On October 31, 2016 Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE (link is external)) reported that the European Medicines Agency (EMA) has validated for review Merck KGaA, Darmstadt, Germany’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 (Press release, Pfizer, OCT 31, 2016, View Source [SID1234516116]).[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]

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"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 KGaA, Darmstadt, Germany, which in the US and Canada operates as EMD Serono. "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.

On October 31, 2016 Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK) reported that the U.S. Food and Drug Administration (FDA) has accepted for review the Abbreviated New Drug Application (ANDA) for generic doxorubicin hydrochloride (HCI) liposome injection submitted by its partner Actavis LLC (an indirect, wholly owned subsidiary of Teva Pharmaceuticals USA, Inc.) (Press release, Merrimack, OCT 31, 2016, View Source [SID1234516115]). This is the first product developed by Merrimack under a partnership agreement with Actavis LLC pursuant to which Merrimack is responsible for the development and commercial supply of bulk drug product and Actavis LLC is responsible for fill/finish activities, regulatory approvals and commercialization in the United States.

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Doxorubicin HCl liposome injection is marketed as DOXIL in the United States by Janssen Products LP, a Johnson & Johnson company. The approved indications for the product are ovarian cancer, AIDS-related Kaposi’s sarcoma and multiple myeloma. DOXIL generated approximately $600 million annually in global revenue prior to Johnson & Johnson’s 2011 manufacturing disruption, which resulted in the placement of DOXIL on the FDA’s drug shortage list. While DOXIL was on the drug shortage list, the FDA approved a generic version of doxorubicin HCl liposome injection marketed by Sun Pharma Global FZE, and both products now share the U.S. market. If approved, Merrimack is eligible to receive a royalty rate in the mid-twenties of net profits on sales of doxorubicin HCl liposome injection under the agreement with Actavis.

"We are pleased to have achieved this important milestone with our partner, Actavis," said Gary Crocker, Chairman of Merrimack’s Board of Directors and interim President and CEO. "This collaboration leverages Merrimack’s proven expertise in the development of liposomal products and provides the opportunity to maximize the use of our state-of-the-art commercial liposomal manufacturing facility. It also could allow us, if the product is approved, to generate an additional revenue stream to not only offset costs but meaningfully improve earnings. We look forward to the FDA’s review of Actavis’s ANDA filing and providing further support as Actavis navigates the regulatory approval process."

Merrimack is a leader in the development and manufacturing of nanoliposomal products. In addition to the generic doxorubicin HCl liposome injection for which the ANDA was just accepted, Merrimack has developed or is developing several novel therapeutic candidates. Merrimack’s first commercial product, ONIVYDE (irinotecan liposome injection), is a novel liposomal formulation of irinotecan that was approved by the FDA in the United States in October 2015.

On October 31, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for ARIAD’s investigational oral anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, in patients with metastatic ALK-positive (ALK+) non-small cell lung cancer (NSCLC) who have progressed on crizotinib (Press release, Ariad, OCT 31, 2016, View Source [SID1234516110]). The FDA granted ARIAD’s request for Priority Review and has set an action date of April 29, 2017 under the Prescription Drug User Fee Act (PDUFA).

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"The FDA acceptance of our application is an important milestone in our ongoing efforts to discover, develop and deliver highly innovative treatments for patients with rare cancers," said Paris Panayiotopoulos, president and chief executive officer of ARIAD. "We are pleased that our significant R&D investments in brigatinib and our work with the FDA are bringing us closer to potentially offering a treatment option for patients with ALK+ NSCLC who are refractory to crizotinib. We look forward to continuing to work closely with the FDA during the brigatinib NDA review and remain committed to developing critical therapies for unserved and underserved small patient populations suffering from rare cancers."

ARIAD’s NDA submission includes clinical data from its Phase 1/2 and pivotal Phase 2 ALTA trials of brigatinib. The FDA’s Priority Review status accelerates the review time from 10 months to a goal of six months from the filing of the application. Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK-positive, ROS1-positive, and EGFR-positive NSCLC. ARIAD plans to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

ARIAD is a small, research-driven biotechnology company. ARIAD has invested more than $1.3 billion in R&D since the Company was founded. In 2015, ARIAD generated $119 million in total revenue and invested $171 million, or 143 percent of revenue, in R&D.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). The global Phase 2 ALTA trial, in patients with locally advanced or metastatic ALK+ NSCLC who were previously treated with crizotinib, is the primary basis for brigatinib’s initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies indicate that chromosomal rearrangements in ALK are key drivers in a subset of NSCLC patients as well. Approximately three to eight percent of patients with NSCLC have a rearrangement in the ALK gene.

On October 31, 2016 Epizyme, Inc. (NASDAQ:EPZM), a clinical-stage biopharmaceutical company creating novel epigenetic therapies, reported that it has entered into two Cooperative Research and Development Agreements (CRADAs) with the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) (Press release, Epizyme, OCT 31, 2016, View Source [SID1234516109]). The CRADAs will evaluate tazemetostat, Epizyme’s first-in-class EZH2 inhibitor, and pinometostat, the Company’s first-in-class DOT1L inhibitor. Both investigational medicines target proteins implicated in the development and regulation of cancer.

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"This collaboration reflects Epizyme’s strategy to enhance our development programs through impactful partnerships," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "These CRADAs broaden the scope of our ongoing tazemetostat clinical program to explore its potential benefit in a wider range of cancer indications. We are also excited to continue the exploration of pinometostat’s potential utility in treating acute leukemias in combination regimens. We look forward to generating additional data to advance our epigenetic pipeline of novel therapies for patients with cancer."

As part of the CRADA for tazemetostat, CTEP will collaborate with Epizyme in clinical trials to evaluate the safety and efficacy of tazemetostat in patients with hematologic malignancies and solid tumors. The initial NCI-sponsored study will evaluate tazemetostat in a phase 2 clinical trial in patients with ovarian cancer. External publications and Epizyme preclinical data indicate that inhibition of EZH2 could be beneficial in subsets of ovarian cancer.

Under the second CRADA, the safety and efficacy of pinometostat will be evaluated in patients with acute leukemias. Initial studies will evaluate the combination of pinometostat with standard-of-care therapies or targeted agents in acute myeloid leukemia, acute lymphoid leukemia, or mixed lineage leukemia characterized by a rearrangement in the mixed lineage leukemia gene (MLL-r). Preclinical studies of pinometostat in MLL-r cell line models have shown synergy with chemotherapies, including acute leukemia standard-of-care agents and select targeted therapies.

As part of both agreements, additional clinical trials will be considered. NCI will predominantly fund the studies and manage study operations.

About the Tazemetostat Clinical Program
Tazemetostat, a first-in-class EZH2 inhibitor, is being evaluated as a monotherapy and in combination with other agents in multiple cancer indications. Phase 2 studies of tazemetostat as a monotherapy are currently ongoing in patients with non-Hodgkin lymphoma; in adults and children with certain genetically defined solid tumors, including INI1-negative and SMARCA4-negative tumors and synovial sarcoma; and in patients with mesothelioma characterized by BAP1 loss-of-function. Tazemetostat has been granted orphan drug status by the U.S. Food and Drug Administration, for the treatment of malignant rhabdoid tumors.

Additionally, tazemetostat is being evaluated in two combination studies in patients with diffuse large B-cell lymphoma (DLBCL). A first-line Phase 1b/2 trial of tazemetostat in combination with R-CHOP, an immunochemotherapy regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, is being conducted as part of Epizyme’s collaboration with the Lymphoma Study Association. A Phase 1b study evaluating tazemetostat in combination with Tecentriq (atezolizumab), an anti-PD-L1 cancer immunotherapy approved by the U.S. Food and Drug Administration, is being conducted as part of a collaboration with Genentech, a member of the Roche Group, in relapsed and refractory patients with DLBCL. For more information on tazemetostat clinical trials, please visit www.epizymeclinicaltrials.com.

About Pinometostat
Pinometostat, a small molecule inhibitor of DOT1L, is under clinical evaluation for the treatment of children with acute leukemias, including a genetically defined leukemia characterized by MLL-r. Pinometostat is being developed in collaboration with Celgene. Epizyme retains all U.S. rights to pinometostat and has granted Celgene an exclusive license to pinometostat outside of the U.S.