Atidarsagene autotemcel for treating metachromatic leukodystrophy

Atidarsagene autotemcel (Libmeldy, Orchard Therapeutics), referred to as OTL‑200 in the company submission, is a gene therapy medicinal product that expresses the human arylsulphatase A (ARSA) gene. Ex vivo autologous CD34+ haematopoietic stem and progenitor cells are collected from the person's bone marrow or peripheral blood. These are then transduced with a lentiviral vector, which inserts copies of human ARSA complementary DNA into the cell genome, and transplanted into the person. When successfully engrafted, the genetically modified cells secrete functional ARSA enzyme, which is absorbed by surrounding cells and used to break down or prevent build‑up of harmful sulphatides. The effects of OTL‑200 are potentially lifelong.

The marketing authorisation indication for atidarsagene autotemcel is for 'metachromatic leukodystrophy (MLD) characterized by biallelic mutations in the arylsulphatase A (ARSA) gene leading to a reduction of the ARSA enzymatic activity:

• in children with late infantile or early juvenile forms, without clinical manifestations of the disease

• in children with the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline'.

Atidarsagene autotemcel is administered as a single-dose intravenous infusion. The minimum recommended dose is 3×10⁶ CD34⁺ cells per kg. The product consists of 1 or more infusion bags containing 2 to 10×10⁶ cells per ml suspended in a cryopreservative solution. A myeloablative conditioning regimen is needed before infusing atidarsagene autotemcel, to promote engraftment of the genetically modified cells. Before starting myeloablative conditioning, the treating clinician should confirm that atidarsagene autotemcel is clinically appropriate for the patient. Atidarsagene autotemcel must be administered in a qualified treatment centre with experience in haematopoietic stem cell transplantation as detailed in the summary of product characteristics for atidarsagene autotemcel.

Adverse reactions because of myeloablative conditioning or atidarsagene autotemcel include febrile neutropenia, stomatitis, mucosal inflammation, veno-occlusive disease and anti-ARSA antibodies. For full details of adverse reactions and contraindications, see the summary of product characteristics for atidarsagene autotemcel.

As a condition of the marketing authorisation for atidarsagene autotemcel, the company has to undertake a long-term study to assess both the efficacy and safety of atidarsagene autotemcel for children in its clinical development program and in the post-authorisation setting, for up to 15 years after treatment. The long-term study will also collect data from an additional 10 children with early symptomatic EJ MLD.

The list price for atidarsagene autotemcel is £2,875,000 (excluding VAT; company submission). The company has a commercial arrangement. This makes atidarsagene autotemcel available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.