months to a goal of six months from the day of filing and is given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. The FDA previously granted avelumab Orphan Drug Designation for MCC, as well as Fast Track and Breakthrough Therapy Designations for the treatment of patients with metastatic MCC whose disease has progressed after at least one previous chemotherapy regimen. Breakthrough Therapy Designation is intended to expedite the development and review of treatments for serious or life-threatening disease where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies for one or more endpoints.[3] Additionally, the European Medicines Agency has validated for review Merck's Marketing Authorization Application (MAA) for avelumab, for the proposed indication of metastatic MCC. The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 3,000 patients evaluated across more than 15 different tumor types. In addition to metastatic MCC, these cancers include breast, gastric/gastroesophageal junction, head and neck, Hodgkin's lymphoma, melanoma, mesothelioma, non-small cell lung, ovarian, renal cell carcinoma and urothelial (primarily bladder). *Avelumab is not approved for any indication in any market. This marks the first acceptance of an application by the US FDA to review the investigational product, avelumab. Metastatic MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings.[1],[4] 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.[5] Risk factors for MCC include sun exposure and having 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 at higher risk). Caucasian males older than 50 are at increased risk.[5] MCC is often misdiagnosed for other skin cancers and grows at an exponential rate on chronically sun-damaged skin.[6]-[9] Current treatment options for MCC include surgery, radiation and chemotherapy.[10] Treatment for metastatic or Stage IV MCC is generally palliative. Avelumab (also known as MSB0010718C) is an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab. In the JAVELIN Merkel 200 trial, treatment-related adverse events (AEs) occurred in 62 (70%) of 88 patients including fatigue and infusion-related reactions. Five grade 3 treatment-related AEs were reported in four of 88 patients and include two patients with lymphopenia and three patients with isolated laboratory abnormalities (elevated blood creatine phosphokinase, blood cholesterol, and hepatic aminotransferase).[1] There were no grade 4 treatment-related AEs or deaths related to treatment.[1] EMD Serono is the biopharmaceutical business of Merck in the US and Canada - a leading science and technology company - focused exclusively on specialty care. For more than 40 years, the business has integrated cutting-edge science, innovative products and industry-leading patient support and access programs. EMD Serono has deep expertise in neurology, fertility and endocrinology, as well as a robust pipeline of potential therapies in oncology, immuno-oncology and immunology as R&D focus areas. Today, the business has 1,200 employees around the country with commercial, clinical and research operations based in the company's home state of Massachusetts. www.emdserono.com 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. All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service. For further details and press materials about Merck in oncology please visit www.merckgroup.com/en/media/media_center_oncology.html 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 2015, Merck generated sales of € 12.85 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. The only exceptions are the United States and Canada, where the company operates as EMD Serono, MilliporeSigma and EMD Performance Materials. Pfizer Inc.: Working together for a healthier world® At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of healthcare products. Our global portfolio includes medicines and vaccines, as well as many of the world's best-known consumer healthcare products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us. To learn more, please visit us at http://www.pfizer.com. In addition, to learn more, follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn and like us on Facebook at Facebook.com/Pfizer. The information contained in this release is as of November 29, 2016. 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 avelumab (MSB0010718C), including a potential indication for avelumab for the treatment of metastatic Merkel Cell carcinoma (the "Potential Indication"), Pfizer's and Merck's immuno-oncology 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, the uncertainties inherent in research and development, including the ability to meet anticipated clinical study commencement and completion dates as well as the possibility of unfavorable study results; 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 drug applications may be filed in other jurisdictions the Potential Indication or whether and when drug applications may be filed in any jurisdictions for any other potential indications for avelumab, combination therapies or other product candidates; whether and when the BLA or MAA for the Potential Indication or any such applications may be approved by regulatory authorities, 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 avelumab, 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, 2015, 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.

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