G-BA assessment of orphan drug gene therapies, Zolgensma and Libmeldy

The gene therapies Zolgensma and Libmeldy, both, are targeting very rare, severe, genetic diseases in children. The G-BA has now assessed the additional benefit of both orphan drugs but came to different conclusions.

Zolgensma

Zolgensma (onasemnogene abeparvovec) is indicated for the treatment of spinal muscular atrophy (SMA). The patient population suffering from SMA is very small. Every year around 80 to 120 children are born with this genetic disease in Germany. It causes muscle weakness and skeletal deformation. If left untreated, the most severe form will lead to death.

Unlike other therapy alternatives, which have to be administered repeatedly, Zolgensma is used only once. The drug aims to stop progressive muscle weakness but does not offer a complete cure. The costs for a single application are around €2.3 million.

The G-BA has initially started an abbreviated orphan drug assessment for Zolgensma in July 2020. However, the sales of Zolgensma were rapidly exceeding the threshold of €50 million. Therefore, the G-BA terminated the orphan drug assessment and commenced a full regular benefit assessment. The assessment considered 4 subgroups: (1) patients with 5q-associated SMA type 1, (2) patients with 5q-SMA type 2 and up to 3 copies of the SMN 2 gene, (3) patients with 5q-SMA type 3, and up to 3 copies of the SMN 2 gene, and (4) presymptomatic patients with 5q-SMA and up to 3 copies of the SMN 2 gene. The appropriate comparator therapy for subgroups 1, 2, and 4 was nusinersen. For subgroup 3, the G-BA chose physician’s choice, considering nusinersen or BSC.

The manufacturer submitted data only for subgroups 1 and 4. However, the dossier was based on a single-arm trial. On the basis of the available data, the G-BA could not derive an additional benefit in any subgroup. The G-BA plans to re-assess Zolgensma again, at the latest in summer 2027, when real-world long-term data are expected to be available. The details on collecting real-world data have already been defined.

Libmeldy

Libmeldy (atidarsagene autotemcel) is approved for the treatment of the metabolic disorder metachromatic leukodystrophy (MLD). This disease is currently not curable.

MDL is caused by a genetic defect. This affects around 1 to 3 patients in Germany each year. People with MDL fail to develop a particular enzyme. This causes massive damage to the nervous system. The disease can occur at any age but often starts already in childhood. The affected children gradually lose their motor and mental abilities until they finally die of the disease. Therapy with Libmeldy is based on a single application and currently costs €2.8 million.

The G-BA assessed Libmeldy in an abbreviated orphan drug assessment based on the regulatory data and a specific siblings analysis. The G-BA differentiated between two subgroups in their assessment: (1) late infantile and early juvenile symptom-free children and (2) early juvenile children with early clinical manifestation of the disease, but who can still walk independently, before the onset of cognitive deterioration.

In the first subgroup, the data on impaired movements demonstrated a hint of major additional benefit. For the second subgroup, the data were not sufficient to derive an additional benefit. Thus, the G-BA awarded a hint of not-quantifiable additional benefit, the minimum rating for an orphan drug. The final analysis of the study is not available yet. The G-BA, therefore, restricted its resolution until July 2024. Once long-term data are available, a new assessment will be triggered.