{ "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": 61, "pageCount": 366, "prevPage": 60, "nextPage": 62, "slideType": "preempt_rebuttal", "function": "preempt_rebuttal", "density": "dense", "nDataPoints": 4, "notes": "The slide uses a combination of narrative text and a supporting data table to argue that certain structural features are predictive of drug safety risks.", "elementsJson": [ "paragraph", "data_table", "footnote" ], "metadataConfidence": 0.95, "imagePath": null, "slideHref": "/slides/019dd923-622c-750b-8b9a-21918ac10c17/61", "deckHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17", "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17.json", "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17#slide-61", "components": [ { "bbox": null, "kind": "callout", "text": "Ominously for pitolisant, the top factor identified in the hERG model was a “nitrogen atom in a saturated ring, like piperidine....”", "attrs": null, "subkind": null, "toolName": "Visual emphasis", "toolSlug": "visual-emphasis", "confidence": null, "componentId": "019dd953-64d0-7099-9ccd-e43a36cc556a", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "metric", "text": "hERG liability probability: 94%", "attrs": null, "subkind": "primary", "toolName": "Quantification", "toolSlug": "quantification", "confidence": null, "componentId": "019dd953-64d0-7099-9ccd-eed2d5fe154f", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.3, "w": 0.68, "x": 0.07, "y": 0.475 }, "kind": "paragraph", "text": "The top five important features extracted from the training set of hERG model included N16 (a positively charged nitrogen atom in a saturated ring, such as piperidine or piperazine), C3 (an aromatic carbon atom with no substitution and adjacent to two aromatic carbon atoms), H2 (a hydrogen bonded to an aromatic carbon), M13 (a number of aromatic rings), and S5 (sulfur in a ring bonded to two aromatic atoms). These features summarize the two key characters of the hERG blockers – an aromatic moiety and a positive charge center, which is in good agreement with commonly recognized pharmacophore models of hERG blockers.[3b] Compounds containing two N16 nitrogen atoms have a greater than 73% chance to block hERG channels, and the probability dropped sharply to 10% for compounds without an N16 atom (Figure 9a). Piperazine and piperidine are two moieties frequently used by medicinal chemists to manipulate molecular flexibility and hydrophobicity. However, both structure features have high potential to trigger undesirable hERG activity, unless the basicity of the ring nitrogen atoms is alleviated by introducing neighboring aromatic rings or carbonyl groups.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "242e7752-8f16-4296-b97b-88a648478020", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.34, "w": 0.925, "x": 0.07, "y": 0.068 }, "kind": "paragraph", "text": "The first paper – by NIH researchers - screened more than 4,000 drug molecules to determine which factors drive drug-induced hERG blockade and QT prolongation. Ominously for pitolisant, the top factor identified in the hERG model was a “nitrogen atom in a saturated ring, like piperidine....” The scientists then validated the model with drugs known to have hERG liability, and it accurately predicted the hERG liability of several histamine-receptor drugs that were recalled. Terfenadine was predicted to have a 62% probability of being hERG active, and astemizole was 94%.", "attrs": null, "subkind": "paragraph", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "fc06159e-a9a8-49c1-80f0-be85433ec25d", "frameworkName": null, "frameworkSlug": null }, { "bbox": null, "kind": "quote", "text": "“nitrogen atom in a saturated ring, like piperidine....” — NIH researchers", "attrs": null, "subkind": null, "toolName": "Authority citation", "toolSlug": "authority-citation", "confidence": null, "componentId": "019dd953-64d0-7099-9ccd-e80ec2a2c193", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.02, "w": 0.35, "x": 0.07, "y": 0.94 }, "kind": "source-note", "text": "Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382096/", "attrs": null, "subkind": null, "toolName": null, "toolSlug": null, "confidence": null, "componentId": "361c8cfe-0534-4b34-803a-e3c8daceea5a", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.1, "w": 0.26, "x": 0.395, "y": 0.815 }, "kind": "table", "text": "Name: Terfenadine, Astemizole; pIC50: 6.70, 8.00; Class: P, P; Probability: 0.619, 0.939", "attrs": null, "subkind": "data", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "a9669a67-d69a-419d-8116-45364bdd126d", "frameworkName": null, "frameworkSlug": null }, { "bbox": { "h": 0.045, "w": 0.575, "x": 0.07, "y": 0.41 }, "kind": "title", "text": "Prediction of hERG Liability", "attrs": null, "subkind": "headline", "toolName": null, "toolSlug": null, "confidence": null, "componentId": "dff42449-cd22-4289-b33e-0c1665cfdf5f", "frameworkName": null, "frameworkSlug": null } ], "metrics": [], "tools": [], "frameworks": [], "arcBeats": [ { "to": 70, "from": 51, "beatId": "f412f440-0381-4eb7-b9f4-292dcebd62be", "arcName": "Overcoming the Monster", "arcSlug": "overcoming-monster", "beatName": "The Victory", "beatSlug": null, "evidence": "The document presents the conclusion that the company is a house of cards", "position": 3, "confidence": 0.8, "parentBeatName": null, "parentBeatSlug": null } ], "loops": [], "imagePathAlt": null, "thumbSrc": null, "thumbSrcAlt": null, "locked": true }