{
  "abstract": "Background/Objectives: Narcolepsy type 1 (NT1) results from loss of hypothalamic orexin neurons. Selective orexin-2 receptor (OX2R) agonists now permit direct receptor-level restoration of deficient signaling, but recent broad reviews do not fully integrate the post-approval, trial-specific efficacy, prescribing, and safety evidence. This review asks what benefits and risks are supported by current data, which toxicities appear class-related versus molecule-specific, and how OX2R agonism should be positioned clinically. Methods: We performed a targeted narrative review of peer-reviewed human studies, major guidelines, trial registries, and regulatory documents updated through 16 October 2026. Peer-reviewed trials and regulatory sources were prioritized; conference- or sponsor-reported data were used only when peer-reviewed evidence was unavailable and were identified as provisional. Results: In the pivotal phase 3 trials, oveporexton produced placebo-adjusted improvements in MWT sleep latency of 13.8–20.1 min, ESS reductions of 8.0–9.8 points, and weekly cataplexy incidence-rate ratios of 0.25–0.38. Clinically important safety considerations include insomnia, urinary frequency/urgency, CPK elevations, CYP3A interactions, and measurable abuse potential. Alixorexton phase 2 data support OX2R agonism as a developing drug class, whereas firazorexton illustrates molecule-specific hepatotoxic risk. Conclusions: OX2R agonists are best described as mechanism-based pharmacological restoration of orexin signaling, not proven disease-modifying therapy. Their comparative clinical position remains uncertain because head-to-head trials with established therapies are lacking.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Rabigh 25732, Saudi Arabia",
    "Pharmacology and Toxicology Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yahya A. Alzahrani"
    },
    {
      "affs": [
        1
      ],
      "name": "Maan H. Harbi",
      "orcid": "0000-0002-8892-5192"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cygafvrbmjvd6.bib",
  "cited_by": 0,
  "doi": "10.3390/jcm15218642",
  "fulltext_url": null,
  "id": "cygafvrbmjvd6",
  "issns": [
    "2077-0383"
  ],
  "landing_url": "https://www.mdpi.com/2077-0383/15/21/8642",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-06",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/cygafvrbmjvd6.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T00:21:23Z",
      "native_id": "10.3390/jcm15218642",
      "source": "crossref",
      "url": "https://www.mdpi.com/2077-0383/15/21/8642"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "journal-openalex:F27",
      "subfield": "general"
    }
  ],
  "title": "Orexin-2 Receptor Agonists in Narcolepsy: Restoring the Missing Signal",
  "title_text": "Orexin-2 Receptor Agonists in Narcolepsy: Restoring the Missing Signal",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T00:23:02Z",
  "url": "https://research.draconitic.com/paper/cygafvrbmjvd6",
  "venue": "Journal of Clinical Medicine",
  "versions": []
}