EU approves autologous hematopoietic stem cell gene therapy for metachromatic leukodystrophy

On December 23, 2020, gene therapy company Orchard Therapeutics announced that the European Commission (EC) had granted full (standard) marketing authorization to Libmeldy (OTL-200) for the treatment of metachromatic leukodystrophy (MLD), including (a) late infantile MLD with reduced ARSA enzyme activity caused by mutations in the ARSA alleles, without clinical manifestations of the disease, and (b) early juvenile MLD, with early clinical features of the disease, where patients can still walk independently but have developed pre-onset cognitive decline. The marketing authorization of Libmeldy is valid in all 27 EU member states as well as the UK, Iceland, Liechtenstein and Norway. Orchard is currently carrying out launch preparation work related to commercial drug manufacturing, treatment site qualification and market access.

Libmeldy is the first therapy approved for eligible patients with early-onset MLD, which includes the disease variants traditionally known as late infantile (LI) and early juvenile (EJ) MLD. MLD is a rare metabolic system disease and genetic disease caused by arylsulfatase A (ARSA) deficiency due to gene mutations, leading to the accumulation of sulfatides in the white matter of the central nervous system, peripheral nerves and tissues such as the kidney, gallbladder and liver, resulting in a progressive, degenerative neurological disease. In the United States, about 1 in every 100,000 live births is an MLD patient; the estimated 5-year mortality rate for patients with late infantile and early juvenile forms from disease onset is 50%, and the 10-year mortality rate is 44%.

Libmeldy is a lentiviral vector-based, autologous hematopoietic stem cell gene therapy that transduces autologous differentiated CD34+ cells with a lentiviral vector carrying the human ARSA gene, enabling the cells to express ARSA and thereby treating MLD. Libmeldy is administered by intravenous injection.

Dr. Bobby Gaspar, CEO of Orchard, said: "Today, the EC's approval of Libmeldy offers new possibilities for these children with devastating diseases who previously had no approved treatment options. At the same time, as Libmeldy is Orchard's first approved product, I am proud to have achieved this milestone and delighted that we can bring this extraordinary innovative technology to young patients in the EU."

It is understood that this marketing authorization was based on clinical research conducted at SR-TIGET for patients with early-onset MLD, involving 29 patients who received treatment with fresh (non-cryopreserved) biologic products. Analysis results showed that a single intravenous dose of Libmeldy can effectively improve the course of early-onset MLD in most patients.

Safety data: among the 29 patients included in the comprehensive efficacy analysis and an additional 6 patients treated with the cryopreserved formulation of Libmeldy (n=35), Libmeldy was well tolerated. The most common adverse reaction was the development of anti-ARSA antibodies in 5 patients (5/35); these 5 patients had low antibody titers, and no negative effects were observed on ARSA activity in peripheral blood or bone marrow cell subpopulations or in cerebrospinal fluid after treatment. In addition to the risks associated with gene therapy, other medical interventions are required before Libmeldy treatment, namely bone marrow harvest or peripheral blood mobilization and collection, followed by myeloablative conditioning; during the clinical study, the safety of these interventions was consistent with their known safety and tolerability.

Dr. Luigi Naldini, Director of the San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET) in Milan, Italy, said: "More than a decade after we treated the first patient, we have finally obtained EC approval, bringing new opportunities for eligible MLD patients. Through fifteen years of research, our SR-TIGET team played an important role in advancing the discovery and early clinical trials of this potentially transformative therapy to support its registration. We are proud of this achievement."

It is worth noting that last month, the U.S. FDA approved the IND application for the gene therapy candidate OTL-200 (Libmeldy) for the treatment of MLD. In addition, the company has applied for Regenerative Medicine Advanced Therapy (RMAT) designation for OTL-200 and will further communicate with the FDA regarding this designation. Source: 医麦客.