{ "docId": "019dd923-622c-750b-8b9a-17a662f06f5c", "docSlug": "883b7cfa22f5", "documentTitle": "Harmony Biosciences (HRMY)", "authorId": "58_Scorpion_Capital", "authorName": "Kir Kahlon", "documentKindSlug": "regulatory-filing", "documentKindLabel": "Regulatory filing", "sourceTypeSlug": "short_seller", "sourceTypeLabel": "Short seller", "presentationDate": "2023-04-03 00:00:00", "orientation": "portrait", "aspectRatio": 0.77272725, "pageNumber": 4, "pageCount": 10, "prevPage": 3, "nextPage": 5, "slideType": "expose_contradiction", "function": "expose_contradiction", "density": "overcrowded", "nDataPoints": 0, "notes": "This appears to be a page from a regulatory petition or legal filing challenging the approval of a drug.", "elementsJson": [ "bullet_list", "paragraph" ], "metadataConfidence": 0.9, "imagePath": null, "slideHref": "/slides/019dd923-622c-750b-8b9a-17a662f06f5c/4", "deckHref": "/decks/019dd923-622c-750b-8b9a-17a662f06f5c", "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-17a662f06f5c.json", "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-17a662f06f5c#slide-4", "components": [ { "bbox": null, "kind": "callout", "text": "The literature documented in Petitioner's report indicates that cardiotoxicity is an unsolvable flaw and Catch-22 for a histamine H3 drug like pitolisant.", "attrs": null, "subkind": null, "toolName": "Visual emphasis", "toolSlug": "visual-emphasis", "confidence": null, "componentId": "019dd953-14dd-72ca-b990-0ccc29adb863", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.15, "w": 0.72, "x": 0.14, "y": 0.09 }, "kind": "list", "text": "A 45-year old female who was diagnosed with hepatic cytolysis 20 days after starting pitolisant. Lab tests for viral causes were negative, suggesting it may be drug-induced. A 62-year old female patient who was hospitalized with a “life-threatening” pulmonary embolism fifteen days after the first dose of pitolisant. The drug was discontinued and the embolism resolved within 13 days.", "attrs": null, "subkind": "bullet", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "aa0172d3-c7f8-435e-b3e0-811bdf22c7f9", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.12, "w": 0.78, "x": 0.11, "y": 0.38 }, "kind": "paragraph", "text": "Ominously, numerous studies indicate that within the histamine class, the H3 receptor sub-class – of which pitolisant is the first and only approved drug – is particularly cardiotoxic, as its structure contains a piperidine ring and other features that are the top predictor of hERG liability in drug screens.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "05ed6953-486e-432d-8658-cf7f23826201", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.1, "w": 0.78, "x": 0.11, "y": 0.65 }, "kind": "paragraph", "text": "In addition, Petitioner details troubling prima facie flaws in the clinical trials upon which pitolisant’s approval was based. The trials were primarily conduced in questionable foreign jurisdictions, with one of the pivotal trials (HARMONY CTP) enrolling 38% of its participants in Russia, per a table in the CDER review.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "28c2be00-b966-4d6c-8f7b-99fe1c9bf59c", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.12, "w": 0.78, "x": 0.11, "y": 0.25 }, "kind": "paragraph", "text": "These adverse events are not surprising, and were in fact entirely predictable pre-approval. As Petitioner documents in the report, histamine receptor antagonists like pitolisant have a uniquely risky molecular structure with a long history of cardiotoxicity and FDA recalls, due to hERG channel blockade and the potential to cause sudden death via QT prolongation and arrhythmia.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "71c09882-dcf6-4aee-97cf-5fd4089dde10", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.12, "w": 0.78, "x": 0.11, "y": 0.51 }, "kind": "paragraph", "text": "Petitioner documents numerous other concerns in the report. For example, Bioprojet, the developer of pitolisant which is alternately listed in the NDA review documents along with Harmony Biosciences as the Sponsor, published a paper in 2012 that unequivocally disproves any association between histamine levels and hypersomnia conditions such as narcolepsy, excessive daytime sleepiness, cataplexy, and others.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "abb066f7-2433-4f2c-859f-0af75b224bf4", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.12, "w": 0.78, "x": 0.11, "y": 0.83 }, "kind": "paragraph", "text": "Petitioner’s report notes that the foundation of each clinical trial that led to FDA approval was the Epworth Sleepiness Scale (ESS), by which the primary endpoint of EDS reduction was assessed. ESS is a subjective, unvalidated patient reported survey that has been condemned in the sleep literature for its bias, inaccuracy, patient confusion, potential for coached answers, and other flaws.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "d25c3fe7-bcd1-4fa8-831b-903972993b5f", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "quote", "text": "results from sites in Russia...cannot be trusted — Study of foreign trials cited in Petitioner's report. \"disturbing and it's good to get it published...offshoring for financial reasons is bad because it raises risk of malfeasance.\" — FDA Commissioner Robert Califf. \"The primary EDS endpoint, the Epworth Sleepiness Scale\" — FDA review.", "attrs": null, "subkind": null, "toolName": "Authority citation", "toolSlug": "authority-citation", "confidence": null, "componentId": "019dd953-14dd-72ca-b990-13a575e20d78", "frameworkName": null, "frameworkSlug": null } ], "metrics": [], "tools": [], "frameworks": [ { "name": "fraud-exposure", "slug": null, "matchId": "9cb41fe2-a199-4305-9622-519afe490a05", "evidence": "The text explicitly details 'troubling prima facie flaws' and 'fraud and integrity issues' in clinical trials.", "confidence": 0.9 } ], "arcBeats": [ { "to": 4, "from": 2, "beatId": "b64df291-51b1-4c28-8f3b-791f9f32796e", "arcName": "Problem-Agitate-Solution", "arcSlug": "problem-agitate-solution", "beatName": "Complication", "beatSlug": "complication", "evidence": "Petitioner critiques Wakix and documents concerns", "position": 0, "confidence": 0.8, "parentBeatName": null, "parentBeatSlug": null } ], "loops": [ { "to": 4, "from": 2, "name": "Pattern Hunter", "slug": "02-pattern-hunter", "bestFor": "Time-pressed audiences, building consensus, when data is strong", "matchId": "7a6211ee-94a8-4515-be2d-fd8d945de76d", "evidence": "Reference to the Seldane (terfenadine) saga", "position": 0, "objective": "Establishing a pattern of concern with pharmaceutical products like Wakix", "structure": "Evidence A -> Evidence B -> Evidence C -> Pattern/Conclusion", "confidence": 0.6, "description": "Group multiple pieces of evidence that together point to a pattern or conclusion" } ], "imagePathAlt": null, "thumbSrc": null, "thumbSrcAlt": null, "locked": true }