The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

BACKGROUND: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. MATERIALS AND METHODS: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. RESULTS: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. CONCLUSION: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Biosimilars: what clinicians should know.

Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators.

The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use.

On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45-0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.

Annexin A2 promotes glioma cell invasion and tumor progression.

Gliomas are highly invasive, lethal brain tumors. Tumor-associated proteases play an important role in glioma progression. Annexin A2 is overexpressed in many cancers and correlates with increased plasmin activity on the tumor cell surface, which mediates degradation of extracellular matrix and promotes neoangiogenesis to facilitate tumor growth. In this study, we used two glioma cell lines, mouse GL261-EGFP and rat C6/LacZ, as well as stable clones transfected with an annexin A2 knockdown construct. We find that the annexin A2 knockdown decreased glioma cell migration in vitro and decreased membrane-bound plasmin activity. In vivo, we injected the glioma cells into the rodent brain and followed glioma progression. Knockdown of annexin A2 in glioma cells decreased tumor size and slowed tumor progression, as evidenced by decreased invasion, angiogenesis, and proliferation, as well as increased apoptosis in the tumor tissue of the annexin A2 knockdown group. Moreover, we report that the levels of expression of annexin A2 in human glioma samples correlate with their degree of malignancy. Together, our findings demonstrate that inhibition of annexin A2 expression in glioma cells could become a new target for glioma therapy.

Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice.

Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine-induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 h prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 h prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.

The European Medicines Agency review of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessment of the European medicines agency committee for medicinal products for human use.

On April 19, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union (EU) for ofatumumab (Arzerra®; Glaxo Group Ltd, Greenford, Middlesex, U.K.). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a conditional marketing authorization for ofatumumab for the treatment of chronic lymphocytic leukemia (CLL) in patients refractory to fludarabine and alemtuzumab. A conditional marketing authorization means that additional data to confirm the benefit-risk balance of ofatumumab are awaited. The active substance of Arzerra® is ofatumumab, a monoclonal antibody medicinal product (ATC code L01XC10). The recommended dose is 300 mg of atumumab for the first infusion and 2,000 mg of atumumab for all subsequent infusions. The infusion schedule is eight consecutive weekly infusions, followed 4-5 weeks later by four consecutive monthly (i.e., every 4 weeks) infusions. Ofatumumab targets CD20, a cell surface marker of B lymphocytes, which is followed by cell lysis via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The benefit of ofatumumab is the control of CLL in patients who are refractory to both fludarabine and alemtuzumab, which was indicated by a high response rate. The most common side effects are infections and infusion reactions. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Proteolytic activation of monocyte chemoattractant protein-1 by plasmin underlies excitotoxic neurodegeneration in mice.

Exposure of neurons to high concentrations of excitatory neurotransmitters causes them to undergo excitotoxic death via multiple synergistic injury mechanisms. One of these mechanisms involves actions undertaken locally by microglia, the CNS-resident macrophages. Mice deficient in the serine protease plasmin exhibit decreased microglial migration to the site of excitatory neurotransmitter release and are resistant to excitotoxic neurodegeneration. Microglial chemotaxis can be signaled by the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 (CC chemokine ligand 2). We show here that mice genetically deficient for MCP-1 phenocopy plasminogen deficiency by displaying decreased microglial recruitment and resisting excitotoxic neurodegeneration. Connecting these pathways, we demonstrate that MCP-1 undergoes a proteolytic processing step mediated by plasmin. The processing, which consists of removal of the C terminus of MCP-1, enhances the potency of MCP-1 in in vitro migration assays. Finally, we show that infusion of the cleaved form of MCP-1 into the CNS restores microglial recruitment and excitotoxicity in plasminogen-deficient mice. These findings identify MCP-1 as a key downstream effector in the excitotoxic pathway triggered by plasmin and identify plasmin as an extracellular chemokine activator. Finally, our results provide a mechanism that explains the resistance of plasminogen-deficient mice to excitotoxicity.

Nitric oxide synthase isoforms undertake unique roles during excitotoxicity.

BACKGROUND AND PURPOSE: Excitotoxicity is a component of many neurodegenerative diseases. The signaling events that lead from excitotoxic injury to neuronal death remain incompletely defined. Pharmacological approaches have shown that nitric oxide production is critical for the progression of neurodegeneration after the initiation of excitotoxicity by the glutamate analog kainate. Although nitric oxide additionally triggers blood-brain barrier (BBB) breakdown, the breakdown does not in itself inevitably lead to neuronal cell death, because neuroprotective pharmacological means can be used subsequently to prevent the neural death. METHODS: In this study, we use a genetic approach to analyze the contribution of 3 nitric oxide synthase (NOS) isoforms, neuronal NOS, endothelial NOS, and inducible NOS, to neurodegeneration and BBB breakdown in this setting. RESULTS: We find that neuronal NOS is critical for the progression of kainate-stimulated neurodegeneration, whereas endothelial NOS is required only for BBB breakdown. Inducible NOS is not required for either event. CONCLUSIONS: The observation that endothelial NOS-deficient mice undergo excitotoxic neurodegeneration in the absence of BBB breakdown unlinks the two processes. These findings suggest that it may be possible to achieve full amelioration of excitotoxic-triggered neurodegeneration through developing isoform-specific inhibitors solely for neuronal NOS.

European Medicines Agency approval summary: Zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer.

On 1 February 2013, a marketing authorisation valid throughout the European Union was issued for aflibercept (Zaltrap) in combination with irinotecan/5-fluorouracil/folinic acid chemotherapy for the treatment of adults with metastatic colorectal cancer resistant to or progressive after an oxaliplatin-containing regimen. Aflibercept is a recombinant fusion protein which blocks the activation of vascular endothelial growth factor (VEGF) receptors and the proliferation of endothelial cells, acting as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as placental growth factor and VEGF-B. The use of aflibercept was studied in a randomised, double-blind, placebo-controlled phase III study, in patients with metastatic colorectal cancer (mCRC) who had previously been treated with an oxaliplatin-based treatment with or without prior bevacizumab. Aflibercept (n=612) was compared with placebo (n=614), both in combination with FOLFIRI (infusional fluorouracil, leucovorin and irinotecan). The primary endpoint of the study was overall survival (OS). The median OS in the intent-to-treat population was 13.5 months in subjects treated with aflibercept compared with 12.1 months for subjects in the control arm (stratified HR=0.817, 95% CI 0.714 to 0.935, stratified pvalue=0.0032). The frequency of adverse events was higher in the aflibercept arm compared with the placebo arm, reflecting the toxicity profile of anti-VEGF agents in combination with chemotherapy. This paper is based on the scientific review of the application leading to approval of aflibercept in the EU. The detailed scientific assessment report and product information for this product are available on the European Medicines Agency website (http://www.ema.europa.eu). Trial registration number NCT00561470, Results.

The changing world of cancer drug development: the regulatory bodies' perspective.

BACKGROUND: Although not a singular disease entity, advanced cancer continues to be a largely intractable disease and a high unmet medical need situation. Discovery of novel therapeutic modalities, including new drugs targeting cancer, is undoubtedly of major public health interest. METHODS: In this article, we discuss current trends in oncology drug development as these are ultimately reflected in regulatory drug approvals. RESULTS AND CONCLUSIONS: These include the shift to targeted therapies which hold the promise of personalized medicine, but also financial pressures, the call for adaptive licensing which places more emphasis on early access and post-authorization studies (patient registries, prospective interventional and observational studies) and real-life effectiveness studies, as well as the emergence of biosimilars in the oncology treatment armamentarium.

Geriatric oncology: European Union regulatory perspectives and initiatives.

The world population is gradually ageing. With cancer being prominently a disease of the elderly, availability of information for oncology drugs in this patient population is becoming critical for their safe and effective use. Drug regulatory thinking and recommendations towards obtaining this information continue to evolve over time accordingly in order to address this information gap.

The European Medicines Agency: an overview of its mission, responsibilities, and recent initiatives in cancer drug regulation.

The European Medicines Agency (EMA) is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union (EU). Since 2005, the agency has become responsible for the approval of all new oncology drugs in the EU. In this article we describe the mission, role, and responsibilities of the EMA, and provide a brief summary of recent initiatives related to cancer drug regulation. The EMA recently published its Road Map to 2015. Over the next 5 years, the agency aims to continue to stimulate drug development in areas of unmet medical needs. Concerning drug safety, one of the priorities over the next few years will be to establish a more proactive approach in ensuring patient safety. This is the result of new EU legislation coming into force in 2012 that will strengthen the way the safety of medicines for human use is monitored in the EU. In terms of its general operation, the agency is committed to increased openness and transparency, and to build on its interactions with stakeholders, including members of academia, health care professionals, patients, and health technology assessment bodies. The agency recently created an oncology working party to expand the current guideline for the development and evaluation of cancer drugs. The guideline focuses on both exploratory and confirmatory studies for different types of agents. The current revision will address a number of topics, including the use of biomarkers as an integrated part of drug development and the use of progression-free survival as a primary endpoint in registration trials.

Decreased serotonin levels associated with behavioral disinhibition in tissue plasminogen activator deficient (tPA-/-) mice.

Tissue Plasminogen Activator (tPA) is a serine protease expressed in different areas of the mammalian brain. It has been used clinically to dissolve clots and shown to have a role in neurodegeneration. Early studies suggested that tPA plays an important role in the processes of learning and memory, demonstrated at the level of behavior and synaptic plasticity. Herein, we extend the behavioral characterization of these mice to the related dimension of exploratory-related behavior using an extensive battery of behavioral tests as well as the neurotransmitter metabolism associated with the behavioral measures. Our results indicate a behavior tendency in these mice consistent with "impulsivity" or reduced exploratory inhibition. These patterns are accompanied by decreased levels of serotonin in several brain regions important in behavioral regulation in the tPA(-/-) mice compared to control animals. Systemic administration of fluoxetine reversed the behavioral disinhibition of tPA(-/-) mice, further supporting an important alteration in behavior regulation mediated by serotonin systems as underappreciated but important element of the behavioral phenotype of these animals.

Tissue-type plasminogen activator as a therapeutic target in stroke.

BACKGROUND: Ischemic stroke is a leading cause of morbidity and mortality worldwide and recombinant human tissue-type plasminogen activator (tPA) is the prominent therapeutic among very few therapeutics used in its treatment. Due to complications attributed to the drug, most notably transformation of ischemia to hemorrhage, tPA is only used in a small number of ischemic stroke cases, albeit significantly more often in specialized stroke centers. OBJECTIVE: What are the mechanisms of tPA action and side effects in ischemic stroke, and can the knowledge about these mechanisms aid in making tPA a more efficacious and safe therapeutic or in developing alternative therapeutics? METHODS: tPA use and alternative/combination therapies in acute ischemic stroke treatment are summarized. The review focuses on literature concerning tPA neurotoxicity and its implications for further development of tPA as a stroke therapeutic. RESULTS/CONCLUSION: Exogenously administered recombinant tPA and endogenous tPA have both turned into promising therapeutic targets for the stroke patient.

Tissue plasminogen activator and glial function.

Tissue plasminogen activator (tPA) is the only FDA-approved treatment of thrombotic stroke and is a major parenchymal serine protease in the brain. However, it has been implicated in a plethora of brain pathologies, raising concern about its use as a safe therapeutic. tPA is thought to regulate physiological processes that entail tissue remodeling and plasticity, purportedly due to its ability to initiate the degradation of extracellular matrix proteins and possibly other substrates. Understanding the physiological role(s) of tPA promises to both elucidate important aspects of brain function and improve the available therapies for neurological disease. In this context, the effects of tPA on glial cells, mainly microglial cells, but also astrocytes and Schwann cells, appear to be of particular importance, given the increasing awareness of the significance of glia in brain physiology and pathology