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

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existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting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.

Licensing of Orphan Medicinal Products-Use of Real-World Data and Other External Data on Efficacy Aspects in Marketing Authorization Applications Concluded at the European Medicines Agency Between 2019 and 2021.

Background: Reference to so-called real-world data is more often made in marketing authorization applications for medicines intended to diagnose, prevent or treat rare diseases compared to more common diseases. We provide granularity on the type and aim of any external data on efficacy aspects from both real-world data sources and external trial data as discussed in regulatory submissions of orphan designated medicinal products in the EU. By quantifying the contribution of external data according to various regulatory characteristics, we aimed at identifying specific opportunities for external data in the field of orphan conditions. Methods: Information on external data in regulatory documents covering 72 orphan designations was extracted. Our sample comprised public assessment reports for approved, refused, or withdrawn applications concluded from 2019-2021 at the European Medicines Agency. Products with an active orphan designation at the time of submission were scrutinized regarding the role of external data on efficacy aspects in the context of marketing authorization applications, or on the criterion of "significant benefit" for the confirmation of the orphan designation at the time of licensing. The reports allowed a broad distinction between clinical development, regulatory decision making, and intended post-approval data collection. We defined three categories of external data, administrative data, structured clinical data, and external trial data (from clinical trials not sponsored by the applicant), and noted whether external data concerned the therapeutic context of the disease or the product under review. Results: While reference to external data with respect to efficacy aspects was included in 63% of the approved medicinal products in the field of rare diseases, 37% of marketing authorization applications were exclusively based on the dedicated clinical development plan for the product under review. Purely administrative data did not play any role in our sample of reports, but clinical data collected in a structured manner (from routine care or clinical research) were often used to inform on the trial design. Two additional recurrent themes for the use of external data were the contextualization of results, especially to confirm the orphan designation at the time of licensing, and reassurance of a large difference in treatment effect size or consistency of effects observed in clinical trials and practice. External data on the product under review were restricted to either active substances already belonging to the standard of care even before authorization or to compassionate use schemes. Furthermore, external data were considered pivotal for marketing authorization only exceptionally and only for active substances already in use within the specific therapeutic indication. Applications for the rarest conditions and those without authorized treatment alternatives were especially prominent with respect to the use of external data from real-world data sources both in the pre- and post-approval setting. Conclusion: Specific opportunities for external data in the setting of marketing authorizations in the field of rare diseases were identified. Ongoing initiatives of fostering systematic data collection are promising steps for a more efficient medicinal product development in the field of rare diseases.

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.

The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

T cell-signaling network analysis reveals distinct differences between CD28 and CD2 costimulation responses in various subsets and in the MAPK pathway between resting and activated regulatory T cells.

To uncover signaling system differences between T cell stimuli and T cell subsets, phosphorylation status of 18 signaling proteins at six different time points following TCR triggering and CD28/CD2 costimulation was examined in human T cell subsets by phospho-epitope-specific flow cytometry of fluorescent cell barcoded samples, thereby providing a high-resolution signaling map. Compared with effector/memory T cells, naive T cells displayed stronger activation of proximal signaling molecules after TCR triggering alone. Conversely, distal phosphorylation events, like pErk and pS6-ribosomal protein, were stronger in effector/memory subsets. CD28 costimulation specifically induced signaling necessary for proper NF-κB activation, whereas CD2 signaled more strongly to S6-ribosomal protein. Analysis of resting regulatory T cells (rTregs; CD4(+)CD45RA(+)FOXP3(+)) and activated regulatory T cells (actTregs; CD4(+)CD45RA(-)FOXP3(++)) revealed that, although rTregs had low basal, but inducible, Erk activity, actTregs displayed high basal Erk phosphorylation and little or no Akt activation. Interestingly, the use of Mek inhibitors to block Erk activation inhibited activation-dependent FOXP3 upregulation in rTregs, their transition to actTregs, and the resulting increase in suppressive capacity. In summary, our systems approach unraveled distinct differences in signaling elicited by CD28 and CD2 costimulation and between rTregs and actTregs. Blocking rTreg transition to highly suppressive actTregs by Mek inhibitors might have future therapeutic applications.