On December 7, 2020 Pfizer Inc. (NYSE:PFE) reported safety and clinical response results from the ongoing Phase 1 study (NCT03269136) for PF-06863135, an investigational B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (Press release, Pfizer, DEC 7, 2020, View Source [SID1234572364]). Data from 30 patients with relapsed or refractory multiple myeloma showed manageable safety across all subcutaneous dose levels with no dose-limiting toxicities observed, and 83% of patients achieved a clinical response at the highest dose level. The results will be presented today at the Virtual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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"Despite treatment advances, multiple myeloma remains incurable and there is a substantial need for breakthroughs for patients," said Jeff Settleman, Senior Vice President & Chief Scientific Officer, Oncology R&D, Pfizer. "The very high response rate observed with PF-06863135, coupled with manageable safety and the convenience of subcutaneous administration, underscores the potential impact this medicine may have for people living with this devastating disease. These findings support continued development of PF-06863135 for people with multiple myeloma, both as monotherapy and in combination with standard or novel therapies."

PF-06863135 is a bispecific antibody designed to bind to BCMA which is highly expressed on the surface of multiple myeloma cells, and the CD3 receptor found on the surface of cancer-fighting T cells, bridging them together to activate an immune response. Binding affinity to BCMA and CD3 has been optimized, enabling more potent T-cell-mediated anti-myeloma activity. Subcutaneous administration of PF-06863135 is intended to allow higher doses than intravenous administration without increasing adverse events.

The primary objectives of this portion of the study were to assess safety and tolerability of PF-06863135 administered subcutaneously, to determine the maximum tolerated dose, and to select the recommended Phase 2 dose. In the study, no dose-limiting toxicities were observed across any of the subcutaneous dose levels evaluated (80 to 1,000 μg/kg weekly) during dose escalation. Cytokine release syndrome (CRS) was reported in 73.3% of patients and was limited exclusively to grade 1 (56.7%) or grade 2 (16.7%). Grade 3 or higher adverse events (AEs) occurring in more than 10% of patients included lymphopenia (53.3%), neutropenia (26.7%), thrombocytopenia (16.7%) and anemia (16.7%).

The overall response rate (ORR) was 80% among the 20 patients treated in cohorts across the efficacious dose range of 215 to 1,000 μg/kg weekly. Among these 20 patients, six achieved stringent complete response or complete response, three achieved very good partial response, and six achieved partial response. Three responding patients had received at least one prior BCMA-targeted therapy. At the highest dose level of 1,000 μg/kg, the ORR was 83% (5/6 patients). Based on these data, 1,000 μg/kg weekly is the recommended Phase 2 dose.

About the PF-06863135 Phase 1 Trial

NCT03269136 is a Phase 1, open-label, multi-dose, multicenter, dose escalation, safety, pharmacokinetic (PK) and pharmacodynamic study of PF-06863135 for adult patients with advanced multiple myeloma who have relapsed after, or are refractory to, standard therapies. Part 1 of this two-part study assessed the safety and tolerability of increasing dose levels of PF-06863135. The study enrolled 80 patients and evaluates PF-06863135 administered intravenously or subcutaneously. Preliminary results for intravenous administration were reported at ASH (Free ASH Whitepaper) in 2019.1 For more information about the trial, visit www.clinicaltrials.gov.

About Multiple Myeloma

Multiple myeloma is a blood cancer that affects plasma cells made in the bone marrow. Healthy plasma cells make antibodies that help the body fight infection. According to the latest figures available, there are approximately 32,270 new cases of multiple myeloma diagnosed annually in the United States and 160,000 globally.2,3 Despite treatment advances, multiple myeloma remains incurable. The median survival is just over 5 years, and most patients receive four or more lines of therapy.4

On December 7, 2020 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that preclinical data from its wholly-owned MALT1 inhibitor program in B-cell lymphomas at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Schrodinger, DEC 7, 2020, View Source [SID1234572362]). MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1, is considered a potential therapeutic target for several non-Hodgkin’s B-cell lymphomas as well as chronic lymphocytic leukemia (CLL). Schrödinger scientists have identified novel MALT1 inhibitors that have shown strong anti-tumor activity in preclinical models alone and in combination with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, and venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, two anti-cancer therapies used to treat certain B-cell lymphomas and CLL.

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"We are pleased our MALT1 inhibitors indicate promising preclinical anti-cancer activity in diffuse large B-cell lymphomas, commonly called DLBCL, as a single agent or in combinations. Our data suggest our lead molecules may expand therapeutic options for lymphoma patients who need alternative therapeutic options after relapse or becoming resistant to existing agents," said Karen Akinsanya, Ph.D., Executive Vice President, Chief Biomedical Scientist and Head of Discovery R&D at Schrödinger. "Our preclinical work is ongoing, and we plan to advance this program into IND-enabling studies in the first half of 2021."

The discovery of lead molecules in Schrödinger’s MALT1 program was accelerated with the company’s differentiated, physics-based platform, which facilitates exploration of vast amounts of chemical space. Schrödinger’s free energy perturbation technology (FEP+) was used in combination with machine learning to prioritize billions of computer- and human-designed compounds to identify and optimize potent, selective inhibitors with favorable drug-like properties in under one year.

Additional Details About the Study

The presentation, "Identification of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies," highlighted preclinical data with multiple lead molecules discovered by Schrödinger scientists. The company’s MALT1 compounds showed potent in vitro inhibition of MALT1 enzymatic activity, with high binding affinity to the protein. Strong in vivo anti-tumor activity was observed in mouse xenograft models of DLBCL. Additionally, strong in vivo anti-proliferative effects were reported in combination with ibrutinib and venetoclax in mouse models. Taken together, these data provide further rationale for developing MALT1 inhibitors as a potential therapeutic approach particularly in combination with existing therapies to potentially treat relapsed/refractory B-cell lymphoma and difficult to treat blood cancers such as DLBCL.

On December 7, 2020 CIBMTR reported that Initial results from a recent study indicate that for patients between the ages of 50 and 75, overall survival nearly doubled when patients with myelodysplastic syndrome (MDS) received allogeneic hematopoietic cell transplantation (alloHCT) when compared to other treatments (Press release, CIBMTR, DEC 7, 2020, View Source [SID1234572361]). Additionally, patients age 65 and older saw a similar benefit to overall survival as those between the ages of 55 and 64. The majority of patients received transplant using matched unrelated donors, and outcomes were similar to those of patients using matched related donors.

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These findings from a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study were presented during the 62nd ASH (Free ASH Whitepaper) Annual Meeting & Exposition.

The initial results of a separate observational study currently being run by the CIBMTR (Center for International Blood and Marrow Transplant Research)—which is a research collaboration between the National Marrow Donor Program (NMDP)/Be The Match and the Medical College of Wisconsin—also demonstrate the patients 65 and older experience similar benefit from allogeneic HCT to patients 55-64 years of age. In addition, the initial analysis of the CIBMTR observational study showed similar non-relapse mortality between these two age groups. The initial results were published in JAMA Oncology.

"In both studies of older adults with MDS, we found that transplantation using either an HLA-matched related or HLA-matched unrelated donor is feasible even in older patients and in the BMT CTN study, provides significant survival benefit relative to non-transplant therapies. This supports the early referral of all patients with MDS to a transplant center for consultation, regardless of age," said Steven Devine, MD, Chief Medical Officer, NMDP/Be The Match, and Associate Scientific Director, CIBMTR.

Early referral to a transplant center for all patients is critical as it allows the search for a donor to start early for those patients who are eligible for transplant. This increases the likelihood a patient will find a suitable donor and proceed to transplant earlier in their disease, which can lead to better outcomes.

"While alloHCT is the only known cure for MDS, many older adults did not receive HCT in the past because the benefits for older adults had not been sufficiently proven for CMS to provide payment coverage. Taken together, these studies support allogeneic HCT for older patients with MDS based on survival improvements," said J. Douglas Rizzo, MD, MS, Senior Scientific Director, CIBMTR.

Currently, the Centers for Medicare and Medicaid Services (CMS) does not cover alloHCT for adults over age 65 unless the patient is enrolled in a qualified Coverage with Evidence Development (CED) study. The NMDP/Be The Match and CIBMTR will provide CMS with the data from these two studies for its use in making coverage policy decisions.

In the meantime, the current CIBMTR observational study meets CED requirements and qualifies for payment under CMS. The study remains open for enrollment for a broad range of clinically eligible Medicare recipients. By enrolling patients in this study, more older patients across the U.S. with MDS will have access to HCT.

Access the BMT CTN study abstract presented by senior study author Corey Cutler, MD, MPH, Dana-Farber Cancer Institute, during the ASH (Free ASH Whitepaper) Annual Meeting:

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

Access the initial results of the CIBMTR observational study published in JAMA Oncology:

Comparison of Patient Age Groups in Transplantation for Myelodysplastic Syndrome: The Medicare Coverage With Evidence Development Study

About the BMT CTN

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducts rigorous multi-institutional clinical trials of high scientific merit, focused on improving survival for patients undergoing hematopoietic cell transplantation and/or receiving cellular therapies. The BMT CTN has completed accrual to 43 Phase II and III trials at more than 100 transplant centers and enrolled over 12,800 study participants. BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, a part of the National Institutes of Health (NIH) and is a collaborative effort of 20 Core Transplant Centers/Consortia, the CIBMTR (Center for International Blood and Marrow Transplant Research), the National Marrow Donor Program/Be The Match and the Emmes Company, LLC, a clinical research organization.

On December 7, 2020 Paige, a global leader in AI-based digital diagnostics, reported that it will present new data evaluating Paige Breast Alpha, a machine learning system designed to detect breast cancer in digital images of breast tissue, at the upcoming 2020 San Antonio Breast Cancer Symposium (SABCS 2020), taking place virtually December 8-11, 2020 (Press release, Paige AI, DEC 7, 2020, View Source [SID1234572360]).

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For pathologists reviewing breast tissue slides under the microscope, the large volume of slides can pose significant challenges for workload management and pathologist productivity. The poster, "Clinical-grade detection of breast cancer in biopsies and excisions using machine learning," will be featured during a spotlight poster discussion, which highlights some of the most noteworthy and groundbreaking research submitted to the conference.

The poster abstract is available online and viewing details are below:

Clinical-grade detection of breast cancer in biopsies and excisions using machine learning
Authors: Hanna MG, et al.
Session: Spotlight Poster Discussion 6 | Thursday, December 10, 2020 | 3:30pm – 4:45pm CST
Poster #: PD6-03

On December 7, 2020 MaaT Pharma reported positive updated clinical results from its lead full-ecosystem microbiome restoration biotherapeutic, MaaT013, at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, MaaT Pharma, DEC 7, 2020, View Source [SID1234572359]). The data stems from a compassionate use/expanded access treatment program in France called Autorisation Temporaire d’Utilisation Nominative (ATUn), using MaaT013 to treat patients that developed acute Graft-versus-Host-Disease with GI involvement (GI aGvHD) following allogeneic hematopoietic cell transplantation (allo-HCT) and were refractory to multiple lines of treatments, including corticosteroids. Treatment with MaaT013 was well tolerated and provided encouraging signs of efficacy with a 6-month overall survival of 52%, demonstrating the positive impact microbiome restoration can achieve in heavily pre-treated patients. The results were presented by leading hemato-oncological expert Florent Malard, MD, PhD, Associate Professor of Hematology at Saint-Antoine Hospital and Sorbonne University, in an oral presentation on December 6, 2020 at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"Acute GvHD is a devastating disease where the transplant donor’s immune cells attack the patient’s tissue following allo-HCT and to date these patients have limited treatment options and a very low long-term survival rate when steroid-refractory," said Dr Florent Malard MD, PhD, Associate Professor of Hematology at Saint Antoine Hospital in Paris. "These data are very encouraging and we are continuing to see clinical benefits in the larger cohort of patients treated with MaaT Pharma’s microbiome restoration therapeutic. The very good overall response observed represents a promising and important step towards providing an effective treatment option for these patients."

In the presented data update, 29 recipients of allo-HCT that progressed to steroid-dependent or steroid refractory aGvHD (22, classical aGvHD; 2, late-onset aGvHD; 5, aGvHD with overlap syndrome) and had failed 1 to 5 lines (median: 3) of systemic treatments were evaluated after treatment with MaaT013. Each patient received a median of three doses of MaaT013 (range, 1-3) and treatment-based responses were observed seven days after each administration and 28 days after administration of the first dose. Nine patients achieved a complete response (CR), 6 a very good partial response (VGPR), and 2 a partial response (PR) at day 28. All 9 patients with a complete response were still alive at the last follow-up (median FU: 444 days (197-654)), suggesting an extended survival in comparison to historic cohorts. In addition, these patients were able to taper or stop steroids as well as immunosuppressants. Notably, 15 patients were still alive at last follow-up (median FU: 313 days (28-654)) and the 6-month and 12-month overall survival were 52% and 46%, respectively. Overall, the data revealed that restoring the microbiome with a full-ecosystem microbiota restoration biotherapeutic provided a positive impact for a majority of the patients and the safety of MaaT013 was satisfactory for all patients.

"These additional positive data from the compassionate use program further support the potential of MaaT Pharma’s products, targeting restoration of a functional gut to treat severe and life-threatening diseases," said John Weinberg, MD, Chief Medical Officer of MaaT Pharma. "Seeing the clinical benefit of MaaT013 together with its continued tolerability profile, we believe that our approach can truly make a difference for aGvHD patients. Additionally, we expect the readout from HERACLES, our fully enrolled Phase 2 trial of MaaT013 in steroid-refractory, GI-predominant aGvHD patients, early next year. This will provide a more complete picture of the potential of our product across clinical settings."

About MaaT013

MaaT013 is a full-ecosystem, off-the-shelf, standardized, pooled-donor, high-richness microbiome biotherapeutic in enema formulation. The product has a stability of up to 24 months and is characterized by a high diversity and consistent richness of microbial species. MaaT013 has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). MaaT013 is currently being investigated in a Phase 2 clinical trial (NCT03359980) to evaluate its safety and efficacy in steroid-refractory, GI aGvHD patients.