Regulatory evaluation of Glybera in Europe-two committees, one mission

publishersversionPeer reviewe

Panzytopenie unter Therapie mit RoACTEMRA® (Tocilizumab)

Seit Januar 2009 ist der monoklonale Antikörper RoACTEMRA® (Tocilizumab) für die Behandlung erwachsener Patienten mit Rheumatoider Arthritis zugelassen. Seit der Zulassung von RoACTEMRA® sind vom Paul-Ehrlich-Institut acht Verdachtsfälle hämatologischer Nebenwirkungen gemeldet worden. Im Folgenden werden die Meldungen als Übersicht dargestellt und der mögliche Pathomechanismus diskutiert

Kombinationstherapien in der Immunonkologie: Differenzierte regulatorische Herangehensweisen

Combination therapies of different drugs are an integral part of medicine. However, there is a scientific and regulatory need to understand the contribution of each drug to the overall effect, i.e., nonclinical and clinical development programs have to consider these aspects and need to be designed accordingly. Many drugs are currently under development that attempt to control malignant diseases in the long term by using and activating components of the patient's own immune system. The term immuno-oncology is often used in this context. Medicines that are developed and used for immuno-oncology can be assigned to completely different classes of medicines.This article provides an analysis of combination therapies in immuno-oncology with medicinal products produced by biotechnological manufacturing. This encompasses checkpoint inhibitors, genetically modified cell therapies, tumor vaccines, and oncolytic viruses. The challenges in clinical development are demonstrated on the basis of this heterogenous group of approved immuno-oncological drugs that have been investigated in combination therapies. Due to the different characteristics and number of combination partners, an individually tailored program must be designed for each development program and there is no standard solution

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer

On 21 January 2021, the European Commission amended the marketing authorisation granted for pembrolizumab to include the first-line treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) in adults. The recommended dose of pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion. Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints. Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving pembrolizumab were diarrhoea, fatigue, pruritus, nausea, increased aspartate aminotransferase, rash, arthralgia, and hypothyroidism. Having reviewed the data submitted, the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit–risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union

Accelerated Development of COVID-19 Vaccines: Technology Platforms, Benefits, and Associated Risks

Multiple preventive COVID-19 vaccines have been developed during the ongoing SARS coronavirus (CoV) 2 pandemic, utilizing a variety of technology platforms, which have different properties, advantages, and disadvantages. The acceleration in vaccine development required to combat the current pandemic is not at the expense of the necessary regulatory requirements, including robust and comprehensive data collection along with clinical product safety and efficacy evaluation. Due to the previous development of vaccine candidates against the related highly pathogenic coronaviruses SARS-CoV and MERS-CoV, the antigen that elicits immune protection is known: the surface spike protein of SARS-CoV-2 or specific domains encoded in that protein, e.g., the receptor binding domain. From a scientific point of view and in accordance with legal frameworks and regulatory practices, for the approval of a clinic trial, the Paul-Ehrlich-Institut requires preclinical testing of vaccine candidates, including general pharmacology and toxicology as well as immunogenicity. For COVID-19 vaccine candidates, based on existing platform technologies with a sufficiently broad data base, pharmacological–toxicological testing in the case of repeated administration, quantifying systemic distribution, and proof of vaccination protection in animal models can be carried out in parallel to phase 1 or 1/2 clinical trials. To reduce the theoretical risk of an increased respiratory illness through infection-enhancing antibodies or as a result of Th2 polarization and altered cytokine profiles of the immune response following vaccination, which are of specific concern for COVID-19 vaccines, appropriate investigative testing is imperative. In general, phase 1 (vaccine safety) and 2 (dose finding, vaccination schedule) clinical trials can be combined, and combined phase 2/3 trials are recommended to determine safety and efficacy. By applying these fundamental requirements not only for the approval and analysis of clinical trials but also for the regulatory evaluation during the assessment of marketing authorization applications, several efficacious and safe COVID-19 vaccines have been licensed in the EU by unprecedentedly fast and flexible procedures. Procedural and regulatory–scientific aspects of the COVID-19 licensing processes are described in this review

No association of IL-12p40 pro1.1 polymorphism with juvenile idiopathic arthritis

Background: IL-12p40 plays an important role in the activation of the T-cell lines like Th17 and Th1-cells. Theses cells are crucial in the pathogenesis of juvenile idiopathic arthritis. A polymorphism in its promoter region and the genotype IL12p40 pro1.1 leads to a higher production of IL-12p40. We studied whether there is a difference in the distribution of the genotype in patients with JIA and the healthy population. Methods: In 883 patients and 321 healthy controls the IL-12p40 promoter genotype was identified by ARMS-PCR. Results: There is no association of IL-12p40 pro polymorphism neither in patients with JIA compared to controls nor in subtypes of JIA compared to oligoarthritis. We found a non-significant tendency of a higher prevalence of the genotype pro1.1 in systemic arthritis (32.4 %) and in rheumatoid factor negative polyarthritis (30.5 %) and a lower pro1.1 genotype in persistent oligoarthritis (20.7 %) and in enthesitis-related arthritis (17 %). Likelihood of the occurrence of genotype IL12-p40 pro1.1 in patients with systemic arthritis (OR 1.722, CI 95 % 1.344-2.615, p 0.0129) and RF-negative polyarthritis (OR 1.576, CI 95 % 1.046-2.376, p 0.0367) compared to persistent oligoarthritis was significantly higher. This was also true for comparison of their homozygous genotypes IL-12p40 pro 1.1 and 2.2 in systemic arthritis (OR 1.779, CI 95 % 1.045-3.029, p 0.0338). However, in Bonferroni correction for multiple hypothesis this was not significant. Conclusion: A tendency of a higher prevalence of the genotype IL-12p40 pro1.1 in systemic arthritis and in rheumatoid factor negative polyarthritis was observed but not significant. Further investigations should be done to clarify the role IL-12p40 in the different subtypes of JIA

Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study.

Item does not contain fulltextBACKGROUND: Candida bloodstream infections cause significant morbidity and mortality among hospitalized patients. Although clinical and microbiological factors affecting prognosis have been identified, the impact of genetic variation in the innate immune responses mediated by cytokines on outcomes of infection remains to be studied. METHODS: A cohort of 338 candidemia patients and 351 noninfected controls were genotyped for single-nucleotide polymorphisms (SNPs) in 6 cytokine genes (IFNG, IL10, IL12B, IL18, IL1beta, IL8) and 1 cytokine receptor gene (IL12RB1). The association of SNPs with both candidemia susceptibility and outcome were assessed. Concentrations of pro- and antiinflammatory cytokines were measured in in vitro peripheral blood mononuclear cell stimulation assays and in serum from infected patients. RESULTS: None of the cytokine SNPs studied were associated with susceptibility to candidemia. Persistent fungemia occurred in 13% of cases. In the multivariable model, persistent candidemia was significantly associated with (odds ratio [95% confidence interval]): total parenteral nutrition (2.79 [1.26-6.17]), dialysis dependence (3.76 [1.46-8.64]), and the SNPs IL10 rs1800896 (3.45 [1.33-8.93]) and IL12B rs41292470 (5.36 [1.51-19.0]). In vitro production capacity of interleukin-10 and interferon-gamma was influenced by these polymorphisms, and significantly lower proinflammatory cytokine concentrations were measured in serum from patients with persistent fungemia. CONCLUSIONS: Polymorphisms in IL10 and IL12B that result in low production of proinflammatory cytokines are associated with persistent fungemia in candidemia patients. This provides insights for future targeted management strategies for patients with Candida bloodstream infections