{ "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": 131, "pageCount": 366, "prevPage": 130, "nextPage": 132, "slideType": "expose_contradiction", "function": "expose_contradiction", "density": "dense", "nDataPoints": 3, "notes": "The slide uses a quote from a pharmacology consultant to argue that safety margins are overestimated due to drug accumulation.", "elementsJson": [ "paragraph", "quote_block" ], "metadataConfidence": 1, "imagePath": null, "slideHref": "/slides/019dd923-622c-750b-8b9a-21918ac10c17/131", "deckHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17", "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17.json", "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17#slide-131", "components": [ { "bbox": { "h": 0.03, "w": 0.45, "x": 0.07, "y": 0.37 }, "kind": "callout", "text": "Comments by a pharmacology consultant engaged by Scorpion Capital", "attrs": null, "subkind": "primary", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "89499ad2-6c8f-46ec-848f-329fd403f428", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "callout", "text": "the peak plasma levels of Pitolisant after 6 consecutive daily doses will be 2.3x higher than they were on Day 1 but the Day 1 plasma concentrations were used to estimate the safety margins for QTcF.", "attrs": null, "subkind": null, "toolName": "Visual emphasis", "toolSlug": "visual-emphasis", "confidence": null, "componentId": "019dd953-64d0-7099-9cd3-7405a163d1f2", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.28, "w": 0.86, "x": 0.07, "y": 0.07 }, "kind": "paragraph", "text": "We engaged two consultants to analyze Harmony’s cardiac safety data, one a pharmacology consultant and the second a prominent expert specifically in hERG/QT and drug-induced cardiotoxicity. The pharmacology consultant characterized Harmony’s data as “intentionally misleading” and “sneaky,” stating that the “statements made about safety margins are therefore overestimated and incorrect.” The consultant strongly disputed the FDA’s interpretation of “clinically insignificant” or “clinically manageable increases in QT at supra-therapeutic doses” as they were inferred from single-dose plasma levels vs. at steady-state.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "17129126-087c-4fc4-95ab-2c2addbd6aae", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.48, "w": 0.86, "x": 0.07, "y": 0.41 }, "kind": "quote", "text": "Basic PK – since the half-life of Pitolisant is approximately 20 hours about half the drug levels will be circulating when the 2nd dose is administered so this is added to the new peak plasma levels on Day 2, and again on day 3, day 4 etc., until steady state plasma levels are reached (for Pitolisant about 6 consecutive days of dosing - rule of thumb for half-life - it takes approximately 6 half lives of a drug to reach steady state). This is what the “accumulation ratio” parameter exemplifies In a nutshell, the peak plasma levels of Pitolisant after 6 consecutive daily doses will be 2.3x higher than they were on Day 1 but the Day 1 plasma concentrations were used to estimate the safety margins for QTcF. Thus, the QTcT study is intentionally misleading, and the statements made about safety margins are therefore overestimated and incorrect. For example, “clinically insignificant QT increases at of only 9.8 msec at 2.5x the highest therapeutic dose” BUT THIS IS TRUE ONLY AFTER A SINGLE DOSE NOT FOR MULTIPLE DAILY DOSES. These measurements should have been made at steady state after at least 6 daily doses in order for these safety margins to be accurate – they would in fact be substantially smaller (safety margins) which may account for the reported QTcF increases seen in the sleep apnea trials.” –Pharmacology consultant engaged by Scorpion Capital", "attrs": null, "subkind": "testimonial", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "b9e5ac11-f7e1-4d36-953c-d44e2b0c543c", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "quote", "text": "“Basic PK – since the half-life of Pitolisant is approximately 20 hours about half the drug levels will be circulating when the 2nd dose is administered so this is added to the new peak plasma levels on Day 2, and again on day 3, day 4 etc., until steady state plasma levels are reached... Thus, the QTcT study is intentionally misleading, and the statements made about safety margins are therefore overestimated and incorrect.” — Pharmacology consultant engaged by Scorpion Capital", "attrs": null, "subkind": null, "toolName": "Authority citation", "toolSlug": "authority-citation", "confidence": null, "componentId": "019dd953-64d0-7099-9cd3-7b648574a4e8", "frameworkName": null, "frameworkSlug": null } ], "metrics": [], "tools": [ { "name": "Authority citation", "slug": "authority-citation", "agent": null, "layer": "slide", "matchId": "c51d960f-0a65-4f39-87a8-c6f63cc577f1", "evidence": "The slide quotes a pharmacology consultant.", "confidence": 0.5 } ], "frameworks": [ { "name": "fraud-exposure", "slug": null, "matchId": "2c375e63-ce15-427e-898e-cb46ac0119b3", "evidence": "The slide explicitly frames the company's data as 'intentionally misleading' and 'sneaky' to expose a potential safety risk.", "confidence": 0.9 } ], "arcBeats": [], "loops": [], "imagePathAlt": null, "thumbSrc": null, "thumbSrcAlt": null, "locked": true }