On December 11, 2017 Genmab A/S (Nasdaq Copenhagen: GEN) reported that it will hold a R&D Update on December 11, 2017 at 8:00 PM Eastern Time (2:00 AM CET / 1:00 AM GMT on December 12) (Press release, Genmab, DEC 11, 2017, View Source [SID1234522510]). The event will take place in Atlanta, Georgia and will also be webcast live and archived on the company’s website. The event will include updates on daratumumab, including presentations by key opinion leaders on data from daratumumab studies presented at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper). The meeting will also feature a review of tisotumab vedotin, including data previously presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) in September and an update on the product pipeline including Genmab’s next IND/CTA candidate, DuoBody-CD40x4.1BB developed jointly with partner BioNTech. Genmab speakers will also discuss the company’s 2017 progress and key goals for 2018.

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The following cancer experts and senior Genmab staff will be at the event:
Key Opinion Leaders:
Professor Maria Victoria Mateos, University Hospital of Salamanca
Professor Philippe Moreau, University Hospital of Nantes
Dr. Saad Usmani, University of North Carolina at Chapel Hill, Levine Cancer Institute
Professor Ignace Vergote, Catholic University of Leuven

Genmab:

Dr. Jan van de Winkel, President and CEO, Genmab
David Eatwell, Executive Vice President and CFO, Genmab
Dr. Judith Klimovsky, Executive Vice President and CDO, Genmab
Dr. Kate Sasser, Corporate Vice President, Clinical Biomarkers, Genmab
The R&D Update is taking place at the Omni Atlanta Hotel at CNN Center, International Ballroom AB, North Tower M2. Those wishing to attend in person may register on site.

The event may also be attended via webcast. To view this webcast, visit: View Source Webcast viewers may submit questions during the Q&A portion of the live webcast via the webcast player. An archive of the webcast will be available on Genmab’s website. The webcast will be conducted in English.
This meeting is not an official program of the ASH (Free ASH Whitepaper) Annual Meeting.

On December 11, 2017 Actinium Pharmaceuticals, Inc. (NYSE American:ATNM) ("Actinium" or "the Company") reported results from an analysis performed on a large U.S. library of samples from 865 multiple myeloma patients which showed that twenty-five percent of patients had CD33 expression on their multiple myeloma cells (Press release, Actinium Pharmaceuticals, DEC 11, 2017, View Source [SID1234522539]). Actinium is currently conducting a Phase 1 clinical trial for its Actimab-M drug candidate in patients with refractory multiple myeloma. Actinium is the first and only company thus far to have a CD33 targeted therapy for multiple myeloma and the results from this analysis provide further rationale for the Company’s myeloma initiative.

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This analysis was the first of its kind to analyze such a large, U.S. based patient sample library as previous studies exploring CD33 expression in multiple myeloma looked at significantly smaller sample sizes from established multiple myeloma cell lines. Patient samples at initial diagnosis were assessed for CD33 expression and CD33 expression was stratified with CD33 expression greater than 40% considered high and greater than 60% very high. The analysis showed that 61.6% of patients in the dataset had high CD33 expression and 41% of patients had very high CD33 expression which translates to approximately fifteen percent of the overall multiple myeloma sample population.

The online abstract can accessed through the following link:
View Source

Dr. Mark Berger, Actinium’s Chief Medical Officer said, "It is generally believed that expression of CD33 on multiple myeloma plasmocytes is in line with the low levels of expression in cells of the lymphoid lineage. The results from this study confirm that CD33 is expressed in a significant sub-set of multiple myeloma patients. Given that CD33 expression levels have been found to be high or very high in a large percentage of patients that do express the antigen, we have great confidence that our Actimab-M drug candidate, which uses an anti-CD33 antibody, can have a beneficial impact on these patients. In a disease like multiple myeloma, which remains incurable, we believe it is important to explore new therapeutic modalities and use of our CD33 targeting ARC or Antibody Radio-Conjugate is supported by these results. Additionally, myeloma cells are sensitive to radiation and targeting them using an ARC like Actimab-M may provide further advantages."

Patients that relapsed were also assessed for CD33 expression and 27.1% of relapsed patients were found to have CD33 expression with 58.3% of these patients having very high expression at initial diagnosis and relapse.

About Actimab-M

Actimab-M is being investigated in patients with refractory multiple myeloma. Multiple myeloma is a currently incurable cancer of plasma cells, which are white blood cells that produce antibodies. Actimab-M is currently being studied in a Phase 1 dose escalation study in up to 12 patients that is designed to establish safety, maximum tolerable dose and proof of concept. Actimab-M is an ARC or Antibody Radio-Conjugate that consists of Actinium-225, an alpha-emitting radioisotope coupled to the anti-CD33 monoclonal antibody, lintuzumab. CD33 has been shown to be expressed on myeloma plasmocytes in 25% of multiple myeloma patients and up to 35% of multiple myeloma patients and has also shown to be correlated with poorer outcomes.

On December 11, 2017 Verastem, Inc. (NASDAQ: VSTM), focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, reported the presentation of new preclinical and Phase 1 clinical data from an investigator-sponsored study evaluating the safety and activity of oral duvelisib in combination with romidepsin (Istodax) or bortezomib (Velcade) in relapsed or refractory T-cell lymphomas (TCL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 Annual Meeting held December 9-12, 2017 in Atlanta (Press release, Verastem, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322203 [SID1234522563]). Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma which is currently being developed for the treatment of relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) and Follicular Lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including both peripheral and cutaneous T cell lymphoma (TCL).

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"The data presented today at ASH (Free ASH Whitepaper) demonstrate that oral duvelisib, combined with either romidepsin or bortezomib, has an acceptable safety profile in patients with relapsed or refractory TCL with response rates, while still preliminary, that appear promising when compared to those seen with currently approved therapies," said Steven Horwitz, MD, Memorial Sloan Kettering Cancer Center (MSKCC), co-principal investigator of the Phase 1 study, and lead author of the oral presentation. "We were especially pleased to see that these response rates were even higher in patients with peripheral TCL (PTCL), a rare and aggressive type of non-Hodgkin lymphoma. These clinical results were further bolstered by important preclinical findings showing duvelisib’s cell killing activity in vitro and its ability to promote beneficial changes within the in vivo tumor microenvironment."

"The preclinical and Phase 1 results reported today by the team at MSKCC are important because they provide further validation for our continued expansion of the duvelisib development program into T-cell malignancies including PTCL," said Diep Le, MD, PhD, Chief Medical Officer of Verastem. "Overall, our data presentations at ASH (Free ASH Whitepaper) this year continue to build upon the strong foundation of preclinical research and clinical investigation for Verastem’s product candidates, demonstrating their anti-cancer activity, either alone or in combination with other agents, across a wide variety of hematologic malignancies."

Phase 1 Safety and Activity Results
This multicenter, Phase I trial is comprised of parallel arms evaluating oral duvelisib in combination with romidepsin (arm A) or bortezomib (arm B) in patients with relapsed/refractory TCL, including PTCL and cutaneous T-cell lymphoma (CTCL). Oral duvelisib was dosed at 25mg, 50mg, or 75mg twice-daily (BID) on days 1-28. Romidepsin 10mg/m2 was dosed on Days 1, 8, and 15 (arm A) or bortezomib 1mg/m2 on Days 1, 4, 8, and 11 (arm B), both cohorts on 28-day cycles.

In arm A, there were 15 patients evaluable for efficacy (PTCL, n=11; CTCL, n=4). Of these, nine responded (4 complete responses (CR) and 5 partial responses (PR) for an overall response rate (ORR) of 60%. Seven of the 11 patients with PTCL responded (4 CR and 3 PR) for an ORR of 64%. Among the 9 patients evaluable for safety (25mg, n=3; 50mg, n=3; 75mg, n=3), there were no dose limiting toxicities (DLT), therefore oral duvelisib 75mg BID in combination with romidepsin 10mg/m2 IV was defined as the maximum tolerated dose (MTD). The most common Grade 1/2 adverse events were fatigue (n=9), nausea (n=8), altered taste (n=8) and diarrhea (n=6), rash (n=5), dysphagia (n=4) and anorexia (n=4). The most common Grade 3/4 adverse events were neutropenia (n=6), thrombocytopenia (n=1), lung infection (n=1), pleural effusion (n=1) and hyponatremia (n=1). There were two deaths (sepsis and diffuse alveolar hemorrhage following allogeneic stem cell transplant) that were both assessed as unrelated to study drug.

In arm B, there were 17 patients evaluable for efficacy (PTCL, n=10; CTCL, n=7). Of these, six responded (3 CRs and 3 PRs) for an ORR of 35%. Five of the 10 patients with PTCL responded (3 CRs and 2 PRs) for an ORR of 50%. Among the 14 patients evaluable for safety (25mg, n=6; 50mg, n=3; 75mg, n=5), there was one DLT (pneumonia) in the 25mg group. The MTD was determined to be oral duvelisib 25mg BID in combination with bortezomib 1mg/m2 IV. The most common Grade 1/2 adverse events were diarrhea/colitis (n=11), nausea/vomiting (n=4), chills (n=4) and fatigue (n=4). The most common Grade 3/4 adverse events were ALT and AST elevation (n=6), rash (n=2) and neutropenia (n=2). There was a case of Stevens-Johnson syndrome resulting in death which was assessed by the investigator as possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was initiated at the start of the study.

A copy of this oral presentation will be available here following the conclusion of the session.

About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular populations and extracellular matrices within the tumor or cancer niche that support cancer cell survival. This includes immunosuppressive cell populations such as regulatory T-cells, myeloid-derived suppressor cells, M2 TAMS, as well as tumor-associated fibroblasts and extracellular matrix proteins which can hamper the entry and therapeutic benefit of cytotoxic immune cells and anti-cancer drugs. In addition to targeting the proliferative and survival signaling of cancer cells, Verastem’s compounds duvelisib and defactinib target the tumor microenvironment as a mechanism of action to potentially improve a patient’s response to therapy.

About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 Duvelisib is currently being evaluated in late- and mid-stage extension trials, including DUO, a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),4 and DYNAMO, a single-arm, Phase 2 monotherapy study in patients with refractory indolent non-Hodgkin lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary endpoints and Verastem intends to submit a New Drug Application (NDA) requesting the full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL). Duvelisib is also being developed by Verastem for the treatment of peripheral T-cell lymphoma (PTCL), and is being investigated in combination with other agents through investigator-sponsored studies.6 Information about duvelisib clinical trials can be found on www.clinicaltrials.gov

About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase encoded by the PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability. Defactinib (VS-6063) and VS-4718 are orally available compounds that are potent inhibitors of FAK. Defactinib and VS-4718 utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. Defactinib is currently being studied in multiple clinical trials for patients with cancer.

On December 11, 2017 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on the development of potentially curative therapeutics using the CRISPR technology, and its collaborator, Novartis, reported initial data from their research collaboration on genome-edited human hematopoietic stem cells (Press release, Intellia Therapeutics, DEC 11, 2017, View Source [SID1234522514]). These data showed successful ex vivo editing of the erythroid specific enhancer of BCL11A, a gene associated with prevention of sickle cell disease, and the ability of these cells to stably engraft in mice while maintaining their desired properties.

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These data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in the platform presentation session: Hemoglobinopathies, Excluding Thalassemia – Basic and Translational Science: Sickle Cell Disease – Hematopoiesis and Fetal Hemoglobin Augmentation. In the presented studies, the companies:

Achieved approximately 80-95 percent target site modification in human hematopoietic stem and progenitor CD34+ cells following electroporation of ribonucleoprotein (RNP) composed of Cas9 and a guide RNA (gRNA), selected for efficacy and potency;

Demonstrated an approximately 40 percent reduction in BCL11A mRNA with a corresponding two-fold increase in γ-globin transcript and 30-40 percent more fetal hemoglobin-positive cells above background. Similar decreases in BCL11A mRNA and increases in γ-globin transcipt were observed when sickle cell disease-derived cells from patient donors were edited;

Achieved engraftment over 16 weeks following transplantation of edited human bone marrow CD34+ cells into immune compromised mice, while maintaining editing levels in engrafted cells; and

Observed no off-target events in CD34+ cells edited with the selected gRNA, as measured by targeted next generation sequencing of sites identified through in silico prediction and based on an unbiased, genome-wide, oligo-insertion detection method.
"We are pleased to be reporting data from studies generated through Intellia’s collaboration with Novartis, demonstrating successful ex vivo CRISPR/Cas9 editing in hematopoietic stem cells," said John Leonard, M.D., executive vice president, Research & Development, Intellia Therapeutics. "These results are significant as we have shown high levels of editing as well as increased production of fetal hemoglobin to clinically relevant levels, which could potentially ameliorate sickle cell disease in affected patients. We are very encouraged to present this progress given that sickle cell disease is a serious condition that currently has limited treatment options."

About Sickle Cell Disease

Sickle cell disease is a life-threatening, hereditary disorder that impacts approximately 30 million people worldwide. The disease results from a single amino acid change in the β-globin gene, which causes polymerization of hemoglobin and the deformation of red blood cells, leading to vaso-occlusion, severe pain crisis and multi-organ dysfunction. The average life expectancy in the developed world is 40 to 60 years. About 80 percent of sickle cell disease cases are believed to occur in sub-Saharan Africa.

On December 11, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported updated data from its completed pilot study1 of NY‑ESO SPEAR T-cell therapy in multiple myeloma patients in the setting of autologous stem cell transplant (ASCT) presented by the main investigator at the annual ASH (Free ASH Whitepaper) meeting (Press release, Adaptimmune, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322198 [SID1234522540]).

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"Mature data from this study in multiple myeloma continues to show promising efficacy and acceptable safety," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "We have observed a high response rate, long response duration, and encouraging long‑term survival in this population of patients with poor prognosis, treatment refractory myeloma. In addition, NY-ESO SPEAR memory T-cells persist long-term and respond to antigen after more than three years post‑treatment. NY-ESO SPEAR T-cell therapy is currently being evaluated in a second study in multiple myeloma patients with or without KEYTRUDA, all without stem cell transplant."

Long-term follow up data from the pilot study of NY-ESO in multiple myeloma in the context of ASCT

During an oral presentation, Dr. Edward Stadtmauer, University of Pennsylvania Abramson Cancer Center, presented an update on all twenty-five multiple myeloma patients treated in Adaptimmune’s pilot study in the setting of ASCT. The data cut-off for this oral presentation was August 16, 2017.

Overall Conclusions

NY-ESO SPEAR T-cell therapy in the setting of ASCT has promising efficacy and acceptable safety in multiple myeloma patients
Durable responses and long-term survival demonstrated in this refractory population
NY-ESO SPEAR T-cells persisted long term (>1000 days), but were are not exhausted
The most common adverse events (summarized below) were generally not unexpected in this patient population
Persisting cells produced multiple cytokines in response to antigen
Persisting cells included highly differentiated effector subsets and a population of self-renewing stem cell memory cells
A follow up study is ongoing in combination with KEYTRUDA, which will transition to GSK
Efficacy Results

Of the twenty-five patients treated in this study, 11 were alive at data cut-off
Three patients remain disease-progression free at 3, 4.5, and 5 years post-treatment
Five of 18 subjects tested were minimal residual disease negative at day 100
The median duration of response was >12 months
The median predicted overall survival is approximately three years
Overall response rate (ORR) at 100 days and one year were 76% and 44%, respectively, using International Myeloma Working Group criteria
Safety Results

There were no fatal adverse events (AEs), and cytokine release syndrome was not reported
Autologous graft versus host disease (GvHD) was reported in six patients; all resolved with corticosteroids and supportive therapy
Most common AEs (any grade AE occurring in >50% of patients) included diarrhea (100%), nausea (100%), anemia (96%), thrombocytopenia (92%), fatigue (88%), pyrexia (84%), rash (84%), hypokalemia (76%), febrile neutropenia (72%), vomiting (72%), neutropenia (68%), back pain (60%), leukopenia (60%), cough (56%), dyspnea (56%), hypocalcemia (56%), peripheral edema (56%), stomatitis (56%), and abdominal pain (52%).
Exploratory Endpoints

TCR-transduced NY-ESO SPEAR T-cells persisted long term (>1000 days) with minimal expression of exhaustion markers, and persisting cells:
Were functional, producing multiple cytokines in response to antigen in vitro
Included highly differentiated effector subsets and a population of self-renewing stem cell memory cells