Atidarsagene autotemcel 2million-10million cells/ml dispersion for infusion bags

ObjectiveTo understand the benefit-risk profile for historical and current treatments for MLD.MethodsA systematic review was conducted on the effectiveness, safety, and costs of MLD treatments: allogeneic haematopoietic stem cell transplantation (HSCT) and atidarsagene autotemcel (arsa-cel) according to best practice.ResultsA total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients.LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients.ConclusionsOverall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies.

Abstract licence: CC BY 4.0

ABSTRACT Introduction Sickle cell disease is the most common hereditary hemoglobinopathy followed by beta-thalassemia. Until recently, allogeneic stem cell transplantation was the only curative approach. Based on the Crispr-Cas9-technology enabling targeting specific genes of interest, fetal hemoglobin which is normally shut-off after birth can be switched on and sufficient levels can alleviate symptoms in sickle cell disease and avoid transfusions in beta-thalassemia. Two first-in-human clinical studies in sickle cell disease and beta-thalassemia aiming to increase the level of fetal hemoglobin by using Crispr-Cas9 to modify autologous hematopoietic stem cells in patients aged 12–35 years have proved safety and efficacy and have shown promising clinical outcomes. Areas covered The paper summarizes the outcome of the results of the two recently published clinical studies and compares them with the other available curative approaches. Expert opinion Based on the currently available safety and efficacy data of the two published clinical results on gene therapy with Crispr-Cas9 modified autologous stem cells (exagamglogene autotemcel), it can be anticipated that this approach will add significantly to the therapeutic options for patients with sickle cell disease and beta-thalassemia and can be considered for all patients above 12 years of age independent of a suitable allogeneic stem cell donor.

Abstract licence: CC BY-NC-ND 4.0

β-thalassemia is an inherited blood disorder characterized by chronic anemia, ineffective erythropoiesis, and in its most severe form, lifelong transfusion dependence. The standard of care for transfusion-dependent thalassemia (TDT) is regular red blood cell transfusions to relieve the anemia and suppress ineffective erythropoiesis and iron chelation therapy to mitigate morbidity and mortality related to iron overload. Allogeneic hematopoietic stem cell transplantation is a curative option but is only available to patients with an appropriate donor and carries risks of graft-versus-host disease and other transplant-related morbidity. In recent years, the therapeutic landscape for TDT has changed dramatically with the approval of two autologous gene therapies in the United States: betibeglogene autotemcel (beti-cel) and exagamglogene autotemcel (exa-cel). Clinical trials for both gene therapies have demonstrated high rates of sustained transfusion independence for both pediatric and adult age groups. However, despite these advances, challenges remain. Gene therapy requires myeloablative busulfan-based conditioning chemotherapy, which carries the risk of short- and long-term toxicities. Furthermore, centralized manufacturing and high treatment costs are likely to limit access to gene therapy. In this review, we discuss the available clinical trial and real-world data for beti-cel and exa-cel. We describe how gene therapy fits into the current treatment landscape and introduce areas of ongoing investigation to improve access to transformative therapy for TDT.

Abstract licence: CC BY-NC