On December 5, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported efficacy and safety findings from a Phase 2 study demonstrating that nearly half (48%) of patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL) had a complete or partial response with single-agent ibrutinib (IMBRUVICA), as assessed by Independent Review Committee (IRC) investigators (Press release, AbbVie, DEC 5, 2016, View Source [SID1234516940]). The median duration of response was not reached.1 These data will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA (abstract #1213). IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

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MZL is a diverse group of slow-growing non-Hodgkin’s lymphomas arising from white blood cells (lymphocytes) at the edges of lymphoid tissue.2 MZL accounts for approximately 12% of all cases of non-Hodgkin’s lymphoma in adults and the median age at diagnosis is 65 years old.3 There are currently no approved treatments or standards of care specifically indicated for patients with MZL in the United States.

"We are pleased with the 48% response rate seen with ibrutinib in this trial, as the hematology-oncology community has a need for effective new therapies to treat marginal zone lymphoma," said Ariela Noy, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center in New York and lead investigator of the study.* "In particular, a non-chemotherapy targeted oral option like ibrutinib could represent an important step forward for patients with MZL to keep this incurable type of cancer under control."

In this multicenter, open-label trial, 63 MZL patients (including splenic MZL [SMZL], nodal MZL [NMZL] and extranodal MZL [EMZL] subtypes) received one or more prior therapies including at least one CD20-directed regimen (chemo-immunotherapy or rituximab monotherapy). In the study, 79% of patients experienced some tumor reduction (50 out of 63 patients) and overall response rates (ORR) was 48%, implying that BTK signaling is an important growth and survival factor in MZL. The median time to initial response was 4.5 months.1

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies. The most common adverse events (AEs) included fatigue (44%), diarrhea (43%), anemia (33%), nausea (25%), thrombocytopenia, peripheral edema and arthralgia (24% each), cough (22%), dyspnea and URTI (21% each). Grade 3 or 4 AEs occurred in 63% of patients. The most frequent were anemia (14%), pneumonia (8%) and fatigue (6%). Grade 1 and 2 atrial fibrillation occurred in four (6%) patients.1

"These findings contribute to the growing body of evidence exploring the use of ibrutinib in different types of hematologic cancers, including marginal zone lymphoma and its three sub-types," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "Results from this study support the recent submission of a supplemental New Drug Application to include more patients who may benefit from treatment with ibrutinib."

About the Study
The Phase 2 study evaluated the safety and efficacy of ibrutinib in patients with R/R MZL. The primary objective of the trial was ORR as assessed by an IRC. Duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety were secondary objectives.1 Data from this study were submitted to the U.S. Food and Drug Administration (FDA) in September 2016 as part of a supplemental New Drug Application (sNDA) to expand the current indication for IMBRUVICA.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.4

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.4

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry with nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia** (64%), thrombocytopenia** (63%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).

**Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On December 5, 2016 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO) reported new clinical data from the ongoing Phase 1 study evaluating single agent AG-120 in advanced hematologic malignancies at the 2016 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) (Press release, Agios Pharmaceuticals, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227727 [SID1234516941]). AG-120 is a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1).

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As of August 1, 2016, data from the completed dose-escalation portion of the Phase 1 trial from 78 patients with advanced IDH1 mutant positive hematologic malignancies treated with AG-120, including 63 patients with relapsed and/or refractory (R/R) acute myeloid leukemia (AML), continue to show a favorable safety profile and durable clinical activity. Data from the ongoing expansion phases were not reported. For all dose escalation patients, an overall response rate of 38% (30 of 78) and a complete remission rate of 18% (14 of 78) were observed. For the 63 R/R AML patients, the overall response rate and complete remission rates were 33% (21 of 63) and 16% (10 of 63) respectively. Patients were on study treatment for up to 24.2 months with a median duration of response of 10.2 months for all responders and 6.5 months for the R/R AML responding patients.

In order to study the depth of response to single agent AG-120, molecular detection of the mutant IDH1 burden in blood and bone marrow samples (collected at pre-treatment and at least one on-treatment time point) were analyzed using next generation sequencing (NGS, FoundationOne Heme assay) in 67 patients from the dose-escalation portion of the study. Molecular clearance was defined as reduction of the IDH1 mutation below the limit of detection of the assay (1% for IDH). Molecular data show that treatment with AG-120 resulted in clearance of the IDH1 mutation in 36% of patients (5 of 14) in complete remission compared to 4% of patients (2 of 53) that did not achieve complete remission (p-value=0.003). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance.

"AG-120 continues to demonstrate an impressive single-agent efficacy and safety profile in this cohort of high-risk relapsed or refractory AML patients, with some responses maintained for approximately two years," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "In addition, new molecular data for AG-120 suggests some patients experience clearance of the IDH1 mutant gene in their blood or bone marrow as assessed by next generation sequencing, demonstrating the depth of response that can occur with AG-120 therapy."

"We are encouraged by the durable clinical activity of AG-120 and are working to bring this medicine to waiting patients with IDH1 mutant positive AML whose disease has progressed after standard treatments," said Chris Bowden, M.D., chief medical officer of Agios. "We plan to explore a similar expedited regulatory strategy for AG-120 that is being utilized for enasidenib (AG-221), which could result in an NDA submission in 2017."

Updated Phase 1 Dose-Escalation Data for AG-120 in Advanced Hematologic Malignancies

Clinical and molecular data reported are from 78 patients treated with AG-120 in the dose escalation phase of the ongoing Phase 1; data from the ongoing expansions were not reported. Doses were administered from 200 mg to 1,200 mg total daily doses. As of August 1, 2016, seven patients (9%) remain on treatment. The median age of these patients is 68 (ranging from 36-89). Patients received a median of two prior chemotherapy regimens (ranging from zero to five). A safety and efficacy analysis was conducted for all 78 treated dose-escalation patients. In addition, longitudinal mutant IDH1 (mIDH1) variant allele frequency (VAF) data were available for 67 patients.

Safety Data

A safety analysis conducted for all 78 treated patients as of the data cut-off shows that AG-120 continues to demonstrate a favorable safety profile.

The majority of adverse events reported by investigators were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhea, pyrexia and peripheral edema.
Fifty-three patients experienced at least one serious adverse event (SAE), the majority being disease related.
The maximum tolerated dose was not reached. The recommended Phase 2 dose was 500 mg once daily, which is being studied in the ongoing expansion phase of the trial.
Nine patients discontinued from the study due to death, including one reported as possibly related to AG-120.
All cause mortality at 30 and 60 days were 12% and 21%, respectively.
Efficacy Data

Thirty out of 78 treated patients achieved investigator-assessed objective responses for an overall response rate of 38%.

Of the 30 patients who achieved an objective response, there were 14 (18%) complete remissions (CR), eight CRs with incomplete neutrophil recovery or platelet recovery (CRi/CRp), six marrow CR (mCR)/morphologic leukemia-free state (MLFS) and two partial remissions (PR).
Of the 63 patients with R/R AML, 21 (33%) achieved an objective response, including 10 (16%) CRs, eight CRi/CRp, two MLFS and one PR.
Responses were durable, with a median response duration of 10.2 months (3.7- not estimable (NE)) overall and 6.5 months (3.7-NE) in the subset of patients with R/R AML.
Median duration of treatment is 3.2 months (ranging from 0.1 to 24.2 months).
IDH1 Mutational Clearance

Longitudinal mIDH1 VAF data were reported for 67 patients. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having:

mIDH1 detected at screening (any sample type), and
no reported mIDH1 mutation in at least one on-study time point (FoundationOne Heme sensitivity of 1%).
Importantly, IDH1-MC was observed in 36% of CRs (5 of 14) and 4% of non-CRs (2 of 53). IDH1-MC was enriched in patients achieving CR (p-value = .003). The median time to mutational clearance was 2.7 months (ranging from 1.1 to 3.8 months). This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance. Agios is continuing to study the potential relationship between IDH1-MC and clinical benefit for patients with AML.

About the Ongoing Phase 1 Trial for AG-120 in Advanced Hematologic Malignancies
AG-120 is being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion arms, including:

Arm 1: 125 IDH1 mutant positive AML patients who relapsed after bone marrow transplantation, are in second or later relapse, refractory to initial induction or reinduction treatment, or who relapse within one year of initial treatment, excluding patients with favorable-risk status
Arm 2: 25 untreated IDH1 mutant positive AML patients who are not candidates for standard-of-care chemotherapy
Arm 3: 25 patients with other non-AML IDH1 mutant, relapsed or refractory advanced hematologic malignancies
Arm 4: 25 patients with relapsed IDH1 mutant positive AML not eligible for arm 1 who have failed or are unable to receive standard of care
About Variant Allele Frequency (VAF)
Sequencing studies have demonstrated that most tumors exhibit extensive intra-tumor genetic heterogeneity characterized by individual cells that have different somatic mutations. For single-nucleotide mutations, or variants, the VAF is defined as the fraction of DNA sequence reads covering the variant position that contains the variant allele. This technique makes it possible to infer the subpopulations of tumor cells by counting the number of DNA sequence reads that contain a specific somatic mutation.

About IDH Mutations and Cancer
IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

About Acute Myelogenous Leukemia (AML)
AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Immature white blood cells known as myeloblasts, or "blasts" proliferate in the bone marrow rather than mature into normal blood cells. The decrease in normal blood cells can result in severe complications for patients including infections and dependence on blood product transfusions. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. Less than 10 percent of U.S. AML patients are eligible for bone marrow transplant and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 and IDH2 mutations are present in about 15 to 23 percent of AML cases.

On December 5, 2016 Acceleron Pharma Inc. (NASDAQ:XLRN) and Celgene Corporation (NASDAQ:CELG), reported preliminary results from an ongoing investigator initiated Phase 2 study with investigational drug sotatercept in patients with myelofibrosis at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California (Press release, Acceleron Pharma, DEC 5, 2016, View Source [SID1234516914]). Sotatercept is being developed as part of the global collaboration between Acceleron and Celgene.

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"These initial and encouraging data support our efforts for further clinical development work with our Acceleron-partnered programs in myelofibrosis," said Michael Pehl, President, Hematology and Oncology for Celgene. "We believe these programs have the potential to address a major unmet need in patients with myelofibrosis."

Highlights of the Sotatercept Myelofibrosis Phase 2 Data Presented at ASH (Free ASH Whitepaper)

Results

19 patients were enrolled and treated with sotatercept (12 patients at 0.75 mg/kg and 7 at 1 mg/kg) and 14 of these patients have received at least 5 doses of sotatercept and are evaluable for response
36% (5/14) of the evaluable patients achieved an anemia response, defined as a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions).
Overall Safety

Most adverse events were grades 1 or 2.
Adverse events at least possibly related to study drug that occurred include grade 3 hypertension leading to discontinuation, grade 1 myalgia, bone pain, pain in extremity and injection site reaction.
13 patients have discontinued from the study: 5 due to no response, 2 proceeded to stem cell transplantation, 2 had MF progression, 1 transformed to AML, 1 each withdrew consent, had unrelated medical problems and hypertension
Sotatercept 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 5, 2016, at 9:00 a.m. EST (6:00 a.m. PST). To participate by teleconference, please dial 877-312-5848 (domestic) or 253-237-1155 (international) and refer to the Acceleron ASH (Free ASH Whitepaper) Review.

To access the live webcast, please select "Events & Presentations" in the Investors section on Acceleron’s website (www.acceleronpharma.com) at least 10 minutes beforehand to ensure time for any downloads that may be required.

An archived webcast recording will be available on the Acceleron website beginning approximately two hours after the event.

About the Phase 2 Study

Data were presented from an ongoing investigator sponsored Phase 2 study of sotatercept in subjects with myelofibrosis at the conference. Subjects enrolled were red blood cell (RBC) transfusion-dependent, have hemoglobin < 10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin < 10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Patients received open-label sotatercept at 0.75 mg/kg or 1 mg/kg, dosed subcutaneously once every three weeks.

The primary outcome measures for the study include anemia response and safety. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response.

About Sotatercept

Sotatercept is an activin receptor type IIA fusion protein that acts as a ligand trap for members in the Transforming Growth Factor-Beta (TGF-β) superfamily involved in fibrosis and late stage erythropoiesis (red blood cell production). Acceleron and Celgene are jointly developing sotatercept as part of a global collaboration. Sotatercept is currently in multiple Phase 2 investigator initiated trials. For more information, please visit www.clinicaltrials.gov.

On December 5, 2016 Bellicum Pharmaceuticals, Inc. (Nasdaq:BLCM), a clinical stage biopharmaceutical company focused on discovering and developing novel cellular immunotherapies for cancers and orphan inherited blood disorders, reported a review of results to date from its multicenter BP-004 clinical trial of BPX-501 in the pediatric setting, and provided an update on the regulatory pathway for product registration in Europe at an investor and analyst event held today (Press release, Bellicum Pharmaceuticals, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227672 [SID1234516942]). Clinical results on BPX-501 in children with hematological malignancies were also presented in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting.

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"We have made significant progress with our BPX-501 program since initiating the BP-004 clinical trial in children two years ago," commented Tom Farrell, President and CEO of Bellicum Pharmaceuticals. "To date, we have treated more than 100 patients at leading pediatric transplant centers in Europe and the U.S. Results thus far have been impressive—including GvHD- and disease-free outcomes in children with a range of blood cancers and genetic diseases, as reported this weekend in several presentations at ASH (Free ASH Whitepaper). We’re also pleased with the progress we’ve made in formalizing an expedient pathway to regulatory approval in Europe with BPX-501 to treat both malignant and nonmalignant diseases. We look forward to providing an update on our U.S. regulatory path in the first half of 2017."

Overall Summary of Results of BP-004 Study with BPX-501 (n=85)

The Company presented a review of results to date of the BP-004 study in pediatric patients with malignant and nonmalignant diseases who underwent a haploidentical hematopoietic stem cell transplant (HSCT) followed by an add-back of genetically modified BPX-501 T cells. Eighty-five patients have been treated with BPX-501 at multiple U.S. and European sites and followed for at least 100 days (out of a total of 105 patients treated to date). Only one case of transplant-related mortality has been reported, unrelated to BPX-501 cells, and none out of 51 patients with nonmalignant disorders. Compared to T-depleted haplo-transplants alone, results have also shown significantly faster immune recoveries, as well as reduced viral infections and reactivation, and reductions in time to hospital discharge and re-hospitalizations due to infection. In five cases where uncontrolled acute GvHD was attributable to BPX-501 cells, rimiducid was administered and symptoms resolved.

Results have been consistent across a range of diseases and disorders where allogeneic HSCT is recognized as curative, including hemoglobinopathies such as Beta Thalassemia Major (β0β0), Sickle Cell Disease and Diamond-Blackfan Anemia; Primary Immune Deficiencies such as Severe Combined Immune Deficiency ("Bubble boy" disease) and Wiskott-Aldrich syndrome; leukemias and lymphomas; and bone marrow failure syndromes. The Company also reported that of six refractory AML patients treated under compassionate use because of their active disease and not included in the BP-004 summary data, 4 remain alive and in remission, including two who are now 11 and 20 months post-transplant.

Regulatory Update for BPX-501 in the European Union

The Company also announced today that the protocol assistance provided by the European Medicines Agency (EMA) for the registration study of BPX-501 in Europe is complete, and the Company is finalizing plans for the BP-004 trial extension. The Company will continue enrolling up to 40 additional patients with malignant and nonmalignant diseases in the trial. Concurrent with this study, the Company will initiate a comparator trial of malignant and nonmalignant patients receiving a matched unrelated donor (MUD) HSCT. This trial will include both retrospective patients and up to 40 prospective patients. The primary endpoint will be event-free survival (death, GvHD and infection) at 6 months.

Bellicum anticipates that it could pursue approval in the EU under the "exceptional circumstances" provision. Exceptional circumstances may be granted for medicines that treat very rare diseases, or where controlled studies are impractical or not consistent with accepted principles of medical ethics. The Company continues to discuss the regulatory path to approval in the U.S. with FDA and expects to provide an update in the first half of 2017.

Also today at the ASH (Free ASH Whitepaper) 2016 annual meeting, updated results were presented in patients with acute myeloid leukemia (AML).

AML Highlights (Abstract #4683)

"T-cell depleted HLA-haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) followed by donor lymphocyte infusion with T cells transduced with the inducible caspase 9 (iC9) suicide gene in children with hematological malignancies"

In a poster session, investigators presented data in 33 children with AML who received an α/β TCR-depleted haplo-HSCT and BPX-501 cells. The data indicate that infusion of BPX-501 results in low non-relapse mortality, and low rates of acute and chronic Graft versus Host Disease. Median follow-up was 8 months (range: 1–19 months). All 33 patients were high-risk CR1 (6/33) or CR2 (27/33). Study outcomes include:

All 33 patients engrafted with no secondary graft failure
One patient with steroid-resistant Grade II skin acute GvHD received rimiducid with complete resolution of disease in 24 hours
One treatment-related mortality from chronic GvHD was determined to be allograft-related and not from BPX-501 T cells
3 of 33 patients have relapsed; the probability of disease-free survival at 15 months is 83.6%
A replay of the investor and analyst meeting held today can be accessed from the News & Events section of the Bellicum website. An archived version of the webcast will be available for at least two weeks following the event.

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 adding back BPX-501 engineered T cells to speed immune reconstitution and provide control over viral infections, without unacceptable risk of uncontrollable GvHD. The ongoing BP-004 Phase 1/2 clinical study of BPX-501 is being conducted at transplant centers in the U.S. and Europe.

On December 5, 2016 BioLineRx Ltd. (NASDAQ/TASE: BLRX), a clinical-stage biopharmaceutical company dedicated to identifying, in-licensing and developing promising therapeutic candidates, reported positive Phase 2a correlative data, as well as detailed mechanism-of-action data, for BL-8040, the Company’s leading oncology platform at the ongoing 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exhibition in San Diego, California (Press release, BioLineRx, DEC 5, 2016, View Source;p=RssLanding&cat=news&id=2227400 [SID1234516915]).

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As previously announced, in an oral presentation at 10:30am PST today, entitled, "The High Affinity CXCR4 Inhibitor, BL-8040, Induces Apoptosis of AML Blasts and their Terminal Differentiation by Blocking AKT/ERK Survival Signals and Downregulating BCL-2, MCL-1 and Cyclin-D1 through Regulation of miR-15a/16-1 Expression," BioLineRx reports detailed data on the mechanism-of-action by which BL-8040 directly induces apoptosis of AML cells. The data, presented by Prof. Amnon Peled, are from in vitro studies using human AML cell lines and human primary AML samples, as well as in vivo studies using human primary AML cells engrafted in NOD scid gamma (NSG) mice.

In addition, yesterday, in a poster titled, "The Selective Anti Leukemic Effect of BL-8040, a Peptidic CXCR4 Antagonist, is Mediated by Induction of Leukemic Blast Mobilization, Differentiation and Apoptosis: Results of Correlative Studies from a Ph2a Trial in Acute Myeloid Leukemia," BioLineRx reported the final correlative results from its Phase 2a trial in acute myeloid leukemia (AML). The trial consisted of 45 AML patients receiving BL-8040 monotherapy on days 1-2, followed by the same dose of BL-8040 plus chemotherapy (Cytarabine) on days 3-7. All patients had poor-risk disease and had been heavily pretreated, with 19% having relapsed after a short first remission (≤12 months), 17% having 2 or more relapses, while 45% were refractory to 1-2 induction treatments. The composite complete remission rate, including both complete remission (CR) and complete remission with incomplete blood count recovery (CRi), was 38% in subjects receiving BL-8040 dose ≥1.0 mg/kg (n=39). These response rates are superior to the historical response rate of approximately 20% reported for high-risk AML patients treated with Cytarabine alone.

Philip Serlin, CEO of BioLineRx, commented, "We are excited to take part in the world’s premier event in malignant and non-malignant hematology, with over 20,000 hematology professionals from every subspecialty in attendance. At this event, we are pleased to present additional positive results about BL-8040. This includes clinical data that supports the rational for incorporation of BL-8040 in front-line AML treatment settings, such as AML consolidation and maintenance. In this regard, we are currently running a large Phase 2b study in consolidation AML, and we expect to initiate a Phase 1b study in maintenance AML under our collaboration with Genentech in mid-2017. We are also pleased to see pre-clinical data that support the mechanism of action of BL-8040 and show synergistic effects of BL-8040 with drugs that are also being investigated as AML treatments. We continue to anticipate that BL-8040, in combination with a growing repertoire of drugs, will be able to offer hope in this difficult to treat condition."

About BL-8040

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and certain hematological indications. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells from the bone marrow, thereby sensitizing these cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing apoptosis. In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, and T, B and NK cells. Furthermore, scientific findings in the field of immuno-oncology suggest that CXCR4 antagonists may be effective in inducing the infiltration of anti-tumor T cells into the tumor. Therefore, when combined with immune checkpoint inhibitors, BL-8040 has the potential to enable activated T cells to better reach tumor cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.