On August 29, 2016 (GLOBE NEWSWIRE) Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a biotechnology company committed to developing enzyme-based therapeutics in the field of amino acid metabolism to treat rare diseases and cancer, reported the dosing of the first patient in a Phase 1 trial of AEB1102, a recombinant human enzyme designed to degrade the amino acid arginine, for the treatment of the hematological malignancies acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Press release, Aeglea BioTherapeutics, AUG 29, 2016, View Source [SID:1234514793]). Schedule your 30 min Free 1stOncology Demo! "Cancer cells such as those found in AML patients are believed to have a metabolic dependence on arginine for growth. Deprivation of arginine by AEB1102 has the potential to impact this challenging disease," said David G. Lowe, Ph.D., co-founder, president and chief executive officer. "We are pleased to expand the AEB1102 oncology program to include hematological malignancies in addition to our ongoing Phase 1 trial in advanced solid tumors."
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"We are rapidly executing on our strategy for AEB1102 in oncology, having now dosed our first patient with AML/MDS refractory to hypomethylating agents," said Sandra Rojas-Caro, M.D., chief medical officer. "Current treatment options for patients who have these forms of hematological malignancies are limited. AEB1102 may have the potential to offer a significant clinical benefit for these patients in need."
About the Trial
The Phase 1, multicenter, single-arm, open-label, dose escalation trial of AEB1102 for the treatment of hematological malignancies is designed to assess the safety and tolerability of AEB1102 as a single agent. The trial will enroll patients with relapsed or refractory AML or MDS refractory to hypomethylating agents. Key objectives of the trial include determining the maximum tolerated dose, pharmacokinetics, pharmacodynamics (including reduction of circulating levels of arginine) and the recommended Phase 2 dose. Disease-specific expansion cohorts will be enrolled at the maximally tolerated or biologically relevant dose.
Please refer to www.clinicaltrials.gov for additional clinical trial details.
About AEB1102
AEB1102 is a recombinant human arginase I enzyme designed to degrade the amino acid arginine. Aeglea is developing AEB1102 to treat two extremes of arginine metabolism, including arginine excess in patients with Arginase I deficiency, as well as some cancers which have been shown to have a metabolic dependency on arginine. In patients with Arginase I deficiency, AEB1102 is intended for use as Enzyme Replacement Therapy to restore the function of arginase I in patients and return elevated blood arginine levels to the normal physiological range. Aeglea is currently conducting a Phase 1 clinical trial in patients with advanced solid tumors to evaluate the safety and tolerability of AEB1102. Data from this trial demonstrated that AEB1102 has the ability to reduce blood arginine levels, providing initial human proof of mechanism.
About Arginine Dependence in Cancer Cells
Dysregulation of amino acid metabolism has been shown to be a key event in tumor growth and development. Unlike healthy cells, these tumors cells have an abnormally high appetite for certain amino acids and are unable to create their own supply, making them vulnerable to starvation through depletion of that amino acid in the blood. AEB1102 is intended to address an unmet need for these tumor types by degrading arginine in the blood, reducing its level below the normal range to starve the tumor.
Author: [email protected]
Syros’ Scientific Founders Publish on First Selective CDK12 and CDK13 Inhibitor as Promising Approach for Treatment of Cancer
On August 29, 2016 Syros Pharmaceuticals (NASDAQ: SYRS) reported today that research from its scientific founders validates CDK12 and CDK13, members of the transcriptional cyclin-dependent kinase family that play a critical role in regulating gene expression, as promising new drug targets for a range of aggressive and difficult-to-treat cancers (Press release, Syros Pharmaceuticals, AUG 29, 2016, View Source [SID:1234514792]). These findings were possible as a result of the discovery of a highly selective CDK12 and CDK13 inhibitor by Syros’ scientific founders and underscore the potential of Syros’ pioneering approach for understanding and drugging transcriptional targets to advance a new wave of medicines that control the expression of disease-driving genes. Schedule your 30 min Free 1stOncology Demo! The research from Nathanael Gray’s lab at Dana-Farber Cancer Institute and Richard Young’s lab at the Whitehead Institute for Biomedical Research, which was published online today in the peer-reviewed scientific journal Nature Chemical Biology (Zhang T., et al., "Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors"), shows that inhibiting CDK12 and CDK13 with a small molecule selectively decreases the expression of DNA damage response genes and super-enhancer associated transcription factors implicated in cancer, including acute leukemia and breast and ovarian cancers. The results suggest that a selective CDK12 and CDK13 inhibitor could be effective as a monotherapy in certain cancers and as a combination therapy in other cancers by increasing their susceptibility to targeted therapies involved in DNA damage repair such as PARP1 inhibitors.
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Transcriptional kinases have been historically difficult to drug selectively, and the absence of selective CDK12 and CDK13 inhibitors has hindered the ability to study the consequences of inhibiting them in healthy and cancerous cells. Using a novel chemistry approach, Syros’ scientific founders designed the first selective CDK12 and CDK13 inhibitors. This novel class of inhibitors achieves its selectivity in part by covalently, or irreversibly, binding to a cysteine residue near the kinase domain that is unique to some transcriptional kinases. This approach was first used to create SY-1365, Syros’ first-in-class selective CDK7 inhibitor, which is on track to begin a Phase 1/2 trial in the first half of 2017.
Syros holds all research, development and commercial rights to the research compound described in the paper, as well as related compounds, through both ownership of the intellectual property and a license from Dana-Farber. Syros is leveraging its unique expertise in drugging transcriptional kinases to create selective CDK12 and CDK13 inhibitors suitable for clinical development.
"A key focus of our proprietary gene control platform is understanding and drugging transcriptional targets, including transcriptional kinases. By modulating these targets with small molecules, we aim to control the expression of the critical set of genes driving the disease with a single drug," said Eric Olson, Ph.D., Syros’ Chief Scientific Officer. "These findings provide further evidence of the therapeutic potential of selectively inhibiting transcriptional kinases as a promising approach for treating a range of aggressive cancers. Building on the work of our founders, as well as our success in creating SY-1365, we believe we are uniquely positioned to create selective inhibitors of CDK12 and CDK13 that can achieve a therapeutic benefit without the toxicities associated with less selective CDK inhibitors."
Selectivity has proven critical in targeting the CDK family. While pan-CDK inhibitors have shown anti-tumor activity, their clinical utility has been limited due to their toxic effect on blood cells. By contrast, Syros’ selective CDK7 inhibitor SY-1365 has been shown to induce tumor regression and prolong survival in preclinical models of acute leukemia, while having minimal effect on blood cells counts, demonstrating a more favorable profile than a non-selective CDK inhibitor.
Kadmon Initiates Phase 2 Clinical Trial Evaluating Tesevatinib in Glioblastoma
On August 29, 2016 Kadmon Holdings, Inc. (NYSE: KDMN) reported that the first patient has been dosed in a Phase 2 clinical trial of tesevatinib, the Company’s oral tyrosine kinase inhibitor, for the treatment of recurrent glioblastoma (Press release, Kadmon, AUG 29, 2016, View Source [SID:1234514791]). The open-label, multicenter study examines tesevatinib monotherapy administered at 300 mg once daily in up to 40 patients in the United States. Schedule your 30 min Free 1stOncology Demo! Tesevatinib is an oral inhibitor of epidermal growth factor receptor (EGFR), a cell surface receptor whose gene is amplified in more than 50% of gliomas. Unlike other EGFR inhibitors, tesevatinib has been observed in animal models to be highly blood-brain barrier penetrant, reaching equal concentrations in the brain and the blood. Published data have shown that other EGFR inhibitors have poor brain penetration, limiting their ability to reach and effectively treat brain tumors. We believe that tesevatinib may also penetrate the blood-brain barrier in humans, based on initial observations in certain patients exhibiting tumor shrinkage and improvement in neurological symptoms in our ongoing Phase 2 clinical trial in EGFR-mutant non-small cell lung cancer (NSCLC) that has metastasized to the brain. Based on its mechanism of action and brain penetrance, we believe tesevatinib is potentially well suited to treat glioblastoma.
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"We are encouraged by tesevatinib’s potential ability to cross the blood-brain barrier in humans, which may lead to meaningful clinical activity against brain tumors," said Harlan W. Waksal, M.D., President and Chief Executive Officer at Kadmon. "With its potent EGFR inhibition and biodistribution, we believe tesevatinib represents an ideal therapeutic candidate for this difficult-to-treat disease."
In addition to glioblastoma and the ongoing Phase 2 clinical trial in EGFR-mutant NSCLC that has metastasized to the central nervous system (the brain and leptomeninges), Kadmon is developing tesevatinib for the treatment of polycystic kidney disease, a genetic kidney disorder in which EGFR plays a central role.
ERYTECH Completes Patient Enrollment in Phase 2b Trial for eryaspase (GRASPA®) in Acute Myeloid Leukemia
On August 29, 2016 ERYTECH Pharma (Paris:ERYP) (ADR:EYRYY) (Euronext Paris: ERYP), the French biopharmaceutical company developing ‘tumor starvation’ treatments for acute leukemia and other oncology indications with unmet medical needs, reported that it has reached full patient enrollment in the Phase 2b trial of eryaspase, also known as ERY-ASP or GRASPA, for the treatment of acute myeloid leukemia (AML) (Press release, ERYtech Pharma, AUG 29, 2016, View Source [SID:1234514790]). Schedule your 30 min Free 1stOncology Demo! The open-label, randomized, multi-center clinical trial, which is being conducted at more than 20 sites in Europe, has completed enrollment of a total of 123 patients and is on track for reporting of primary data in the second half of 2017. Patients enrolled in the trial are over the age of 65, newly-diagnosed with AML, and unable to receive intensive chemotherapy. The primary endpoint is overall survival (OS) at one year.
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"We are pleased to have reached this important clinical milestone of complete enrollment in our trial for AML and expect to reporting primary data from the trial in the second half of 2017," said Gil Beyen, Chairman and CEO of ERYTECH. "AML is a very aggressive cancer. We are developing eryaspase with the goal of contributing to the treatment of these patients, many of whom may respond to L-asparaginase, but have difficulty with the side effects associated with the current available forms. Therefore, we believe the increased tolerability profile obtained through the encapsulation of L-asparaginase in the red blood cells could result in a new innovative approach to treatment of AML patients."
Eryaspase, or GRASPA, consists of the L-asparaginase enzyme encapsulated inside donor-derived red blood cells through ERYTECH’s proprietary ERYCAPS technology platform. The enzyme degrades asparagine, an amino acid that is essential for the tumor cells to grow and multiply, which starves and eventually kills the cancer cells. The Phase 2b trial was designed to evaluate the efficacy of GRASPA when added to low-dose cytarabine, the current standard of care. The study is performed in collaboration with Orphan Europe (Recordati Group), ERYTECH’s partner for the anticipated commercialization of GRASPA for the treatment of ALL and AML in Europe.
About acute myeloid leukemia (AML)
With about 34 000 new patients per year in Europe and the US, AML is the most common type of acute leukemia. Affecting mainly the adult and senior patient population that often cannot tolerate the existing forms of asparaginase products, AML represents one of the highest mortality rates among all type of cancers and an important unmet medical need.
CTI BioPharma Announces Top-Line Results From PERSIST-2 Phase 3 Trial Of Pacritinib For High-Risk Patients With Advanced Myelofibrosis
On August 29, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported top-line results from PERSIST-2, a randomized, controlled Phase 3 clinical trial comparing pacritinib, an investigational oral multikinase inhibitor, with physician-specified best available therapy (BAT), including ruxolitinib, for the treatment of patients with myelofibrosis whose platelet counts are less than 100,000 per microliter — a patient population with high-risk advanced disease (Press release, CTI BioPharma, AUG 29, 2016, View Source;p=RssLanding&cat=news&id=2197807 [SID:1234514783]).
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Three hundred eleven (311) patients were enrolled in the study, which formed the basis for the safety analysis. Two hundred twenty-one (221) patients who had a chance to reach Week 24 (the primary analysis time point) at the time the clinical hold was imposed and constituted the intent-to-treat (ITT) analysis population utilized for the evaluation of efficacy. Preliminary results demonstrated that the PERSIST-2 trial met one of the co-primary endpoints showing a statistically significant response rate in spleen volume reduction (SVR) in patients with myelofibrosis treated with pacritinib compared to BAT, including the approved JAK2 inhibitor ruxolitinib (p<0.01). Although the PERSIST-2 trial did not meet the other co-primary endpoint of greater than 50 percent reduction in Total Symptom Score (TSS), the preliminary analysis approached marginal significance compared to BAT (p=0.0791).
"Unlike patients with myelofibrosis who have normal baseline platelet counts where median survival is reported at 88 months, we recently reported from our institution’s experience that patients with severe thrombocytopenia (low platelets) had a median survival of about 14 months," said Srdan (Serge) Verstovsek, M.D., Ph.D., Director, Clinical Research Center for MPNs at the University of Texas MD Anderson Cancer Center and principal investigator for the PERSIST-2 Phase 3 clinical trial of pacritinib. "These patients represent up to 30 percent of all myelofibrosis patients and an unmet medical need. Data from the PERSIST-2 prospective randomized, controlled trial is encouraging because we need an effective therapy to treat the most challenging patients with low platelet counts we see in our practice."
The co-primary endpoints of the trial were the proportion of patients achieving a 35 percent or greater reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) and the proportion of patients achieving a Total Symptom Score (TSS) reduction of 50 percent or greater using MPN-SAF TSS 2.0 diary from baseline to Week 24.
The most common treatment emergent adverse events for pacritinib were generally manageable diarrhea, nausea and vomiting. The incidence of cardiac and bleeding adverse events (all grades and grade 3-4 including deaths) were similar across the arms. Overall mortality rates were comparable between arms. Additional data from ongoing analyses along with top-line results from PERSIST-2 will be submitted for presentation at an upcoming scientific meeting.
Myelofibrosis is associated with significantly reduced quality of life and shortened survival. Spleen enlargement (splenomegaly) is a common and debilitating symptom of myelofibrosis. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia and red blood cell transfusion requirements increase significantly.
"Having analyzed data from two Phase 3 trials with the only JAK inhibitor to be studied in severely thrombocytopenic patients, including patients on JAK2 therapy or those who failed prior JAK2, we are encouraged by pacritinib’s clinical profile in this difficult-to-treat group of patients with myelofibrosis," said James A. Bianco, M.D., President and Chief Executive Officer, CTI BioPharma. "We are grateful for the support and commitment of the investigators, our steering committee and, most importantly, all the patients who participated in PERSIST-2."
About PERSIST-2
PERSIST-2 was a randomized (1:1:1), controlled, open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to best available therapy (BAT), including the approved JAK1/JAK2 inhibitor ruxolitinib, for patients with myelofibrosis whose platelet counts were less than or equal to 100,000 per microliter (≤100,000/μL). Three hundred eleven (311) patients were randomized to receive 200 mg pacritinib twice daily (BID), 400 mg pacritinib once daily (QD) or BAT. Clinical studies for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration (FDA) in February 2016. The study was originally designed to enroll, and the Special Protocol Assessment (SPA) requires enrollment of 300 patients to evaluate the study objectives. Two hundred twenty-one (221) patients were enrolled at least 24 weeks prior to the full clinical hold and thus were potentially evaluable for efficacy. These patients were the population used to evaluate the study efficacy endpoints. The co-primary endpoints, originally agreed upon under the SPA, were the percentage of patients achieving a 35 percent or greater reduction in spleen volume measured by MRI or CT scan from baseline to Week 24 of treatment and the percentage of patients achieving a Total Symptom Score (TSS) reduction of 50 percent or greater using seven key symptoms as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to Week 24. The primary objective of the study was to compare pooled pacritinib arms vs BAT. As a result of the full clinical hold on pacritinib, the SPA agreement is no longer in effect for PERSIST-2 and CTI BioPharma is no longer entitled to the benefit of the SPA.
About the Phase 3 Development Program of Pacritinib
Pacritinib was evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis, with one trial in a broad set of patients without limitations on platelet counts, the PERSIST-1 trial; and the other in patients with low platelet counts, the PERSIST-2 trial. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy.
Clinical studies under the CTI BioPharma investigational new drug (IND) for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016.
PERSIST-1 was a randomized (2:1), controlled, open-label, multinational Phase 3 trial evaluating the efficacy and safety of pacritinib compared to BAT, excluding JAK2 inhibitors, which included a broad range of currently utilized treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis), regardless of the patients’ platelet counts. The study included patients with severe or life-threatening thrombocytopenia. Patients were randomized to receive 400 mg pacritinib once daily or BAT, excluding JAK2 inhibitors. As previously reported, the trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan) in the intent-to-treat population (ITT).
About Pacritinib
Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.
CTI BioPharma and Shire are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Shire will jointly commercialize pacritinib in the U.S. while Shire has exclusive commercialization rights for all indications outside the U.S.
About Myelofibrosis and Myeloproliferative Neoplasms
Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of progressive blood cancers. The three main types of MPNs are primary myelofibrosis (PMF), polycethemia vera (PV) and essential thrombocythemia (ET).1
Myelofibrosis is a serious and life-threatening bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain.
The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S., of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis3 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia (AML).4 The median survival for high-risk myelofibrosis patients is less than 1.5 years, while the median survival for patients with myelofibrosis overall is approximately 6 years.4