{ "_meta": { "title": "Withdrawn / Discontinued Anti-Obesity Drug Registry", "domain": "Obesity", "category": "Research idea generation (hypothesis generation, literature gap analysis, ontology-driven derivation)", "note": "Curated from publicly known historical facts (market withdrawals, regulatory refusals, program terminations). Detailed fields (de-risking levers, plausibility scores, inheritance edges) are SYNTHETIC DEMO content for tooling demonstration, NOT clinical guidance.", "version": "2026-06-05", "open_sources": [ "WITHDRAWN (withdrawn drugs DB, ETH/CECAD)", "FDA Drug Safety / withdrawal notices", "EMA CHMP refusal/withdrawal assessment reports", "ClinicalTrials.gov (program status)", "FAERS (post-market signal context)", "Open Targets (target-tissue expression context)" ], "disclaimer": "Reference / research hypothesis-generation tool only. NOT clinical decision support, NOT medical advice." }, "harm_mechanisms": [ { "id": "HM_5HT2B_VALVE", "name": "5-HT2B receptor agonism -> cardiac valvulopathy", "tissue": "cardiac valve fibroblasts (heart valve)", "mechanism": "Agonism at 5-HT2B receptors on valvular interstitial cells drives fibroblast proliferation and ECM deposition -> valve thickening/regurgitation.", "vulnerable_groups": ["pre-existing valvular disease", "prolonged high-dose exposure"] }, { "id": "HM_5HT_PPH", "name": "Non-selective serotonergic / serotonin-transporter effect -> pulmonary arterial hypertension (PPH)", "tissue": "pulmonary vascular smooth muscle / endothelium", "mechanism": "Increased serotonergic tone and SERT-mediated uptake in pulmonary vasculature promotes vasoconstriction and vascular remodeling -> elevated pulmonary pressure.", "vulnerable_groups": ["genetic PAH predisposition (e.g., BMPR2)", "prolonged exposure"] }, { "id": "HM_CB1_CNS", "name": "Central CB1 inverse agonism/antagonism -> psychiatric / suicidality", "tissue": "CNS (limbic / prefrontal endocannabinoid signaling)", "mechanism": "Blockade of central CB1 endocannabinoid tone dysregulates mood/reward circuits -> depression, anxiety, suicidal ideation.", "vulnerable_groups": ["history of depression/anxiety", "active psychiatric disorder"] }, { "id": "HM_SYMPATH_CV", "name": "Sympathomimetic / monoamine reuptake -> cardiovascular (BP, HR, MACE)", "tissue": "cardiovascular system (myocardium, vasculature)", "mechanism": "Increased noradrenergic/sympathetic tone raises heart rate and blood pressure -> increased nonfatal MI/stroke risk in at-risk populations.", "vulnerable_groups": ["established cardiovascular disease", "uncontrolled hypertension"] }, { "id": "HM_CARCINOGEN_SIGNAL", "name": "Carcinogenicity signal (preclinical/long-term)", "tissue": "multiple (rodent tumor signal)", "mechanism": "Long-term carcinogenicity studies and/or numeric imbalance in malignancy raised a benefit-risk concern outweighing modest weight effect.", "vulnerable_groups": ["long-term chronic use population"] }, { "id": "HM_METABOLIC_TOXICITY", "name": "Uncoupler / direct metabolic toxicity", "tissue": "systemic mitochondria", "mechanism": "Mitochondrial uncoupling produces uncontrolled thermogenesis -> hyperthermia, multi-organ failure, death; narrow therapeutic index.", "vulnerable_groups": ["any unsupervised use", "overdose-prone"] }, { "id": "HM_THROMBOSIS", "name": "Pro-thrombotic / venous thromboembolism signal", "tissue": "vascular endothelium", "mechanism": "Mechanism-associated thrombotic events (e.g., VTE) emerged in trials, raising fatal-event concern.", "vulnerable_groups": ["thrombophilia", "prior VTE"] }, { "id": "HM_HEPATOTOX", "name": "Hepatotoxicity", "tissue": "liver (hepatocytes)", "mechanism": "Idiosyncratic or dose-related hepatocellular injury -> elevated transaminases / liver failure risk.", "vulnerable_groups": ["pre-existing liver disease"] } ], "drugs": [ { "id": "fenfluramine", "name": "Fenfluramine", "class": "Serotonin releaser / 5-HT agonist", "targets": ["5-HT release", "5-HT2B receptor", "SERT"], "status": "Withdrawn (market)", "event_year": 1997, "withdrawal_reason": "Cardiac valvulopathy and pulmonary hypertension (fen-phen)", "harm_nodes": ["HM_5HT2B_VALVE", "HM_5HT_PPH"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["SUBTYPE_SELECTIVITY", "PERIPHERAL_RESTRICTION", "DOSE_REDESIGN"] }, { "id": "dexfenfluramine", "name": "Dexfenfluramine", "class": "Serotonin releaser / 5-HT agonist (d-isomer)", "targets": ["5-HT release", "5-HT2B receptor", "SERT"], "status": "Withdrawn (market)", "event_year": 1997, "withdrawal_reason": "Valvulopathy / PPH (same serotonergic class as fenfluramine)", "harm_nodes": ["HM_5HT2B_VALVE", "HM_5HT_PPH"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["SUBTYPE_SELECTIVITY", "PERIPHERAL_RESTRICTION"] }, { "id": "sibutramine", "name": "Sibutramine", "class": "Serotonin-norepinephrine reuptake inhibitor (SNRI)", "targets": ["SERT", "NET"], "status": "Withdrawn (market)", "event_year": 2010, "withdrawal_reason": "Increased nonfatal MI/stroke (SCOUT trial) in CV-risk population", "harm_nodes": ["HM_SYMPATH_CV"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["VULNERABLE_EXCLUSION", "DOSE_REDESIGN", "TISSUE_SELECTIVITY"] }, { "id": "rimonabant", "name": "Rimonabant", "class": "CB1 inverse agonist", "targets": ["CB1 receptor"], "status": "Withdrawn (market, EU) / never approved US", "event_year": 2008, "withdrawal_reason": "Psychiatric adverse events: depression, anxiety, suicidality", "harm_nodes": ["HM_CB1_CNS"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["PERIPHERAL_RESTRICTION", "BIASED_PARTIAL_AGONISM", "VULNERABLE_EXCLUSION"] }, { "id": "taranabant", "name": "Taranabant", "class": "CB1 inverse agonist (next-gen attempt)", "targets": ["CB1 receptor"], "status": "Discontinued (development)", "event_year": 2008, "withdrawal_reason": "Dose-related psychiatric adverse events (same CB1 central class)", "harm_nodes": ["HM_CB1_CNS"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["PERIPHERAL_RESTRICTION", "BIASED_PARTIAL_AGONISM"] }, { "id": "lorcaserin", "name": "Lorcaserin", "class": "5-HT2C selective agonist", "targets": ["5-HT2C receptor"], "status": "Withdrawn (market)", "event_year": 2020, "withdrawal_reason": "Possible increased cancer incidence signal (CAMELLIA-TIMI long-term)", "harm_nodes": ["HM_CARCINOGEN_SIGNAL"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["DOSE_REDESIGN", "VULNERABLE_EXCLUSION", "SUBTYPE_SELECTIVITY"] }, { "id": "phenylpropanolamine", "name": "Phenylpropanolamine (PPA)", "class": "Sympathomimetic amine", "targets": ["adrenergic (alpha/beta)"], "status": "Withdrawn (market)", "event_year": 2000, "withdrawal_reason": "Hemorrhagic stroke signal", "harm_nodes": ["HM_SYMPATH_CV"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["VULNERABLE_EXCLUSION", "TISSUE_SELECTIVITY", "DOSE_REDESIGN"] }, { "id": "aminorex", "name": "Aminorex", "class": "Anorectic / sympathomimetic", "targets": ["monoamine release", "SERT"], "status": "Withdrawn (market)", "event_year": 1972, "withdrawal_reason": "Epidemic of pulmonary arterial hypertension", "harm_nodes": ["HM_5HT_PPH", "HM_SYMPATH_CV"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["SUBTYPE_SELECTIVITY", "VULNERABLE_EXCLUSION"] }, { "id": "dnp", "name": "2,4-Dinitrophenol (DNP)", "class": "Mitochondrial uncoupler", "targets": ["mitochondrial proton gradient"], "status": "Banned (never modern approval)", "event_year": 1938, "withdrawal_reason": "Fatal hyperthermia, cataracts, narrow therapeutic index", "harm_nodes": ["HM_METABOLIC_TOXICITY"], "central_acting": false, "evidence_grade": "established (historical)", "de_risking_levers": ["TISSUE_SELECTIVITY", "DOSE_REDESIGN"] }, { "id": "phenformin", "name": "Phenformin (metabolic context)", "class": "Biguanide", "targets": ["mitochondrial complex I"], "status": "Withdrawn (market)", "event_year": 1977, "withdrawal_reason": "Lactic acidosis (illustrative metabolic-class withdrawal)", "harm_nodes": ["HM_METABOLIC_TOXICITY"], "central_acting": false, "evidence_grade": "established (historical)", "de_risking_levers": ["TISSUE_SELECTIVITY", "VULNERABLE_EXCLUSION"] }, { "id": "beloranib", "name": "Beloranib", "class": "MetAP2 inhibitor", "targets": ["MetAP2"], "status": "Discontinued (development)", "event_year": 2016, "withdrawal_reason": "Venous thromboembolism / fatal thrombotic events in trials", "harm_nodes": ["HM_THROMBOSIS"], "central_acting": false, "evidence_grade": "established (historical)", "de_risking_levers": ["TISSUE_SELECTIVITY", "VULNERABLE_EXCLUSION", "DOSE_REDESIGN"] }, { "id": "tesofensine", "name": "Tesofensine", "class": "Triple monoamine reuptake inhibitor", "targets": ["SERT", "NET", "DAT"], "status": "Discontinued/stalled (development)", "event_year": 2010, "withdrawal_reason": "Blood pressure / heart rate increases raised CV concern at efficacious doses", "harm_nodes": ["HM_SYMPATH_CV"], "central_acting": true, "evidence_grade": "reported (historical)", "de_risking_levers": ["DOSE_REDESIGN", "VULNERABLE_EXCLUSION", "TISSUE_SELECTIVITY"] }, { "id": "ephedra", "name": "Ephedra (ephedrine alkaloids)", "class": "Sympathomimetic", "targets": ["adrenergic (alpha/beta)"], "status": "Banned (dietary supplement)", "event_year": 2004, "withdrawal_reason": "Cardiovascular events / stroke", "harm_nodes": ["HM_SYMPATH_CV"], "central_acting": true, "evidence_grade": "established (historical)", "de_risking_levers": ["VULNERABLE_EXCLUSION", "DOSE_REDESIGN"] }, { "id": "cetilistat_note", "name": "Mitratapide/MTP-class (illustrative)", "class": "MTP inhibitor (lipid)", "targets": ["MTP"], "status": "Limited / liver-signal caution", "event_year": 2012, "withdrawal_reason": "Hepatic/lipid accumulation class caution (illustrative hepatotox node)", "harm_nodes": ["HM_HEPATOTOX"], "central_acting": false, "evidence_grade": "illustrative (synthetic demo)", "de_risking_levers": ["TISSUE_SELECTIVITY", "DOSE_REDESIGN"] } ], "de_risking_levers": { "PERIPHERAL_RESTRICTION": { "name": "Peripheral restriction (BBB-impermeant)", "description": "Engineer the molecule to not cross the blood-brain barrier, keeping the target engaged peripherally while removing central CNS harm.", "best_for": ["HM_CB1_CNS"], "plausibility": 0.78, "precedent": "Peripherally-restricted CB1 antagonists pursued specifically to retain metabolic benefit while avoiding central psychiatric harm.", "validation_design": "Brain/plasma ratio PK (Kp,uu) study; CNS occupancy PET; rodent forced-swim/anxiety battery to confirm no central effect." }, "BIASED_PARTIAL_AGONISM": { "name": "Biased / partial agonism", "description": "Use functionally-selective or partial ligands that engage the beneficial pathway while sparing the harm-linked signaling arm.", "best_for": ["HM_CB1_CNS", "HM_5HT2B_VALVE"], "plausibility": 0.62, "precedent": "Biased agonism explored to separate efficacy from on-target liabilities (e.g., GPCR arrestin vs G-protein bias).", "validation_design": "Pathway-resolved (Gq vs beta-arrestin) signaling assays; comparison of efficacy vs harm-arm EC50 separation." }, "SUBTYPE_SELECTIVITY": { "name": "Receptor subtype selectivity (5-HT2C vs 5-HT2B)", "description": "Maximize selectivity for the efficacy subtype (5-HT2C) and minimize the harm subtype (5-HT2B) to avoid valvulopathy.", "best_for": ["HM_5HT2B_VALVE", "HM_5HT_PPH"], "plausibility": 0.70, "precedent": "5-HT2C-selective agonism was the explicit rationale separating lorcaserin from fenfluramine's 2B valvulopathy.", "validation_design": "Functional selectivity index (2C/2B EC50 ratio); 5-HT2B counter-screen; echocardiographic valve surveillance in chronic tox." }, "TISSUE_SELECTIVITY": { "name": "Tissue-selective delivery", "description": "Restrict drug exposure or activation to target tissue (e.g., adipose, gut) to avoid harm in off-target tissues (CV, mitochondria).", "best_for": ["HM_SYMPATH_CV", "HM_METABOLIC_TOXICITY", "HM_THROMBOSIS", "HM_HEPATOTOX"], "plausibility": 0.55, "precedent": "Gut-restricted and adipose-targeted approaches reduce systemic exposure and off-target toxicity.", "validation_design": "Tissue distribution PK; prodrug activation assay; systemic vs local exposure ratio." }, "VULNERABLE_EXCLUSION": { "name": "Vulnerable-population pre-exclusion", "description": "Pre-specify exclusion / screening of patients whose baseline risk amplifies the harm mechanism (CVD, psychiatric history, thrombophilia).", "best_for": ["HM_SYMPATH_CV", "HM_CB1_CNS", "HM_THROMBOSIS", "HM_5HT_PPH"], "plausibility": 0.68, "precedent": "Post-SCOUT, CV-disease patients excluded; psychiatric-history exclusion proposed for CB1 agents.", "validation_design": "Enrichment trial design; baseline risk stratification; protocolized surveillance + stopping rules." }, "DOSE_REDESIGN": { "name": "Dose / exposure redesign", "description": "Lower or restructure dosing (or intermittent regimen) to keep efficacy above threshold while staying below the harm-onset exposure.", "best_for": ["HM_SYMPATH_CV", "HM_CARCINOGEN_SIGNAL", "HM_METABOLIC_TOXICITY"], "plausibility": 0.50, "precedent": "Therapeutic-window narrowing strategies in metabolic agents with exposure-dependent toxicity.", "validation_design": "Exposure-response (E-R) modeling for efficacy vs harm endpoints; identify therapeutic index window." } }, "inheritance_classes": [ { "class_key": "CB1", "match_terms": ["cb1", "cannabinoid", "endocannabinoid"], "central_required_for_harm": true, "harm_nodes": ["HM_CB1_CNS"], "ancestor_drugs": ["rimonabant", "taranabant"], "monitoring_hypothesis": "Any centrally-acting CB1 modulator inherits psychiatric/suicidality risk class -> require C-SSRS screening, peripheral-restriction PK proof, psychiatric-history exclusion." }, { "class_key": "5HT2B", "match_terms": ["5-ht2b", "5ht2b", "serotonin", "5-ht", "serotonergic"], "central_required_for_harm": false, "harm_nodes": ["HM_5HT2B_VALVE", "HM_5HT_PPH"], "ancestor_drugs": ["fenfluramine", "dexfenfluramine", "aminorex", "lorcaserin"], "monitoring_hypothesis": "Any serotonergic agonist inherits valvulopathy/PPH class -> require 5-HT2B counter-screen, 2C/2B selectivity index, echocardiographic surveillance." }, { "class_key": "SYMPATHOMIMETIC", "match_terms": ["sympathomimetic", "norepinephrine", "noradrenergic", "net", "adrenergic", "snri", "monoamine"], "central_required_for_harm": false, "harm_nodes": ["HM_SYMPATH_CV"], "ancestor_drugs": ["sibutramine", "phenylpropanolamine", "tesofensine", "ephedra"], "monitoring_hypothesis": "Any sympathomimetic/monoamine-reuptake agent inherits CV (BP/HR/MACE) class -> require ambulatory BP/HR monitoring, CV-disease exclusion, MACE adjudication." }, { "class_key": "METAP2", "match_terms": ["metap2", "methionine aminopeptidase"], "central_required_for_harm": false, "harm_nodes": ["HM_THROMBOSIS"], "ancestor_drugs": ["beloranib"], "monitoring_hypothesis": "MetAP2-class inherits thrombotic (VTE) risk -> require D-dimer/coagulation monitoring, thrombophilia exclusion, VTE stopping rules." }, { "class_key": "UNCOUPLER", "match_terms": ["uncoupler", "mitochondrial", "dnp", "thermogenic", "complex i"], "central_required_for_harm": false, "harm_nodes": ["HM_METABOLIC_TOXICITY"], "ancestor_drugs": ["dnp", "phenformin"], "monitoring_hypothesis": "Mitochondrial uncoupler/metabolic-toxicity class inherits hyperthermia/acidosis risk -> require core-temp + lactate monitoring, tissue-selective activation proof, strict TI window." } ] }