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  "documentTitle": "Harmony Biosciences (HRMY)",
  "authorId": "58_Scorpion_Capital",
  "authorName": "Scorpion Capital",
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  "presentationDate": "2023-03-28 00:00:00",
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  "notes": "The slide uses a combination of narrative argument and a supporting data table to challenge the safety profile of the drug.",
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      "kind": "callout",
      "text": "Regression formula (see slide __) indicates 38-80 msec QT prolongation at plasma levels within the range for poor CYP2D6 metabolizers of pitolisant",
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      "text": "QT prolongation: 80 msec",
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      "text": "The danger from elevated pitolisant plasma levels in poor CYP2D6 metabolizers is self-evident. Even using Harmony’s asserted plasma level of 153 ng/mL – a misleadingly low number – it can spike by four-fold within a 90% CI per their own graph in the label. That results in 612 ng/mL, and far higher at a 95% CI. The expected QT prolongation at 612 ng/mL is 38 msec - well into the danger zone for cardiovascular toxicity - using the regression model developed by our pharmacology consultant using Bioprojet’s papers (see section on cardiac safety data). If, as we suspect, the CYP2D6 study used a 17.8mg dose (half the normal dose) to calculate the 153 ng/mL plasma level, then the true level is 306 ng/mL. At a four-fold change, the 306 can spike to 1224 ng/mL which leads to an expected QT prolongation of 80 msec, which of course explains the prevalence of serious cardiac events in the FDA’s adverse events database as well as potentially the cardiac-related fatality in the HAROSA sleep apnea trial. Merely suggesting half the dose per the label does little to nothing to mitigate the risk.",
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      "text": "Source: Pharmacology analysis commissioned by Scorpion Capital",
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      "text": "Table showing dose, n, Cmax, CV%, 95% CI Upper Limit, AUC, TQT/Tmax, and Upper limit TQT.",
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      "text": "Regression analysis shows expected QT prolongation at various plasma levels",
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