{ "_meta": { "dataset": "DiaRescueMiner-Kor curated terminated/withdrawn diabetes & complication programs", "version": "0.1.0-demo", "built": "2026-06-05", "disclaimer": "Drug names and high-level historical reasons for discontinuation are based on publicly known facts (ClinicalTrials.gov, FDA/EMA actions, post-mortem literature). All numeric scores, sub-scores, sample-size suggestions and rescue-lever weightings are SYNTHETIC demo values produced by a rule-based heuristic and must not be treated as validated evidence. Research-/reference-use only. Not clinical decision support.", "public_sources": [ "ClinicalTrials.gov API v2 (terminated/withdrawn status + why_stopped free text)", "Inxight Drugs / NCATS (development status)", "Open Targets Platform (genetic / MR target support)", "PubMed / Europe PMC (post-mortem & mechanism literature)" ], "failure_axes": [ "efficacy_insufficient", "safety_cardiovascular", "safety_hepatic", "safety_renal", "safety_oncologic", "safety_skeletal", "endpoint_design", "commercial", "futility_interim" ] }, "programs": [ { "id": "muraglitazar", "drug": "Muraglitazar", "target": "PPAR-alpha/gamma (dual)", "class": "Glitazar (dual PPAR agonist)", "indication": "Type 2 diabetes", "max_phase": "Filed/Phase 3 (non-approval)", "year_stopped": 2006, "ctgov_status": "terminated", "why_stopped_text": "Development discontinued after FDA advisory review raised excess cardiovascular events (composite of death, MI, stroke, TIA, CHF) versus comparators.", "failure_attribution": { "primary": ["safety_cardiovascular"], "secondary": ["endpoint_design"], "notes": "CV safety signal in adjudicated composite; questions over comparator/dose balance." }, "target_validity": { "genetic_support": "partial", "mr_support": "PPARG coding variants (e.g. Pro12Ala) link to insulin sensitivity; supports glucose axis, not CV safety", "same_target_other_drugs": "Other glitazars (tesaglitazar, aleglitazar) also failed -> class-level rather than molecule-level liability", "verdict": "target_partially_valid_for_glucose__class_safety_liability" }, "rescue_levers": [ {"lever": "biomarker_stratified_responder", "detail": "Restrict to insulin-resistant, low-CV-risk phenotype; exclude prevalent HF.", "weight": 0.5}, {"lever": "tissue_selective_reformulation", "detail": "Liver-/adipose-selective partial PPAR modulation to decouple glucose benefit from fluid retention.", "weight": 0.7}, {"lever": "combination_de_risking", "detail": "Pair with SGLT2i to offset fluid/CHF risk.", "weight": 0.65}, {"lever": "alternative_endpoint", "detail": "MASLD/MASH resolution instead of glycemia, where PPAR engagement may show favorable benefit-risk.", "weight": 0.6} ], "scores": {"plausibility": 0.58, "feasibility": 0.62, "impact": 0.7} }, { "id": "tesaglitazar", "drug": "Tesaglitazar", "target": "PPAR-alpha/gamma (dual)", "class": "Glitazar (dual PPAR agonist)", "indication": "Type 2 diabetes / dyslipidemia", "max_phase": "Phase 3", "year_stopped": 2006, "ctgov_status": "terminated", "why_stopped_text": "Program halted due to declines in eGFR and increased serum creatinine considered unfavorable to overall benefit-risk.", "failure_attribution": { "primary": ["safety_renal"], "secondary": ["endpoint_design"], "notes": "Reversible eGFR decline / creatinine rise dominated benefit-risk." }, "target_validity": { "genetic_support": "partial", "mr_support": "PPARA lipid effects supported; renal hemodynamic effect not target-validated as on-mechanism", "same_target_other_drugs": "Class pattern of off-target tolerability across glitazars", "verdict": "target_partially_valid__renal_hemodynamic_liability" }, "rescue_levers": [ {"lever": "alternative_dosing_chronotherapy", "detail": "Lower-exposure titration to keep eGFR change within reversible window.", "weight": 0.45}, {"lever": "biomarker_stratified_responder", "detail": "Enrich for preserved baseline eGFR; exclude CKD>=3.", "weight": 0.6}, {"lever": "combination_de_risking", "detail": "Co-administer renoprotective backbone (ACEi/ARB/SGLT2i) and monitor eGFR dip as expected.", "weight": 0.55}, {"lever": "alternative_endpoint", "detail": "Atherogenic dyslipidemia endpoint where PPAR-alpha effect is strongest.", "weight": 0.5} ], "scores": {"plausibility": 0.52, "feasibility": 0.6, "impact": 0.6} }, { "id": "aleglitazar", "drug": "Aleglitazar", "target": "PPAR-alpha/gamma (balanced dual)", "class": "Glitazar (dual PPAR agonist)", "indication": "Type 2 diabetes post-ACS (CV outcomes)", "max_phase": "Phase 3 (ALECARDIO)", "year_stopped": 2013, "ctgov_status": "terminated", "why_stopped_text": "Phase 3 CV outcome trial stopped for futility plus safety signals (heart failure, renal events, bone fractures, GI bleeding).", "failure_attribution": { "primary": ["futility_interim", "safety_cardiovascular"], "secondary": ["safety_renal", "safety_skeletal"], "notes": "No CV efficacy at interim; multi-organ safety burden." }, "target_validity": { "genetic_support": "weak_for_outcome", "mr_support": "No MR support that PPAR-alpha/gamma agonism lowers MACE post-ACS", "same_target_other_drugs": "Consistent class failure on hard CV outcomes", "verdict": "target_invalid_for_cv_outcome__glucose_axis_only" }, "rescue_levers": [ {"lever": "alternative_endpoint", "detail": "Abandon CV-outcome positioning; reposition to metabolic/MASH surrogate endpoints.", "weight": 0.55}, {"lever": "biomarker_stratified_responder", "detail": "Diabetic dyslipidemia subgroup with high remnant cholesterol.", "weight": 0.5}, {"lever": "tissue_selective_reformulation", "detail": "Selective modulator to drop fracture/fluid liabilities.", "weight": 0.6} ], "scores": {"plausibility": 0.4, "feasibility": 0.55, "impact": 0.65} }, { "id": "fasiglifam", "drug": "Fasiglifam (TAK-875)", "target": "GPR40 / FFAR1", "class": "GPR40 agonist (free fatty acid receptor 1)", "indication": "Type 2 diabetes", "max_phase": "Phase 3", "year_stopped": 2013, "ctgov_status": "terminated", "why_stopped_text": "Phase 3 program terminated due to concerns about liver safety (elevated liver enzymes / hepatotoxicity signal).", "failure_attribution": { "primary": ["safety_hepatic"], "secondary": [], "notes": "Idiosyncratic hepatotoxicity; mechanism linked to inhibition of bile-acid transporters (BSEP/NTCP) and reactive metabolites rather than GPR40 pharmacology." }, "target_validity": { "genetic_support": "moderate", "mr_support": "GPR40/FFAR1 is glucose-dependent insulin secretagogue; efficacy on glycemia was demonstrated -> target valid, liability is off-target chemotype", "same_target_other_drugs": "Later GPR40 agonists pursued with improved hepatic margins -> supports chemotype, not target, as culprit", "verdict": "target_valid__off_target_chemotype_hepatotoxicity" }, "rescue_levers": [ {"lever": "tissue_selective_reformulation", "detail": "Backup chemotype lacking BSEP/NTCP inhibition; gut-restricted exposure to limit hepatic load.", "weight": 0.85}, {"lever": "biomarker_stratified_responder", "detail": "Exclude baseline hepatic risk; monitor with DILI biomarkers (e.g. miR-122, total bile acids).", "weight": 0.6}, {"lever": "alternative_dosing_chronotherapy", "detail": "Lower Cmax pro-drug to reduce transporter inhibition peaks.", "weight": 0.55} ], "scores": {"plausibility": 0.72, "feasibility": 0.6, "impact": 0.7} }, { "id": "piragliatin", "drug": "Piragliatin (RO4389620)", "target": "Glucokinase (allosteric activator)", "class": "Glucokinase activator (GKA)", "indication": "Type 2 diabetes", "max_phase": "Phase 2", "year_stopped": 2009, "ctgov_status": "terminated", "why_stopped_text": "Discontinued in Phase 2; class beset by hypoglycemia, hepatic steatosis/transaminase rise, and loss of glycemic durability over time.", "failure_attribution": { "primary": ["efficacy_insufficient", "safety_hepatic"], "secondary": [], "notes": "Durability loss (efficacy fade) plus hepatic lipogenesis liability typical of systemic GKAs." }, "target_validity": { "genetic_support": "strong", "mr_support": "GCK activating mutations cause hyperinsulinemic hypoglycemia; inactivating cause MODY2 -> target causally validated for glucose", "same_target_other_drugs": "Hepatoselective / dual-acting GKAs (e.g. dorzagliatin approved in some regions) overcame durability -> target valid, design-dependent success", "verdict": "target_valid__systemic_design_liability" }, "rescue_levers": [ {"lever": "tissue_selective_reformulation", "detail": "Hepatoselective or pancreas-sparing GKA to avoid hepatic lipogenesis and hypoglycemia.", "weight": 0.8}, {"lever": "alternative_dosing_chronotherapy", "detail": "Partial activator / glucose-threshold-tuned binding to restore durability.", "weight": 0.7}, {"lever": "combination_de_risking", "detail": "Combine with DPP4i to stabilize glycemic durability.", "weight": 0.55} ], "scores": {"plausibility": 0.74, "feasibility": 0.58, "impact": 0.62} }, { "id": "mk0916", "drug": "MK-0916 (11b-HSD1 inhibitor)", "target": "11-beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1)", "class": "11b-HSD1 inhibitor", "indication": "Type 2 diabetes / metabolic syndrome", "max_phase": "Phase 2", "year_stopped": 2010, "ctgov_status": "terminated", "why_stopped_text": "Phase 2 showed only modest HbA1c effect; small LDL/BP changes and HPA-axis compensation; benefit-risk judged insufficient to advance.", "failure_attribution": { "primary": ["efficacy_insufficient"], "secondary": ["endpoint_design"], "notes": "Mechanistically clean but underpowered effect size; compensatory ACTH/HPA upregulation blunts target effect." }, "target_validity": { "genetic_support": "moderate", "mr_support": "HSD11B1 tissue cortisol regeneration links to adiposity/insulin resistance; effect size genetically bounded", "same_target_other_drugs": "Multiple 11b-HSD1 inhibitors showed similar modest glycemic effect -> ceiling effect, target real but low-yield for HbA1c", "verdict": "target_valid_but_low_effect_for_glycemia__reposition" }, "rescue_levers": [ {"lever": "alternative_endpoint", "detail": "Reposition to NAFLD/MASH, central obesity, or cognitive/glucocorticoid-excess endpoints where effect may be larger.", "weight": 0.7}, {"lever": "biomarker_stratified_responder", "detail": "Enrich for high-tissue-cortisol phenotype (e.g. visceral adiposity, elevated urinary cortisol metabolite ratios).", "weight": 0.65}, {"lever": "combination_de_risking", "detail": "Add to incretin backbone for additive metabolic effect.", "weight": 0.45} ], "scores": {"plausibility": 0.6, "feasibility": 0.66, "impact": 0.5} }, { "id": "atrasentan_renal", "drug": "Atrasentan (early DKD program)", "target": "Endothelin-A receptor (ETA)", "class": "Selective endothelin receptor antagonist (ERA)", "indication": "Diabetic kidney disease", "max_phase": "Phase 3 (SONAR; earlier programs halted)", "year_stopped": 2017, "ctgov_status": "terminated_then_revived", "why_stopped_text": "Earlier DKD development slowed/halted over fluid retention and heart-failure risk typical of the ERA class; later enriched trial (SONAR) used a responder-enrichment design.", "failure_attribution": { "primary": ["safety_cardiovascular"], "secondary": ["endpoint_design"], "notes": "Fluid retention / HF is on-target ERA class effect; original all-comers design diluted renal benefit." }, "target_validity": { "genetic_support": "moderate", "mr_support": "Endothelin pathway causally linked to proteinuria/renal hemodynamics", "same_target_other_drugs": "Other ERAs (avosentan failed on HF; sparsentan/atrasentan revived with enrichment) -> target valid, design-rescuable", "verdict": "target_valid__design_and_safety_rescuable" }, "rescue_levers": [ {"lever": "biomarker_stratified_responder", "detail": "Enrichment by early UACR response + fluid-retention non-responders excluded (SONAR-style run-in).", "weight": 0.85}, {"lever": "combination_de_risking", "detail": "Mandatory SGLT2i + diuretic backbone to offset sodium/fluid retention.", "weight": 0.75}, {"lever": "alternative_dosing_chronotherapy", "detail": "Ultra-low-dose ETA-selective exposure preserving renal benefit below HF threshold.", "weight": 0.7} ], "scores": {"plausibility": 0.8, "feasibility": 0.7, "impact": 0.78} }, { "id": "bardoxolone", "drug": "Bardoxolone methyl", "target": "Keap1-Nrf2 pathway activator", "class": "Nrf2 activator (antioxidant inflammation modulator)", "indication": "Diabetic kidney disease (CKD)", "max_phase": "Phase 3 (BEACON)", "year_stopped": 2012, "ctgov_status": "terminated", "why_stopped_text": "BEACON trial terminated early due to excess heart-failure events and CV mortality in advanced CKD/T2D patients.", "failure_attribution": { "primary": ["safety_cardiovascular"], "secondary": ["endpoint_design"], "notes": "eGFR rose (hemodynamic, not structural); fluid overload precipitated HF in fluid-vulnerable population. Benefit may be eGFR-cosmetic." }, "target_validity": { "genetic_support": "weak", "mr_support": "No clear MR support that Nrf2 activation improves hard renal outcomes; eGFR rise may not reflect true GFR preservation", "same_target_other_drugs": "Subsequent programs (e.g. Alport/rare CKD) restrict population -> conditional validity", "verdict": "target_questionable_for_dkd__population_dependent" }, "rescue_levers": [ {"lever": "biomarker_stratified_responder", "detail": "Exclude HF-prone/high-BNP patients; enrich earlier-stage CKD without fluid vulnerability.", "weight": 0.7}, {"lever": "alternative_endpoint", "detail": "Use measured GFR / structural markers, not eGFR change, to avoid hemodynamic artifact.", "weight": 0.6}, {"lever": "combination_de_risking", "detail": "Strict fluid management + BNP-guided monitoring.", "weight": 0.55} ], "scores": {"plausibility": 0.45, "feasibility": 0.55, "impact": 0.6} }, { "id": "avosentan", "drug": "Avosentan", "target": "Endothelin-A receptor (ETA, less selective)", "class": "Endothelin receptor antagonist (ERA)", "indication": "Diabetic nephropathy", "max_phase": "Phase 3 (ASCEND)", "year_stopped": 2009, "ctgov_status": "terminated", "why_stopped_text": "ASCEND trial stopped early for excess fluid overload and congestive heart failure events at the doses studied.", "failure_attribution": { "primary": ["safety_cardiovascular"], "secondary": ["endpoint_design"], "notes": "Dose too high; insufficient ETA selectivity drove sodium/fluid retention." }, "target_validity": { "genetic_support": "moderate", "mr_support": "Endothelin causal in proteinuria; same as atrasentan", "same_target_other_drugs": "Atrasentan succeeded with lower dose + enrichment -> avosentan failure is dose/selectivity, not target", "verdict": "target_valid__dose_and_selectivity_failure" }, "rescue_levers": [ {"lever": "alternative_dosing_chronotherapy", "detail": "10-100x lower dose within ETA-selective window.", "weight": 0.8}, {"lever": "tissue_selective_reformulation", "detail": "Higher ETA/ETB selectivity backup molecule.", "weight": 0.7}, {"lever": "combination_de_risking", "detail": "Diuretic/SGLT2i fluid management backbone.", "weight": 0.65} ], "scores": {"plausibility": 0.68, "feasibility": 0.66, "impact": 0.6} }, { "id": "torcetrapib_dm", "drug": "Torcetrapib (metabolic/CV context)", "target": "CETP", "class": "CETP inhibitor", "indication": "Dyslipidemia in high CV risk incl. T2D", "max_phase": "Phase 3 (ILLUMINATE)", "year_stopped": 2006, "ctgov_status": "terminated", "why_stopped_text": "Halted for increased mortality and CV events driven by off-target aldosterone/BP elevation, despite favorable HDL/LDL changes.", "failure_attribution": { "primary": ["safety_cardiovascular"], "secondary": [], "notes": "Off-target mineralocorticoid effect (BP/aldosterone) — molecule-specific, not CETP-class." }, "target_validity": { "genetic_support": "moderate", "mr_support": "CETP variants link to lipids; anacetrapib later showed modest MACE benefit -> target partly valid", "same_target_other_drugs": "Anacetrapib (modest benefit), evacetrapib (futile) -> mixed; torcetrapib failure off-target", "verdict": "target_partially_valid__off_target_molecule_toxicity" }, "rescue_levers": [ {"lever": "tissue_selective_reformulation", "detail": "Backup CETP inhibitor without mineralocorticoid off-target.", "weight": 0.75}, {"lever": "biomarker_stratified_responder", "detail": "Enrich by genetically-informed LDL/ApoB responders.", "weight": 0.55}, {"lever": "alternative_endpoint", "detail": "ApoB-lowering / Lp(a) endpoints instead of HDL-raising hypothesis.", "weight": 0.6} ], "scores": {"plausibility": 0.5, "feasibility": 0.6, "impact": 0.55} }, { "id": "sotagliflozin_early", "drug": "Sotagliflozin (early T1D label setback)", "target": "SGLT1/SGLT2 (dual)", "class": "Dual SGLT1/2 inhibitor", "indication": "Type 1 diabetes adjunct", "max_phase": "Filed (initial T1D non-approval in some regions)", "year_stopped": 2019, "ctgov_status": "withdrawn_indication", "why_stopped_text": "Initial T1D indication setback over diabetic ketoacidosis (DKA) risk; later repositioned successfully to heart failure / CKD outcomes.", "failure_attribution": { "primary": ["safety_renal"], "secondary": ["endpoint_design"], "notes": "Euglycemic DKA is on-target SGLT class effect; benefit-risk failed in T1D framing, succeeded in HF/CKD framing." }, "target_validity": { "genetic_support": "strong", "mr_support": "SLC5A2 (SGLT2) loss-of-function genetically protective for cardio-renal outcomes", "same_target_other_drugs": "SGLT2i class validated in HF/CKD -> target strongly valid; failure was indication/population framing", "verdict": "target_strongly_valid__indication_reframing_rescue" }, "rescue_levers": [ {"lever": "alternative_endpoint", "detail": "Reposition from T1D glycemia to HF/CKD outcome endpoints (already realized).", "weight": 0.85}, {"lever": "biomarker_stratified_responder", "detail": "DKA-risk screening + ketone monitoring run-in to exclude high-risk T1D.", "weight": 0.6}, {"lever": "combination_de_risking", "detail": "Structured sick-day/ketone-monitoring protocol.", "weight": 0.55} ], "scores": {"plausibility": 0.82, "feasibility": 0.72, "impact": 0.8} }, { "id": "imeglimin_offtarget_demo", "drug": "Generic GKA backup (demo entry)", "target": "Glucokinase (hepatoselective)", "class": "Glucokinase activator (next-gen, demo)", "indication": "Type 2 diabetes", "max_phase": "Phase 1 (demo placeholder)", "year_stopped": 2018, "ctgov_status": "terminated", "why_stopped_text": "[SYNTHETIC DEMO ENTRY] Discontinued in Phase 1 for portfolio reasons (commercial), not safety/efficacy.", "failure_attribution": { "primary": ["commercial"], "secondary": [], "notes": "Synthetic example of a commercial-only termination where mechanism remains intact and rescue is most justified." }, "target_validity": { "genetic_support": "strong", "mr_support": "GCK causal for glucose (see piragliatin entry)", "same_target_other_drugs": "Hepatoselective GKAs viable", "verdict": "target_valid__commercial_termination_high_rescue_priority" }, "rescue_levers": [ {"lever": "combination_de_risking", "detail": "Out-license / reposition; mechanism de-risked by class precedent.", "weight": 0.6}, {"lever": "biomarker_stratified_responder", "detail": "GCK-pathway responder enrichment.", "weight": 0.55} ], "scores": {"plausibility": 0.7, "feasibility": 0.75, "impact": 0.55} }, { "id": "dapagliflozin_dkd_demo", "drug": "Generic 11b-HSD1 backup (demo)", "target": "11b-HSD1 (CNS-penetrant, demo)", "class": "11b-HSD1 inhibitor (repositioned, demo)", "indication": "MASH / metabolic (demo)", "max_phase": "Phase 2 (demo placeholder)", "year_stopped": 2016, "ctgov_status": "terminated", "why_stopped_text": "[SYNTHETIC DEMO ENTRY] Stopped at interim for futility on HbA1c endpoint chosen for the wrong indication.", "failure_attribution": { "primary": ["futility_interim", "endpoint_design"], "secondary": ["efficacy_insufficient"], "notes": "Synthetic example: right mechanism, wrong endpoint/indication framing -> classic endpoint-design rescue." }, "target_validity": { "genetic_support": "moderate", "mr_support": "HSD11B1 tissue cortisol (see mk0916)", "same_target_other_drugs": "Modest glycemia, possibly larger MASH effect", "verdict": "target_valid__endpoint_misframed" }, "rescue_levers": [ {"lever": "alternative_endpoint", "detail": "Switch primary endpoint to MASH histology / liver fat.", "weight": 0.75}, {"lever": "biomarker_stratified_responder", "detail": "Enrich high-tissue-cortisol MASH phenotype.", "weight": 0.6} ], "scores": {"plausibility": 0.62, "feasibility": 0.6, "impact": 0.58} } ] }