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]).

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"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."

"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.

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.

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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.

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.

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.

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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.

"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.

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]).

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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.

"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.