{ "docId": "019dd923-622c-750b-8b9a-21918ac10c17", "docSlug": "f3db2294dcf9", "documentTitle": "Harmony Biosciences (HRMY)", "authorId": "58_Scorpion_Capital", "authorName": "Scorpion Capital", "documentKindSlug": "research-note", "documentKindLabel": "Research note", "sourceTypeSlug": "short_seller", "sourceTypeLabel": "Short seller", "presentationDate": "2023-03-28 00:00:00", "orientation": "landscape", "aspectRatio": 1.3333334, "pageNumber": 142, "pageCount": 366, "prevPage": 141, "nextPage": 143, "slideType": "preempt_rebuttal", "function": "preempt_rebuttal", "density": "overcrowded", "nDataPoints": 4, "notes": "The slide uses direct excerpts from regulatory documents to challenge the company's claims regarding drug safety and pharmacokinetics.", "elementsJson": [ "paragraph", "screenshot", "footnote" ], "metadataConfidence": 0.95, "imagePath": null, "slideHref": "/slides/019dd923-622c-750b-8b9a-21918ac10c17/142", "deckHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17", "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17.json", "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17#slide-142", "components": [ { "bbox": null, "kind": "callout", "text": "The FDA relied upon an absurdly small Harmony PK study in CYP2D6 poor metabolizers (n=3) to conclude that steady-state plasma levels in such patients are twice those of normal metabolizers.", "attrs": null, "subkind": null, "toolName": "Visual emphasis", "toolSlug": "visual-emphasis", "confidence": null, "componentId": "019dd953-70f3-714d-84c6-057ffa17daf3", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.12, "w": 0.86, "x": 0.07, "y": 0.8 }, "kind": "paragraph", "text": "CYP2D6 Genetic Deficiencies:\nAn approximate 2-fold increase in exposure was observed in CYP2D6 poor metabolizers (PMs) as compared to CYP2D6 normal metabolizers (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 2x -fold higher in CYP2D6 PMs. Therefore, the dose of WAKIX should be capped at 17.8 mg/day in known CYP2D6 PMs. The details are provided in Clinical Pharmacology Questions (3.3).", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "5909e18a-ac4f-4f8f-adbb-29a2c1495d8d", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.15, "w": 0.86, "x": 0.07, "y": 0.56 }, "kind": "paragraph", "text": "12.5 Pharmacogenomics\nApproximately 3 to 10% of Caucasians and 2 to 7% of African Americans generally lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers. The AUC of pitolisant was approximately 2.4 times higher in CYP2D6 poor metabolizers than in normal metabolizers and is similar to the exposure of pitolisant when administered concomitantly with a CYP2D6 inhibitor [see Dosage and Administration (2.5), Drug Interactions (7.1)].\nIn CYP2D6 poor metabolizers, the Cmax of pitolisant is 153 (151 to 157) ng/mL and the AUC is 1920 (1854 to 2000) ng*hr/mL after steady state dosing with 35.6 mg once daily.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "b12b488f-a18f-40ec-819e-a4e0ba25d1eb", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.45, "w": 0.86, "x": 0.07, "y": 0.07 }, "kind": "paragraph", "text": "We have already noted – in the section on cardiotoxicity – that pitolisant’s steady-state plasma levels are far higher and more variable/unpredictable than asserted by Bioprojet and Harmony. Pitolisant displays a dose-dependent risk of QT prolongation and cardiovascular danger, which we believe Harmony is trying to conceal by significantly understating actual blood levels of the drug. The fact that pitolisant has a CYP2D6 liability further escalates an already significant risk, as already elevated plasma levels can spike many multiples from there. The critical question then becomes: how much do pitolisant levels increase in poor 2D6 metabolizers? The FDA relied upon an absurdly small Harmony PK study in CYP2D6 poor metabolizers (n=3) to conclude that steady-state plasma levels in such patients are twice those of normal metabolizers – 73 ng/ML in normal metabolizers at the 35.6mg dose, and 153 ng/mL in poor metabolizers – and hence recommends cutting the dose in half.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "d82adb2f-cad3-4e93-ba92-446912f6d3c2", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "quote", "text": "Approximately 3 to 10% of Caucasians and 2 to 7% of African Americans generally lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers. The AUC of pitolisant was approximately 2.4 times higher in CYP2D6 poor metabolizers than in normal metabolizers — Pitolisant package insert.", "attrs": null, "subkind": null, "toolName": "Authority citation", "toolSlug": "authority-citation", "confidence": null, "componentId": "019dd953-70f3-714d-84c6-0829e39f3da2", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.05, "w": 0.5, "x": 0.07, "y": 0.93 }, "kind": "source-note", "text": "Source: https://www.wakix.com/assets/pdf/WAKIX_pitolisant_tablets_PI_Dec_2022.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211150Orig1s000ClinPharmR.pdf", "attrs": null, "subkind": null, "toolName": null, "toolSlug": null, "confidence": null, "componentId": "a46f1ae5-14e6-415c-8147-54faed596502", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.03, "w": 0.35, "x": 0.07, "y": 0.76 }, "kind": "title", "text": "FDA CDER Clinical Pharmacology Review", "attrs": null, "subkind": "headline", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "4e5d064b-d24a-42f2-a99a-553cb8f61fee", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.03, "w": 0.55, "x": 0.07, "y": 0.51 }, "kind": "title", "text": "Pitolisant package insert and full prescribing information, excerpts", "attrs": null, "subkind": "headline", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "e87e034b-45c9-4784-a9f9-b472fa3c1fbd", "frameworkName": null, "frameworkSlug": null } ], "metrics": [], "tools": [], "frameworks": [], "arcBeats": [], "loops": [], "imagePathAlt": null, "thumbSrc": null, "thumbSrcAlt": null, "locked": true }