On December 13, 2017 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo), reported results from the Hokusai-VTE CANCER study evaluating oral edoxaban (known by the brand names LIXIANA outside the U.S. and SAVAYSA in the U.S.), and found that edoxaban is non-inferior to subcutaneous injectable LMWH dalteparin for the treatment of cancer-associated VTE and major bleeding (Press release, Daiichi Sankyo, DEC 13, 2017, View Source [SID1234522607]). The results of the study were simultaneously published in the New England Journal of Medicine (NEJM) and presented during the late-breaker session at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia.

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Hokusai-VTE CANCER is the first study with a direct oral anticoagulant (DOAC), edoxaban, to meet pre-specified non-inferiority criteria versus the standard of care dalteparin in this patient population.2,3 The study met the primary objective of non-inferiority of edoxaban for the composite outcome of first recurrent VTE or ISTH-defined major bleeding during a 12-month study period, which occurred in 67 of 522 patients (12.8%) in the edoxaban group compared with 71 of 524 patients (13.5%) in the dalteparin group (hazard ratio with edoxaban, 0.97; 95% CI, 0.70 to 1.36; P = 0.006 for non-inferiority) for a risk difference (edoxaban minus dalteparin) of -0.7% (95% CI, -4.8 to 3.4).2,3 The difference in risk for recurrent VTE was -3.4% (95% CI, -7.0 to 0.2) whereas the corresponding difference in risk for major bleeding was 2.9% (95% CI, 0.1 to 5.6).3 The frequencies of severe major bleeding events at presentation (categories 3 and 4) were similar during treatment with edoxaban or dalteparin (12 patients in each group, respectively).2,3 There was no fatal bleed in the edoxaban group versus two fatal bleedings in the dalteparin arm.3

The study also met the secondary outcome of event-free survival (free of recurrent VTE, major bleeds or death) at 12 months, and rates were similar between edoxaban and dalteparin (55.0% and 56.5%, respectively).2,3 The trial was a PROBE design study and included a broad spectrum of patients (n=1,050) with primarily active cancer (98%): 53% of which had metastatic cancer and 72% of which were receiving cancer therapy at randomisation.2,3 This is the largest prospectively randomised clinical trial to have studied the benefit risk of DOACs in cancer patients versus the current injectable standard of care, dalteparin. Hokusai-VTE CANCER is the first study to demonstrate that a DOAC, edoxaban, is non-inferior to the standard of care, injectable LMWH (dalteparin), in this population.2,3

"Cancer patients have a significantly increased risk of VTE, and are a high-risk population since 82% of patients have one or more pre-specified bleeding risk factors," said co-principal study investigator Professor Harry Büller, from the Department of Vascular Medicine at Academic Medical Center, Amsterdam, The Netherlands. "We saw a lower rate of recurrent VTE with edoxaban compared to dalteparin over the one-year study period. In addition, in the edoxaban arm, we saw no bleeding fatalities and similar severity of clinical presentation of major bleeding events compared to dalteparin. The risk for VTE persists beyond six months for cancer patients, therefore, the study duration of 12 months enabled the evaluation of edoxaban over a longer time period."

VTE includes both deep vein thrombosis (DVT) and pulmonary embolism (PE) and is the second leading cause of death in cancer patients receiving chemotherapy.4 Current guidelines recommend LMWH for at least six months as the standard of care in cancer patients,5,6,7 and currently there is poor adherence to VTE cancer treatment guidelines due to the requirement for daily injections. The treatment of cancer-associated VTE is challenging because these patients are at increased risk of both recurrent VTE and major bleeding.2 The occurrence of VTE increases the risk of death 2-6-fold in cancer patients4 and can interrupt cancer treatment.8

"The use of an oral anticoagulant that alleviates the burdens associated with a daily injectable drug, without loss of clinical benefit, would represent an advance for cancer patients with VTE," said Hans J. Lanz, MD, Vice President, Global Medical Affairs, Daiichi Sankyo. "The data will continue to add to the growing body of knowledge in the Edoxaban Clinical Research Programme, which provides key insights into the potential effects of edoxaban in VTE and AF patients."

About the Hokusai-VTE CANCER study
Hokusai-VTE CANCER is a multinational, prospective, randomised, open-label, blinded endpoint evaluation (PROBE) study, evaluating the efficacy and safety of once-daily edoxaban compared to dalteparin for the treatment of VTE associated with cancer.1,2,3 The purpose of the study was to evaluate edoxaban in comparison with dalteparin in preventing the combined outcome of VTE recurrence or major bleeding in patients with VTE associated with cancer.1,2,3 Other objectives include assessing the effects of treatment on VTE recurrence, clinically relevant bleeding and event-free survival, defined as the proportion of subjects over time free of recurrent VTE, major bleeding events and death.1,2,3 The study enrolled 1,050 patients across 13 countries in North America, Europe, Australia and New Zealand.2,3 Patients were randomised to receive edoxaban 60 mg once-daily (reduced to 30 mg edoxaban for patients with creatinine clearance [CrCL] 30-50 mL/min, body weight ≤ 60 kg, or concomitant use of P-glycoprotein [P-gp] inhibitors), following treatment with LMWH for at least five days; or dalteparin SC 200 IU/kg once-daily for 30 days, then 150 IU/kg once-daily for the remainder of the 12-month study.1,2,3

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About Venous Thromboembolism
Venous thromboembolism (VTE) is an umbrella term for two conditions, deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a disease caused by a blood clot found in deep veins, usually within the lower leg, thigh or pelvis, although they can occur in other parts of the body as well.10 PE occurs when part of a clot detaches and lodges in the pulmonary arteries, causing a potentially fatal condition.11

About VTE and Cancer
VTE is a major cause of morbidity and mortality in patients with cancer, with an annual incidence that can be as high as 20 percent depending on the cancer type, background risk and time since diagnosis.12,13 Patients with cancer have multiple risk factors for VTE and the risk of VTE events increases in patients with cancer receiving chemotherapy.14 In addition, patients with cancer and VTE have a lower survival rate than those without VTE.14

About Edoxaban
Edoxaban is an oral, once-daily, direct factor Xa (pronounced "Ten A") inhibitor. Factor Xa is one of the key components responsible for blood clotting, so inhibiting this makes the blood thin and less prone to clotting. Edoxaban is currently marketed by Daiichi Sankyo and its partners in more than 20 countries around the world.

About Edoxaban Clinical Research Programme (ECRP)
Daiichi Sankyo is committed to expanding scientific knowledge about edoxaban, as demonstrated through our research programmes evaluating its use in a broad range of cardiovascular conditions, patient types and clinical settings in AF and VTE. The edoxaban clinical research programme includes multiple RCTs (randomised, controlled trials), registries and non-interventional studies, with the goal of generating new clinical and real-world-data regarding its use in AF and VTE populations. Daiichi Sankyo expects that more than 100,000 patients will participate in the edoxaban clinical research programme, including completed, ongoing, and future research.

The RCTs include:
− ENSURE-AF (EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation), in AF patients undergoing electrical cardioversion
− ENTRUST-AF PCI (EdoxabaN TReatment versUS VKA in paTients with AF undergoing PCI), in AF patients undergoing percutaneous coronary intervention
− Hokusai-VTE CANCER (Edoxaban in Venous Thromboembolism Associated with Cancer), in patients with cancer and an acute VTE event
− ELDERCARE-AF (Edoxaban Low-Dose for EldeR CARE AF patients), in elderly AF patients in Japan
− ELIMINATE-AF (EvaLuatIon of edoxaban coMpared with VKA IN subjects undergoing cAThEter ablation of non-valvular Atrial Fibrillation)
− ENVISAGE-TAVI AF (EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation (TAVI) – Atrial Fibrillation)

In addition, global and regional registry studies will provide important real-world data about the use of edoxaban and other oral anticoagulants in everyday practice, and include:
− ETNA-AF (Edoxaban Treatment in routiNe clinical prActice in patients with non valvular Atrial Fibrillation)
− ETNA-VTE (Edoxaban Treatment in routiNe clinical prActice in patients with Venous ThromboEmbolism)
− EMIT-AF/VTE (Edoxaban Management In diagnostic and Therapeutic procedures-AF/VTE);
− Prolongation PREFER in AF (PREvention oF thromboembolic events – European Registry) in patients with AF
− ANAFIE (All Nippon AF In Elderly) Registry in Japan
− Cancer-VTE Registry in Japan

We are committed to adding to the scientific body of knowledge around edoxaban in a variety of AF and VTE patients, including those who are vulnerable.

On December 12, 2017 Cyclenium reported the signing of a drug discovery collaboration agreement with Ono Pharmaceutical Co., Ltd., a leading Japanese pharmaceutical research and development company (Press release, Cyclenium, DEC 12, 2017, View Source [SID1234635926]). The collaboration will exploit Cyclenium’s proprietary QUEST Library of next generation synthetic small-molecule macrocycles and associated optimization expertise to identify clinical candidates effective against multiple pharmacological targets selected by Ono in their therapeutic focus areas.

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While Cyclenium will be responsible for all medicinal chemistry efforts, starting from hit validation, to generate new macrocyclic compounds by employing its CMRTTM Technology, Ono will utilize its internal resources for the characterization of biological and pharmacological properties of these new macrocycles, as well as having full rights and responsibility for development and commercialization of the resulting drug candidates worldwide. In return, Cyclenium will receive an upfront payment and research funding from Ono, as well as development milestones and royalties on marketed products.

"We are very excited about entering this collaboration with Ono, our second with a major, globallyoperating, Japanese pharmaceutical partner," stated Helmut Thomas, Ph.D., President, Chief Executive Officer & Chief Scientific Officer of Cyclenium. "We are confident that our CMRT Technology and proven success in the macrocycle area combined with the excellent research team at Ono will provide new insight into the modulation of their difficult targets and enable the discovery of novel macrocyclic therapeutic agents."

"We highly appreciate Cyclenium’s expertise in the macrocycle area and their technology platform to generate new drug candidates for high priority targets in our portfolio," said Hiromu Habashita, Ph.D., Corporate Officer and Executive Director, Discovery and Research of Ono. "We are very pleased to work with Cyclenium on identifying and developing the next generation of innovative drugs and we believe novel macrocyclic drugs to be generated through this collaboration will fulfill unmet medical needs."

Cyclenium has translated its over 18 years of pioneering experience, extensive knowledge base and unparalleled expertise in small molecule macrocyclic chemistry into the next generation CMRT ("smart") drug discovery technology that addresses the shortcomings of earlier efforts in this increasingly important domain.

Arrowhead Research Corporation has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission (Filing, 10-K, Arrowhead Research Corporation, 2017, DEC 12, 2017, View Source [SID1234522590]).

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On December 12, 2017 TapImmune Inc. (NASDAQ: TPIV), a leading clinical-stage immuno-oncology company with ongoing clinical trials in ovarian and breast cancer, reported that the first patient has been enrolled in a Phase 2 randomized, multi-center, double-blinded, placebo-controlled clinical trial of TapImmune’s novel therapeutic vaccine candidate TPIV200 (Press release, TapImmune, DEC 12, 2017, View Source [SID1234523779]). The 280-patient trial, sponsored by Mayo Clinic, received $13.3 million in grant funding from the U.S. Department of Defense (DoD) to evaluate the prevention of cancer recurrence in women with triple-negative breast cancer (TNBC) who have completed first-line surgery and radiotherapy/chemotherapy.

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TPIV200 is a novel, multi-epitope, peptide-based cancer vaccine that has been shown to induce a robust and long-lasting "memory" T-cell immune response directed against folate receptor alpha (FRa), a molecule that is overexpressed on the surface of the vast majority of TNBC cancer cells and is associated with cancer recurrence. As an off-the-shelf vaccine consisting of several carefully chosen FRa peptides, TPIV200 is uniquely able to stimulate both T "helper" cells and T "killer" cells to target tumor cells and is expected to cover greater than 85% of human genotypes worldwide.

"We remain grateful to the U.S. Department of Defense and Mayo Clinic for enabling TapImmune to gain invaluable clinical safety and efficacy insight for TPIV200 under this grant," said TapImmune President and CEO Peter Hoang. "We believe TPIV200 and our other vaccine candidates have an important role to play within the current immuno-oncology ecosystem by potentially bridging a critical gap not currently addressed by other immunotherapies, which have shown promise in only a small number of patients. Unlike current approaches, TapImmune’s vaccines are designed to produce broad-based, durable T-cell responses in the vast majority of patients, which we believe are essential for improving clinical outcomes and ensuring potential regulatory and commercial success. We look forward to providing updates appropriately as this exciting Phase 2 study continues to enroll patients."

TapImmune and its clinical partners are evaluating TPIV200 in multiple ongoing Phase 2 trials for treating ovarian and breast cancer, including a randomized dosing trial in TNBC that recently completed patient enrollment. The four-arm trial is designed to help determine the optimal TPIV200 vaccine dose and regimen to maximize patients’ anti-tumor immune responses. Interim immunogenicity results from this ongoing study are anticipated in the first half of 2018.

Keith L. Knutson. Ph.D., Professor of Immunology in the Department of Immunology, and Edith A. Perez, M.D., Professor of Medicine in the Division of Hematology and Oncology, both at Mayo Clinic’s Florida campus in Jacksonville, Florida, are the recipients of the U.S. Department of Defense grant and are leading the Phase 2 trial.

Mayo Clinic and Dr. Knutson have a financial interest in TapImmune for the triple negative breast cancer treatment.

On December 12, 2017 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and Puma Biotechnology, Inc. (Nasdaq: PBYI) reported a preclinical research collaboration with Memorial Sloan Kettering Cancer Center (MSK) to explore the combination of Daiichi Sankyo’s investigational antibody drug conjugate DS-8201 and Puma Biotechnology’s irreversible pan-HER tyrosine kinase inhibitor neratinib (NERLYNX) in HER2-mutated or HER2-positive solid tumors (Press release, Daiichi Sankyo, DEC 12, 2017, View Source [SID1234522606]).

A team of scientists led by Maurizio Scaltriti, PhD, and in collaboration with a team of clinical investigators led by Bob Li, MD, will use isogenic models and established patient-derived xenograft models to assess the susceptibility of HER2-mutated or HER2-positive cancers to DS-8201, neratinib and other HER2-targeting therapies, elucidate mechanisms of action and resistance of these various tumor types, and evaluate the potential for synergistic combinations. Daiichi Sankyo and Puma Biotechnology will co-sponsor the research.

"Since early clinical data suggest that DS-8201 may have activity beyond breast and gastric cancers, the archetype HER2-driven tumors, we are interested in studying this asset on a molecular level as well as in combination with other HER2-targeting agents," said Tom Held, Vice President, Global Head, Antibody Drug Conjugate Task Force, Daiichi Sankyo. "In this collaboration, we are examining whether combining DS-8201 and neratinib, with its specific covalent binding to the HER2 receptor and associated increased internalization, is a rational combination therapy strategy to pursue. We are excited to join forces with Memorial Sloan Kettering and Puma to advance the understanding of combining HER2-targeted therapies to potentially treat various forms of HER2-mutated cancer."

"We are pleased to enter into this research collaboration with Memorial Sloan Kettering and Daiichi Sankyo to explore the combination of neratinib and DS-8201," said Alan Auerbach, Puma’s Chief Executive Officer and President. "Combination therapy with agents that address different and complementary pathways, with neratinib targeting the HER2 kinase and DS-8201 providing an innovative targeted delivery of a potent cytotoxic, represents an intriguing approach to the treatment of HER2 mutated tumors and helps to maximize the potential for both agents in treating cancers with a HER2 mutation."

About DS-8201

DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

DS-8201 is currently in phase 2 clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), phase 2 development for HER2-positive advanced gastric resistent or refractory to trastuzumab (DESTINY-Gastric01) and phase 1 development for other HER2-expressing advanced/unresectable or metastatic solid tumors.

DS-8201 has been granted Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine (T-DM1), and Fast Track designation for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including T-DM1 by the U.S. Food and Drug Administration (FDA). DS-8201 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About NERLYNX (neratinib)

Neratinib was approved by the FDA in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets.

Important Safety Information (ISI)
NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.

Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.

Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at
1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.

USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.

Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

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