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  "documentTitle": "Harmony Biosciences (HRMY)",
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  "authorName": "Scorpion Capital",
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  "presentationDate": "2023-03-28 00:00:00",
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  "notes": "The slide uses a specific scientific paper (Lin et al., 2007) to argue that the drug's mechanism is scientifically implausible based on the provided data.",
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      "text": "Key 2007 rodent paper – Lin, Dauvilliers, Schwartz et al: “An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin-/- mice and patients”",
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      "text": "Brain concentration (top) is ~20X higher than in blood (bottom)",
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      "text": "drug concentration: ~20X",
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      "text": "In addition to a general lack of bioavailability, pitolisant’s purported mechanism of action is doubtful due to blood/brain barrier permeability and CNS uptake. The blood/brain barrier is a major obstacle in the development of CNS drug delivery and a class problem with H3 receptor antagonists/inverse agonists – one of many impediments conveyed to us by scientists involved in failed H3 receptor drug programs at several large pharma companies. The only CNS uptake data we can locate for pitolisant is from rodent studies in the 2000’s – no human data appears to be available. Our pharmacology consultant reviewed the data and found it suspect and troubling. First, the study failed to use a standard methodology for measuring CNS uptake in rodents called quantitative whole-body autoradiography (QWBA). The study instead homogenized the brains after sacrificing the mice, presumably centrifuging to measure ng/g concentrations. Second, the data is highly suspicious, as it shows brain levels of pitolisant that appear ~20X higher than those in the blood – the opposite of the typical pattern.",
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      "text": "An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: Studies in orexin-/- mice and patients — Lin, Dauvilliers, Schwartz et al.",
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      "text": "Source: https://pubmed.ncbi.nlm.nih.gov/18295497/",
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