Atidarsagen autotemcel OTL-200 (1) – Libmeldy®

• Clinical trials
  • To assess the extent of the additional benefit of OTL-200, results from an integrated data set (IDS) were used, comprising the four marketing authorisation trials 201222, the Compassionate Use Programme (CUP) 207394, CUP 206258 and Hospital Exemption (HE) 205029, compared with a historical control reflecting the natural course of the disease (TIGET-NHx study).

a) Children with forms of metachromatic leukodystrophy (MLD) presenting in late infancy (Late Infantile (LI)) or early childhood (Early Juvenile (EJ)) without clinical manifestation of the disease

• mortality
  • In the sibling analysis, 0 events occurred in children treated with OTL-200 and 4 events in the natural history cohort.
  • There is a statistically significant difference between the treatment groups in favour of OTL-200.
  • Overall, however, the duration of follow-up for children treated with OTL-200 is too short to draw reliable conclusions regarding the quantification of the additional benefit.
• Morbidity – GMFC-MLD level (Gross Motor Function Classification)
  • The GMFC-MLD is a classification system for describing gross motor functions in children with MLD who are at least 18 months old.
  • The pharmaceutical manufacturer has submitted a time-to-event analysis for ‘age at the time of GMFC-MLD level ≥ 5’.
  • In the sibling analysis, 1 event (8 %) occurred among children treated with OTL-200, whereas 11 events (100 %) were reported in the natural history cohort.
  • In the natural history study, a loss of the ability to move independently and sit was observed at a median age of 3.6 years.
  • It should be noted, however, that in the OTL-200 arm, 58 per cent of patients had already been censored by the age of 2, and thus, for more than half of the children treated with OTL-200, no further GMFC-MLD levels were recorded at the age at which children in the natural history cohort showed a loss of motor function.
  • Due to a lack of information on the reasons for censoring, this endpoint is used only as a supplementary measure.
• quality of life
  • No endpoints relating to quality of life were recorded.
• Side effects
  • In the absence of safety data for the sibling analysis, the results for the safety endpoints in the integrated data set (IDS), which comprises the four registration trials, were presented descriptively for individual trial phases.
  • From the start of busulfan conditioning up to the respective data cut-off, most adverse events (AEs) with a CTCAE grade ≥ 3 were reported in the SOC ‘Blood and Lymphatic System Disorders’ and the PT ‘Febrile Neutropenia’, but also under the SOC ‘Gastrointestinal disorders’ and the PT ‘Stomatitis’.
  • All AEs coded under the PT ‘Febrile Neutropenia’ and the PT ‘Stomatitis’ in this study phase were severe AEs.
  • Due to the duration of follow-up to date in the studies and the minor number of children treated with OTL-200, it is not possible to make a definitive assessment of the safety of OTL-200.
  • No data on adverse events are available for children in the historical control group.
  • Overall, therefore, the available data do not allow any conclusions to be drawn regarding the quantification of the additional benefit for OTL-200 in the ‘side effects’ endpoint category.
• Overall assessment
  • Results from an integrated dataset comprising the four authorisation studies, compared with a historical control, are available for assessing the extent of the additional benefit of OTL-200.
  • Given the existing uncertainties regarding the extent to which the course of the disease—in terms of the presence of symptoms and the manifestation of the condition—is sufficiently comparable across the patient groups covered by the therapeutic indication, such that an analysis without differentiating between patients would appear appropriate, no quantification of the additional benefit is possible.
  • The quantification of the additional benefit was based primarily on the sibling analysis carried out.
  • Despite the uncertainties and limitations also present in the sibling analysis, the comparison presented is used for the quantification of the added benefit due to the very similar disease progression among siblings and the associated sufficient structural similarity of the comparison arms, the large effects in the morbidity endpoint category, which cannot be explained solely by random effects based on these uncertainties, is used to quantify the additional benefit.
  • This also takes into account the severity and progressive nature of the disease, which, in the natural course of the disease, has a high probability of leading to severe physical limitations, and even death.
  • With regard to overall survival, the sibling analysis revealed a statistically significant difference in favour of OTL-200 compared with the natural course of the disease.
  • Overall, however, the duration of follow-up for children treated with OTL-200 is too short to draw reliable conclusions regarding this endpoint.
  • For the morbidity endpoint category, results are available for the GMFC (Gross Motor Function Classification) MLD level and the GMFM (Gross Motor Function Measure) endpoints.
  • Here, despite the uncertainties inherent in the historical control and the partly retrospective collection of endpoint data, a dramatic effect compared with the natural course control group can be inferred, largely based on the results for the GMFM.
  • No manifestation of the conditions had yet been observed 3 years after treatment with OTL-200.
  • The siblings in the natural history control group exhibited severe motor impairments at this point in time.
  • Overall, a very clear advantage for OTL-200 can be inferred for the morbidity endpoint category.
  • No data are available for the ‘quality of life’ endpoint category.
  • For the ‘side effects’ endpoint category, it is not possible to assess the extent of the additional benefit of OTL-200.
  • Consequently, the available results can only be assessed with limited conclusiveness due to the lack of control data and the small patient population.
  • In the overall assessment of the available effects—some of which are dramatic—on patient-relevant endpoints, and against the background of the high probability of severe physical and cognitive impairments, including death, in untreated children, a very clear advantage of OTL-200 can be inferred in the morbidity endpoint category.
  • Overall, the G-BA has determined that OTL-200 provides major additional benefit in the treatment of children with forms of MLD occurring in late infancy (LI) or early childhood (EJ) without clinical manifestation of the disease.

b) Children with the EJ form of metachromatic leukodystrophy who show early clinical manifestations of the disease but are still able to walk unaided, prior to the onset of cognitive decline

• Hint for a non-quantifiable additional benefit, as the scientific data do not permit quantification
• On balance, the G-BA therefore classifies the extent of the additional benefit of OTL-200, on the basis of the criteria in Section 5(8), first sentence, 2 in conjunction with Section 5(7), first sentence, number 4 of the AM-NutzenV as non-quantifiable for patient group b), as the scientific evidence does not permit quantification.
• The strength of the evidence is classified as ‘hint’.
• For the assessment of OTL-200 for the treatment of metachromatic leukodystrophy (MLD), which is characterised by mutations in both alleles of the gene for arylsulfatase A (ARSA) gene, leading to a reduction in ARSA enzymatic activity, results are available from an integrated dataset comprising the four registration studies, compared with a historical control reflecting the natural course of the disease (TIGET-NHx study).
• With regard to this integrated dataset, there are uncertainties as to the extent to which the disease course, in terms of the presence of symptoms and the manifestation of the disease, is sufficiently comparable and transferable from the patient groups covered by the therapeutic indication to the patient group to be considered separately here, for which no separate analyses are available.
• Consequently, the available data are insufficient to quantify the additional benefit.

Courtesy translation only, please refer to the German original.