Affimed N.V. (AFMD) is a clinical-stage biopharmaceutical company focused on discovering and developing highly targeted cancer immunotherapies. Its product candidates are being developed in the field of immuno-oncology, which represents an innovative approach to cancer treatment that seeks to harness the body’s own immune defenses to fight tumor cells. The most potent cells of the human defense arsenal are types of white blood cells called Natural Killer cells, or NK-cells, and T-cells. Its proprietary, next-generation bispecific antibodies, which it call TandAbs because of their tandem antibody structure, are designed to direct and establish a bridge between either NK-cells or T-cells and cancer cells. The company TandAbs have the ability to bring NK-cells or T-cells into proximity and trigger a signal cascade that leads to the destruction of cancer cells. Due to their novel tetravalent architecture (which provides for four binding domains), its TandAbs bind to their targets with high affinity and have half-lives that allow regular intravenous administration, with different dosing schemes being explored to allow for improved exposure in heavily pretreated patient populations. The company believe, based on their mechanism of action and the preclinical and clinical data it have generated to date, that its product candidates, alone or in combination, may ultimately improve response rates, clinical outcomes and survival in cancer patients and could eventually become a cornerstone of modern targeted oncology care.

Affimed was founded in 2000 based on technology developed by the group led by Professor Melvyn Little at Deutsches Krebsforschungszentrum, the German Cancer Research Center, or DKFZ, in Heidelberg.

Focusing its efforts on antibodies specifically binding NK-cells through CD16A, a dominant activating receptor on innate immune cells, The company have built a clinical and preclinical pipeline of NK-cell-engaging bispecific antibodies designed to activate both innate and adaptive immunity. Compared to a variety of T-cell-engaging technologies, its 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. Their safety profiles also make its molecules suitable for development as combination therapies (e.g. with checkpoint inhibitors, or CPIs, or adoptive NK-cells). Building on its leadership in the NK-cell space, The company are also developing tetravalent, bispecific alternative antibody formats (AAFs) for NK-cell engagement offering varying PK/PD profiles relevant to certain diseases.

As of today, The company has focused its research and development efforts on four proprietary programs for which The company retain global commercial rights. Because its TandAbs bind with receptors that are known to be present on a number of types of cancer cells, each of its TandAb product candidates could be developed for the treatment of several different cancers. The company intend to initially develop its two clinical stage product candidates in orphan or high-medical need indications, including as a salvage therapy for patients who have relapsed after, or are refractory to, that is who do not respond to treatment with, standard therapies, which The company refer to as relapsed/refractory. These patients have a limited life expectancy and few therapeutic options. The company believes this strategy will allow for a faster path to approval and will likely require smaller clinical studies compared to indications with more therapeutic options and larger patient populations. The company believes such specialized market segments in oncology can be effectively targeted with a small and dedicated marketing and sales team. The company currently intend to establish a commercial sales force in the United States and/or Europe to commercialize its product candidates when and if they are approved.

The company also see an opportunity in the clinical development of its TandAbs in combination with other agents that harness the immune system to fight cancer cells, such as CPIs. Such combinations of cancer immunotherapies may ultimately prove beneficial for larger patient populations in earlier stages of diseases, beyond the relapsed/refractory disease setting.

Affimed N.V. offices and laboratories are located at the Technology Park adjacent to the DKFZ in Heidelberg, where the company employ 53 personnel, approximately 70% of whom have an advanced academic degree. Including AbCheck and Affimed Inc. personnel, its total headcount is 83 (74 full time equivalents). The company is led by experienced executives with a track record of successful product development, approvals and launches, specifically of biologics. Its supervisory board includes highly experienced experts from the pharmaceutical and biotech industries, with a specific background in hematology.

In 2009, The company formed AbCheck, its 100% owned, independently run antibody screening platform company, located in the Czech Republic. AbCheck is devoted to the generation and optimization of fully human antibodies. Its technologies include a combined phage and yeast display antibody library and a proprietary algorithm to optimize affinity, stability and manufacturing efficiency. AbCheck also uses a super human library as well as their newly developed mass humanization technology to discover and optimize high-quality human antibodies. In addition to providing candidates for Affimed projects, AbCheck is recognized for its expertise in antibody discovery throughout the United States and Europe and has been working with globally active pharmaceutical companies such as Eli Lilly, Daiichi Sankyo, Pierre Fabre and others.

Business Strategy

  • Affimed N.V. goal is to engineer targeted immunotherapies, seeking to cure patients by harnessing the power of innate and adaptive immunity (NK- and T-cells). The company are developing single and combination therapies to treat cancers and other life-threatening diseases. For this, The company has developed an entirely novel antibody platform that delivers different types of next-generation antibodies, bispecific and trispecific Abs, as well as tetravalent, bispecific alternative antibody formats (AAFs). Based on the unique properties and mechanism of action of these products and supported by the preclinical and clinical data the company has generated to date, The company believe that its product candidates, alone or in combination, may ultimately improve clinical outcomes in cancer patients and could eventually become a key element of modern targeted oncology care. Key elements of its strategy to achieve this goal are to:
  • Rapidly Advance the Development of its Clinical Stage Product Candidates, including Combinations with Other Immunotherapies. Its product development strategy initially targets relapsed or refractory cancer patients who have limited therapeutic alternatives, which it believe will enable it to utilize an expedited regulatory approval process. In the second quarter of 2015, a phase 2a proof of concept study of AFM13 as a monotherapy was initiated by the German Hodgkin Study Group (GHSG) in HL patients that have received all standard therapies and have relapsed after or are refractory to Adcetris. Due to delays in opening study sites and the availability of anti-PD-1 antibodies for the treatment of relapsed/refractory HL patients, The company has experienced slower recruitment into the study than anticipated. The company has worked with GHSG to revise the overall study design in order to adapt to the changing treatment landscape, namely the 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 antibodies. Different dosing protocols of AFM13 are being explored to allow for improved exposure in more heavily pretreated patient populations. The study is expected to begin recruiting under the new study design in the first half of 2017 and it anticipate providing an update on the study in the second half of 2017. The company are also planning a clinical study of AFM13 in patients with CD30+ lymphoma. In addition, The company has expanded its development strategy to combination therapies. In the first half of 2016 the company initiated a phase 1b clinical study to investigate AFM13 in combination with pembrolizumab (Keytruda) in HL patients that have relapsed after or are refractory to chemotherapy and Adcetris. The study is ongoing and has recently completed recruitment into the third dose cohort. The company intend to provide an update on the study in the second half of 2017. For AFM11, The company has initiated a phase 1 dose ranging study of AFM11 designed to evaluate safety and tolerability and to potentially assess anti-tumor activity after four weeks of therapy in NHL patients. The amended study protocol was approved by the applicable regulatory authorities in the third quarter of 2015. The company has opened new study sites to expedite recruitment into the study. A phase 1 dose-finding clinical study of AFM11 in patients with acute lymphocytic leukemia, or ALL, commenced in the third quarter of 2016 and is enrolling. The company anticipate providing a progress update on both studies in the first half of 2017.
  • Establish R&D and Commercialization Capabilities in Europe and in the United States While it plan to retain rights for its product candidates, in the future it may enter into additional collaborations that provide value for its shareholders. The company intend to build a focused marketing and specialty sales team in Europe and in the United States to commercialize any of its product candidates that receive regulatory approval. The company has established a U.S. presence in order to expand its access to the U.S. talent pool, to maintain a close relationship to the financial and pharmaceutical community and to continuously measure and adapt to its strategic position in the competitive landscape.
  • Use its Technology Platforms and Intellectual Property Portfolio to Continue to Build its Cancer Immunotherapy Pipeline. The company generate its product candidates from its proprietary antibody engineering technology platforms consisting of NK-cell TandAbs, T-cell TandAbs, trispecific Abs and AAFs. The company plan to continue to leverage these technologies to develop new pipeline product candidates. The company believe it can utilize its platforms to address additional targets that it may in-license in the future or identify internally. The company intend to continue to innovate in its field and create additional layers of intellectual property in order to enhance the platform value and extend the life cycle of its products. The company believe its strong intellectual property position can be used to support internal development as well as out-licensing and collaboration opportunities.
  • Maximize the Value of its Collaboration Arrangements with LLS, Merck and MD Anderson. The company has a research agreement with LLS under which LLS has committed to co-fund the development of AFM13, with the focus having been shifted towards combination therapy in June 2016 due to the recent changes within the rapidly evolving cancer immunotherapy treatment landscape. The company believe that this collaboration will also allow it to expedite patient enrollment for future studies by leveraging the LLS’s existing relationships with key U.S. investigators. In January 2016, The company entered into a clinical research collaboration with Merck & Co to investigate the combination of Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab), with AFM13 for the treatment of patients with relapsed/refractory HL. In January 2017, The company entered into a clinical development and commercialization collaboration with The University of Texas MD Anderson Cancer Center, or MD Anderson, to evaluate AFM13 in combination with MD Anderson’s NK-cell product. MD Anderson will be responsible for conducting preclinical research activities aimed at investigating its NK-cells derived from umbilical cord blood in combination with AFM13, which are intended to be followed by a phase 1 study. The company will fund research and development expenses for this collaboration and hold an option to exclusive worldwide rights to develop and commercialize any product developed under the collaboration. The company believe that these collaborations help to validate and more rapidly advance its discovery efforts, technology platforms and product candidates, and will enable it to leverage its platforms through additional high-value partnerships. As part of its business development strategy, The company aim to enter into additional research collaborations in order to derive further value from its platforms and more fully exploit their potential.
  • Intensify its Collaboration with Academia. The company has entered into multiple collaborations with academic partners including the German Hodgkin Study Group, the Mayo Clinic, the Columbia University, MD Anderson Cancer Center, as well as the German Cancer Research Center (DKFZ). The company finalized the establishment of a Scientific Advisory Board in 2015. The company will continue to engage with key experts in its areas of interest with activities.
  • Utilize AbCheck to Generate and Optimize Antibodies. The company formed AbCheck in 2009 to leverage its antibody screening platform and partner with other biopharmaceutical companies in fee-for-service engagements. The company use AbCheck’s state-of-the-art phage and yeast display screening technologies as well as a proprietary batch humanization process and bioinformatics tools to identify and optimize antibodies that are highly specific for the targets ihe company or its customers select, and that The company engineer into TandAbs, trispecific Abs or AAFs. AbCheck’s high-quality capabilities have been validated through multiple international collaborations including a clinical research partnership with globally active pharmaceutical companies, as well as a strategic research partnership with Pierre Fabre.

Strengths

The company believe to be a leader in developing cancer immunotherapies due to several factors:

  • Affimed N.V.'s Business Lead Product Candidate, AFM13, is a First-in-Class NK-Cell Mediated Cancer Immunotherapy. AFM13 is a targeted immunotherapy that is currently in development for HL as a salvage therapy. To engage and activate NK-cells, The company has engineered AFM13 with a unique binding specificity for CD16A. AFM13 binds to CD16A with approximately 1,000-fold higher affinity than native antibody molecules via the constant region. While native antibodies bind to CD16A and CD16B with similar affinity, AFM13 does not bind to CD16B at all. CD16B is expressed on the surface of neutrophils, which show very limited anti-tumor activity and exist in such large amounts that little would be left for NK-cell binding and tumor cell killing were AFM13 not to be so selective for only CD16A. The company believe that AFM13 is the only antibody in development that can specifically engage CD16A+ cells, in particular NK-cells, with very high affinity. In the second quarter of 2015, a phase 2a proof of concept study of AFM13 was initiated by the German Hodgkin Study Group (GHSG) in HL patients that have received all standard therapies and have relapsed after or are refractory to Adcetris. The Leukemia and Lymphoma Society, or LLS, has agreed to co-fund a portion of the development of AFM13. In addition, it is planning a clinical study of AFM13 in patients with CD30+ lymphoma. The company initiated a clinical phase 1b study investigating the combination of AFM13 with Merck’s Keytruda (pembrolizumab) in patients with relapsed/refractory HL in the first half of 2016. The study is designed to establish a dosing regimen for the combination therapy and assess its safety and efficacy. The company has also entered into a clinical development and commercialization collaboration with MD Anderson to evaluate AFM13 in combination with MD Anderson’s NK-cell product.
  • Business T-cell-engaging Lead Product Candidate, AFM11. By leveraging its technology platform, The company has built a growing pipeline of additional product candidates. Its second product candidate, AFM11, has demonstrated in preclinical studies highly specific and effective engagement of T-cells, inducing rapid and potent in vitro and in vivo tumor cell killing. Although the PK of TandAbs is longer as compared to Amgen’s BiTEs such as Blincyto, The company is exploring different dosing regimens in its clinical studies to address specific features relating to T-cell engagement, which may require longer infusion times. The company has initiated a phase 1 dose ranging study of AFM11 designed to evaluate safety and tolerability and to potentially assess anti-tumor activity after four weeks of therapy in NHL patients. The amended study protocol was approved by the applicable regulatory authorities in the third quarter of 2015. A phase 1 clinical study of AFM11 in patients with ALL commenced in the third quarter of 2016 and is enrolling. The company anticipate providing a progress update on both studies in the first half of 2017.
  • Growing Pipeline of Product Candidates Focused on Key Cancer Indications. A CD16A NK-cell TandAb, called AFM24, targeting EGFR-wild type, a validated solid tumor target has been engineered and characterized preclinically and expect to provide an update on the program in the first half of 2017. In addition, it is developing AFM26 preclinically, a CD16A NK-cell TandAb targeting another validated tumor target, B-cell maturation antigen (BCMA), in multiple myeloma.
  • Retained Global Commercial Rights for its Four Candidates in its Product Pipeline. Its four pipeline product candidates AFM13, AFM11, AFM24 and AFM26 are unencumbered. The company retain all options to derive value from its product candidates, including commercialization in all or select markets when and if they are approved. To maximize the value of its platform, it will continue to explore partnerships to support the development or commercialization of its programs in certain territories.
  • Experienced Management Team with Strong Track Record in the Development and Commercialization of New Medicines. Members of its management team have extensive experience in the biopharmaceutical industry, and key members of its team have played an important role in the development and commercialization of approved drugs. Its Chief Executive Officer Adi Hoess was a member of the team that developed and commercialized Firazyr®, while its Chief Operating Officer Jörg Windisch played a leading role in the development of Omnitrope®, Binocrit® and Zarzio®.
  • Strong Technology Base and Solid Patent Portfolio in the Field of Targeted Immuno-Oncology. The company is a leader in the field of bi-and trispecific antibody therapeutics for the treatment of cancer. The company has a patent portfolio that includes the tetravalent antibody platform itself. Further, The company has a proprietary position in NK-cell engagement, specifically regarding binding domains directed at CD16A with no cross-reactivity to CD16B. The company has more than a decade of experience in the discovery and development of such complex antibodies, and its molecular architecture allows for efficient and cost-effective manufacturing. In addition to supporting internal product development, The company believe its strong intellectual property position can be used to support out-licensing and collaboration opportunities in the field of immuno-oncology.

Research and development pipeline

Affimed N.V. is developing a pipeline of immune-cell engagers for the treatment of cancer as below:

The company's lead candidate, AFM13, is a first-in-class NK-cell TandAb designed for the treatment of certain CD30-positive (CD30+) B- and T-cell malignancies, including Hodgkin lymphoma, or HL. AFM13 selectively binds with CD30, a clinically validated target in HL patients, and CD16A, an integral membrane glycoprotein receptor expressed on the surface of NK-cells, triggering a signal cascade that leads to the destruction of tumor cells that carry CD30. In contrast to conventional full-length antibodies, AFM13 does not bind to CD16B, which prevents binding to other cells, e.g. neutrophils.

Affimed N.V. is initially developing AFM13 for HL in the salvage setting for patients who have relapsed after, or are refractory to, Adcetris (brentuximab vedotin), a CD30-targeted chemotherapy approved by the U.S. Food and Drug Administration, or FDA, in August 2011 as a salvage therapy for HL. Approximately half of the patients treated with Adcetris experience disease progression in less than half a year after initiation of therapy. In a recent phase 1 dose-escalation clinical study, AFM13 was well-tolerated and demonstrated tumor shrinkage or slowing of tumor growth, with disease control shown in 16 of 26 patients eligible for efficacy evaluation. AFM13 also stopped tumor growth in patients who are refractory to Adcetris. Six out of seven patients who became refractory to Adcetris as the immediate prior therapy experienced stabilization of disease under AFM13 treatment according to Cheson’s criteria, standard criteria for assessing treatment response in lymphoma. The company believe that based on its novel mode of action, AFM13 may be beneficial to patients who have relapsed or are refractory to treatment with Adcetris and may provide more durable clinical benefit.

In the second quarter of 2015, a phase 2a proof of concept study of AFM13 as a monotherapy was initiated by the German Hodgkin Study Group (GHSG) in HL patients that have received all standard therapies and have relapsed after or are refractory to Adcetris. The company has worked with GHSG to revise the overall study design in order to adapt to the changing treatment landscape, namely the 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 antibodies. Different dosing protocols of AFM13 are being explored to allow for improved exposure in more heavily pretreated patient populations. The study is expected to begin recruiting under the new study design in the first half of 2017 and The company anticipate providing an update on the study in the second half of 2017.

In order to prepare for further clinical development, The company performed preclinical studies investigating the combination of AFM13 with check-point modulators (CPM) with collaboration partners. The company believe that AFM13 and immunomodulators administered together could lead to greater tumor cell killing because these molecules may have a synergistic anti-tumor effect involving both NK-cells and T-cells. Based on the preclinical data, it entered into a collaboration with Merck and have initiated a clinical phase 1b study investigating the combination of AFM13 with Merck’s anti-PD-1 antibody Keytruda (pembrolizumab) in patients with relapsed/refractory HL in the first half of 2016. The study is ongoing and has recently completed recruitment into the third dose cohort. The company intend to provide an update on the study in the second half of 2017. The LLS has committed to co-fund the development of AFM13 with the focus having been shifted towards combination therapy in June 2016 following the greater focus of combination therapies in immunooncology. In addition, it is planning a clinical study of AFM13 in patients with CD30+ lymphoma. In January 2017, The company entered into a clinical development and commercialization collaboration with MD Anderson to evaluate AFM13 in combination with MD Anderson’s NK-cell product. MD Anderson will be responsible for conducting preclinical research activities aimed at investigating its NK-cells derived from umbilical cord blood in combination with AFM13, which are intended to be followed by a phase 1 study. The company will fund research and development expenses for this collaboration and hold an option to exclusive worldwide rights to develop and commercialize any product developed under the collaboration.

The company second clinical stage candidate, AFM11, is a T-cell TandAb designed for the treatment of certain CD19+ B-cell malignancies, including non-Hodgkin Lymphoma, or NHL and Acute Lymphocytic Leukemia, or ALL. AFM11 binds selectively with CD19, a clinically validated target in B-cell malignancies. It also binds to CD3, a component of the T-cell receptor complex, triggering a signal cascade that leads to the destruction of tumor cells that carry CD19. Based on its molecular characteristics, in particular its molecular weight, we expect AFM11 will have a longer half-life than blinatumomab, a bispecific antibody also targeted against CD19 and CD3 developed by Amgen, and approved in the United States and Europe. AFM11 has shown 100-fold higher affinity to CD3 resulting in up to 40-fold greater cytotoxic potency at low T-cell counts compared to blinatumomab. The company therefore believe it may have an efficacy advantage, especially in immunocompromised patients. Although the PK of TandAbs is longer as compared to Amgen’s BiTEs such as Blincyto, AFM11 might have a convenience advantage due to its half-life and we are exploring different dosing regimens in its clinical studies to address specific features relating to T-cell engagement, which may require longer infusion times. The company has initiated a phase 1 dose ranging study of AFM11 designed to evaluate safety and tolerability and to potentially assess anti-tumor activity after four weeks of therapy in NHL patients. The amended study protocol was approved by the applicable regulatory authorities in the third quarter of 2015. The company has opened new study sites to expedite recruitment into the study. A phase 1 dose-finding clinical study of AFM11 in patients with acute lymphocytic leukemia, or ALL, commenced in the third quarter of 2016 and is enrolling. The company anticipate providing a progress update on both studies in the first half of 2017.

The company is developing AFM24, an NK-cell-engaging bispecific antibody targeting EGFR-wild type, which represents another validated antigen expressed by a variety of solid tumors. Constitutive EGFR activation through amplification or dysregulation plays an important role in the pathophysiology of numerous solid cancers, such as colorectal cancer (CRC), non-small cell lung cancer (NSCLC) or squamous cell carcinomas of the head and neck (HNSCC). Based on the preclinical efficacy and safety data in cynomolgus monkey, the company expect to provide an update on the program in the first half of 2017. As planned, following the selection of AFM24 as a solid tumor candidate, it has deprioritized development of its preclinical solid tumor programs, AFM21 and AFM22, targeting Epidermal Growth Factor Receptor variant III, or EGFRvIII.

Amphivena’s product candidate, AMV564, is a CD33/CD3-specific T-cell TandAb. Amphivena plans to advance AMV564 into the clinic for the treatment of acute myeloid leukemia (AML) and other hematologic malignancies. In preclinical studies, AMV564, which was derived from its TandAb platform, has demonstrated potent and selective cytotoxic activity in AML patient samples as well as robust tumor growth inhibition and a complete elimination of leukemic blasts in xenograft models. The IND application for AMV564 was accepted in July 2016 and The company is continuing to support its future clinical development.

In addition, The company has been exploring trispecific Abs for various undisclosed targets which are currently at a discovery stage to be developed for indications such as multiple myeloma (MM), as well as tetravalent, bispecific alternative antibody formats (AAFs) for NK-cell engagement offering varying PK/PD profiles relevant to certain diseases.

Tags: US:AFMD
Created by Asif Farooqui on 2019/09/09 07:13
     
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