On December 20, 2018 Servier reported the the Food and Drug Administration approved calaspargase pegol-mknl (ASPARLAS, Servier Pharmaceuticals LLC), an asparagine specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years (Press release, Servier, DEC 20, 2018, View Source [SID1234645703]). This new product provides for a longer interval between doses compared to other available pegaspargase products.

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Approval was based on a demonstration of the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when using calaspargase pegol-mknl, 2500 U/m2 intravenously, every 3 weeks. The pharmacokinetics of calaspargase pegol-mknl were studied when administered in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL.

The most common (incidence ≥ 10%) grade ≥ 3 adverse reactions were elevated transaminase, increased bilirubin, pancreatitis, and abnormal clotting studies. In a randomized trial, the safety profile of calaspargase pegol-mknl administered every 3 weeks was similar to that of pegaspargase administered every 2 weeks.

The recommended calaspargase pegol-mknl dose is 2,500 units/m2 intravenously administered at a minimum dosing interval of every 21 days.

View full prescribing information for ASPARLAS.

Calaspargase pegol-mknl received FDA orphan product designation.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

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Check out recent approvals at the OCE’s podcast, Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.).

On December 20, 2018 Merck KGaA, Darmstadt, Germany, a leading science and technology company, reported that through its wholly owned subsidiary, Ares Trading, it has evolved its agreement with Intrexon Corporation (NASDAQ: XON) for the development of Chimeric Antigen Receptor T-cell (CAR-T) therapies, genetically engineered T-cells with synthetic receptors that recognize a specific antigen expressed on tumor cells (Press release, Merck KGaA, DEC 20, 2018, View Source;utm_medium=email&utm_campaign=press-mailer&utm_content=en&global_redirect=1 [SID1234532177]). The agreement with Intrexon and its wholly-owned subsidiary, Precigen, Inc. enables Merck KGaA, Darmstadt, Germany, to continue to implement its focused R&D strategy, while maintaining an investment in the future potential of next-generation CAR-T development.

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Under the terms of the agreement, Merck KGaA, Darmstadt, Germany, will assign its exclusive CAR-T development rights to Intrexon. Merck KGaA, Darmstadt, Germany will receive shares of Intrexon common stock valued at $150 million in exchange for assigning Intrexon its CAR-T rights.

"Merck KGaA, Darmstadt, Germany, is excited to maintain its interest in the potential of CAR-T technology, which may offer significant future benefits to patients fighting cancer," said Belén Garijo, Member of the Executive Board and CEO Healthcare, Merck KGaA, Darmstadt, Germany. "The agreement is also illustrative of our efforts to enhance our focus on accelerating the delivery of our innovative clinical pipeline to patients."

Merck KGaA, Darmstadt, Germany, first entered into a collaboration and license agreement with Intrexon in 2015 to develop and commercialize CAR-T cancer therapies utilizing Intrexon’s proprietary RheoSwitch Therapeutic System and the Sleeping Beauty non-viral gene integration technology. The combination of these platforms enables regulation of gene expression and delivery with a non-viral approach and preclinical data indicate the potential to improve therapeutic safety and facilitate shortened manufacturing to improve time-to-treatment. As of December 31, 2017, these rights were considered intangible assets not yet available for use with a carrying amount of € 104 million.

"Merck KGaA, Darmstadt, Germany’s leading immuno-oncology research and commitment to developing innovative medicines made them an ideal partner for us in advancing targeted and controllable CAR-T therapies," said Helen Sabzevari, PhD, President of Precigen. "We look forward to continued development of these promising treatments with the goal of delivering more cost-effective, powerful, and precise therapies to patients in need."

In addition to receiving $150 million of Intrexon common stock, this agreement also includes a further $25 million investment in Intrexon. In return, Merck KGaA, Darmstadt, Germany, will receive a $25 million convertible note, providing the option to receive either Precigen or Intrexon stock. The closing of the transactions contemplated by the agreement is subject to customary closing conditions, including the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act.

On December 20, 2018 Transgene (Paris:TNG), a biotechnology company that designs and develops virus-based immunotherapies against cancers and infectious diseases, reported that the primary endpoint (safety and tolerability) was met in the Phase 1b part of a trial combining TG4001 and avelumab, a human anti-programmed death ligand (PD-L1) antibody, as a treatment for HPV-16+1 recurrent or metastatic malignancies, such as oropharyngeal squamous cell carcinoma of the head and neck (SCCHN) (Press release, Transgene, DEC 20, 2018, View Source [SID1234532193]).

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In the Phase 1b part of the trial, 9 patients received escalating doses of TG4001 combined with a fixed dose of avelumab. No dose-limiting toxicity was observed, confirming a satisfactory tolerability profile for the combined regimen, allowing the trial to progress to the Phase 2 part.

The Phase 2 part of the trial will enroll 40 patients with HPV16+ recurrent or metastatic SCCHN. Patients will receive the highest TG4001 dose tested in the Phase 1b part of the trial, in combination with avelumab at 10 mg/kg, until disease progression. The first patients have already been enrolled.

The first data from this trial on the activity of the combination are expected during the second half of 2019.

About the trial
This multi-center, open-label trial will assess the safety and tolerability, as well as the anti-tumor activity of this immunotherapy combination regimen (TG4001 + avelumab) in up to 50 patients (NCT03260023). Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, and a world expert in head and neck cancers, is the Principal Investigator of the study. The trial is conducted in collaboration with Merck KGaA, Darmstadt, Germany, a leading science and technology company which in the US and Canada operates its biopharmaceutical business as EMD Serono, and Pfizer Inc (NYSE: PFE).

More information on the trial is available on clinicaltrials.gov.

-End-

Notes to editors

About TG4001
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated vaccinia vector (MVA), which is engineered to express HPV-16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to HPV-16-infected cells that have started to undergo precancerous transformation (cells presenting the HPV-16 E6 and E7 antigens) and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety, significant HPV clearance rate and promising efficacy results. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.

About Avelumab
Avelumab is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.1-3 Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro3-5. In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

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

Avelumab is currently approved for patients with MCC in more than 45 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

Important Safety Information from the US FDA-Approved Label
The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions), infusion-related reactions and embryo-fetal toxicity.

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

For full prescribing information and medication guide for BAVENCIO, please see www.BAVENCIO.com.

About HPV-Positive Head and Neck Cancer
Squamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous group of cancers that can affect the oral cavity, pharynx, and larynx.

The incidence of HPV-related SCCHN has significantly increased in recent years. HPV-16 infection is associated with more than 85% of oropharynx squamous cell carcinomas in the US (Kreimer et al., 2005), i.e. more than 25,000 patients (Source: meta-analysis, IARC – De Martel et al., 2017, International Journal of Cancer).

Current treatments include surgical resection with radiotherapy, chemoradiotherapy or immune checkpoint inhibitors. However, better options are needed for advanced and metastatic HPV+ SCCHN. It is thought that immunotherapy combined with immune checkpoint inhibitors could provide a promising potential treatment option that would address this strong medical need.

On December 20, 2018 Epigenomics AG (FSE: ECX, OTCQX: EPGNY) reported the initiation of a multi-center validation and development study of its methylated cell free DNA biomarkers to aid in the detection of hepatocellular carcinoma (HCC) in patients with cirrhosis (Press release, Epigenomics, DEC 20, 2018, View Source [SID1234532209]).

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As an expansion of its molecular diagnostic product offering, the company recently CE marked the HCCBloodTest for cirrhotic patients at risk for HCC, based on a published clinical study, demonstrating a high sensitivity of 90.6 percent at a specificity of 87.2 percent. Furthermore, the blood test exhibited higher diagnostic accuracy compared to alpha-fetoprotein (AFP), a widely used serum diagnostic marker for liver cancer.

The company is now initiating a cross-sectional, prospective clinical trial at three medical centers to assess its methylated cell free DNA biomarkers and validate the performance of HCCBloodTest for a similar indication in the U.S. population. Key findings from this current study will bridge to a longitudinal study for FDA submission that will initiate in the second half of 2019.

According to the World Health Organization (WHO), liver cancer is the second most common cause of death from cancer worldwide with hepatocellular carcinoma (HCC) accounting for 70-90 percent of primary liver cancers (PLC)*. A major risk factor for developing HCC is liver cirrhosis. Globally, Epigenomics estimates the liver cirrhosis surveillance market to be in excess of ten million tests per year making it more than a three billion euro market opportunity globally.

In Europe, liver cirrhosis is responsible for over 170,000 deaths per year* and Epigenomics estimates approximately three million patients per year in Western Europe are eligible for liver surveillance resulting in a total available market of over one billion euro per year.

"The current methods for diagnosing the progression of liver cancer in cirrhotic patients are not perfect," said Dr. Edward Mena, Hepatologist and Medical Director of the Pasadena Liver Center, President and CEO of California Liver Research Institute (CLRI), "and, I am optimistic that potential new biomarkers may improve outcomes in these patients."

"We feel this important cross-sectional, prospective study of cirrhotic patients will further support the applicability of HCCBloodTest in early liver cancer detection", said Greg Hamilton, CEO of Epigenomics AG. "Reliably detecting liver cancer is a worldwide challenge. Based on the initial performance data of the test, we have made this prospective clinical study a corporate priority."

*Journal of Hepatology Volume 58, Issue 3 March 2013, Blachier et.al.

On December 20, 2018 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the European Commission (EC) has granted marketing authorization for a split dosing regimen for DARZALEX (daratumumab) (Press release, Genmab, DEC 20, 2018, View Source [SID1234532178]). The approval will be included in an update of the Summary of Product Characteristics in order to provide health care professionals the option to split the first infusion of DARZALEX over two consecutive days. The EC approval follows a positive opinion issued for DARZALEX by the European Committee for Medicinal Products for Human Use (CHMP) on November 18th, 2018. In August 2012, Genmab granted Janssen an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

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"We are hopeful that the availability of this more flexible dosing option will make the first infusion of DARZALEX more convenient for European multiple myeloma patients," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

This approval was based on data from the Phase Ib EQUULEUS (MMY1001) clinical trial, which demonstrated DARZALEX pharmacokinetics (PK) concentrations were comparable regardless of whether the first dose was administered as a split infusion or as a single first infusion in patients with multiple myeloma. The safety profile of DARZALEX was comparable when administered initially as either a split or a single dose.

About the EQUULEUS (MMY1001) Study
The Phase Ib EQULLEUS open-label study includes up to 240 patients with the goal of evaluating the safety, tolerability and dose of daratumumab when administered in combination with various backbone treatment regimens for different settings of multiple myeloma.

About DARZALEX(daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (U.S. FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy; and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. In Japan, DARZALEX is approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma. DARZALEX is the first human CD38 monoclonal antibody to reach the market in the United Stated, Europe and Japan. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).1,2,3,4,5

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies in smoldering, relapsed and frontline multiple myeloma settings and in amyloidosis. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases, such as NKT-cell lymphoma, myelodysplastic syndromes, B and T-ALL. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.