Marc C. Patterson, MD, Professor of Neurology, Pediatrics, and Medical Genetics, and Chair of the Division of Child and Adolescent Neurology, at Mayo Clinic, discusses 24-month interim results from an open-label extension (OLE) of the phase 2/3 NPC-002 study of arimoclomol in Niemann-Pick disease type C (NPC). Data from this study was recently presented at WORLDSymposium 2022.
NPC is a disabling neurogenetic disorder that has been diagnosed prenatally, neonatally, during childhood, and even into adulthood. This very rare genetic disorder is marked by progressive motor dysfunction and a highly variable symptom profile and onset of symptoms. The underlying, principal abnormality is the cell’s inability to adequately move fatty molecules (e.g., cholesterol) out of the cell’s lysosomes. This dysfunction has been associated with mutations in one of two genes (NPC1 or NPC2). It can result in the patient’s death soon after birth or manifest as a chronic disorder with symptoms worsening slowly over time.
Last summer, the FDA denied approval of arimoclomol based on the need for additional qualitative and quantitative evidence to further support the validity of the 5-domain NPC Clinical Severity Scale (NPCCSS) used in the phase 2/3 trial as a measure of its primary endpoint. Additionally, the FDA noted in the complete response letter that data beyond the single phase 2/3 clinical trial are needed to support the benefit-risk assessment of the NDA.
With that regulatory hurdle to overcome, the phase 2/3 trial is still ongoing and 24-month interim results from an open-label extension (OLE) of the trial was presented at WORLDSymposium. All patients in the OLE received arimoclomol as an add-on therapy to their current standard of care. The primary endpoint is change in disease severity based on the 5-domain NPC Clinical Severity Scale (5D-NPCCSS) scores from baseline to months 18, 24, 30 and 36. A total of 41 participants enrolled in the OLE and 33 continued until month 36. At month 36, a sustained and clinically meaningful effect of arimoclomol was observed on the 5D-NPCCSS compared with estimated progression on routine clinical care. Mean (SE) change from DB baseline was +3.5 (1.22) for the arimoclomol-arimoclomol group (3 years arimoclomol treatment) and +0.9 (0.61) for the placebo-arimoclomol group (2 years arimoclomol treatment). In comparison, mean (SE) change in 5D-NPCCSS score with routine clinical care including miglustat, estimated by extrapolation from NPC-001 observational and NPC-002 placebo data, was +5.2 (1.41) over 3 years, and +3.5 (0.94) over 2 years. A clinically meaningful effect of arimoclomol compared to estimated disease progression was also observed in the predefined subgroups at month 36. This predefined subgroup included participants 4 years old who were treated with miglustat. Finally, the proportion of patients who experienced adverse events during the OLE (92.7%) was similar to the original study (88.2%).
To learn more about NPC and other lysosomal storage diseases, visit checkrare.com/diseases/lysosomal-storage-disorders/
