On August 30, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported it has completed the rolling submission of the New Drug Application (NDA) for its investigational anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, to the U.S. Food and Drug Administration (FDA) (Press release, Ariad, AUG 30, 2016, View Source [SID:1234514794]). ARIAD is seeking U.S. marketing approval of brigatinib for patients with metastatic ALK-positive (ALK+) non-small cell lung cancer (NSCLC) who are resistant or intolerant to crizotinib. The Company is seeking accelerated approval for brigatinib from the FDA and has requested a priority review of the application, which, if granted, would allow for approval of brigatinib eight months after the NDA submission, as opposed to 12 months for a standard review.

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"Many patients with ALK-positive non-small cell lung cancer eventually develop disease progression," said Corey Langer, M.D., director of thoracic oncology in the Abramson Cancer Center of the University of Pennsylvania and a professor of Hematology-Oncology in Penn’s Perelman School of Medicine. "We are excited that the brigatinib NDA submission is now complete and are hopeful that brigatinib’s data, including the observation of complete responses and activity in the central nervous system, will provide patients and their oncologists with a new treatment option."

ARIAD’s NDA submission includes clinical data from its Phase 1/2 and pivotal Phase 2 ALTA trials of brigatinib. Data from the ALTA trial, in which patients who had experienced disease progression on crizotinib therapy were randomized to one of two brigatinib regimens, were presented at the 2016 Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). With a median follow-up of 8.3 months, the data show that, for patients treated with the 180 mg regimen with a seven day lead-in at 90 mg (Arm B), 54 percent achieved an investigator-assessed confirmed objective response, the trial’s primary endpoint. In this arm, the median progression free survival (PFS) exceeded one year (12.9 months). Additionally, a 67% confirmed intracranial objective response rate was achieved in patients with measurable brain metastases. The most common treatment-emergent adverse events (TEAEs; ≥ 25% of all patients in Arm B), regardless of relationship to treatment, were nausea (40%), diarrhea (38%), cough (34%), increased blood creatine phosphokinase (30%), headache (27%) and fatigue (27%). TEAEs, ≥ grade 3, occurring in ≥ 5 percent of all patients in Arm B, were increased blood creatine phosphokinase (9%), hypertension (6%) and pneumonia (5%). A subset of pulmonary adverse events with early onset (median: Day 2; range: Day 1-9) occurred in 6 percent of all patients (≥ grade 3 in 3% of patients); no such events with early onset occurred after dose escalation to 180 mg QD in Arm B.

"With the completion of the brigatinib submission this week, we are excited by its potential, if approved, to offer additional hope to patients and their families," stated Paris Panayiotopoulos, president and chief executive officer of ARIAD. "We are thankful to the patients and physicians who participated in the clinical trials of brigatinib. We remain grateful to the FDA for granting brigatinib a breakthrough designation and the benefit of a rolling submission process, unique to the U.S. regulatory system."

Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK+ NSCLC. ARIAD plans to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell cancer (NSCLC). The global Phase 2 ALTA trial is the basis for brigatinib’s initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.

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.