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Glioblastoma is the most common and aggressive malignant tumor of the central nervous system. Despite the existing high unmet medical needs, the past few decades have seen no notable improvement in overall survival for glioblastoma patients. One active area of research to develop new therapeutic options for this disease is focusing on the CD95/Fas receptor and its ligand CD95L/FasL. It is now recognized that in addition to its role in programmed cell death, CD95/CD95L signaling is involved in a wide range of other apoptotic and non-apoptotic pathways directed toward T-effector cells and cells in the tumor microenvironment involved in tumor progression and invasiveness. Asunercept is a first-in-class recombinant glycosylated fusion protein, which has been designed to selectively bind to CD95L and therefore disrupt CD95/CD95L signaling. The current report provides a brief overview of the role of the CD95/CD95L signaling pathway in cancer pathogenesis and discusses how asunercept was designed to bind and neutralize CD95L and disrupt signaling thereby potentially improving outcomes in glioblastoma and other malignancies. Keywords: CD95/CD95L, apoptosis, asunercept, APG101, glioblastoma, immuno-oncology

Background Febrile neutropenia (FN) is a common occurrence during chemotherapy. Granulocyte colony-stimulating factors (G-CSFs) can significantly reduce the risk of FN. International guidelines recommend G-CSF for patients receiving chemotherapy with FN risk of ≥20% or 10% to 20% with defined risk factors. Prophylaxis is not typically recommended for FN risk of < 10%; however, few studies have investigated FN incidence in lower-risk patients in real-world settings and tried to identify higher-risk subgroups. Methods This real-world prospective, observational, multinational study aims to estimate the rate of development of FN with a chemotherapy line expected to be associated with a 10% to 20% risk of FN. Eligible patients (> 18 years of age) will have a solid tumour or Hodgkin/non-Hodgkin lymphoma and a planned chemotherapy regimen with expected risk of FN of 10% to 20% (according to published guidelines). Patients will be observed for the duration of the chemotherapy line (first cycle administered without FN prophylaxis). Primary endpoint is incidence of FN after the first chemotherapy cycle. Secondary outcomes include: FN-associated morbidity and mortality; time to first FN occurrence; other FN risk factors and impact of FN on quality of life. A risk model using occurrence of FN as a binary outcome will be developed. Data will be stratified by age, comorbidities and other risk factors. Discussion This study will provide insight into the real FN risk for common chemotherapy regimens and predictive factors for FN, including patients generally excluded from randomised clinical trials, from which reported FN rates have been variable. This study builds on knowledge of predictive factors from other research and will provide information on patients with 10% to 20% FN risk.

The ability of FasL/CD95L to induce apoptosis in various Fas/CD95-expressing cells has been described in the context of hematopoiesis or thymic elimination of self-reactive T cells and resolution of an acute immune response under physiological conditions. At the same time, non-apoptotic CD95 activation is widely described in cancer and shown to stimulate invasiveness of cancer cells, promote cancer progression as well as stemness of cancer cells. This paper puts emphasis on the evolving understanding of expression and the non-apoptotic activities of the CD95/CD95L signaling pathway on the function of tumor cells, tumor microenvironment and immune cells. The emerging evidence to support the role of CD95/CD95L signaling in the anti-tumor immune response will be presented in the context of various malignancies and the modalities of potential therapeutic interventions via selective CD95L inhibition in combination with traditional interventions such as RT, chemotherapy and immune checkpoint inhibitors.

Patent expirations for several biological products have prompted the development of alternative versions, termed ‘biosimilars’, which have comparable quality, safety and efficacy to a licensed biological medicine (also referred to as the ‘reference’ medicine). The first biosimilars developed in oncology were the supportive-care agents filgrastim and epoetin. Binocrit® (HX575) is a biosimilar version of epoetin alfa, indicated in the oncology setting for the treatment of chemotherapy-induced anemia (CIA). The process for development and approval of Binocrit® as a biosimilar included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program comprising phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory phase III study to confirm therapeutic effectiveness in CIA. Since its approval, Binocrit® has been extensively used and studied in real-world clinical practice. The accumulated data confirm that Binocrit® is an effective and well-tolerated option for the treatment of CIA in patients with cancer.

Erythropoiesis-stimulating agents, such as recombinant human erythropoietin, are commonly used for the treatment of anemia in patients with chronic kidney disease (CKD). In 2007, HX575 (Binocrit ) became the first biosimilar epoetin alfa to be approved by the European Medicines Agency (EMA). The decision to approve a biosimilar is based on the totality of evidence obtained in a comprehensive comparability exercise that involves extensive analytical characterization, nonclinical studies and clinical studies. The development process for HX575 included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program, comprising Phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory Phase III study to demonstrate therapeutic effectiveness in anemia related to CKD. In addition to the comparability exercises, extensive clinical experience over the last decade also confirms that HX575 provides an effective treatment for CKD-related anemia, with a favorable safety profile. Growing clinical experience with EMA-approved biosimilars, including HX575, should offer additional reassurance to health care professionals and patients that these agents are as effective and well tolerated as others in the therapeutic class.

Background DOPPS reported that thousands of life-years could be gained in the US and Europe over 5 years by correcting six modifiable haemodialysis practices. We estimated potential life-years gained across 10 European countries using MONITOR-CKD5 study data. Methods The DOPPS-based target ranges were used, except for haemoglobin due to label changes, as well as DOPPS-derived relative mortality risks. Percentages of MONITOR-CKD5 patients outside targets were calculated. Consistent with the DOPPS-based analyses, we extrapolated life-years gained for the MONITOR-CKD5 population over 5 years if all patients were within targets. Results Bringing the 10 MONITOR-CKD5 countries’ dialysis populations into compliance on the six practices results in a 5-year gain of 97,428 patient-years. In descending order, survival impact was the highest for albumin levels, followed by phosphate levels, vascular access, haemoglobin, dialysis adequacy, and interdialytic weight gain. Conclusions Optimal management of the six modifiable haemodialysis practices may achieve 6.2% increase in 5-year survival. Trial Registration NCT01121237 . Clinicaltrials.gov registration May 12, 2010 (retrospectively registered).

The recombinant G-CSF filgrastim was first approved in 1991, and its value has been evolving ever since. Initial health technology assessments suggested low value due to high drug cost and no evidence for significant gain in overall survival. However, more recent meta-analyses of placebo-controlled randomized trial data show falling costs due to biosimilar competition and absolute overall survival gains of 3.2% (95% CI: 2.1-4.2%) from filgrastim support of cytotoxic chemotherapy. The launch of biosimilar alternatives merits a re-evaluation of decisions by health technology assessments and explains the first inclusion of filgrastim in the WHO Essential Drug List for cancer >20 years after its original approval in 1991, thus demonstrating the power of biosimilar medicines in transforming healthcare.

Innovative medicinal products are required to achieve progress in oncology; however, these are associated with high financial investments, extensive development times, and significant risk of potential failure in the pivotal clinical trials required for marketing authorization. With increasing budgetary constraints and requirements to demonstrate value, effective strategies to develop and commercialize innovative oncology products are more important than ever. Strategies that have proved successful in other industries require major revision for use in the oncology field, both during preclinical and clinical development as well as in the post approval value chain. This paper will examine how medicinal product strategy development differs from other industries. In particular, it will look at how the global trend toward value-based healthcare requires strategies that are based on an in-depth scientific understanding of the disease area and product-specific characteristics supported by clinical evidence. The findings are complemented by a review of the available literature and a survey of industry representatives.

Innovative medicinal products are required for progress in many therapeutic areas, and in particular, oncology. For these products to succeed, pharmaceutical companies must generate the relevant and robust clinical data required to meet the needs of regulators and healthcare providers. In addition, real-world and health economic evidence is increasingly required to support pricing and reimbursement for innovative medicinal products. To incorporate all of these requirements into the innovative medicinal product strategy early in development, the core principles of how product strategies are developed and applied must be revisited and end-to-end strategic planning implemented. This paper reviews the hurdles faced during development of the integrated strategy for innovative medicinal products, particularly in the oncology field, and examines which functions of a pharmaceutical company should play the greatest role in addressing patient and different stakeholders’ needs. It will then illustrate how Medical Affairs activities are evolving to take on this strategic leadership role.

Biosimilar filgrastim (Sandoz) was approved in Europe in 2009 and, in 2015, was the first biosimilar approved in the USA. These authorizations were based on the “totality of evidence” concept, an approach that considers data from structural and functional characterization and comparability analysis and non-clinical and clinical studies. For biosimilar filgrastim, phase III confirmatory clinical studies were performed in the most sensitive population, patients with breast cancer undergoing myelosuppressive chemotherapy. In Europe and the USA, approval was granted for all indications of the reference biologic. Hence, stem cell mobilization and severe chronic neutropenia indications were approved on the basis of extrapolation, with no clinical data available at the time of market authorization in the EU. Although extrapolation is well-accepted in biologic development and regulatory contexts, it remains a misunderstood part of the biosimilarity concept in the medical community. Since approval, more than a decade of obtained clinical experience supports the totality of evidence and reassures clinicians regarding the efficacy and safety of biosimilar filgrastim. This includes real-world data from MONITOR-GCSF, a multicenter, prospective, observational study describing treatment patterns and clinical outcomes of patients with cancer ( n  = 1447) receiving biosimilar filgrastim for the prophylaxis of chemotherapy-induced neutropenia in solid tumors and hematological malignancies. Evidence is also available from unrelated healthy donors and those with severe chronic neutropenia. Together, the experience from a decade of use of biosimilar filgrastim includes over 24 million patient-days of exposure, which can help reassure oncologists that extrapolation is based on strong scientific evidence and works in practice.