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 3, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported the presentation of data from preclinical studies supporting the clinical development of the company’s proprietary monoclonal antibody (mAb) BION-1301, a humanized anti-APRIL (A PRoliferation-Inducing Ligand) antibody for the treatment of multiple myeloma (Press release, Aduro BioTech, DEC 3, 2016, View Source;p=RssLanding&cat=news&id=2227318 [SID1234516873]). Data from these in vivo and in vitro preclinical studies demonstrated that BION-1301 effectively neutralized APRIL, preventing its binding to BCMA (B cell maturation antigen), an essential receptor expressed on multiple myeloma cells. Based on the mechanism of action and anti-tumor activity observed in earlier preclinical studies with the parental anti-APRIL antibody, hAPRIL.01A, BION-1301 has the potential to inhibit multiple myeloma tumor growth, survival and chemoresistance. These data, which will be highlighted in a poster presentation (Poster #2112) at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, further underscore the potential application of BION-1301 for use as a single agent, or in combination with current standard of care therapies, for the treatment of multiple myeloma.

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"In patients with multiple myeloma, there is an overabundance of APRIL, a ligand which plays a critical role in the proliferation of multiple myeloma cells," stated Andrea van Elsas, Ph.D., chief scientific officer of Aduro Biotech Europe. "With BION-1301, which was derived from Aduro’s proprietary B-select antibody platform, we are blocking APRIL from binding to its target receptor, thereby inhibiting the growth and survival of multiple myeloma cells."

Dr. van Elsas continued, "Based on the data to be presented later today, we believe BION-1301 represents a novel antibody with a novel mechanism of action that has potential in the treatment of multiple myeloma, alone or in combination regimens. We look forward to advancing BION-1301 into clinical development in the coming year in our effort to bring much needed new treatment options to patients with multiple myeloma."

Researchers conducted in vivo and in vitro studies in preclinical models of multiple myeloma comparing anti-tumor activity achieved with BION-1301 and its parental antibody, hAPRIL.01A. Data from these studies demonstrate the successful creation and functional characterization of BION-1301 as a novel APRIL-neutralizing antibody.

In April 2016, Aduro announced the publication of a study entitled, "APRIL and BCMA promote human multiple myeloma growth, chemoresistance, and immunosuppression in the bone marrow microenvironment," by Kenneth Anderson, M.D. Ph.D., and Tai Yu-Tzu, Ph.D. of the Dana-Farber Cancer Institute. The article appeared in the June 2016 issue (Volume 127, Number 25) of the peer-reviewed journal Blood. The publication elucidates the roles of BCMA and its ligand APRIL in multiple myeloma, highlighting the potential therapeutic use of an agent that targets APRIL and fully blocks its interaction with its receptors. The authors demonstrated through in vivo and in vitro preclinical studies that the APRIL/BCMA ligand/receptor pair drives multiple myeloma tumor growth and survival, and activates immunosuppressive mechanisms that allow the tumor to thrive. Importantly, the studies demonstrated that the parental antibody to BION-1301 halts tumor growth and overcomes drug resistance to chemotherapeutic agents lenalidomide and bortezomib in preclinical models.

About Multiple Myeloma
Lymphocytes (B cells and T cells) are the primary cell types within the immune system that work together to fight infection and disease. As B cells respond to normal infection in the body, they mature and change into plasma cells, which in turn make antibodies that help the body attack infection. While lymphocytes circulate throughout the body, plasma cells remain primarily in the bone marrow. Multiple myeloma is a blood cancer that occurs when malignant plasma cells proliferate uncontrollably. Approximately 50,000 new cases of multiple myeloma will be diagnosed in the United States and Europe each year. While many new therapies have become available in recent years, multiple myeloma remains incurable and significant unmet needs exist among patients who relapse following, are resistant to, or cannot tolerate currently available agents.

About APRIL and BION-1301
APRIL is a member of the tumor necrosis factor (TNF) superfamily and is primarily secreted by bone marrow and/or myeloid cells. APRIL is overproduced in patients with multiple myeloma and binds to BCMA to stimulate a wide variety of responses that promote multiple myeloma growth and suppress the immune system so that the tumor cells are allowed to proliferate. The team at Aduro Biotech Europe, in collaboration with Jan Paul Medema, Ph.D. of the Amsterdam Medical Center, developed BION-1301, a humanized antibody that blocks APRIL from binding to its receptors, using Aduro’s B-select monoclonal antibody platform. In preclinical studies, BION-1301 eliminated malignant cells and reduced resistance to therapy in models of multiple myeloma. In addition to multiple myeloma, APRIL’s role in other cancers and in B cell dependent autoimmune and inflammatory diseases indicate that BION-1301 may also be useful in treating chronic lymphocytic leukemia, colorectal cancer and Berger’s disease (caused by IgA antibody lodging in the kidneys).

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.

On December 2, 2016 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported data examining the combination of entrectinib and trametinib in overcoming resistance to TRK inhibition during a late-breaking oral plenary presentation (during the Exceptional Response and Expected Resistance Session) at the 2016 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Molecular Targets and Cancer Therapeutics Symposium in Munich, Germany (Press release, Ignyta, DEC 2, 2016, View Source [SID1234516880]). Entrectinib is the company’s orally available, CNS-penetrant tyrosine kinase inhibitor, targeting tumors that harbor TRK, ROS1 or ALK fusions, and is currently in a registration-enabling Phase 2 clinical trial known as STARTRK-2.

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"This presentation is a great example of the successful translation of preclinical observations into clinical practice for the benefit of patients," said Alexander Drilon, M.D., of Memorial Sloan Kettering Cancer Center, who presented the data on behalf of the abstract authors at ENA. "The patient experience described in today’s presentation highlights the ability of entrectinib, in combination with a MEK inhibitor, to overcome potential treatment resistance that has been described for TRK inhibitors."

Data presented describe results from a single patient protocol designed to allow co-administration of entrectinib and trametinib, a commercially-approved MEK inhibitor. The patient, diagnosed with mammary analog secretory carcinoma (or MASC) with an NTRK3 fusion—~90-100% of MASC cases have TRK fusions—and previously treated with multiple surgeries, radiation, vinorelbine, carboplatin/paclitaxel, doxorubicin and crizotinib, experienced a rapid and confirmed partial response (89% reduction) with single-agent entrectinib treatment and remained on therapy for nine months. However, during the course of therapy, the patient’s tumor developed a solvent front point mutation, the predicted mechanism of resistance to first generation TRK inhibitors and analogous to a common mechanism of resistance for other TKIs against other fusion targets.

Based on both in vitro and in vivo data developed by Ignyta, indicating that entrectinib plus a MEK inhibitor could overcome such TRK inhibitor resistance, a single patient protocol was created, reviewed by the FDA and implemented to allow for dose escalation of entrectinib in combination with trametinib. While on the combination, all drug-related adverse events (AEs) were grade 1 or 2, and no new AEs specific to the combination were encountered. The patient achieved a 22% reduction in tumor volume and remained on the combination regimen for nearly seven months.

"This single-patient protocol is an excellent example of our vision at Ignyta, leveraging the molecular alterations responsible for cancer’s growth to design rational treatment strategies for patients in their fight against cancer," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "In addition to STARTRK-2, our global Phase 2 basket trial of entrectinib in multiple tumor histologies and STARTRK-NG, our Phase 1/1b trial of entrectinib in pediatric patients with solid tumors, we look forward to further exploration of entrectinib in combination with a MEK inhibitor in a Phase 1/1b clinical trial anticipated to initiate in the second half of 2017."

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 [SID1234556812]). 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.