On June 25, 2015 Merrimack and Baxalta Incorporated, a wholly-owned subsidiary of Baxter International reported that the New Drug Application (NDA) for MM-398 (irinotecan liposome injection), also known as "nal-IRI," has been accepted for review by the U.S. Food and Drug Administration (FDA) (Press release, Merrimack, JUN 25, 2015, View Source [SID:1234505800]). Merrimack is seeking U.S. marketing approval of MM-398 for the treatment of patients with metastatic adenocarcinoma of the pancreas who have been previously treated with gemcitabine-based therapy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

In addition, the FDA has classified the NDA as having Priority Review status. A Priority Review designation is for drugs that treat serious conditions and, if approved, would provide significant improvements in the safety or effectiveness of the treatment of serious conditions compared to available therapies. The FDA has set a goal of October 24, 2015 to take action under the Prescription Drug User Fee Act (PDUFA).

"The rapid timeline associated with Priority Review designation brings Merrimack closer to our goal of making MM-398 available to patients with pancreatic cancer who have been previously treated with gemcitabine and are in significant need of treatment options," said Robert Mulroy, President and CEO at Merrimack. "We look forward to working with the FDA as they review the application over the next several months."

Merrimack’s application is based upon the results of an international Phase 3 study (NAPOLI-1) conducted in patients with metastatic pancreatic cancer who previously received gemcitabine-based therapy. MM-398 in combination with 5-fluorouracil (5-FU) and leucovorin achieved its primary and secondary endpoints by demonstrating a statistically significant improvement in overall survival, progression free survival and overall response rate compared to the control group of patients who received a combination of 5-FU and leucovorin. The most common Grade 3 or higher adverse events in patients receiving MM-398 and 5-FU/LV were neutropenia, fatigue and gastrointestinal effects. This was the first global Phase 3 study in a post-gemcitabine setting to show a survival benefit in this aggressive disease. Data for the study were presented at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (ESMO GI) in June 2014 and the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2015 Gastrointestinal Cancers Symposium (ASCO GI) in January 2015.

The European Medicines Agency (EMA) has also accepted for review a Marketing Authorization Application (MAA) for MM-398 for the treatment of patients with metastatic adenocarcinoma of the pancreas who have been previously treated with gemcitabine-based therapy. The acceptance of the MAA marks the beginning of the review process in the European Union for MM-398 in this indication.

"The acceptance of our Marketing Authorization Application for review by the European Medicines Agency is a positive indicator of the promise of this treatment to address a significant unmet need for patients with metastatic pancreatic cancer and the support for innovative new options," said David Meek, head of Oncology at Baxalta. "We are actively advancing our plans to introduce nal-IRI following approval and look forward to extending the utility of the treatment to patients around the world."

The FDA and EMA have granted MM-398 orphan drug designation for patients with metastatic pancreatic cancer. MM-398 was granted Fast Track designation by the FDA in November 2014.

Merrimack and Baxalta have entered into an exclusive licensing agreement to develop and commercialize MM-398 outside of the United States. PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize MM-398 in Taiwan.

About MM-398

MM-398 (irinotecan liposome injection), also known as "nal-IRI," is a novel encapsulation of irinotecan in a long-circulating liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death.

About Pancreatic Cancer 1,2

Pancreatic cancer is rare and deadly, accounting for only three percent of all cancer cases worldwide but is the fourth leading cause of cancer death. An estimated 140,000 new cases are diagnosed every year around the world, two-thirds of which are among people aged 65 or older.

Because the signs and symptoms of pancreatic cancer are non-specific and may not appear until the disease has spread to other sites, approximately 80% of patients are diagnosed with late stage disease. These patients are not candidates for surgery, instead receiving chemotherapy as the mainstay of their therapy. This contributes to the five year survival rate for all patients being less than six percent; fewer than 20 percent of newly diagnosed patients survive more than two years. There is no consensus on the standard of care for patients with metastatic pancreatic cancer previously treated with a gemcitabine-based therapy.

On June 24, 2015 Tokai Pharmaceuticals reported the initiation of ARMOR3-SV, Tokai’s pivotal Phase 3 clinical trial of galeterone in men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors express the AR-V7 splice variant, which is a truncated form of the androgen receptor (AR) that has been associated with non-responsiveness to commonly-used oral therapies for mCRPC (Press release, Tokai Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505799]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

Tokai also announced today that the components of the AR-V7 clinical trial assay have been finalized by its collaborator, Qiagen (NASDAQ: QGEN; Frankfurt Prime Standard: QIA), and that global deployment of the assay is now underway.

"ARMOR3-SV represents an important step forward in bringing precision medicine to patients with prostate cancer, and we are pleased with the progress made by our valued collaborator Qiagen in readying the AR-V7 clinical assay for global implementation," said Jodie Morrison, President and Chief Executive Officer of Tokai. "With worldwide commercial rights to galeterone, our pivotal clinical trial on track to read out by the end of 2016, and a strong financial position, Tokai is well positioned to realize its mission of bringing new therapeutic treatment options to patients with prostate cancer."

"Based on the evidence reported thus far, a diagnostic tool that can predict patient responsiveness to certain therapies should lead to more informed treatment decisions and ultimately better care for prostate cancer patients," said Mary Ellen Taplin, M.D., Director of Clinical Research, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and lead U.S. investigator of ARMOR3-SV. "Given the encouraging clinical data reported to date for galeterone and the precision medicine approach being employed in Tokai’s pivotal trial, this study has the opportunity to alter the treatment landscape for metastatic CPRC patients."

ARMOR3-SV will compare galeterone to Xtandi (enzalutamide) in 148 mCRPC treatment-naïve patients whose prostate tumors express the AR-V7 splice variant. These truncated ARs are missing the C-terminal end of the AR that contains the ligand-binding domain, which is known as C-terminal loss. AR-V7 is the most common form of C-terminal loss. The pivotal trial will employ a precision medicine approach for selection of patients with the AR-V7 splice variant by using an AR-V7 clinical trial assay successfully optimized for global use by Qiagen. The primary endpoint of ARMOR3-SV is radiographic progression-free survival assessed by blinded independent central review. The design of ARMOR3-SV is aligned with feedback obtained from the U.S. Food and Drug Administration and the European Medicines Agency.

ARMOR3-SV has been initiated at more than 15 sites in the United States, with site initiations in Canada and the United Kingdom anticipated later in June. Additional study centers throughout North America, Western Europe and Australia are expected to join the study in the coming months. In addition, with recent finalization of the components of the AR-V7 clinical trial assay, technology transfer activities and training of the global central laboratories are underway, and screening of eligible patients for the splice variant is expected to begin in July. The company expects topline data from ARMOR3-SV to be available by the end of 2016.

On June 24, 2015 Agios Pharmaceuticals reported dose administration for the first patient in a Phase 1, open-label, dose-escalation and expansion study of single agent AG-881, a small molecule that has shown in preclinical studies to fully penetrate the blood-brain barrier and inhibit isocitrate dehydrogenase-1 (IDH1) and IDH2 mutations in cancer models (Press release, Agios Pharmaceuticals, JUN 24, 2015, View Source [SID:1234505798]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

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

                  Schedule Your 30 min Free Demo!

"The initiation of this study represents a significant milestone for Agios, as it marks the third program from our portfolio of IDH inhibitors to enter the clinic in less than two years," said Chris Bowden, M.D., chief medical officer of Agios. "We look forward to producing important early data to guide our future development plans and continuing to demonstrate Agios’ leadership in cancer metabolism and drug development for IDH inhibitors."

"We are eager to explore the profile of AG-881 as we continue to investigate the role of IDH inhibitors for the treatment of patients with IDH mutant-positive tumors," said Howard Burris, M.D., Sarah Cannon Research Institute, an investigator for the study. "The Phase 1 study of this second-generation IDH inhibitor expands the opportunities for clinical development in the genetically defined spectrum of IDH1 or IDH2 mutant-positive tumors."

About the AG-881 Phase 1 Study in Advanced Solid Tumors, including Gliomas, with an IDH1 or IDH2 Mutation

The purpose of the Phase 1 multi-center, open-label study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-881 in advanced solid tumors. AG-881 will be administered continuously as a single agent dosed orally in a 28-day cycle. The first portion of the study includes a dose-escalation phase in which cohorts of patients will receive ascending oral doses of AG-881 to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose based on safety and tolerability. The second portion of the study is a dose expansion phase where patients will receive AG-881 to further evaluate the safety, tolerability and clinical activity of the recommended Phase 2 dose. Please refer to www.clinicaltrials.gov for additional clinical trial information.

Upcoming Milestones for AG-881

A second dose-escalating and expansion trial, for patients with advanced IDH1 or IDH2 mutant-positive hematologic malignancies whose cancer has progressed on a prior IDH inhibitor therapy, is expected to begin shortly.

About IDH Mutations and Cancer

IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including acute myeloid leukemia (AML) and gliomas. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells’ epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

Summary of Agios and Celgene Collaboration on IDH Mutant Inhibitors

Agios and Celgene entered a global, strategic collaboration in April 2010, and to date, three potential new distinct investigational medicines have emerged – the IDH2 mutant inhibitor, AG-221; the IDH1 mutant inhibitor, AG-120; and the pan-IDH mutant inhibitor, AG-881, which was recently announced as part of a new collaboration between the companies. These three investigational medicines aim to improve treatment outcomes for patients whose cancers carry IDH mutations, including difficult-to-treat AML and glioma, a type of aggressive brain tumor with a poor prognosis.

Each of these investigational medicines carries different financial terms and rights under the collaboration:

AG-221: Celgene has worldwide development and commercialization rights for AG-221. Agios is eligible for up to $120 million in milestone payments and royalties on any net sales.
AG-120: Agios retains U.S. development and commercialization rights, while Celgene has development and commercialization rights outside the U.S. Agios is eligible to receive royalties on any net sales outside the U.S. and up to $120 million in milestone payments. Celgene is eligible to receive royalties on any net sales in the U.S.
AG-881: Joint worldwide development and 50/50 profit share collaboration. Agios is eligible to receive regulatory milestone payments up to $70 million.