This year, Darmstadt, Germany-based Merck KGaA — the oldest pharmaceutical and chemical company in the world, established in 1668 — is celebrating 125 years of business in the U.S. The company operates in the U.S. as EMD Serono, EMD Millipore and EMD Performance Materials. Georg Merck established the company’s U.S. presence in 1890. In 2015, Merck KGaA, Darmstadt, Germany scientists are focused on confronting new challenges in science and technology, including developing new ways to help the body harness its own immune system to fight cancer and making it possible for developing countries to manufacture vaccines more easily and efficiently.
EMD Serono’s Focus on Cancer And Immuno-Oncology
On the product research and development front for EMD Serono, Merck KGaA, Darmstadt, Germany’s healthcare business, a major current and ongoing focus for EMD Serono is the emerging field of Immuno-Oncology (iONC) — finding ways to harness the body’s own immune system to mount an immune response against cancer, and which the company believes has potential to change the cancer landscape. EMD Serono’s immuno-oncology research and early development platform, integrating research, early development and biomarker strategies, concentrates on discovering and developing the potential for new therapies intended to stimulate, activate or augment the body’s natural anti-tumor immune response.
EMD Serono’s lead immuno-oncology product candidate is avelumab, a compound the company discovered and developed by EMD Serono. An investigational, fully human anti-PD-L1 IgG1 monoclonal antibody avelumab (also known as Anti-PD-L1 mAb MSB0010718C) is thought to enable activation of T-cells and the adaptive immune system by inhibiting PD-L1 interactions. By retaining a native Fc-region, avelumab is thought to engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC).
In November, 2014, EMD Serono and Pfizer Inc. announced a strategic alliance to co-develop and co-commercialize avelumab, enabling the companies to benefit from and complement each others’ strengths and capabilities and to further explore the drug’s therapeutic potential. The global collaboration with Pfizer is expected to accelerate the development of avelumab in multiple tumor types. Avelumab will be developed as a single agent as well as in various combinations with Pfizer’s and EMD Serono’s respective broad portfolios of approved and investigational pipeline candidates. The immuno-oncology alliance will also combine resources and expertise to advance Pfizer’s anti-PD-1 antibody, and collaborate on up to 20 high priority immuno-oncology clinical development programs, including combination trials, several of which are expected to commence in 2015. Early data demonstrates advances in the understanding of avelumab as an investigational immuno-oncology therapy across multiple tumor types.
EMD Serono and Pfizer jointly presented multiple studies evaluating the preliminary safety and efficacy of avelumab at the 2015 American Society of Clinical Oncology (ASCO) annual meeting held at Chicago May 29 – June 2 — the first presentations pertaining to the drug candidate at a major global medical meeting since the alliance’s formation last fall, and the first time the two partners will be presenting data on avelumab as an alliance.
“Immuno-oncology continues to be an exciting area of clinical investigation, and we are eager to share the latest early data for avelumab at ASCO,” said Dr. Luciano Rossetti, Global Head of Research and Development for EMD Serono’s biopharmaceuticals business. “Our ovarian data represent the largest reported dataset of patients with recurrent ovarian cancer treated with an anti-PD-L1 therapy, underscoring our commitment as an alliance to bring new therapies in difficult-to-treat tumor types.” The Avelumab presentations at ASCO brought attendees up to date on the latest clinical updates available across various tumor types, including an oral presentation on ovarian cancer and posters on gastric cancer, non-small cell lung cancer (NSCLC) and several other studies in a range of patient populations.
“The field of immuno-oncology offers a vast opportunity for the development of new therapies that have the potential to change the way cancer is treated, and we believe the combined assets of our alliance allow us to further the science in this space,” observes Dr. Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology, adding, “By leveraging the combined strengths of our two companies in oncology, we will advance the clinical trial program for avelumab, further the understanding of anti-PD-L1 in the treatment of cancer, and look to bring treatments to market that have the potential to improve the lives of people with cancer.”
The clinical trial program for avelumab, JAVELIN, is an expansive international clinical trial program exploring the use of PD-L1 inhibition with avelumab to treat multiple types of cancer. The JAVELIN program includes an international Phase III trial to investigate avelumab in patients with non-small cell lung cancer; an international Phase II trial to investigate avelumab in patients with metastatic Merkel cell carcinoma; an international Phase I trial to investigate avelumab in patients with metastatic or locally advanced solid tumors; and a Phase I trial to investigate avelumab in Japanese patients with metastatic or locally advanced solid tumors with an expansion part in Asian patients with gastric cancer.
The Phase I program for avelumab includes more than 840 patients treated across multiple tumor types, including NSCLC, breast cancer, gastric cancer, ovarian cancer, bladder cancer, melanoma and mesothelioma. For more information about the EMD Serono/Pfizer oncology clinical trials, visit:
Strategic Immuno-oncology Collaboration With MorphoSys To Develop Therapeutic Antibodies Against Checkpoint Inhibitors
EMD Serono has also entered into a strategic immuno-oncology collaboration with German biotechnology company MorphoSys to discover and develop therapeutic antibodies against immune checkpoints. Under the terms of the agreement, the two companies will join forces to develop therapies that modulate the immune system’s natural ability to fight tumors. MorphoSys will apply its proprietary Ylanthia antibody phage library and technology platform — a fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties — to identify antibodies against targets of interest. With its strong portfolio and capabilities in the field of immuno-oncology and clinical development, EMD Serono will be fully responsible for execution of development from Phase I onwards.
Strategic Collaboration With Intrexon To Develop And Commercialize CAR-T Cancer Therapies
EMD Serono has additionally announced an exclusive strategic collaboration and license agreement with Intrexon to develop and commercialize Chimeric Antigen Receptor T-cell (CAR-T) cancer therapies, thereby advancing their comprehensive, science-driven strategy to develop innovative therapies that modulate the immune system’s natural ability to fight tumors.
Researchers at EMD Serono’s U.S. biopharmaceutical division believe that the combination of therapies targeting different tumor escape mechanisms can change the way physicians treat a complex disease such as cancer in the future. Their comprehensive, science-driven strategy has been embodied in three focused areas of research called innovation clusters: 1) therapeutic cancer vaccines (also called antigen-specific cancer immunotherapy) 2) cancer stem cells, and 3) tumor immunotolerance.
Therapeutic Cancer Vaccines
Therapeutic cancer vaccines seek to stimulate a specific immune response against a tumor and generate immunological memory to keep the tumor in check. Development of cancer vaccines involves first identifying tumor-associated antigens that are capable of generating anti-tumor immune responses and then formulating these antigens into investigational agents for clinical testing against the tumors.
Cancer Stem Cells
Cancer stem cells represent a rare population of tumor cells required for perpetuating tumor growth. These stem cells can migrate from a primary tumor into the blood stream and travel throughout the body, resulting in the formation of tumor metastases at distant sites. Cancer stem cells are thought to be a cause of disease recurrence due to their inherent drug-resistance and ability to lie dormant for long periods of time.
EMD Serono is targeting specific mechanisms of tumor immune suppression for therapeutic intervention. These therapies are designed to attempt to eliminate or circumvent inhibitory mechanisms in the immune system. Tumors develop diverse mechanisms that allow them to stay unrecognized by natural immune surveillance and escape elimination by the immune system. As a consequence, tumors grow and metastasize unconstrained. By modulating these immunosuppressive mechanisms, the tumor immune environment can be shifted from an immune tolerant state toward an immune activated state and the immune system may be redirected to eliminate the cancer cells. Exploring mechanisms of tumor inflammation is another core component of this innovation cluster. The inflammatory signals present in a tumor directly influence the composition of the immune cell infiltrate, the way the immune cells interact with each other and with tumor cells, and the milieu of soluble factors that influence tumor growth, invasion and immunosuppression.
NHS-IL12 (also known as MSB0010360) is another investigational cancer immunotherapy (immunocytokine) — designed to target interleukin-12 to necrotic regions found in solid tumors.
EMD Serono and Dynavax Announce New Collaboration Investigating the Combination of Immuno-Oncology Therapies
Yet another EMD Serono Immuno-Oncology alliance, announced on June 1st, is with Dynavax Technologies Corporation — a clinical-stage biopharmaceutical company with cutting edge immunotherapies based on Toll-Like Receptor (TLR) biology and its ability to modulate the immune system. Dynavax’s lead cancer immunotherapy product candidate is SD-101, a proprietary, second-generation, TLR9 agonist CpG-C class oligodeoxynucleotide designed specifically for cancer and capable of maximal type 1 IFN induction and efficient maturation of plasmacytoid dendritic cells (PDC) to antigen-presenting cells.
SD-101 activates multiple anti-tumor activities of innate immune cells and activates plasmacytoid dendritic cells to stimulate T cells specific for antigens released from dying tumor cells. TLR9 agonists such as SD-101 enhance T and B cell responses and provide potent Type 1 interferon induction and maturation of plasmacytoid dendritic cells to antigen-presenting cells. SD-101 is being evaluated in several Phase 1/2 oncology studies to assess its preliminary safety and activity.
The company’s approach provides multiple mechanisms for attacking the tumors along with developing immune memory associated with antigens found in the tumor.
The EMD Serono/Dynavax alliance partners have entered into two clinical trial collaboration agreements to investigate potential synergistic effects of combining immunotherapies from both companies’ pipelines: Dynavax’s investigational SD-101, and EMD Serono’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab), a humanized monoclonal antibody that blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
The companies’ collaborative efforts will include the first in-human trial for EMD Serono’s investigational anti-interleukin-10 (anti-IL-10) immunomodulator, MK-1966 which blocks IL-10 activity known to down modulate the immune activation that is needed to kill tumor cells in the tumor microenvironment. These effects include a decrease in cytokine production, up-regulation of T regulatory cell activity and down-regulation of antigen-presenting cell activity. Based on preclinical data, co-administration of an anti-IL-10 with a TLR9 agonist may provide clinical benefit in the treatment of certain cancers.
“The collaboration with Dynavax is rooted in EMD Serono’s commitment to advancing breakthrough science in the field of immuno-oncology in order to address the complex interplay between the immune system and cancer,” says Dr. Eric Rubin, vice president and therapeutic area head, oncology early stage development at EMD Serono Research Laboratories. “We are pleased that this latest collaboration not only investigates the potential of KEYTRUDA as a combination therapy, but also includes our new immunomodulator candidate, MK-1966.”
“Our interest in working with EMD Serono on these clinical collaborations was propelled by the synergistic activity we have seen when SD-101 is combined with checkpoint inhibitors in preclinical models,” observes Eddie Gray, chief executive officer of Dynavax. These collaborations with EMD Serono will facilitate our objective to demonstrate SD-101s potential to complement multiple therapeutic modalities and thereby provide benefit to patients.
American Society of Clinical Oncology (ASCO)
Dynavax Technologies Corporation