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  "documentTitle": "Harmony Biosciences (HRMY)",
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      "text": "In the absence of this information - given the already absurd n=3 - the steady plasma estimate of poor metabolizers is meaningless.",
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      "text": "CYP2D6 Genetic Deficiencies: The PK of pitolisant in PMs of CYP2D6 vs. Normal metabolizers (NMs) of CYP2D6 was assessed in 8 genotyped healthy adult, male subjects in a mass balance clinical study (P15-02). The PK after single dose as well as after steady state (on day 7) at 40 mg dose (in salt form) was used to compare the exposure in PMs (N=3) vs NMs (N=5). CYP2D6 alleles tested and genotyping methods were appropriate for determining CYP2D6 PM and NM status. An approximate 2-fold increase in exposure was observed in CYP2D6 PMs as compared to CYP2D6 NMs. Additionally, a dedicated drug interaction study with paroxetine (a strong CYP2D6 inhibitor) also resulted in a similar increase in exposure of pitolisant which supports the conclusion that exposures can be expected to be 2-fold higher in CYP2D6 PMs.",
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      "text": "The second red flag: Bioprojet/Harmony don't state which CYP2D6 phenotypes were selected for the three “poor” metabolizers tested – how are “poor” and “normal” defined? Further muddying the waters, the terms NM (“normal metabolizers”) and EM (“extensive metabolizers”) are used interchangeably for the 5 “normal” subjects, although the terms refer to different CYP2D6 phenotypes. The FDA’s description, which we suspect is a cut and paste summary from the company, is tellingly vague: “CYP2D6 alleles tested and genotyping methods were appropriate for determining CYP2D6 PM [poor metabolizer] and NM [normal metabolizer] status.” In the absence of this information – given the already absurd n=3 – the steady plasma estimate of poor metabolizers is meaningless. We suspect Bioprojet simply chose metabolizers with CYP2D6 phenotypes for decreased activity vs. those with little to none, thereby dramatically underestimating plasma levels.",
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      "text": "“CYP2D6 alleles tested and genotyping methods were appropriate for determining CYP2D6 PM [poor metabolizer] and NM [normal metabolizer] status.” — FDA CDER Clinical Pharmacology Review",
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      "text": "Source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000ClinPharmR.pdf",
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      "text": "The second red flag: Bioprojet/Harmony don't state which CYP2D6 phenotypes were selected for the three “poor” metabolizers tested",
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