On December 5, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the presentation of data from a Phase 2 clinical trial of oral rigosertib and azacitidine in higher-risk myelodysplastic syndromes (HR-MDS) at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California (Press release, Onconova, DEC 5, 2016, View Source [SID1234516918]).

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"The complete remission rate amongst HMA-naïve HR-MDS patients is higher and responses occur more rapidly and durably with the oral rigosertib combination compared to historic single-agent azacitidine," commented Lewis R. Silverman, M.D., lead investigator in the trial and Associate Professor of Medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai. "Furthermore, the addition of oral rigosertib to azacitidine does not substantially change the adverse event profile of single-agent azacitidine, and thus may overcome the limitations identified in other HMA-based combinations."

The current standard of care for higher-risk MDS patients is one of two approved hypomethylating agents (azacitidine and decitabine, approved by the FDA in 2004 and 2006). Although these drugs are currently the standard of care in HR-MDS therapy, their overall response rate and duration of benefit is limited to a subset of eligible patients and all responding patients ultimately progress. Thus, there is an urgent need for improving therapeutic options for newly diagnosed HR-MDS patients. The 09-08 trial tested oral rigosertib in combination with injectable azacitidine in a dose ranging study (Phase 1), followed by an expansion cohort (Phase 2) to evaluate the efficacy and safety of the combination. Both 1st-line and 2nd-line HR-MDS patients were included in the study.

Summary of Presented Data from the 09-08 Combination Therapy Trial

Patient Demographics:

Thirty-three of 40 MDS patients enrolled were evaluable for response at the time of this analysis.
The median age was 66, with 73% of male patients. ECOG performance status was 0 or 1 in 95% of the patients. IPSS-R distribution was: 7.5% Low, 12.5% Intermediate, 37.5% High, 32.5% Very High and 10% unknown.
Safety/Tolerability of the Combination:

Oral rigosertib (560 mg qAM, 280 mg qPM) was administered on Day 1-21 of a 28-day cycle. Azacitidine 75 mg/m2/day SC or IV was administered for 7 days starting on Day 8.
The combination of oral rigosertib and azacitidine was well tolerated.
Adverse events of Grade ≥3 experienced across all cycles with the combination included thrombocytopenia (33%), neutropenia (30%), haematuria (13%), dysuria (8%), diarrhoea (3%) and arthralgia (3%).
Notably, the side effects were similar to those previously reported for azacitidine administered alone.
Efficacy of the Combination:

Thirty-three (20 HMA naïve; 13 HMA resistant) MDS patients were evaluable for efficacy analysis per IWG 2006 criteria (Cheson et al., Blood 2006).
25 of 33 (76%) patients responded per IWG — 85% of HMA naïve patients experienced a response and 62% of HMA resistant patients experienced a response.
7 of 20 (35%) HMA naïve and 1 of 13 (8%) HMA-resistant patients achieved a complete remission (CR). The median duration of CR was 8.0 months, which compares very favorably to the historic duration of CR and PR with single-agent azacitidine of 3.2 months1.
Hematologic improvement (HI) was observed in 11 of 33 patients (33%) and the median duration of response was 7.4 months for erythroid response, 8 months for platelet response, and 6.2 months for neutrophil response. Marrow CR was observed in 16 of 33 (48%) patients and the median duration of response was 12.3 months. Marrow CR combined with HI was observed in 10 of 33 (30%) patients.
The poster entitled, "Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study," was presented by Dr. Shyamala Navada of Mount Sinai School of Medicine at the Myelodysplastic Syndromes Session on Sunday, December 4, 2016 at the ASH (Free ASH Whitepaper) Annual Meeting in San Diego, California. A copy of the poster is available by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website.

"We are pleased by the positive efficacy signal observed over extended periods of treatment, and the acceptable tolerability of oral rigosertib and azacitidine in 1st-line HR-MDS," stated Ramesh Kumar, Ph.D., President and CEO of Onconova. "We presented Phase 2 data to the FDA as part of our End-of-Phase 2 meeting in September 2016, and based on these discussions, we are designing a randomized, placebo controlled Phase 3 clinical trial comparing the combination of oral rigosertib plus azacitidine to azacitidine plus placebo in 1st-line HR-MDS patients with the primary composite endpoint of CR and PR rate per 2006 IWG criteria. Based on our discussions with the FDA the primary efficacy endpoint of this trial will be composite response and not survival, permitting accelerated evaluation of outcomes."

Comprehensive Safety Assessment of Rigosertib in MDS Patients

In a second poster at the conference a safety review of 557 MDS/AML patients treated with rigosertib in clinical studies, including the randomized Phase 3 ONTIME trial was presented. The poster entitled, "Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)," can be accessed by visiting the Scientific Presentations section under the Investors & Media tab of Onconova’s website.

On December 5, 2016 Dynavax Technologies Corporation (NASDAQ: DVAX) reported clinical data from an ongoing Phase 1/2, two-part clinical trial evaluating intratumoral administration of SD-101 in the treatment of low-grade lymphoma (Press release, Dynavax Technologies, DEC 5, 2016, View Source [SID1234516916]). The combination of intratumoral SD-101 and low-dose irradiation resulted in tumor regression in untreated tumor sites as well as in the treated tumors. Treatment was well-tolerated and changes in T cell populations consistent with stimulation of anti-tumor immunity were observed in the treated lesions. These data were presented in a poster session on Sunday at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California.

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Data from the dose escalation and expansion phase of the study were reported from 28 evaluable patients. None of the patients had received prior treatment for their low-grade lymphoma. The primary endpoints of the trial are maximum tolerated dose (MTD) and evaluation of the safety of intratumoral SD-101 in combination with low dose radiotherapy. In addition, the trial is evaluating anti-tumor activity, pharmacodynamics, and duration of response. Doses ranged from 1 mg to 8 mg per injection in successive cohorts.

Key findings presented include:

Of the 28 evaluable patients treated across all dose levels, 3 had a partial response (PR) and1 had a complete response (CR) as measured by Cheson criteria.
Durable abscopal tumor shrinkage was observed in the majority of patients.
Confirming observations in the dose escalation phase, the most common treatment-related treatment emergent adverse events (TEAEs) in the expansion phase were flu-like symptoms, consistent with the engagement of TLR9 and the induction of interferon-alpha.
Increases in CD8+ cells were observed in the injected tumor, and correlated with an increased abscopal tumor shrinkage
"The clinical data emerging from our SD-101 program continues to be encouraging. We look forward to providing updates from our ongoing clinical trials," stated Eddie Gray, chief executive officer of Dynavax Technologies. "We will discuss this program and our oncology pipeline in our cancer R&D Day which will be webcast live on December 9th at 8:30 a.m. EST."

About SD-101

SD-101 is Dynavax’s proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. SD-101 is being studied for its multiple anti-tumor activities in innate immune cells and activation of plasmacytoid dendritic cells to stimulate T cells specific for antigens released from dying tumor cells. TLR9 agonists such as SD-101 enhance T and B cell responses and provide potent Type 1 interferon induction and maturation of plasmacytoid dendritic cells to antigen-presenting cells. SD-101 is being evaluated in several Phase 1/2 oncology studies to assess its safety and activity.

For information about SD-101 trials that are currently recruiting patients, please visit www.clinicaltrials.gov.

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.

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.