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  "documentTitle": "Harmony Biosciences (HRMY)",
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  "notes": "The slide uses direct citations from FDA and research documents to highlight the discrepancy between single-dose study designs and the need for steady-state peak plasma concentration analysis.",
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      "text": "Summary of studies P09-11 (TQT study) and P14-05 (SAD study) per 2016 review paper",
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      "text": "FDA CDER Clinical Review, Dec 2018 – indicates the QT studies were both single-dose",
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      "text": "The problem is that these supra-therapeutic doses were only SINGLE-DOSE and would not cover the steady-state peak plasma concentrations which are 2.3 times higher what they would be after a single dose, given pitolisant’s half-life and the implied accumulation ratio.",
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      "text": "The designs of the two studies and assessments of study endpoints of interest are briefly summarized below. The TQT study (40- and 120-mg single doses) was conducted during March–August 2010 whereas the high-dose SAD study (160-, 200-, and 240-mg single doses) was conducted during October–November 2014 in order to extend even higher the dose range investigated in the TQT study.",
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      "text": "The FDA’s interpretation of Harmony’s QT data is deeply flawed. First, although it clearly states that there is a dose-dependent QT prolongation, it incorrectly assumes that the 35.6 mg dose is below the threshold at which it manifests. The FDA simply assumes that Harmony’s assertion of average plasma levels at 35.6 mg (73 ng/mL) is correct, despite clear red flags indicating it is far higher. Second, the FDA’s entire analysis depends on the safety margins in the two cardiac safety studies (P09-11 and P14-05), which measured QT prolongation at supra-therapeutic doses of 120 to 240 mg. The problem is that these supra-therapeutic doses were only SINGLE-DOSE and would not cover the steady-state peak plasma concentrations which are 2.3 times higher what they would be after a single dose, given pitolisant’s half-life and the implied accumulation ratio.",
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      "text": "The Sponsor evaluated the effect of pitolisant on the QT interval in two studies (Studies P09-11 and P14-05) [...] Study P09-11 was a total QT (TQT) study that evaluated doses up to 120 mg (single dose). Study P14-05 was a single ascending dose (SAD) study that evaluated doses up to 240 mg. The TQT study did not find a clinically significant QTc prolonging effect with the recommended pitolisant dose of 40 mg once daily, though a dose of 120 mg was associated with QTc prolongation of approximately 10 milliseconds (msec).",
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      "text": "“The Sponsor evaluated the effect of pitolisant on the QT interval in two studies (Studies P09-11 and P14-05) [...] Study P09-11 was a total QT (TQT) study that evaluated doses up to 120 mg (single dose). Study P14-05 was a single ascending dose (SAD) study that evaluated doses up to 240 mg.” — FDA CDER Clinical Review, Dec 2018",
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      "text": "Source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/211150Orig2s000MedR.pdf; https://pubmed.ncbi.nlm.nih.gov/26879827/",
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