{
  "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": 59,
  "pageCount": 366,
  "prevPage": 58,
  "nextPage": 60,
  "slideType": "problem_statement",
  "function": "diagnose_problem",
  "density": "balanced",
  "nDataPoints": 0,
  "notes": "The slide highlights a fundamental design constraint in medicinal chemistry.",
  "elementsJson": [
    "paragraph",
    "footnote"
  ],
  "metadataConfidence": 0.9,
  "imagePath": null,
  "slideHref": "/slides/019dd923-622c-750b-8b9a-21918ac10c17/59",
  "deckHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17",
  "deckJsonHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17.json",
  "deckAnchorHref": "/decks/019dd923-622c-750b-8b9a-21918ac10c17#slide-59",
  "components": [
    {
      "bbox": null,
      "kind": "callout",
      "text": "cardiotoxicity is a feature, not a bug, and explains one of the many reasons why virtually large pharma company went after the H3 receptor for more than two decades – with a 100% failure rate due to lack of efficacy or toxicity.",
      "attrs": null,
      "subkind": null,
      "toolName": "Visual emphasis",
      "toolSlug": "visual-emphasis",
      "confidence": null,
      "componentId": "019dd953-64d0-7099-9ccd-3468233f5ffc",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.35,
        "w": 0.86,
        "x": 0.07,
        "y": 0.07
      },
      "kind": "paragraph",
      "text": "More importantly, the paper explained the unsolvable fatal flaw and Catch-22 for a histamine H3 drug like pitolisant: if the drug is tweaked to have less affinity for the hERG channel, then that “dramatically affects[s] its on-target activity” and “high inhibitory affinity” for the H3 receptor – there is no way to win. There is no way to thread the needle and bind to the H3 receptor but not to the hERG channel – so again, cardiotoxicity is a feature, not a bug, and explains one of the many reasons why virtually large pharma company went after the H3 receptor for more than two decades – with a 100% failure rate due to lack of efficacy or toxicity.",
      "attrs": null,
      "subkind": "paragraph",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "a7fff455-59c7-4546-b46f-fbb8a490c2ed",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.25,
        "w": 0.86,
        "x": 0.07,
        "y": 0.57
      },
      "kind": "paragraph",
      "text": "The obvious goal of a H3R drug discovery program, therefore, is to design molecules that have high inhibitory affinity for the H3R but not for the hERG channel. But changing/removal of a whole pharmacophore point from a molecule series is likely to dramatically affect its on-target activity, especially in the case of H3R, where the target and hERG pharmacophore maps are so similar. In this article,",
      "attrs": null,
      "subkind": "paragraph",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "ebcb4fea-ef0d-4f71-b8d8-0b743ef58666",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.03,
        "w": 0.25,
        "x": 0.07,
        "y": 0.95
      },
      "kind": "source-note",
      "text": "Source: https://pubmed.ncbi.nlm.nih.gov/21133680/",
      "attrs": null,
      "subkind": null,
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "a557312a-70c3-4561-8542-dfb5dd934a98",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.12,
        "w": 0.55,
        "x": 0.07,
        "y": 0.41
      },
      "kind": "title",
      "text": "Using Electrophysiology and In Silico Three-Dimensional Modeling to Reduce Human Ether-à-go-go Related Gene K+ Channel Inhibition in a Histamine H3 Receptor Antagonist Program",
      "attrs": null,
      "subkind": "headline",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "41ba6b20-2d85-46fa-a277-350013ce7494",
      "frameworkName": null,
      "frameworkSlug": null
    },
    {
      "bbox": {
        "h": 0.03,
        "w": 0.55,
        "x": 0.07,
        "y": 0.37
      },
      "kind": "title",
      "text": "Adverse event reporting rates for various histamine receptor drugs",
      "attrs": null,
      "subkind": "subtitle",
      "toolName": null,
      "toolSlug": null,
      "confidence": null,
      "componentId": "a353d36c-1a90-4df5-945d-7600ae0c0ce2",
      "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": [
    {
      "to": 60,
      "from": 50,
      "name": "The Reveal",
      "slug": "05-the-reveal",
      "bestFor": "Product launches, strategic pivots, unexpected findings",
      "matchId": "38dece92-a555-4683-9dd1-5ac3416bf9fd",
      "evidence": "The document presents a detailed analysis of the company's problems",
      "position": 1,
      "objective": "To reveal the extent of the company's problems",
      "structure": "Setup the Question -> Build Suspense -> The Big Reveal",
      "confidence": 0.8,
      "description": "Build mystery and anticipation, then deliver a surprising or powerful conclusion"
    }
  ],
  "imagePathAlt": null,
  "thumbSrc": null,
  "thumbSrcAlt": null,
  "locked": true
}