Long-term efficacy and safety of arimoclomol in Niemann-Pick disease type C: Final results of the phase 2/3 NPC-002 48-month open-label extension trial.

Background
This paper presents efficacy and safety outcomes from the 48-month open-label extension (OLE) of the phase 2/3 NPC-002 trial (NCT02612129) which evaluated arimoclomol treatment in patients with Niemann-Pick disease type C (NPC). Arimoclomol was recently approved by the US Food and Drug Administration for treatment of NPC in combination with miglustat.Methods
Patients with NPC who completed the double-blind (DB) phase of the randomized controlled NPC-002 trial were eligible to continue in the OLE, during which all patients received arimoclomol in addition to routine clinical care. Primary efficacy outcomes were the 5-domain NPC Clinical Severity Scale (5DNPCCSS), and the rescored 4-domain NPCCSS (R4DNPCCSS), which was introduced post-hoc. Additional outcomes included NPC-specific measures (full scale NPCCSS, and NPC clinical database [NPC-cdb] score), and safety evaluations.Results
Of the 50 patients who started the DB phase, 41 entered the OLE phase, with 29 completing 48 months. During the OLE, mean (SD) 5DNPCCS and R4DNPCCSS scores increased by 3.2 (4.8) and 2.7 (4.2) over 48 months, respectively. Among patients switching from placebo to arimoclomol after the DB phase, mean annual change in 5DNPCCSS decreased from 2.0 (on placebo) to 0.1 in the first year of receiving arimoclomol and mean annual change in R4DNPCCSS decreased from 1.9 to 0.2, indicating slowing of disease progression. Annual scores for both endpoints remained numerically smaller throughout the OLE than during the DB phase. The score pattern in the subset of patients who received miglustat as part of their standard care regime in addition to arimoclomol (N = 33) was similar to that seen in the total population. 17-domain NPCCSS (excluding hearing domains) and NPC-cdb results further supported sustained efficacy of arimoclomol. Arimoclomol was well-tolerated over 48 months, with no new safety concerns identified.Conclusion
The OLE of the NPC-002 trial provides evidence for a sustained reduction in disease progression for at least 5 years in a heterogeneous population of NPC patients receiving arimoclomol in addition to routine clinical care, with no new safety concerns. These results align with the statistically significant and clinically meaningful reduction in disease progression observed over 12-months in the DB phase, further highlighting the potential of arimoclomol as an effective and well tolerated disease modifying treatment for NPC.