LENMELDY^® Approval by FDA Relied on RWE

FDA approved LENMELDY^® (atidarsagene autotemcel), a gene therapy indicated for the treatment of metachromatic leukodystrophy (MLD), a rare disease, in March 2024. Real-world evidence (RWE) played a crucial role in supporting the demonstration of the efficacy and safety of LENMELDY, leveraged in the interventional arm, for pooled data analyses, and constituting the only source of control data. 

MLD is a rare disease affecting one in 40,000 individuals. MLD is caused by a deficiency of the enzyme arylsulfatase A (ARSA) due to a genetic autosomal recessive mutation. MLD typically manifests in early childhood, although onset can vary depending on the type of MLD (late-infantile, juvenile, or adult-onset). MLD is characterized by progressive degeneration of the central nervous system’s white matter, manifesting in loss of motor and cognitive function and early death.

LENMELDY, manufactured by Orchard Therapeutics, is a one-time, individualized single-dose infusion made from the patient’s own hematopoietic (blood) stem cells (HSCs), genetically modified to include functional copies of the ARSA gene. The FDA granted LENMELDY orphan designation in March 2018 and approved LENMELDY for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) MLD, on March 18, 2024.

The safety and effectiveness of LENMELDY were demonstrated based on pooled data from two single arm, open label clinical trials and a European Early Access Program (EAP) of children treated with LENMELDY. The disease progression of treated individuals was compared with an historical observational retrospective and prospective external control arm (NHx study).

Treatment with LENMELDY, as shown in the pooled data from the EAP and the clinical trials, dramatically extended severe motor impairment-free survival and overall survival in children with MLD compared with untreated children from the external control. All PSLI MLD children treated with LENMELDY, with sufficient follow-up time, were alive at six years of age, compared to merely 58% of children in the external control. Regarding cognition and language, 19 of 20 children with PSLI MLD treated with LENMELDY had performance standard scores above the threshold of severe cognitive impairment, radically contrasting with children from the external control, with completed neuropsychological assessments, who demonstrated severe cognitive impairment early in their disease course. Children with PSEJ MLD and ESEJ MLD, also benefited from LENMELDY treatment.

LENMELDY (named LIBMELDY® in Europe) has been available in Europe since 2020, receiving orphan designation in April 2007 and EMA marketing authorization in December 2020. The EMA authorization was based on a single arm trial, two EAPs, and a single-patient compassionate use program (CUP). The interventional arm also included pooled data from the single arm trial, the EAPs and the CUP, compared with the same natural history external control (NHx study).

RWE played a crucial role in the approval of LENMELDY in MLD by both the FDA and the EMA. Factors influencing health authorities’ receptiveness for RWE may have included the context of a rare disease, the pediatric target patient population, and high unmet need due to the lack of curative therapies in MLD (before LENMELDY, treatment focused on symptom management and best supportive care). Lastly, the magnitude treatment effect was dramatic with 100% of LENMELDY-treated PSLI children remaining event-free for the primary endpoint of severe motor impairment-free survival, followed until at least five years of age, compared with 0% of untreated children from the historical external control.