Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit-The EU Regulator's Perspective

Since the implementation of the EU Orphan Regulation in 2000, the Committee for Orphan Medicinal Products at the European Medicines Agency has been evaluating the benefits of proposed orphan medicines vs. satisfactory treatment methods. This type of evaluation is foreseen in the Orphan Regulation as the orphan designation criterion called the "significant benefit." In this article, based on 20 years of experience, we provide a commentary explaining what is considered a satisfactory method of treatment in the context of the EU Orphan Regulation and for the purpose of the assessment of significant benefit. We discuss the challenges posed by continuously changing clinical practise, which is associated with the increasing number of treatment options, evolving nature of medicinal therapeutic indications and our understanding of them

Studies on cytokine mRNA expression in mononuclear cells in neuroimmunological diseases

Studies on cytokine mRNA expression in mononuclear cells in neuroimmunological diseases Darius Matusevicius, M.D. Background. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), characterized by perivascular accumulation of blood mononuclear cells (MNC) and patchy demyelination. High levels of circulating myelin antigen specific T and B cells, with an accumulation in cerebrospinal fluid (CSF), suggest the involvement of cytokines in the pathogenesis of MS. Aseptic meningo-encephalitis (AM) may serve as a relevant control for immunological studies for MS since it is an inflammatory disease of the CNS but with a benign and self-limiting course. Myasthenia gravis (MG) is a neuromuscular disorder mediated by autoantibodies against the nicotinic acetylcholine receptor (AChR) on the postsynaptic membrane of the neuromuscular junction. The production of autoantibodies is regulated by T cells by means of immunoregulatory cytokines. The aim of the study was to investigate whether any specific cytokine profile exists in MS or MG and how cytokine profiles may be altered by immunomodulatory treatment. Materials and method. Blood MNC were obtained from patients with MS, AM, MG, other neurological diseases (OND) and healthy individuals. In parallel, CSF was taken from patients with MS and AM. In situ hybridization with synthetic oligonucleotide probes was used to detect and enumerate MNC expressing LT-a, TNF-a, IL-6, IL-13, IL-12, perforin, IFN-y, TGF-B and IL-10 mRNA. Results are presented as numbers of cytokine mRNA expressing cells per 100.000 MNC. In some studies ELISA was used to detect plasma levels of cytokines IL-12 and IL-13, and soluble vascular cell adhesion molecule-l (sVCAM-I). Results. Levels of LT-a, TNF-a, IL-6, IL-12, IL-13 and perforin mRNA expressing blood MNC were similar in patients with MS and AM, and higher than in healthy subjects. In CSF compared to paired blood samples from MS and AM patients higher numbers of spontaneously LT-a, TNF-a, IL-6, IL 12, IL-13 and perforin mRNA expressing MNC were detected, reflecting compartmentalized inflammation in both diseases. In contrast to MS, MG was not associated with a general increase in cytokine mRNA expressing cells with the exception for IL-12 which was elevated. Stimulation of blood MNC with MBP or PLP in MS, and AChR in MG resulted in higher numbers of LT-a, TNF-a, IL-6, IL-12, IL-13 and perforin mRNA expressing MNC compared to unstimulated cultures. This was not seen in control patients with AM, OND or healthy subjects. Numbers of organ specific autoantigen reactive cytokine mRNA expressing MNC were also higher in MS and MG compared to controls. In MS, numbers of MBP-reactive LT-a and TNF-a mRNA expressing MNC were also higher in CSF than blood. Levels of MBP-specific TNF-a mRNA expressing CSF MNC correlated with MS exacerbations. Immunosuppresive drugs decreased numbers of AChR-reactive perforin mRNA expressing MNC in MG, probably reflecting one effector mechanism of immunosuppresive treatment. IFN-Blb treatment of MS patients had little effects on levels of MNC spontaneously expressing cytokine mRNA with the exception of transient increase of MNC expressing TNF-a and perforin, and decrease of IL-10 mRNA expressing MNC. IFN-Blb treatment had no effects on MBP-reactive IFN-y, TNF-a, TGF-B, IL-10 or perforin mRNA expressing MNC, but resulted in higher plasma levels of sVCAM- I . Conclusions. Similarly upregulated levels of spontaneously LT-a, TNF-a, IL-6, IL-13, IL-12 and perforin mRNA expressing blood and CSF MNC observed in patients with MS and AM suggest that cytokine mRNA expression in MS reflects a non-specific inflammatory process. Correlation of numbers of TNF-a mRNA expressing CSF MNC with MS exacerbations may implicate a disease promoting role for TNF-a. Increased plasma levels of sVCAM-I in MS patients treated with IFN-Blb may reflect the mechanism preventing the migration of autoreactive T cells through the blood-brain barrier. ISBN 91-628-2582-

The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear

Advancing rare disease treatment: EMA’s decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation

Abstract Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation. This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency’s Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation. This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication

Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that results in damage to myelin sheaths and axons in the central nervous system and which preferentially affects young adults. We performed a proteomics-based biomarker discovery study in which cerebrospinal fluid (CSF) from MS and control individuals was analyzed (n=112). Ten candidate biomarkers were selected for evaluation by quantitative immunoassay using an independent cohort of MS and control subjects (n=209). In relapsing remitting MS (ARMS) patients there were significant increases in the CSF levels of alpha-1 antichymotrypsin (A1AC), alpha-1 macroglobulin (A2MG) and fibulin 1 as compared to control subjects. In secondary progressive MS (SPMS) four additional proteins (contactin 1, fetuin A, vitamin D binding protein and angiotensinogen (ANGT)) were increased as compared to control subjects. In particular, ANGT was increased 3-fold in SPMS, indicating a potential as biomarker of disease progression in MS. In PPMS, A1AC and A2MG exhibit significantly higher CSF levels than controls, with a trend of increase for ANGT. Classification models based on the biomarker panel could identify 70% of the RRMS and 80% of the SPMS patients correctly. Further evaluation was conducted in a pilot study of CSF from RRMS patients (n=36), before and after treatment with natalizumab. (C) 2010 Elsevier B.V. All rights reserved