On December 10, 2017 Acceleron Pharma Inc. (NASDAQ:XLRN), a leading biopharmaceutical company in the discovery and development of TGF-beta therapeutics to treat serious and rare diseases, reported preliminary results from the ongoing Phase 2 trials with luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Georgia (Press release, Acceleron Pharma, DEC 10, 2017, View Source [SID1234522480]). Luspatercept is being developed as part of a global collaboration between Acceleron and Celgene.

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"As the Phase 2 results in MDS mature, we are excited to see luspatercept achieving a clinically meaningful erythroid response in over 50% of patients. Luspatercept continues to provide long-term benefit to multiple patients now nearing three years on treatment. These results further reinforce luspatercept’s potential to be a transformative treatment option for patients living with lower-risk MDS," said Habib Dable, President and Chief Executive Officer of Acceleron. "We look forward to the upcoming MEDALIST and BELIEVE Phase 3 trial top-line data readouts in mid-2018, and we and Celgene continue to make considerable progress toward initiating the COMMANDS Phase 3 trial during the first half of 2018."

Phase 2 Results

A total of 99 lower-risk MDS patients have been treated with therapeutic dose levels of luspatercept (≥ 0.75 mg/kg) in the ongoing Phase 2 trials.

53% (52 of 99 patients) achieved a clinically meaningful erythroid response of an increase in hemoglobin or reduction in red blood cell (RBC) transfusion burden as per the International Working Group’s Hematologic Improvement Erythroid (IWG HI-E) response criteria.
43% (29 of 67 patients) with an RBC transfusion burden at baseline of ≥ 2 units per 8 weeks achieved RBC transfusion independence (RBC-TI) for ≥ 8 weeks.
In an updated analysis of the 23 RBC-TI responders previously reported at EHA (Free EHA Whitepaper) 2017, the median duration of treatment increased to 19.0 months from 14.7 months. The current duration of treatment for RBC-TI responders ranges from 2.8 months to 37.3 months.
Patients with a low transfusion burden at baseline ( < 4 RBC units per 8 weeks and hemoglobin < 10 g/dL) demonstrated a clinically meaningful increase in hemoglobin for up to 34 months, with multiple ongoing.
The results presented at ASH (Free ASH Whitepaper) 2017 confirm and extend previously reported results across the lower-risk MDS patient subpopulations, showing erythroid responses regardless of prior use of erythropoiesis-stimulating agents (ESA), baseline erythropoietin (EPO) levels, and ring sideroblast (RS) status.

Phase 2 Safety Summary

A total of 106 lower-risk MDS patients have been treated with luspatercept in the ongoing Phase 2 trials (all dose levels).

The majority of adverse events (AEs) were Grade 1 or 2. AEs possibly or probably related to study drug that occurred in at least three patients during the studies were headache, hypertension, fatigue, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and edema peripheral.
Grade 3 non-serious AEs possibly related to study drug were ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, mucosal inflammation, platelet count increase, and pleural effusion. These Grade 3 non-serious AEs occurred in seven individual patients with one patient reporting both the ascites and pleural effusion.
Serious AEs (SAEs) possibly related to study drug were general physical health deterioration, muscular weakness, musculoskeletal pain, and myalgia. These SAEs occurred in three individual patients with one patient reporting both the muscular weakness and musculoskeletal pain.
The MEDALIST trial, a global Phase 3 trial of luspatercept in lower-risk MDS patients, is fully enrolled with top-line results expected in mid-2018. The MEDALIST trial enrolled patients who are RS-positive, RBC transfusion dependent, and are ESA-refractory or ESA-treatment ineligible, based on EPO levels greater than 200 units per liter at baseline. Acceleron and Celgene plan to initiate the COMMANDS Phase 3 trial in first-line, lower-risk MDS patients during the first half of 2018.

The MDS clinical poster presentation is available under the Science page of the Company’s website at www.acceleronpharma.com.

Luspatercept is an investigational product that is not approved for use in any country.

Acceleron ASH (Free ASH Whitepaper) Conference Call Information

Acceleron will host a conference call and live webcast to discuss data presented at the ASH (Free ASH Whitepaper) meeting on December 11, 2017, at 7:00 a.m. EST.

Individuals can participate in the conference call by dialing 877-312-5848 (domestic) or 253-237-1155 (international) and refer to the "Acceleron ASH (Free ASH Whitepaper) 2017 Update."

The webcast will be accessible under "Events & Presentations" in the Investors/Media page of the Company’s website at www.acceleronpharma.com.

A replay of the webcast will be available approximately two hours after the event.

About the Ongoing MDS Phase 2 Studies

Data from two Phase 2 trials were presented at the conference: the base study in which patients received treatment with luspatercept for three months and the long-term extension study in which patients who completed the base study may receive treatment with luspatercept for up to an additional five years. In both the three-month base study and the long-term extension study, lower-risk MDS patients were enrolled and treated with open-label luspatercept, dosed subcutaneously once every three weeks.

The outcome measures for the trials included the proportion of patients who had an erythroid response (IWG HI-E) or achieved RBC transfusion independence (RBC-TI). IWG HI-E was defined as hemoglobin increase ≥ 1.5 g/dL sustained for ≥ 8 weeks in patients with < 4 units RBC / 8 weeks transfusion burden at baseline and hemoglobin levels below 10 g/dL. For patients with a ≥ 4 units RBC / 8 weeks transfusion burden at baseline, erythroid response was defined as a reduction of ≥ 4 units RBC sustained for ≥ 8 weeks. RBC-TI was defined as receiving no RBC transfusions for ≥ 8 weeks in patients with a ≥ 2 units RBC / 8 weeks baseline transfusion burden.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members of the TGF-beta superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept is a first-in-class erythroid maturation agent (EMA) that regulates late-stage erythrocyte (red blood cell) precursor cell differentiation. This mechanism of action is distinct from that of erythropoiesis stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials are underway to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). A Phase 3 trial is being planned in first-line, lower-risk, myelodysplastic syndromes patients (the COMMANDS trial). For more information, please visit www.clinicaltrials.gov.

On December 9,2017 Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported results from a leading European transplant center participating in the BP-004 trial in children with blood cancers and nonmalignant disorders (Press release, Bellicum Pharmaceuticals, DEC 9, 2017, View Source;p=RssLanding&cat=news&id=2321945 [SID1234522457]). Patients were treated with BPX-501 following an alpha/beta T cell and CD19+ B cell depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT). Results demonstrated that donor BPX-501 cells infused after transplant expanded in vivo and persisted over time, contributing to improved immune recovery for patients in the study as compared to historical controls from the same transplant center. The data were reviewed in an oral presentation today during the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).

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According to study author and presenter Pietro Merli of Ospedale Pediatrico Bambino Gesù in Rome, "These data show that administering BPX-501 cells following a haplo-HSCT may result in improved immune recovery and infection control, addressing significant risks in children undergoing a stem cell transplant who do not have access to a matched donor. Adding BPX-501 to a haplo-HSCT has the potential to improve outcomes and to make the curative benefits of transplants available to more children with cancers and genetic blood diseases."

Study Design and Highlights (Abstract #211)

Investigators evaluated immune recovery and outcomes of 112 pediatric patients who underwent a haplo-HSCT followed by treatment with BPX-501. Children in the study had acute leukemia (n=53), Primary Immune Deficiencies (n=26), erythroid disorders (n=17), Fanconi anemia (n=7), and other diseases (n=9). All patients were transplanted after depletion of donor alpha/beta T cells and CD19 B cells to prevent graft-versus-host disease (GvHD) and post-transplant lymphoproliferative disorders (PTLD). BPX-501 cells were scheduled to be infused approximately two weeks post-transplant.

Results showed:

BPX-501 cells infused after haplo-HSCT expand and persist in patients, potentially contributing to improved recovery of adaptive immunity.
Peak expansion of BPX-501 cells is reached at nine months after infusion, and BPX-501 cells are consistently detected after two years.
CMV infection is a main driver of BPX-501 cell expansion, suggesting that BPX-501 cells cooperate in clearing the viral infection.
The overall pattern of immune recovery in 112 children studied may be improved when compared to patients who received a similar haplo-HSCT without BPX-501.
"Improved immune recovery and control over infections, as demonstrated in this study, may have a direct impact on treatment-related morbidity and mortality," commented Rick Fair, Bellicum’s President & Chief Executive Officer. "We look forward to reporting on these and other outcomes from our ongoing BP-004 trial in 2018."

A copy of the ASH (Free ASH Whitepaper) presentation will be made available in the "Investors & Media" section of the Company’s website.

About BPX-501
BPX-501 is an adjunct T cell therapy administered after allogeneic HSCT, comprising genetically modified donor T cells incorporating Bellicum’s CaspaCIDe safety switch. It is designed to provide a safety net to eliminate alloreactive BPX-501 T cells (via administration of activator agent rimiducid) should uncontrollable GvHD occur. This enables physicians to more safely perform stem cell transplants by administering BPX-501 engineered T cells to speed immune reconstitution, provide control over viral infections and enhance Graft-versus-leukemic effect without unacceptable GvHD risk. The ongoing BP-004 clinical study of BPX-501 is being conducted at transplant centers in the U.S. and Europe.

On December 9, 2017 Magenta Therapeutics, a biotechnology company developing therapeutics to improve and extend the use of curative bone marrow transplant for more patients, reported the presentation of preclinical data from its CD117 antibody-drug conjugate (ADC) conditioning program (Press release, , DEC 9, 2017, View Source [SID1234522521]). These data were presented at the 59th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Atlanta, Ga.

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Magenta is developing a portfolio of ADC-based conditioning agents that specifically deplete target cells using an approach that may be less toxic than the current chemotherapy-based conditioning regimens for bone marrow transplant. One of Magenta’s programs, CD117-ADC, is a conditioning agent that selectively binds to host hematopoietic stem and progenitor cells (HSPCs). CD117 (also known as C-KIT) is highly expressed on HSPCs and an ideal target for conditioning across broad sets of diseases, including hematological malignancies and hemoglobinopathies, with potential applicability in both bone marrow transplant and stem cell gene therapy. CD117 is also frequently overexpressed on tumor cells in patients with acute myelogenous leukemia (AML). The CD117-ADC-based transplant conditioning approach has the potential to limit systemic toxicity for transplant patients and additionally reduce tumor burden in transplant patients with AML.

"For patients undergoing bone marrow transplant, the toxicity and mortality associated with current conditioning protocols remain significant challenges and prevent more patients from benefitting from this life-saving and potentially curative procedure. Current conditioning regimens use highly toxic and non-specific chemotherapy drugs or irradiation that can result in infections, organ failure, infertility and even death," said Michael Cooke, Ph.D., chief scientific officer, Magenta Therapeutics. "Given the significant unmet need for new conditioning options for bone marrow transplant, we are pleased to see that CD117-ADC was capable of selective depletion of human hematopoietic stem cells in the bone marrow of humanized mice and showed anti-leukemia effects in vivo. This conditioning regimen has the potential to increase the number of patients eligible for transplant for both malignant and non-malignant diseases by reducing the toxicity of the procedure."

Non-Genotoxic Conditioning for Hematopoietic Stem Cell Transplant Using a Human Antibody Drug Conjugate Targeting C-KIT (Abstract #1894)
Overview and results, presented by Adam Hartigan, Ph.D., Magenta Therapeutics, include:

Magenta Therapeutics developed CD117-ADC, a fully human ADC targeting CD117 (also known as C-KIT) capable of depleting both proliferating and quiescent cells.
Humanized NSG mice treated with a single dose of CD117-ADC had greater than 90% depletion of human hematopoietic stem and progenitor cells in the bone marrow after a single administration of the ADC.
Magenta scientists demonstrated the specificity of CD117-ADC for hematopoietic stem and progenitor cells in humanized animal studies.
CD117-ADC demonstrated greater than 90% killing of the human leukemia cell line Kasumi-1, and was equally effective at killing primary human CD34+ bone marrow cells during in vitro culture.
Preliminary data suggest that a single dose of CD117-ADC is also effective at reducing tumor burden and conferring survival benefits in mice challenged with C-KIT-expressing AML cells.
About Bone Marrow Transplant

Healthy bone marrow stem cells and the blood cells they form are crucial for survival, but certain diseases can affect the bone marrow, interfering with its ability to function properly. A bone marrow transplant is a process to replace unhealthy bone marrow with healthy bone marrow stem cells. Bone marrow transplant can save the lives of patients with blood cancers and genetic diseases and is a potential cure for patients with severe, refractory autoimmune diseases. However, the high risks, toxic side effects and complexity of the procedure currently prevent many patients from being able to benefit.

On December 9, 2017 Amphivena Therapeutics Inc., a privately held biotechnology company developing AMV564, a CD33/CD3 T cell redirector for the treatment of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS), reported that it will present in an oral presentation at the 59th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) preclinical data that demonstrate that treatment with AMV564 selectively depletes myeloid-derived suppressor cells (MDSCs) in bone marrow cells from patients with MDS with resultant reactivation of T lymphocytes (Press release, Amphivena Therapeutics, DEC 9, 2017, View Source [SID1234522520]). AMV564-induced restoration of immune homeostasis was accompanied by a significant improvement in hematopoiesis. AMV564 is a CD33/CD3 bivalent bispecific antibody that binds both CD33 and CD3 with strong avidity and results in T-cell directed lysis of CD33-expressing myeloid cells.

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"These preclinical data provide a strong rationale for clinical investigation of this innovative approach in patients with MDS, who have limited treatment options today. The data also underscore an opportunity to develop AMV564 for patients with other malignancies where MDSCs have been shown to contribute to the immunosuppressive tumor microenvironment," said Eric J. Feldman, M.D., Amphivena’s Senior Vice President, Clinical Development.

Alan List, M.D., President and CEO of Moffitt Cancer Center, who presented on behalf of the investigators, said, "AMV564 eliminated CD33+ MDSCs in a dose-dependent manner and restored critical aspects of immune homeostasis. In addition, proliferation of CD4+ and CD8+ T cells more than doubled with AMV564 treatment as compared to baseline; IFN-γ production, as measured by gene expression, markedly increased in AMV564-treated cells. AMV564-directed elimination of MDSCs was associated with decreased DNA damage in CD34+ stem cells and improved colony-forming capacity. Finally, the presentation concluded, AMV564 and anti-PD-1 treatment are synergistic for T-cell activation."

Amphivena plans to launch a Phase 1 clinical study in patients with MDS in early 2018. Currently, the company is conducting a Phase 1 clinical study of AMV564 in relapsed or refractory AML and is also exploring the utility of AMV564 in solid tumors.

On December 9, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported preliminary clinical data from an ongoing Phase 1b trial of its investigational Bruton’s Tyrosine Kinase (BTK) inhibitor zanubrutinib (BGB-3111) in patients with non-Hodgkin’s lymphoma (NHL) in an oral presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, GA (Press release, BeiGene, DEC 9, 2017, View Source;p=RssLanding&cat=news&id=2321942 [SID1234522476]). The preliminary data included patients with aggressive NHL subtypes such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) as well as indolent NHL subtypes such as follicular lymphoma (FL) and marginal zone lymphoma (MZL). The Phase 1b data suggest that zanubrutinib was generally well-tolerated and had anti-tumor activity across these NHL subtypes.

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"In this Phase 1b trial, zanubrutinib was well-tolerated across multiple NHL subtypes, with very low rates of toxicity-related treatment discontinuation in both indolent and aggressive disease settings. These preliminary data also indicate that zanubrutinib’s complete and sustained BTK occupancy translates into high response rates in NHL subtypes beyond Waldenström’s macroglobulinemia and Chronic lymphocytic leukemia, for which data have previously been reported," commented Constantine Tam, MD, Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Centre, Director of Haematology at St. Vincent’s Hospital, Australia, and lead author of the presentation.

"Building upon the promising Phase 1b data we have presented for zanubrutinib, we are pleased to report results from additional NHL subtypes enrolled in our Phase 1b trial. We continue to pursue broad development of zanubrutinib with ongoing pivotal trials in a range of NHL subtypes both globally and in China," commented Jane Huang, MD, Chief Medical Officer, Hematology at BeiGene.

Summary of Results from the Ongoing Phase 1b Trial

The multi-center, open-label Phase 1b trial of zanubrutinib in patients with B-cell malignancies is being conducted in Australia, New Zealand, South Korea, the United States, and Europe, and consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts. The ongoing dose-expansion component is testing doses of 160 mg twice daily (BID) or 320 mg once a day (QD). As of September 15, 2017, the date of the most recent data cutoff, 99 patients with NHL subtypes other than chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström’s macroglobulinemia were enrolled in the study, including 34 patients in the indolent lymphoma cohort, which consisted of 24 patients with FL and 10 patients with MZL, and 65 patients in the aggressive lymphoma cohort, which consisted of 27 patients with DLBCL and 38 patients with MCL. The median follow-up time was 5.6 months (0.3-22.3 months) and 5.1 months (0.1-31.9) for indolent and aggressive lymphoma, respectively.

At the time of data cutoff, the most frequent adverse events (AEs) (occurring in ≥15% of patients) of any attribution among 34 patients with indolent lymphoma were petechiae/purpura/contusion (24%), upper respiratory tract infection (URTI) (21%), nausea (18%) and pyrexia (15%). The most frequently reported grade 3 or greater AEs (occurring in ≥5% of patients) of any attribution were anemia (9%), neutropenia (9%), urinary tract infection (6%), and abdominal pain (6%). Serious AEs were reported in 11 patients (32%). Of those, four patients had serious AEs that were considered possibly related to zanubrutinib, including one case each of nausea, urinary tract infection, diarrhea, and creatinine increase.

The most frequent AEs (occurring in ≥15% of patients) of any attribution among 65 patients with aggressive lymphoma were petechiae/purpura/contusion (25%), diarrhea (23%), constipation (22%), fatigue (18%), URTI (18%), anemia (17%), cough (15%), pyrexia (15%), and thrombocytopenia (15%). The most frequently reported grade 3 or greater AEs (occurring in ≥5% of patients) of any attribution were anemia (11%), neutropenia (9%), thrombocytopenia (9%), and pneumonia (6%). Serious AEs were reported in 26 patients (40%). Of those, three patients had serious AEs that were considered possibly related to zanubrutinib, including one case each of peripheral edema and joint effusion (occurring in the same patient), pneumonia, and pneumonitis.

At the time of data cutoff, 26 patients with indolent lymphoma including 17 patients with FL and nine patients with MZL were evaluable for efficacy. In patients with FL, the overall response rate (ORR) was 41% with complete responses (CRs) in 18% and partial responses (PRs) in 24% of patients. Stable disease (SD) was observed in 41% of patients. Progressive disease (PD) was observed in one patient. In patients with MZL, the ORR was 78% with no CR, and PRs in 78% of patients. SD was observed in 22% of patients. No PD was observed.

Fifty-eight patients with aggressive lymphoma including 26 patients with DLBCL and 32 patients with MCL were evaluable for efficacy. In patients with DLBCL, the ORR was 31% with CRs in 15% and PRs in 15% of patients. In patients with MCL, the ORR was 88% with CRs in 25% and PRs in 63% of patients.

About Zanubrutinib

Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of BTK that has demonstrated higher selectivity against BTK than ibrutinib (a BTK inhibitor currently approved by the U.S. Food and Drug Administration and the European Medicines Agency) based on biochemical assays, higher exposure than ibrutinib based on their respective Phase 1 experience in separate studies, and sustained 24-hour BTK occupancy in both the peripheral blood and lymph node compartments.