On December 3, 2016 Trillium Therapeutics Inc. (NASDAQ: TRIL; TSX: TR), a clinical-stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported data from an ongoing study with its lead drug candidate, TTI-621, in patients with relapsed or refractory hematologic malignancies, at the American Society of Hematology (ASH) (Free ASH Whitepaper) 58th Annual Meeting in San Diego (Press release, Trillium Therapeutics, DEC 3, 2016, View Source [SID1234516895]).

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"We are encouraged by the initial results from the study of TTI-621 in advanced hematologic malignancies, as we have seen decreased tumor volume and/or reduced metabolic activity over extended intervals of continued dosing in several patients," commented Niclas Stiernholm, Ph.D., president and chief executive officer of Trillium Therapeutics. "We believe that data from this study provide preliminary evidence that TTI-621 monotherapy is both active and well tolerated, supporting our hypothesis that neutralization of the inhibitory CD47 signal enables macrophage anti-tumor activity. We have determined an optimal dose level, which we are taking forward into the Phase 1b cohort expansion phase of the trial, as we seek to further define the benefit of TTI-621 in patients with multiple types of blood cancers."

TTI-621 Dose-Escalation Phase 1a

CD47 is an immune checkpoint that binds to SIRPa and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells often overexpress CD47 and exploit this pathway to avoid macrophage-mediated destruction. TTI-621 (SIRPaFc) is a novel immune checkpoint inhibitor designed to bind human CD47 and block the "do not eat" signal, promoting both innate and adaptive immunity. The lgG1 region of TTI-621 can engage Fc-gamma receptors on macrophages, enhancing phagocytosis and anti-tumor activity.

A first-in-human, Phase 1a/b, open label, multicenter study (NCT02663518) began in February 2016. During the Phase 1a portion of the study, 18 patients with relapsed/refractory lymphomas were enrolled in sequential dose cohorts (3 + 3 design) and received weekly IV infusions of TTI-621 to characterize safety, tolerability, pharmacokinetics, and to determine the optimal dose for subsequent enrollment in the expansion phase.

The results presented demonstrate that an optimal dose of 0.2 mg/kg/week was well-tolerated and associated with predictable, transient thrombocytopenia – consistent with augmented systemic phagocytosis. Importantly, this dose level obtained both CD47 receptor occupancy in circulating leukocytes and elevations in macrophage-associated cytokines that are both associated with high phagocytosis of tumor targets in vitro. Finally, decreasing volume and/or reduced metabolic activity over extended intervals of continued dosing were observed in several patients and one patient achieved a partial response.

The TTI-621 Phase 1a study poster presented at ASH (Free ASH Whitepaper) can be found on the company’s website at www.trilliumtherapeutics.com. Additional information about this clinical trial of TTI-621 is available at www.clinicaltrials.gov using identifier: NCT02663518.

TTI-621 Cohort Expansion Phase 1b

With the dose-escalation phase of TTI-621 in patients with lymphoma completed, patient enrollment across a broad spectrum of hematologic malignancies commenced in November in the Phase 1b multi-cohort expansion portion of the trial. The trial’s objectives are to further characterize the safety of TTI-621 and gain preliminary evidence of anti-tumor activity in patients with a variety of hematologic malignancies.

In addition to the eight original expansion cohorts, indolent B cell lymphoma, aggressive B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome, the Phase 1b expansion will also include patients with myeloproliferative neoplasms.

In a separate expansion cohort, patients with CD20-positive lymphomas will be treated with TTI-621 in combination with rituximab.

On December 2, 2016 Surface Oncology, an immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, reported that it will present preclinical data on its CD47 program at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Surface Oncology, DEC 2, 2016, View Source [SID1234516902]). The data demonstrate that SRF231, a fully human CD47 antibody, induces robust tumor cell phagocytosis and clearance, both alone and in combination with existing standard of care treatment.

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"These data highlight the strong anti-tumor activity of SRF231 in hematological disease models," said Vito Palombella, PhD, Chief Scientific Officer at Surface Oncology, "and further suggest that SRF231 has the potential to be the best-in-class CD47 antibody to help patients with a wide range of cancers."

CD47 is an important immune escape mechanism exploited by multiple tumor types, making it a target with broad therapeutic potential. CD47 acts as a macrophage checkpoint or "don’t eat me" signal that prevents cells from being eliminated by a macrophage-mediated process called phagocytosis.

The data presented at ASH (Free ASH Whitepaper) demonstrate that SRF231 enhances tumor cell phagocytosis alone and in combination with opsonizing antibodies (e.g., anti-CD20 Ab). SRF231 also leads to profound tumor growth inhibition in models of multiple myeloma and non-Hodgkin’s lymphoma.

Previously, Surface presented data at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s annual meeting demonstrating that SRF231 binds with high affinity to CD47, stimulates phagocytosis of cancer cells in vitro, and has potent anti-tumor activity in multiple in vivo disease models. These data also demonstrate that SRF231 does not induce detectable hemagglutination or phagocytosis of red blood cells in vitro, a potentially important safety advantage. SRF231 is expected to enter clinical trials in 2017.

On December 2, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the discovering and developing novel small molecule drugs directed against tumor metabolism and tumor immunology targets for the treatment of cancer, reported that preclinical data for its lead drug candidate CB-839, the company’s novel, orally bioavailable glutaminase inhibitor, will be presented at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, which is being held from December 3-6, 2016 in San Diego, California (Press release, Calithera Biosciences, DEC 2, 2016, View Source;p=RssLanding&cat=news&id=2227168 [SID1234516878]). Data to be presented include the following two poster presentations:

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Glutaminase Inhibitor CB-839 Enhances Proteasome Inhibitor Sensitivity in Multiple Myeloma Cells
Presenter: Ravyn Thompson, Nathan Dolloff, Medical University of South Carolina
Oral and Poster Abstracts Session 652: Myeloma: Pathophysiology and Preclinical Studies, Hall GH, Abstract 3294
Sunday, December 4, 2016, 6:00 p.m.-8:00 p.m. PT
Gls Inhibitor CB-839 Modulates Cellular Metabolism in AML and Potently Suppresses AML Cell Growth When Combined with 5-Azacitidine
Presenter: Tianyu Cai, Marina Konopleva, The University of Texas, MD Anderson Cancer Center
Oral and Poster Abstracts Session 616: Acute Myeloid Leukemia: Novel Therapy, Hall GH, Abstract 4064
Monday, December 5, 2016, 6:00 p.m.-8:00 p.m. PT

On December 2, 2016 Acetylon Pharmaceuticals reported that it has entered into an agreement to be acquired by Celgene Corporation (Press release, Acetylon, DEC 2, 2016, View Source [SID1234516903]). Prior to the consummation of the acquisition, Acetylon will spin out a new company, Regenacy Pharmaceuticals, LLC, which will focus on the development of novel drug candidates that selectively regenerate intracellular transport and upregulate gene expression to modify the course of disease. Regenacy will receive exclusive worldwide rights to Acetylon’s Phase 2 selective histone deacetylase 6 (HDAC6) inhibitor, ricolinostat (ACY-1215), for the treatment of certain non-cancer disease indications including neuropathies, as well as Acetylon’s preclinical selective HDAC1,2 inhibitor candidates and patent families for development in all human disease indications including sickle cell disease and beta-thalassemia.

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The acquisition will provide Celgene with, among other things, worldwide rights to Acetylon’s selective HDAC6 inhibitor programs and intellectual property in oncology, neurodegeneration, and autoimmune disease, including its lead drug candidates citarinostat (ACY-241) and ricolinostat (ACY-1215).

Financial terms of the acquisition are not being disclosed. The transaction is subject to customary closing conditions, including the expiration of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976. BMO Capital Markets Corp. served as exclusive financial advisor to Acetylon in the transaction.

Key members of the Acetylon executive team will join Regenacy, which will operate out of Acetylon’s former headquarters in Boston’s Seaport District. Regenacy will be owned by Acetylon shareholders (excluding Celgene) and will receive net working capital in Acetylon to fund Regenacy operations.

"Since its founding in 2008, Acetylon has made substantial progress in the development of selective HDAC inhibitors for enhanced therapeutic outcomes," said Walter C. Ogier, President and Chief Executive Officer of Regenacy. "We are excited to continue Acetylon’s legacy through the receipt of rights to many of Acetylon’s most promising compounds and the continued advancement of these clinical and preclinical programs in disease indications outside of Celgene’s areas of strategic focus, where we believe patients may especially benefit from selective HDAC inhibition."

"Acetylon has had a longstanding partnership with Celgene, and their acquisition of our HDAC6 inhibitor programs is a positive event for patients and a favorable outcome for our shareholders and employees," said Marc A. Cohen, Chairman of Acetylon. "Celgene is the optimal partner to realize the fullest potential of Acetylon’s selective HDAC6 inhibitor programs in multiple myeloma and other oncology indications. Their intimate knowledge of citarinostat and extensive experience in oncology make them uniquely qualified to continue development of these exciting programs."

About Selective HDAC Inhibition

Histone deacetylases (HDACs) comprise a family of 18 related enzymes found in most human cells, 11 of which utilize zinc atoms to catalyze the removal of acetyl groups from intracellular proteins. By this function, HDACs can induce structural changes in the DNA-histone complex to result in altered gene expression and protein synthesis. Inappropriate deacetylation can disrupt these processes and contribute to a wide range of diseases, whereas regeneration of acetylation selectively causes apoptosis (cell death) in cancer cells and also induces favorable immunomodulatory effects. Currently available HDAC drugs non-selectively affect the expression of numerous other genes in normal cells as well as disease-causing cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage, and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDACs is anticipated to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

On December 2, 2016 Promedior, Inc., a clinical stage biotechnology company developing novel therapeutics for the treatment of fibrosis, reported that it completed enrollment in two Phase 2 clinical trials to evaluate PRM-151, its lead product candidate (Press release, Promedior, DEC 2, 2016, View Source [SID1234516904]). The idiopathic pulmonary fibrosis (IPF) trial completed the enrollment of 117 patients while the myelofibrosis trial completed enrollment of 84 patients. Promedior plans to present the results of these Phase 2 clinical studies at appropriate medical meetings once they are completed and analyzed.

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"We believe attaining these enrollment milestones speaks to both the need for new disease-modifying therapies for IPF and myelofibrosis and the promise that others see in PRM-151, Promedior’s lead product candidate" said Rick Jack, Ph.D., Promedior’s President and COO. "We look forward to completing these trials with the goal to bring PRM-151 forward as a potential new treatment option for patients with IPF and myelofibrosis, and ultimately for other fibrotic diseases."

The IPF clinical trial is a Phase 2 randomized, double-blind, placebo-controlled, pilot study designed to evaluate the efficacy and safety of PRM-151 administered once-a-month to subjects with IPF. The primary endpoint is forced vital capacity (FVC)% predicted change from baseline. For additional details about this clinical trial (NCT02550873), please visit www.clinicaltrials.gov.

The myelofibrosis clinical trial is a randomized, double blind Phase 2 study to determine the efficacy and safety of three different doses of PRM-151 in subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), or Post-Essential Thrombocythemia MF (post-ET MF). Subjects were randomized to one of three dose cohorts: 0.3 mg/kg, 3.0 mg/kg or 10 mg/kg of PRM-151 administered once-a-month. The primary endpoint is bone marrow response rate, defined as the percent of subjects with a reduction in bone marrow fibrosis score by at least one grade according to WHO criteria at any time during the study. For additional details about this clinical trial (NCT01981850), please visit www.clinicaltrials.gov.

About Idiopathic Pulmonary Fibrosis
IPF is a serious, life-limiting lung disease characterized by fibrosis and scarring of lung tissue with a median survival of 3–5 years after diagnosis. Replacement of normal lung tissue by fibrosis results in restriction in the ability to fill the lungs with air and decreased transfer of oxygen from inhaled air into the bloodstream resulting in lower oxygen delivery to the brain and other organs. Patients with IPF most often suffer from progressive shortness of breath, particularly with exertion; chronic, sometimes debilitating, hacking cough; fatigue and weakness, and chest discomfort. Currently available approved drugs slow down but do not halt disease progression and the only curative therapy is lung transplant, an option merely available for a small group of patients. While estimates vary, it is believed that IPF could affect approximately 130,000 patients in the US and approximately 76,000 patients in Europe.

About Myelofibrosis
Myelofibrosis (MF), a type of myeloproliferative neoplasm, is a serious, life-limiting cancer that is characterized by fibrosis of the bone marrow. Replacement of the bone marrow by scar tissue prevents the normal production of blood cells, leading to anemia, fatigue, and increased risk of bleeding and infection. Production of blood cells shifts to the spleen and liver (extramedullary hematopoiesis), which become enlarged, causing severe discomfort, inability to eat, and weakness. Symptomatic myelofibrosis affects approximately 18,000 people per year in the US, with a median age of 61-66.1 The only potentially curative treatment is allogeneic bone marrow transplant, which results in reversal of fibrosis and all symptoms, but is a realistic option for only a small number of patients. Other currently available therapies address the symptoms, but have minimal if any impact on the underlying fibrosis.

About PRM-151
PRM-151, Promedior’s lead product candidate, is a recombinant form of the endogenous human innate immunity protein, pentraxin-2 (PTX-2), which is specifically active at the site of tissue damage. PRM-151 is an agonist that acts as a macrophage polarization factor to prevent and potentially reverse fibrosis. PRM-151 has shown broad anti-fibrotic activity in multiple preclinical models of fibrotic disease, including pulmonary fibrosis, myelofibrosis2, acute and chronic nephropathy, liver fibrosis, and age-related macular degeneration.

Phase 1a and 1b clinical studies in healthy subjects and IPF patients have demonstrated that PRM-151 was well tolerated. Additionally, a Phase 1b study in patients with IPF showed encouraging results in exploratory efficacy end points3. In an earlier Phase 2 trial in myelofibrosis, PRM-151 treatment was well-tolerated and demonstrated decreases in bone marrow fibrosis and stable or improved hematologic parameters4.