Discussion
sleepiness, IH, PVT, SOREMP
OBSTRUCTIVE SLEEP APNEA, PATHOPHYSIOLOGY
The orexin system plays an important role in the regulation of wakefulness, and although CSF orexin neuropeptide levels are normal in most people with IH [Overall, there were no serious TEAEs, no discontinuations due to TEAEs, no markedly abnormal laboratory values, and few markedly abnormal vital signs associated with danavorexton administration, consistent with a previous evaluation of danavorexton in a similar study involving people with obstructive sleep apnea [We found that a single, constant infusion of danavorexton 112 mg over 9 h resulted in improvements in objective (MWT) and subjective (KSS) measures of wakefulness and improvements in sustained attention/vigilance (PVT) in people with IH. In our study, most participants receiving danavorexton remained awake for the maximum time of 40 min from the first MWT session at 2 h post-infusion start and in all subsequent MWT sessions over the infusion period, achieving sleep latency times comparable to or higher than those of healthy participants [Participants receiving danavorexton reported levels of sleepiness on the KSS that were comparable with the general population. In addition, improvements in sustained attention/vigilance were observed using the PVT, a simple RT test, after initiation of the danavorexton infusion, despite the fact that most participants did not present with a clinically relevant impairment in vigilance with this test at baseline (clinical impairment defined as mean RT ≥ 500 ms [Limitations of the study include a short treatment duration and small participant numbers that, although typical for phase 1b studies, limits the generalizability of our findings to other populations outside the United States and Japan and to non-inpatient settings. Of note, findings were not evaluated for participants from the United States and Japan separately, and thus geographic differences have not been determined. Furthermore, the standard nPSG performed does not allow the identification of long sleepers, as the mean total sleep time on the standard 8-h nPSG was 7.1 h. Finally, the literature is consistent in stating an accurate and reproducible diagnosis of IH and differentiation from NT2 is difficult. Taking that into consideration, we utilized the only presently validated criteria for the diagnosis of IH; that is, we used the ICSD-3 criteria for categorization of IH, using the results of PSG/MSLT data provided by individual investigators, showing a mean sleep onset latency of < 8 min over 5 naps and the presence of ≤ 1 sleep onset REM period (SOREMP), along with MWT data showing a sleep latency of < 20 min.Additional studies with other orexin agonists in larger samples of IH patients are needed to extend on these promising findings. Further, research aimed at better understanding the role or impact of the orexin system in the pathophysiology of IH is also needed.