On January 11, 2017 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported that it has entered into a licensing agreement with Merck KGaA, Darmstadt, Germany for the worldwide development and commercialization of four promising research and development programs that represent novel approaches to the treatment of cancer (Press release, Vertex Pharmaceuticals, JAN 11, 2017, View Source [SID1234517357]). As part of the agreement, Merck KGaA, Darmstadt, Germany will license two clinical-stage programs targeting DNA damage and repair, along with two additional novel pre-clinical programs. Vertex will receive an upfront payment of $230 million, in addition to royalties on future net sales. Merck KGaA, Darmstadt, Germany will assume full responsibility for the development and commercialization of all the programs.

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"The Vertex R&D team has produced a portfolio of first-in-class compounds with the potential to enhance the therapy of multiple cancers," said Jeffrey Leiden, M.D., Ph.D, Chairman, President and CEO of Vertex. "We are pleased to partner with Merck KGaA, Darmstadt, Germany, a leader in oncology with exciting complementary assets that will help fully realize the value of these unique compounds and accelerate the programs’ potential benefits for patients."

"With this strategic deal, we significantly strengthen our oncology pipeline in two attractive areas where we have leading competence, DNA damage and repair and immuno-oncology – areas which also have promising therapeutic synergy," said Belen Garijo, CEO Healthcare and Member of the Executive Board of Merck KGaA, Darmstadt, Germany. "This deal underscores our commitment to accelerate innovation for cancer patients, and we are excited for the opportunity to build on Vertex’s rigorous science and advance these leading programs."

The two clinical-stage programs represent first-in-class approaches to inhibit the DNA repair pathways that are fundamental to the survival and proliferation of certain cancers:

An ataxia telangiectasia and Rad3 related (ATR) protein kinase inhibitor program comprised of two compounds, VX-970 and VX-803. VX-970 is being investigated broadly through 10 ongoing Phase 1 and Phase 2 trials across a variety of tumors and patient subtypes expected to be responsive to ATR inhibition based on biomarker data. Preliminary VX-970 clinical data were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. VX-803 is an orally dosed ATR inhibitor currently in Phase 1 trials evaluating escalating doses of VX-803 alone and in combination with chemotherapy.
A DNA-dependent protein kinase (DNA-PK) inhibitor program including the clinical candidate VX-984. A Phase 1 trial is now evaluating escalating doses of VX-984 alone and in combination with pegylated liposomal doxorubicin in subjects with advanced solid tumors. Merck KGaA, Darmstadt, Germany will combine these assets with its existing DNA-PK assets into a single development program.
The pre-clinical programs include one immuno-oncology program against an attractive target with first-in-class potential, and a program against a completely novel target. For both of these programs, Vertex research has demonstrated efficacy in relevant pre-clinical models, including demonstration of combination potential with immune checkpoint inhibition for the immuno-oncology program. Merck KGaA, Darmstadt, Germany will continue to characterize the Vertex compounds in these programs with the goal of taking them forward into the clinic.

The strength of the oncology R&D program at Merck KGaA, Darmstadt, Germany, including a leading presence in immunotherapy and DNA damage and repair, demonstrates how the company is re-imagining the way cancer can be treated.

The collaboration, and the related $230 million upfront payment, is subject to the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act.

On January 11, 2017 PIQUR Therapeutics AG, a Swiss clinical-stage pharmaceutical company, and Pierre Fabre, the second largest private French pharmaceutical group reported that they have signed a collaboration agreement for the development of PIQUR’s lead compound PQR309 in dermato-oncology (Press release, PIQUR Therapeutics, JAN 11, 2017, View Source [SID1234517355]). The exclusive deal will see PIQUR and Pierre Fabre’s R&D teams work together on the evaluation and development of dermatological formulations of PI3K/mTOR inhibitors across multiple therapeutic indications.

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Following the first stage of the collaboration, Pierre Fabre will have the option to enter into exclusive negotiations to license global rights for the program in selected skin cancer conditions. Terms and conditions of the collaboration were undisclosed.

Pierre Fabre is strategically positioned in both oncology and dermatology from discovery all the way through commercialization with multiple products at various stages of development and already launched on the market.

"The collaboration with Pierre Fabre, a worldwide leader in dermatology is an important milestone for PIQUR, validating its potential to bring novel solutions to patients for the treatment of dermato-oncology diseases with unmet medical needs," said Hervé Girsault, Chief Business Officer of PIQUR.

"We are looking forward to working with PIQUR as part of our commitment to external innovation. This collaboration with PIQUR marks an additional milestone in our partnering strategy. Combining our capabilities will accelerate the drug discovery process and bringing forward transformative therapies for patients." said Laurent Audoly, Head of Research & Development at Pierre Fabre Pharmaceuticals.

On January 11, 2017 Affimed N.V. (Nasdaq: AFMD), a clinical stage biopharmaceutical company focused on discovering and developing highly targeted cancer immunotherapies, reported an update on its NK-cell engager platform (Press release, Affimed, JAN 11, 2017, View Source [SID1234517347]).

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"In 2016, we have significantly expanded our activities to optimize the elimination of malignant cells through NK-cell engagement, namely advancing our Phase 1b clinical trial of AFM13 in combination with Merck’s Keytruda and broadening our approach to include the combination of our NK-cell engagers with adoptive transfer of activated NK-cells developed at MD Anderson," said Adi Hoess, Ph.D., CEO of Affimed.

"We further progressed our preclinical NK-cell engager pipeline with our EGFR-targeting solid tumor candidate AFM24 and BCMA-targeting multiple myeloma candidate AFM26," added Martin Treder, Ph.D., CSO of Affimed. "Due to their high affinity and specificity to CD16A, our molecules offer a novel mechanism of action for NK-cell and macrophage engagement and avoid competition by high IgG serum levels, which currently limits the efficacy of monoclonal antibody-based treatments. In addition, we have gathered important insights into NK-cell biology in various preclinical studies which will allow us to explore further treatment options, for example combining our NK-cell engagers with cytokines such as IL-15 or IL-2."

Leadership position in activating innate and adaptive immunity through engaging NK-cells and macrophages

Focusing its efforts on antibodies specifically binding NK-cells through CD16A, a dominant activating receptor on innate immune cells, Affimed has built a clinical and preclinical pipeline of NK-cell-engaging bispecific antibodies (TandAbs) designed to activate both innate and adaptive immunity. Compared to a variety of T-cell-engaging technologies, Affimed’s NK-cell engagers appear to have a better safety profile and have the potential to achieve more potent and deeper immune responses through enhancing crosstalk of innate to adaptive immunity. Building on its leadership in the NK-cell space, Affimed is also developing tetravalent, bispecific alternative antibody formats (AAFs) for NK-cell engagement offering varying PK/PD profiles relevant to certain diseases.

Product candidate AFM13: The most advanced NK-cell engager in clinical development

The Company’s lead product candidate, AFM13 targeting CD16A on NK-cells and CD30 on tumor cells, is the most advanced NK-cell engager in the clinic. Its development is focused on combination therapy and supported by The Leukemia & Lymphoma Society (LLS).

AFM13 is differentiated from monoclonal antibodies as it displays a 1000-fold higher binding affinity to CD16A, shows very limited competition for NK-cell binding with circulating IgG, as well as higher potency compared to full-length CD30 antibodies. Safety and clinical/pharmacodynamic activity in heavily pretreated Hodgkin lymphoma (HL) patients was established in a Phase 1 study and based on its favorable safety profile and preclinical data, AFM13 is currently under investigation as a combination therapy.

NK-cell engagers in combination therapy

Combination therapies have demonstrated improved outcomes for cancer patients and are widely pursued to maximize efficacy of immunotherapeutic approaches. Further broadening the therapeutic opportunities for its NK-cell engagers, Affimed is investigating AFM13 in several combination therapies.

It is becoming increasingly clear that modulation of immune effectors or the immunosuppressive environment result in higher overall response rates and extended durability of response. In vivo studies in a patient-derived xenograft (PDX) model have shown that combining AFM13 with checkpoint inhibitors leads to synergistic efficacy of AFM13 when combined with anti-PD-1, likely attributable to the combination of both agents inducing crosstalk between innate and adaptive immunity. Consequently, AFM13 is being investigated with Merck’s anti-PD1 antibody Keytruda in a Phase 1b clinical trial.

Currently in early clinical development in a number of hematological malignancies, the adoptive transfer of activated NK-cells provides a strong combination rationale with Affimed’s NK-cell platform to better exploit the therapeutic power of NK-cells. For this, the Company has entered into an exclusive strategic clinical development and commercialization collaboration with MD Anderson Cancer Center (MDACC), in which Affimed intends to investigate AFM13 preclinically and clinically in combination with MDACC’s proprietary NK-cell product in HL. Beyond HL, this approach has potential applications in further medically underserved indications such as multiple myeloma or acute myeloid leukemia.

Cytokines such as IL-2 or IL-15 boost NK-cell activity and are tested clinically in a variety of cancers. In recent preclinical studies, Affimed demonstrated that AFM13 induced the upregulation of specific interleukin receptors on NK-cells and the subsequent addition of IL-2 or IL-15 had a synergistic effect on AFM13-mediated NK-cell expansion. Hence, the combination of NK-cell engagers with such cytokines may be clinically useful to deepen responses.

Ongoing Clinical Studies

AFM13 in combination with Merck’s PD-1 inhibitor Keytruda

Affimed is developing AFM13 in combination with the anti-PD-1 antibody Keytruda (pembrolizumab) in relapsed/refractory HL in collaboration with Merck, with Affimed being the study’s sole sponsor and Merck supplying Affimed with Keytruda for the trial. The Company has initiated a Phase 1b dose-escalation combination study and safety was determined in the first dose cohort, in which three patients were treated with Keytruda at active dose and AFM13 at 0.5 mg/kg, a level below its active dose when used as single agent. At restaging after 3 months, 2 out of 3 patients had a partial response, which is in line with expectations. With the second dose cohort now fully recruited, Affimed anticipates to provide a further update on the study in the first half of 2017.

AFM13 Phase 2a monotherapy in HL

In Affimed’s investigator-sponsored Phase 2a monotherapy of AFM13 in HL, the Company and the study’s sponsor, the German Hodgkin Study Group (GHSG), have revised the overall study design in order to adapt to the changing treatment landscape, namely the earlier availability of anti PD-1 antibodies. The study will now include HL patients relapsed or refractory to treatment with both brentuximab vedotin (Adcetris) and anti-PD-1. The study is expected to begin recruiting under the new study design in the first quarter of 2017 and Affimed anticipates providing an update on the study in the second half of 2017.

Preclinical Product Candidates

AFM24 and AFM24+ (targeting EGFR/CD16A)

Affimed is developing its first-in-class NK-cell engager AFM24 to address the critical unmet need to effectively treat epidermal growth factor receptor (EGFR)-expressing solid tumors such as lung, head & neck and colon cancers,. The molecule has been shown to be well differentiated from other EGFR-targeting therapies such as cetuximab through its more potent cytotoxic activity in vitro and in vivo and being able to kill tumor cells when they express mutated proto-oncogene RAS, a negative predictive biomarker for EGFR-targeting monoclonal antibodies. In contrast to cetuximab, AFM24 shows very limited competition of NK-cell-binding by circulating IgG. Together with the synergy shown for combining an NK-cell engager (AFM13) and an anti-PD1 antibody in in vivo models, the recent approval of anti-PD-1/anti-PD-L1 antibodies in non-small lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN), offer a therapeutic rationale for a combination with AFM24 in these indications. IND-enabling toxicology studies for AFM24 are progressing. AFM24+, which is based on AFMD’s newly developed AAFs, is a tetravalent bispecific antibody offering a different PK/PD profile. Affimed expects to provide a further update on these programs in the first half of 2017.

AFM26 and AFM26+ (targeting BCMA/CD16A)

Multiple myeloma (MM) is characterized by very high serum levels of M-protein, clonal immunoglobulins produced in excess by malignant plasma cells in patients. M-protein strongly impairs ADCC of conventional monoclonal antibodies and MM patients currently suffer from very high relapse rates, leaving the need for improved and durable therapies. Affimed is developing AFM26, a TandAb targeting B-cell maturation antigen (BCMA), a validated target in MM. AFM26-mediated NK-cell-binding has been shown to be largely unaffected by circulating IgG, indicating the potential for NK-cell activation in the presence of M-protein, thus introducing a novel mechanism of action. Comparable to other NK-cell engagers AFM26 is characterized by its high affinity to tumor cells and NK-cells, prolonged cell retention time, as well as high in vitro potency towards BCMA-expressing myeloma cell lines. AFM26+, which is based on AFMD’s newly developed AAFs, is a tetravalent bispecific antibody with a different PK/PD profile. Affimed expects to provide a first update on these programs in the first half of 2017.

On January 11, 2017 Mylan N.V. (NASDAQ, TASE: MYL) and Biocon Ltd. (BSE code: 532523, NSE: BIOCON) reported that the U.S. Food and Drug Administration (FDA) has accepted Mylan’s biologics license application (BLA) for MYL-1401O, a proposed biosimilar trastuzumab, for filing through the 351(k) pathway (Press release, Mylan, JAN 11, 2017, View Source [SID1234517346]). This product is a proposed biosimilar to branded trastuzumab, which is indicated to treat certain HER2-positive breast cancers. The anticipated FDA goal date set under the Biosimilar User Fee Act (BsUFA) is Sept. 3, 2017.

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Mylan President Rajiv Malik commented: "The FDA acceptance of our BLA for proposed biosimilar trastuzumab marks an important step toward increasing access to this treatment option for patients in the U.S. We believe that our comprehensive package of analytical similarity, non-clinical and clinical data submitted with the BLA will demonstrate similarity of the proposed biosimilar trastuzumab to the reference product. We are committed to bringing this product to market and look forward to working with FDA over the next months. This is Mylan and Biocon’s first U.S. regulatory submission through the 351(k) pathway and reinforces the strength of our collaboration to increase access to a broad portfolio of high-quality, affordable biosimilars worldwide."

Dr. Arun Chandavarkar, CEO and Joint Managing Director, Biocon, said: "We are delighted by the FDA’s acceptance of the BLA for our proposed biosimilar trastuzumab. It is a major milestone for the Mylan and Biocon collaboration since it is the first U.S. regulatory submission through our joint global biosimilars program. This development positions Biocon and Mylan among the first companies to be able to address the critical need of U.S. patients for a high-quality biosimilar to treat certain HER2-positive breast cancers in the near future."

Mylan and Biocon’s proposed biosimilar trastuzumab is also under review by the European Medicines Agency (EMA).

Worldwide, nearly 2 million women are diagnosed with breast cancer each year, making it the second most common cancer in the world. HER2-positive metastatic breast cancer is an aggressive form of breast cancer that tests positive for the human epidermal growth factor receptor 2 (HER2), which promotes cancer cell growth. Approximately 20% to 30% of primary breast cancers are HER2-positive.

About the Biocon and Mylan Partnership

Mylan and Biocon are exclusive partners on a broad portfolio of biosimilar and insulin products. The proposed biosimilar trastuzumab is one of the six biologic products co-developed by Mylan and Biocon for the global marketplace. Mylan has exclusive commercialization rights for the proposed biosimilar trastuzumab in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.