On October 28, 2015 Astellas Pharma Inc. (TSE: 4503) reported dosing of the first patient in a randomized Phase 3 registration trial of gilteritinib (ASP2215) versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) (Press release, Astellas, OCT 28, 2015, View Source [SID:1234507827]). The primary endpoint of the trial is overall survival (OS).

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Gilteritinibis a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinibhas demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.

The gilteritinib Phase 3 trial follows a Phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the Phase 1/2 trial presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting demonstrated a 57.5 percent overall response rate and a 47.2 percent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10%) observed in the study were diarrhea (13.4%), fatigue (12.4%) and AST increase (11.3%). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.

On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE.

About the Phase 3 Study

The Phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with Acute Myeloid Leukemia (AML). The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS. For more information about this trial go to www.clinicaltrials.gov, trial identifier NCT02421939.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib.

About Acute Myeloid Leukemia

Acute myeloid leukemia is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.

About SAKIGAKE

The SAKIGAKE designation system can shorten the review period in the following three approaches: 1.) Prioritized Consultation 2.) Substantial Pre-application Consultation and 3.) Prioritized Review.

Also, the system will promote development with the following two approaches: 4.) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5.) Substantial Post-Marketing Safety Measures.

On October 28, 2015 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported that Servier has given MacroGenics notice that it will not exercise its option to license regional rights for enoblituzumab (MGA271), a clinical-stage monoclonal antibody targeting B7-H3, a member of the B7 family of immune regulators (Press release, MacroGenics, OCT 28, 2015, View Source [SID:1234507817]). As a result, MacroGenics now controls worldwide rights to all programs within its B7-H3 franchise.

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"Enoblituzumab is the cornerstone of MacroGenics’ B7-H3 franchise, a portfolio of complementary therapeutic product candidates aimed at a promising immune regulatory target," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "As we highlighted at our recent R&D Day, we have significantly expanded our research and development efforts across B7-H3-directed therapies, including the advancement of MGD009, a B7-H3 x CD3 bispecific DART molecule, into the clinic, as well as research efforts around a B7-H3-targeted antibody drug conjugate. Servier’s decision enables us to integrate development and commercial strategies across these assets in the future."

Enoblituzumab is currently being evaluated in patients with a variety of tumor types in three clinical studies, including a monotherapy trial as well as in combination with either ipilimumab or pembrolizumab. In October 2015, MacroGenics provided an overview of initial clinical data from the ongoing monotherapy trial of enoblituzumab. Results presented to date suggest that enoblituzumab is well tolerated and tumor regression has been observed in heavily-treated patients across different tumor types, including prostate and bladder cancer, as well as in melanoma patients who have progressed following treatment with one or more checkpoint inhibitor therapies. In addition, evidence of T-cell immunomodulatory function has been observed in patients treated with enoblituzumab. Data from the ongoing monotherapy trial will be presented as a late-breaking abstract session at the 2015 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting on November 7, 2015.

In November 2011, MacroGenics entered into an agreement with Servier regarding enoblituzumab. Under the terms of that agreement, MacroGenics retained full development and commercialization rights to enoblituzumab in the United States, Canada, Mexico, Japan, Korea and India. Servier obtained an option to develop and commercialize enoblituzumab in Europe and other countries. Servier was required to exercise this option within 90 days after receipt of a data package delivered in July 2015 containing initial monotherapy data. Because Servier has not exercised this option, the agreement is now expired and MacroGenics controls worldwide development and commercialization rights to enoblituzumab. The collaboration with Servier related to the development of Dual-Affinity Re-Targeting, or DART, molecules is unaffected by this decision.

About MacroGenics’ B7-H3 Franchise and Enoblituzumab

MacroGenics is pursuing therapeutic product candidates utilizing three different and complementary mechanisms of action targeting B7-H3, an immunomodulatory molecule expressed in a broad range of tumor types. The leading program, enoblituzumab, is an Fc-optimized monoclonal antibody directed against B7-H3 and currently in clinical testing against a variety of tumor targets, both as monotherapy and in combination with either ipilimumab or pembrolizumab. The second program, MGD009, also in clinical testing, is a bispecific DART molecule designed to target tumors expressing B7-H3 by recruiting and expanding T cells at the tumor site. The third program, currently in pre-clinical development, is an antibody-drug conjugate (ADC) directed against solid tumors expressing B7-H3. MacroGenics retains worldwide development and commercialization rights to all three of these programs.

On October 28, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported that the independent committee of the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) clinical trial has chosen LOXO-101 as the sole, dedicated treatment arm for patients with tropomyosin receptor kinase, or TRK, gene fusions (Press release, Loxo Oncology, OCT 28, 2015, View Source [SID:1234507816]). The NCI-MATCH trial will initially enroll 3,000 patients with tumor biopsies available for comprehensive genomic profiling and assign these patients to an appropriate targeted therapy arm based on the molecular abnormalities of each tumor. NCI-MATCH, which began enrolling patients in August 2015, currently has 10 open treatment arms employing drugs from multiple sponsors, and plans to open as many as 25 additional arms over the next year. Each arm of the study pairs specific genetic alterations to a specific targeted treatment.

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"We are honored that an independent committee of the NCI-MATCH trial has selected LOXO-101 for the TRK fusion arm of the NCI-MATCH trial," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "NCI-MATCH captures the true spirit of precision medicine, and should answer many important questions for patients with advanced cancer. We look forward to working closely with NCI and its national network of investigators."

About NCI-MATCH

NCI-MATCH is supported by NCI and coordinated by the ECOG-ACRIN Cancer Research Group, part of the NCI’s National Clinical Trials Network (NCTN). The NCTN has national reach and NCI-MATCH is opening at NCTN clinical sites across the United States. The trial opened for enrollment in August 2015 at more than 700 clinical trial sites in 48 states with the initial goal of analyzing tumor biopsies from 3,000 patients. Each arm utilizes only one targeted therapy and enrolls adults with advanced of genetically defined solid tumors and lymphomas that are no longer responding (or never responded) to standard therapy and have begun to grow. Additional arms will be added to NCI-MATCH through 2016. The primary endpoint for NCI-MATCH is the objective response rate, or ORR, defined as the percentage of patients whose tumors have a complete or partial response to treatment.

Biopsy specimens removed from patients’ tumors are sent to a central pathology core site at the MD Anderson Cancer Center. Nucleic acids are isolated and assayed for more than 4,000 different variants across 143 genes at one of four clinical genetic testing labs. To efficiently investigate the effectiveness of molecularly targeted therapies for patients with the corresponding driver mutations, a broad-based genomic pre-screening effort such as this is necessary to find and assign patients whose tumors harbor these mutations, regardless of tumor origin. The trial covers the cost of the biopsy and molecular tests, and patients will receive the drugs without charge if they are eligible to enroll for an NCI-MATCH treatment. Neither the patients nor a health plan/insurance company will have to pay for any study-related biopsies or the assigned study drug(s) that were matched to a patient’s cancer.

For more information, see the NCI’s website here. Patients, families, and clinicians can also call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for assistance in English and Spanish or contact NCI’s LiveHelp service.

About LOXO-101

LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions. For additional information about both the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.

On October 28, 2015 Ipsen (Euronext: IPN) (ADR: IPSEY) and Telesta Therapeutics Inc. (TSX: TST) (PNK: BNHLF) reported that they have entered into an exclusive licensing agreement for Ipsen to develop and commercialize MCNA1 for the treatment of high risk non-muscle invasive bladder cancer (NMIBC) in all countries of the world, with the exception of the United States, where Telesta is establishing commercial operations, Canada, South Africa, Mexico, South Korea and Japan (Press release, Ipsen, OCT 28, 2015, View Source [SID:1234507815]).

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Telesta recently filed a Biologics License Application (BLA) with the U.S. Food and Drug Administration (FDA) for MCNA for the treatment of high risk non-muscle invasive bladder cancer patients who are refractory or relapsing from BCG front-line treatment. The FDA has assigned priority review to Telesta’s BLA with a review (PDUFA) date of February 27, 2016. Telesta retains full and sole ownership of MCNA rights in the US and Japan and will be responsible for the commercial launch of MCNA in the United States while Ipsen will initiate discussions with regulatory authorities to identify the regulatory path and potential requirements for the product in Europe and other key licensed territories.

Commenting on this partnership, Dr. Michael Berendt, Chief Executive Officer and Chief Scientist of Telesta Therapeutics noted: "Ipsen is the ideal commercial partner to bring MCNA to patients in the key pharmaceutical markets outside of the United States. They are a recognized development and commercial leader in the field of uro-oncology and are committed to collaborating with our team to ensure that MCNA is brought forward as rapidly as possible to provide a therapeutic option for this underserved patient population. Their extensive knowledge of the regulatory and commercial landscape, their commercial presence in more than 100 countries across the globe, as well as their commitment to their core urology franchise, particularly bladder cancer, is why we are convinced that they will successfully bring MCNA to urologists and their patients, outside of the United States, and generate significant value for Telesta’s shareholders."

Marc de Garidel, Chairman and Chief Executive Officer of Ipsen stated: "Ipsen is pleased to enter into a partnership with Telesta Therapeutics for Europe and key Rest of the World territories. We believe MCNA, which received priority review from FDA, is a promising second line bladder cancer treatment that would perfectly fit our urology-oncology portfolio in Europe." Marc de Garidel added: "This licensing agreement fits our business development strategy, focusing on selected niche therapeutic areas".

Under the financial terms of the agreement, Telesta is eligible to receive up to US$137 million in upfront and milestone payments comprising a US$10 million upfront payment and additional payments contingent upon achievement of regulatory and sales milestones. In addition, Telesta is eligible to receive meaningful tiered double-digit royalties on net sales of MCNA in the licensed territories.

About MCNA

MCNA is a biologic therapy developed to provide high risk non-muscle invasive bladder cancer patients who are refractory to or relapsing from first line therapy with bacillus Calmette-Guérin (BCG), with a therapeutic alternative to surgery. MCNA is derived from the cell wall fractionation of a non-pathogenic bacteria. Its activity is believed to be through a dual mechanism of immune stimulation and direct anti-cancer effects. MCNA was developed to be delivered as a sterile suspension for intravesical administration by urologists and urology nurses, following the same dosing paradigm as first line BCG therapy, with the advantage that it can be prepared, handled and disposed of easily and safely. The efficacy, duration of response and safety data from MCNA’s pivotal Phase 3 trial was recently published2 in The Journal of Urology. The FDA has set February 27, 2016 as its review goal date for MCNA’s potential approval. MCNA offers a new therapeutic option for high risk NMIBC patients and, if approved, will represent the first new therapeutic approved for these patients in the United States since 1989.

About non-muscle invasive bladder cancer (NMIBC)

Treatment options for high risk NMIBC patients who fail first line BCG treatment are extremely limited and treatment guidelines in most countries around the world call for radical cystectomy, which entails a surgical removal of the bladder and adjacent organs and glands. Bladder removal is a complex surgery associated with at least 28% to 45% surgical complications and up to 8% mortality, in addition to negatively impacting multiple aspects of quality of life. Patients who refuse or are not medically fit to undergo bladder removal face an increased risk of progression to muscle-invasive disease, likely leading to metastases and death.