The U.S. FDA approved Orchard Therapeutics plc’s BLA for gene therapy atidarsagene autotemcel, making it the first treatment option for metachromatic leukodystrophy (MLD) in the U.S. The one-time treatment, branded Lenmeldy, is indicated for children with presymptomatic late infantile, presymptomatic early juvenile or early symptomatic early juvenile disease.

The FDA’s decision came on the PDUFA date of March 18, 2024. Lenmeldy – also known as Libmeldy, arsa-cel or OTL-200 – gained priority review in September 2023. An ex vivo autologous hematopoietic stem cell (HSC) gene therapy, it is already approved in the EU, U.K., Iceland, Liechtenstein and Norway for early onset MLD in children. 

MLD, a rare genetic disorder caused by a deficiency of the enzyme arylsulfatase-A, can cause infants to rapidly lose the ability to walk, talk and interact. In the U.S., MLD affects an estimated one in every 40,000 individuals, with existing treatment limited to supportive care and symptom management.

Enter Lenmeldy, a single-dose infusion that is tailormade for each person by using individual blood stem cells for genetic modification – adding a functional copy of the ARSA gene – and re-injecting the modified cells into the patient. Patients undergo high-dose chemotherapy prior to treatment.

London-based Orchard obtained the asset via an acquisition of GSK plc’s rare disease gene therapy portfolio in 2018, which first originated from a collaboration between GSK and Italy’s San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget)

U.S. approval of Lenmeldy also settles Kyowa Kirin Co. Ltd.’s final bill of ¥70.7 billion (US$477.6 million) for the all-cash acquisition of Orchard, based on an initial deal inked in October 2023. Kyowa completed the acquisition on Jan. 24, 2024, to make Orchard a wholly owned subsidiary.

First for MLD 

Lenmeldy’s BLA filing was based on data of 39 pediatric patients with early onset MLD who were enrolled in two prospective, non-randomized clinical studies (n=30) or treated under expanded access frameworks (n=9). Enrolled patients were administered Lenmeldy and subsequently monitored at Ospedale San Raffaele in Milan, Italy. Data were compared against those of 49 untreated patients’ natural history. 

Results showed one-time administration of Lenmeldy significantly improved severe motor impairment-free survival (sMFS) across the three cohorts, including presymptomatic late infantile MLD (100% vs. 0%; p<0.001); presymptomatic early juvenile MLD (87.5% vs. 11.2%; p=0.042); and early symptomatic early juvenile MLD (80% vs. 11.2%; p<0.001).

Safety results from cumulative 250 patient-years of follow-up showed the therapy was generally well-tolerated, with no treatment-related serious adverse events or deaths. Three patient deaths were reported, although not “considered related to treatment” with Lenmeldy, according to investigators, adding to registry data findings in 2019, as previously reported by BioWorld.

In its category, Lenmeldy has long been the leading candidate for MLD, although about 20 preclinical therapeutic approaches and assets are currently under investigation. French research organization Inserm’s arylsufatase A gene therapy, AAvrh.10, is the only candidate to reach the phase I/II stage, according to Cortellis. Then-Shire plc, acquired by Takeda Pharmaceutical in 2019, had two assets in the running, but both were discontinued, including a Metazym (arylsulfatase-A) candidate acquired from Denmark’s Zymenex A/S.

No therapies are yet approved in the U.S. to address the loss of function and deterioration caused by MLD. Allogeneic blood or marrow transplantation is the standard of care. 

‘Most expensive drug’

Pricing for the U.S. market was not immediately disclosed. But Libmeldy, as it is sold in other markets, is known as the world’s most expensive therapy, and the most expensive one approved by the U.K.’s National Health Service at a list price of £2.9 million (US$3.9 million) for one-time treatment. 

Following launch in the EU and approved countries, Orchard reported that Libmeldy revenue reached $8.2 million in the first half of 2022 and grew to $18.8 million in the second half of 2022. Libmeldy sales in the first half of 2023 totaled $25.9 million. 

In the U.S., the Institute of Clinical and Economic Review (ICER) calculated that Libmeldy “would achieve common thresholds for cost-effectiveness if priced between $2.3 million to $3.9 million” in its final evidence report in September 2023.  

For reference, the latest FDA-approved gene therapies – Casgevy (exagamglogene autotemcel) and Lyfgenia’s (lovotibeglogene autotemcel) – for American sickle cell patients with recurring vaso-occlusive events (VOEs) also carry million-dollar list prices. 

Vertex Pharmaceuticals Inc.’s wholesale acquisition cost for Casgevy’s (WAC) is $2.2 million, translating to about $4 million in direct lifetime medical costs. The WAC for Bluebird Bio Inc.’s  Lyfgenia’s of $3.1 million means about $6 million in direct lifetime medical costs. Patients with frequent VOEs also face about $1.3 million in lost earnings to manage sickle cell disease, as previously reported by BioWorld. 

Kyowa-Orchard pipeline

Next to Lenmeldy, Orchard also has two assets – OTL-203 and OTL-201 – engineered with the same HSC gene therapy technology platform. Both are currently in phase I/II studies. 

OTL-203 is a targeted treatment for the multisystemic neurometabolic condition mucopolysaccharidosis type I Hurler’s syndrome (MPS-IH), known to affect cognition, growth and skeletal function. 

OTL-201, in development for mucopolysaccharidosis type IIIA (MPS-IIIA), also known as Sanfilippo syndrome type A, is under investigation with a proof-of-concept phase I/II trial. Early results were presented orally at the American Society of Gene and Cell Therapy meeting in May 2023.

In rare diseases, Orchard’s parent firm, Kyowa, holds several therapies in its pipeline, including a human monoclonal antibody (MAb) for X-linked hypophosphatemia and tumor-induced osteomalacia called Crysvita (burosumab); and a MAb for relapsed or refractory mycosis fungoides and Sézary disease called Poteligeo (mogamulizumab).