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.

On January 11, 2017 Eli Lilly and Company (NYSE: LLY) reported the expansion of an existing immuno-oncology collaboration with Merck, known as MSD outside the U.S. and Canada, through a subsidiary, to add a new study of Lilly’s LARTRUVO (olaratumab) with KEYTRUDA (pembrolizumab) in patients with previously treated advanced or metastatic soft tissue sarcoma (STS) (Press release, Eli Lilly, JAN 11, 2017, View Source [SID1234517345]).

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Notably, the U.S. Food and Drug Administration (FDA) recently granted accelerated approval for LARTRUVO (olaratumab injection, 10 mg/mL), in combination with doxorubicin, for the treatment of adults with STS with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. LARTRUVO (olaratumab injection, 10 mg/mL), in combination with doxorubicin, also recently received conditional marketing authorization from the European Medicines Agency for the treatment of adults with advanced STS not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin.

"We look forward to further expanding our collaboration with Merck to include this combination study focused on advanced soft tissue sarcoma, a rare and difficult-to-treat disease with limited treatment options," said Sue Mahony, Ph.D., senior vice president and president, Lilly Oncology. "This collaborative study builds on the exciting data we have seen with olaratumab and supports our focus on investigating the potential of rational combinations to enhance efficacy and change the standards of care for people with cancer."

"Historic and present day scientific advances continue to reinforce the role of combination therapies in extending the lives of people with cancer," said Eric Rubin, M.D., vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "Our collaboration with Lilly exemplifies our commitment to fully exploring combination regimens with KEYTRUDA to help arm physicians with the treatment tools they need to help their patients."

Lilly is the sponsor of the Phase 1 study and enrollment is expected to begin mid-2017. Financial details of the collaboration were not disclosed.

In addition to the study announced today, other ongoing trials between Lilly and Merck, through a subsidiary, include:

Studies of pemetrexed (plus carboplatin) and pembrolizumab in first-line nonsquamous non-small cell lung cancer (NSCLC), including a Phase 3 study that is currently enrolling patients;
A Phase 1 study examining the combination of ramucirumab with pembrolizumab in NSCLC, gastric cancer and bladder cancer;
A Phase 1 study examining the combination of necitumumab with pembrolizumab in NSCLC; and
A Phase 1 study examining the combination of abemaciclib, a CDK 4 and 6 inhibitor, with pembrolizumab. Based on the Phase 1 trial results, the collaboration has the potential to progress to Phase 2 trials in patients who have been diagnosed with either metastatic breast cancer or NSCLC.
Olaratumab (marketed under the brand name LARTRUVO) is a platelet-derived growth factor receptor alpha (PDGFR-α) blocking antibody that specifically binds PDGFR-α and prevents receptor activation. LARTRUVO exhibits in vitro and in vivo anti-tumor activity against selected sarcoma cell lines and disrupted the PDGFR-α signaling pathway in in vivo tumor implant models.

Pembrolizumab (marketed under the brand name KEYTRUDA) is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes, which may affect both tumor cells and healthy cells.

NOTES TO EDITORS

About Sarcomas

Sarcomas are a diverse and relatively rare type of cancer that usually develop in the connective tissue of the body, which include fat, blood vessels, nerves, bones, muscles, deep skin tissues and cartilage. Soft tissue sarcoma is a complex disease with multiple subtypes, making it very hard to diagnose and difficult to treat. For decades, there have been no front-line therapeutic advancements for STS that have improved overall survival. According to the American Cancer Society, in 2015, there were an estimated 12,000 new STS cases diagnosed and nearly 5,000 deaths in the U.S. alone.

INDICATION

LARTRUVO is indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

This indication is approved under Accelerated Approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

IMPORTANT SAFETY INFORMATION FOR LARTRUVO

Warnings and Precautions

Infusion-Related Reactions

Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade ≥3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest. Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication. Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR.
Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-α) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-α antibody to pregnant mice during organogenesis caused malformations and skeletal variations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose.
Most Common Adverse Reactions/Lab Abnormalities

The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%; 2% vs 3%), fatigue (69% vs 69%; 9% vs 3%), musculoskeletal pain (64% vs 25%; 8% vs 2%), mucositis (53% vs 35%; 3% vs 5%), alopecia (52% vs 40%; 0% vs 0%), vomiting (45% vs 19%; 0% vs 0%), diarrhea (34% vs 23%; 3% vs 0%) decreased appetite (31% vs 20%; 2% vs 0%), abdominal pain (23% vs 14%; 3% vs 0%), neuropathy (22% vs 11%; 0% vs 0%), and headache (20% vs 9%; 0% vs 0%).
The most common laboratory abnormalities (all grades; grade 3-4) occurring in ≥20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%; 44% vs 37%), neutropenia (65% vs 63%; 48% vs 38%) and thrombocytopenia (63% vs 44%; 6% vs 11%), hyperglycemia (52% vs 28%; 2% vs 3%), elevated aPTT (33% vs 13%; 5% vs 0%), hypokalemia (21% vs 15%; 8% vs 3%), and hypophosphatemia (21% vs 7%; 5% vs 3%).
Use in Specific Populations

Lactation: Because of the potential risk for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LARTRUVO and for at least 3 months following the last dose.
For more information about LARTRUVO, please see full Prescribing Information at View Source

OR HCP ISI 19OCT2016