On December 3, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN), a global biotechnology company, reported phase 1b data evaluating vadastuximab talirine (SGN-CD33A; 33A) in combination with the frontline standard of care regimen for induction (cytarabine and daunorubicin, also known as 7+3) for younger patients with newly diagnosed acute myeloid leukemia (AML) in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016 (Press release, Seattle Genetics, DEC 3, 2016, View Source [SID1234516877]). The data were also featured in an ASH (Free ASH Whitepaper) press program and selected to be included in the 2017 Highlights of ASH (Free ASH Whitepaper) post-meeting program. 33A is an investigational antibody-drug conjugate (ADC) targeted to CD33, a protein which is expressed on leukemic cells in nearly all AML patients. Schedule your 30 min Free 1stOncology Demo! "Our clinical trial data reported at ASH (Free ASH Whitepaper) demonstrate that adding vadastuximab talirine, also known as 33A, to standard of care treatment results in a rapid, high rate of remissions in frontline, younger AML patients with poor prognosis. Notably, seventy-eight percent of patients who achieved remissions in this trial tested negative for minimal residual disease, which means no cancer could be detected with a sensitive test," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "In this trial, 33A in combination with 7+3 was well-tolerated, with a low early mortality rate. Based on these promising, early data, we plan to initiate a randomized phase 2 clinical trial in 2017 in younger newly diagnosed AML patients to further evaluate the potential benefit of adding 33A to standard of care."
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"People with acute myeloid leukemia die of infections or bleeding within weeks or a few months of diagnosis without effective, aggressive chemotherapy. Even with current treatment regimens, fewer than 50% of younger adults are successfully treated. The phase 1 results of 33A in combination with standard of care show a high rate of remissions in younger newly diagnosed AML patients without significantly adding to the toxicity of the treatment. Notably, 94 percent of remissions occur with only one cycle of treatment," said Harry P. Erba, M.D., Ph.D., University of Alabama-Birmingham and presenter of the phase 1 data at ASH (Free ASH Whitepaper). "Furthermore, the majority of these patients have no evidence of disease following the 33A combination even using a very sensitive test for residual leukemia (minimal residual disease negative). The rate at which patients become minimal residual disease negative following 33A combination treatment offers encouraging preliminary evidence that 33A in combination with 7+3 could reduce relapse rates and improve long-term outcomes for these patients."
The following interim results from the ongoing phase 1 study evaluating 33A in combination with 7+3 in frontline AML will be presented by Dr. Harry P. Erba, University of Alabama-Birmingham, in an oral session on Saturday, December 3, 2016:
A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) (Abstract #211, oral presentation on Saturday, December 3, 2016 at 4:00 p.m. PT)
Data were reported from 42 newly diagnosed AML patients with a median age of 46 years and intermediate or adverse cytogenetic risk of 50 percent and 36 percent, respectively. Seventeen percent of patients had secondary AML. Key findings include:
Of 42 patients evaluable for response, 32 patients (76 percent) achieved a complete remission (CR) or complete remission with incomplete platelet or neutrophil recovery (CRi). Ninety-four percent of the remissions (CR or CRi) occurred with one cycle of therapy.
Twenty-five of the 32 patients (78 percent) who achieved remission were negative for minimal residual disease (MRD). MRD-negative remission post-induction is generally correlated with reduced rates of relapse and improved overall survival.
Remissions were observed in higher-risk patients, including 18 of 21 (86 percent) and nine of 15 (60 percent) patients with intermediate or adverse cytogenetics, respectively.
Overall survival (OS) is still evolving and median OS has not yet been reached. The 30-day mortality rate was two percent. Twenty-one of 42 patients (50 percent) went on to receive an allogenic stem cell transplant.
The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were febrile neutropenia, thrombocytopenia, anemia and neutropenia. No non-hematologic treatment-emergent adverse events of Grade 3 or higher were reported in 15 percent or more of patients. No veno-occlusive disease/sinusoidal obstruction syndrome or significant hepatotoxicity was observed on treatment.
The most common Grade 1 and 2 treatment-emergent adverse events occurring in 20 percent or more of patients were nausea, diarrhea, constipation, hypokalemia and decreased appetite. No infusion-related reactions occurred.
This phase 1 study continues to enroll patients. A randomized phase 2 trial of 33A plus 7+3 versus 7+3 alone is planned.
Seattle Genetics is broadly evaluating 33A across multiple lines of therapy in patients with myeloid malignancies. The ongoing global phase 3 CASCADE study is a randomized, double-blind, multi-center trial designed to evaluate 33A in combination with hypomethylating agents (HMAs) in approximately 500 previously untreated AML patients. Further, phase 1 and 2 clinical trials for relapsed AML and for previously untreated myelodysplastic syndrome (MDS) are currently underway. More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.
About Acute Myeloid Leukemia
Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive cancer of the bone marrow and blood that progresses rapidly without treatment. Cancerous cells called leukemic blasts multiply and crowd out normal cells in the bone marrow and interfere with normal blood cell production leading to anemia, infection, and bleeding. According to the SEER database and Kantar Health Sciences, in 2016 approximately 33,000 new cases of AML (mostly in adults) will be diagnosed in the U.S. and Europe. In the U.S. alone, nearly 10,500 deaths will occur from AML this year. Treatment options for AML have remained virtually unchanged for nearly 40 years and frontline treatment consists primarily of chemotherapy. A subset of patients (typically those over 60 years of age) cannot tolerate such therapy and are typically given lower intensity agents, supportive care, or are recommended for clinical trials.
About Vadastuximab Talirine (SGN-CD33A)
Vadastuximab talirine (SGN-CD33A; 33A) is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ proprietary ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.
33A was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.
Year: 2016
Regenacy Pharmaceuticals to be Launched by Acetylon Pharmaceuticals and Celgene Corporation Agrees to Complete Acquisition of Acetylon
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.
Promedior Announces Completion of Patient Enrollment Milestones in Phase 2 Clinical Studies of PRM-151 in Both Idiopathic Pulmonary Fibrosis and Myelofibrosis
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.
Regenacy Pharmaceuticals to be Launched by Acetylon Pharmaceuticals and Celgene Corporation Agrees to Complete Acquisition of Acetylon
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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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
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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.
Surface Oncology CD47 Program Demonstrates Promising Anti-Tumor Activity in Hematological Disease Models
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.