[
 {
  "id": "lecanemab",
  "name": "Lecanemab",
  "inn_name": "lecanemab-irmb",
  "brand_name": "Leqembi",
  "mechanism": "Humanized monoclonal antibody that selectively binds soluble amyloid-beta protofibrils, promoting their clearance",
  "target": "amyloid-beta protofibrils",
  "modality": "monoclonal-antibody",
  "route": "IV infusion 10 mg/kg every 2 weeks for 18 months (starting regimen) then IV 10 mg/kg every 4 weeks or subcutaneous maintenance; OR subcutaneous LEQEMBI IQLIK autoinjector for both initiation (500 mg once weekly as two 250 mg injections; sBLA approved 2026-07-13) and maintenance (360 mg once weekly; approved 2025-08-29). Routes can be switched.",
  "status": "approved",
  "fda_approval_date": "2023-01-06",
  "ema_status": "approved 2025-04-15 (EU indication restricted to ApoE4 non-carriers or heterozygotes with confirmed amyloid pathology)",
  "accelerated_approval": true,
  "indication_population": {
   "stage": "early AD (MCI or mild dementia)",
   "biomarker_requirement": "biomarker-defined (confirmed amyloid pathology)"
  },
  "pivotal_trial": "Clarity AD (NCT03887455)",
  "pivotal_n": 1795,
  "primary_endpoint": "CDR-SB change from baseline at 18 months",
  "primary_endpoint_result": "-0.45 point difference vs placebo, a 27% slowing of clinical decline (p<0.0001)",
  "aria_risk_pct": 21.3,
  "annual_cost_usd_list": 26500,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": "Confirm amyloid beta pathology before treatment; obtain a recent baseline brain MRI, then MRI after 1, 2, 3 and 6 months of treatment (e.g. before the 3rd IV dose or 5th SC dose for the 1-month scan); enhanced clinical vigilance for ARIA during the first 14 weeks; ApoE e4 testing should be performed before initiation to inform ARIA risk (current label wording; the stored 'prior to the 5th, 7th and 14th infusions' schedule is from the 2023 label and is no longer in the label).",
  "sources": [
   "https://www.fda.gov/media/169337/download",
   "https://www.drugs.com/history/leqembi.html",
   "https://www.eisai.com/news/2023/news202302.html",
   "https://www.alzforum.org/therapeutics/leqembi",
   "https://www.bioarctic.com/en/eu-approves-leqembi-lecanemab-for-treatment-of-early-alzheimers-disease/"
  ],
  "notes": "Initially approved via accelerated pathway 2023-01-06; converted to traditional approval 2023-07-06 following confirmatory Clarity AD phase 3 results. ARIA-E rate reported 12.6% (vs 1.7% placebo); ARIA-H 17.3% (vs 9.0% placebo); combined/any-ARIA figure of ~21.3% reported in some analyses -- figures vary slightly by source/subgroup (e.g., ApoE4 genotype), cite Clarity AD NEJM publication and Eisai ARIA analyses for exact breakdowns. Subcutaneous maintenance dosing approved later (2025) per Biogen press release.\n\nlisted price year: 2023\n2026 list price detail: Eisai Inc. product price list effective 2026-07-13: Leqembi IV 500 mg/5 mL vial $679.60, 200 mg/2 mL vial $271.83 (WAC per vial); LEQEMBI IQLIK 360 mg/1.8 mL autoinjector $385.00; IQLIK 250 mg/1.25 mL carton of two $770.00 (effective on or about 2026-08-24). Eisai IQLIK pricing statement: WAC $385 per autoinjector. Annual IV cost is weight-based, so no single 2026 annual list figure is published by Eisai; $26,500 is the 2023 launch statement figure.",
  "aria_risk_definition": "Any ARIA (including asymptomatic radiographic events), Clarity AD: 21% (191/898) vs 9% (84/897) placebo; ARIA-E 13% (113/898) vs 2%; ARIA-H 17% (152/898) vs 9%.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://dailymed.nlm.nih.gov/dailymed/services/v2/spls/9d1ff786-e577-410a-a273-c4d7d0e4e975.xml (current LEQEMBI/LEQEMBI IQLIK label, published 2026-07-27, 'Revised: 7/2026')",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:BLA761269 (ORIG approved 2023-01-06 priority; efficacy supplement S-001 approved 2023-07-06 [traditional approval]; S-005 efficacy approved 2025-01-24 [IV maintenance]; S-013 labeling 2025-08-21 [ARIA-E safety labeling per 505(o)(4) letter]; S-011 approved 2026-01-16 [PMR 4384-3 immunogenicity])",
    "https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/716269Orig1s013ltr.pdf",
    "https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/761269Orig1s011ltr.pdf",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/leqembi (opinion adopted 14/11/2024; marketing authorisation issued 15/04/2025; indication limited to ApoE4 non-carriers or heterozygotes with confirmed amyloid pathology; controlled access programme)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx (Leqembi EMEA/H/C/005966 Authorised 15/04/2025; list generated 27/09/2026)",
    "https://media-us.eisai.com/2025-08-29-FDA-Approves-LEQEMBI-R-IQLIK-TM-lecanemab-irmb-Subcutaneous-Injection-for-Maintenance-Dosing-for-the-Treatment-of-Early-Alzheimers-Disease",
    "https://media-us.eisai.com/2026-07-13-FDA-Approves-LEQEMBI-IQLIK-R-lecanemab-irmb-Subcutaneous-Injection-as-an-Initiation-Dose-for-Early-Alzheimers-Disease",
    "https://us.eisai.com/-/media/Files/USEisaiRedesign/EisaiIncPriceList.pdf (Eisai Inc Price List effective 7.13.26)",
    "https://us.eisai.com/-/media/Files/USEisaiRedesign/Leqembi_iQLIK_Statement_Pricing.pdf"
   ],
   "note": "Checked 2026-09-27. CORRECT and current: status approved; fda_approval_date 2023-01-06 (Drugs@FDA ORIG); accelerated_approval true with conversion to traditional approval 2023-07-06 (efficacy supplement S-001) as the stored notes say; ema_status date 2025-04-15 and ApoE restriction (EMA EPAR page + EMA medicines list); pivotal_trial Clarity AD, pivotal_n 1795 (label: 'In Study 2, 1795 patients were enrolled and randomized'); requires_biomarker_confirmation true (label 2.1). STALE/WRONG: (1) monitoring_requirements describes the superseded 2023 MRI schedule; current label requires MRIs after 1, 2, 3 and 6 months. (2) route understates SC approval: SC initiation dosing approved 2026-07-13 in addition to SC maintenance (2025-08-29). (3) aria_risk_pct 21.3 is not a label figure; label states 21% any-ARIA (191/898) with ARIA-E 13% and ARIA-H 17% - the stored notes' 'ARIA-E 12.6%, ARIA-H 17.3%"
  }
 },
 {
  "id": "donanemab",
  "name": "Donanemab",
  "inn_name": "donanemab-azbt",
  "brand_name": "Kisunla",
  "mechanism": "Humanized IgG1 monoclonal antibody targeting pyroglutamate Aβ(p3-42), a form aggregated in amyloid plaques; clears existing plaque",
  "target": "amyloid-beta plaque (pyroglutamate Aβ)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion (monthly)",
  "status": "approved",
  "fda_approval_date": "2024-07-02",
  "ema_status": "approved 2025-09-24 (EMA: CHMP opinion adopted 24/07/2025 after re-examination; marketing authorisation issued 24/09/2025; EMEA/H/C/006024; indication restricted to ApoE4 non-carriers or heterozygotes with confirmed amyloid pathology; controlled access programme) - stored date 2025-09-25 is off by one day",
  "accelerated_approval": false,
  "indication_population": {
   "stage": "early symptomatic AD (MCI or mild dementia)",
   "biomarker_requirement": "biomarker-defined (confirmed amyloid pathology via PET or CSF)"
  },
  "pivotal_trial": "TRAILBLAZER-ALZ 2 (NCT04437511)",
  "pivotal_n": 1736,
  "primary_endpoint": "iADRS change from baseline at 18 months (integrated Alzheimer's Disease Rating Scale)",
  "primary_endpoint_result": "35% slowing of decline vs placebo in low/medium tau population; 22% slowing in combined (overall) population",
  "aria_risk_pct": 16.0,
  "annual_cost_usd_list": 32000,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": "Brain MRI required at baseline and prior to 2nd, 3rd, 4th, and 7th infusions to monitor for ARIA; ApoE4 genotype testing recommended prior to treatment to inform ARIA risk; treatment can be stopped once amyloid plaques are cleared",
  "sources": [
   "https://www.fda.gov/media/180803/download",
   "https://www.alzforum.org/therapeutics/kisunla",
   "https://pricinginfo.lilly.com/kisunla",
   "https://www.alzint.org/news-events/news/ema-recommends-marketing-authorization-for-donanemab-kisunla/"
  ],
  "notes": "Approval label states an approximately 21% ARIA-E rate and 17% ARIA-H rate vs 9% each in placebo (FDA label); alzforum separately cites ARIA-E ~25% and ARIA-H ~one-third in trial-wide safety data -- reported ARIA figures vary by source/subgroup analysis. Enrollment figure varies slightly across sources (1736 randomized vs ~1800 total screened/enrolled); used 1736 as the treated/randomized population commonly cited in trial reporting; primary endpoint result also commonly cited as 35% in low/medium tau subgroup specifically, per FDA and Lilly.\n\nlisted price year: 2024\nlist price detail: Lilly press release 2024-07-02: 'The price of each vial of Kisunla is $695.65'; course-of-therapy cost $12,522 (6 months, 6 infusions), $32,000 (12 months, 13 infusions), $48,696 (18 months, 19 infusions). Lilly's pricinginfo.lilly.com/kisunla page (CMAT-08352 06/2026) renders the current WAC dynamically and returned no price text to curl/jina/WebFetch, so the 2026 WAC could not be captured; 32,000 remains a 2024 figure.\ncorrection: Stored notes say 'Approval label states an approximately 21% ARIA-E rate and 17% ARIA-H rate vs 9% each in placebo (FDA label)' - this does not match the Kisunla label; those numbers resemble the Leqembi label. Kisunla label (revised 07/2025) figures are given in aria_risk_definition. The label also states: FDA approved the modified titration (350/700/1050/1400 mg) via efficacy supplement S-004 on 2025-07-01 (Lilly press release 2025-07-09).",
  "aria_risk_definition": "ARIA-E on the currently recommended modified titration (Dosing Regimen 2, TRAILBLAZER-ALZ 6, n=212, through 12 months). The original regimen in TRAILBLAZER-ALZ 2 gave ARIA-E 24%, any ARIA 36%; with the modified titration these are 16% and 29%.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://dailymed.nlm.nih.gov/dailymed/services/v2/spls/190352d4-ef62-4679-b4fa-e846e2766afa.xml (current KISUNLA label, published 2026-01-02; Boxed Warning/Dosage/Warnings revised 07/2025)",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:BLA761248 (ORIG approved 2024-07-02 priority, Type 1/4; efficacy supplement S-004 approved 2025-07-01)",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/kisunla (opinion adopted 24/07/2025; marketing authorisation issued 24/09/2025; page updated 26/02/2026)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx (Kisunla EMEA/H/C/006024 Authorised 24/09/2025)",
    "https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-approved-fda-treatment-early (2024-07-02; $695.65 per vial; $32,000 for 12 months)",
    "https://investor.lilly.com/news-releases/news-release-details/fda-approves-updated-label-lillys-kisunla-donanemab-azbt-new (2025-07-09)",
    "https://pricinginfo.lilly.com/kisunla (price field not rendered server-side)"
   ],
   "note": "Checked 2026-09-27. CORRECT: status approved; fda_approval_date 2024-07-02 (Drugs@FDA ORIG, traditional approval - accelerated_approval false is right); pivotal_trial TRAILBLAZER-ALZ 2; pivotal_n 1736 (label: 'In Study 1, 1736 patients were randomized 1:1'); primary_endpoint iADRS at 76 weeks/18 months (label: iADRS difference 2.92 combined population, 3.25 low/medium tau, both p<0.0001; CDR-SB -0.70); monitoring_requirements matches label (baseline MRI, MRIs before 2nd, 3rd, 4th and 7th infusions; consider stopping at minimal amyloid on PET; ApoE testing); requires_biomarker_confirmation true. CORRECTED: ema_status date 2025-09-24 not 09-25; aria_risk_pct reflects superseded titration - label now reports ARIA-E 16% with the recommended regimen; notes misattribute ARIA figures to the label; cost is a 2024 figure. CHMP's initial March 2025 negative opinion (stored notes) was not re-verifi"
  }
 },
 {
  "id": "aducanumab",
  "name": "Aducanumab",
  "inn_name": "aducanumab-avwa",
  "brand_name": "Aduhelm",
  "mechanism": "Human monoclonal antibody targeting aggregated soluble oligomers and insoluble fibrils of amyloid-beta",
  "target": "amyloid-beta aggregates (oligomers and fibrils)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion (monthly)",
  "status": "discontinued",
  "fda_approval_date": "2021-06-07",
  "ema_status": "application withdrawn: CHMP recommended refusal in December 2021; Biogen requested re-examination but withdrew the application on 20 April 2022 before re-examination concluded (EMA withdrawn-applications page; EMA medicines list status 'Application withdrawn', EMEA/H/C/005558)",
  "accelerated_approval": true,
  "indication_population": {
   "stage": "early AD (MCI or mild dementia)",
   "biomarker_requirement": "biomarker-defined (confirmed amyloid pathology)"
  },
  "pivotal_trial": "EMERGE (NCT02484547) and ENGAGE (NCT02477800)",
  "pivotal_n": 3285,
  "primary_endpoint": "CDR-SB change from baseline at 78 weeks",
  "primary_endpoint_result": "EMERGE met primary endpoint at high dose (significantly slower decline vs placebo); ENGAGE, an identically designed trial, did not meet its primary endpoint -- discordant results were central to controversy over approval",
  "aria_risk_pct": 35,
  "annual_cost_usd_list": 28200,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": "Obtain a recent (within one year) brain MRI prior to initiating treatment; obtain MRIs prior to the 5th infusion (first 6 mg/kg dose), 7th (first 10 mg/kg dose), 9th and 12th infusions (label revised 8/2023) - stored 'prior to 7th and 12th infusions' omits the 5th and 9th",
  "sources": [
   "https://www.alzforum.org/therapeutics/aducanumab",
   "https://www.alz.org/news/2024/alzheimers-drug-aducanumab-aduhelm-discontinued",
   "https://en.wikipedia.org/wiki/Aducanumab"
  ],
  "notes": "Approved via accelerated pathway 2021-06-07 based on amyloid-lowering as a surrogate marker, despite an FDA advisory committee having voted against approval; highly controversial approval. Launch price was $56,000/year, cut ~50% to $28,200 in December 2021 amid backlash and restricted CMS coverage. Biogen announced discontinuation on 2024-01-31, ending the confirmatory ENVISION trial; stated reason was business reprioritization toward lecanemab and other pipeline assets, explicitly not safety or efficacy concerns (per Biogen statement), though analysts widely attribute the decision to poor commercial uptake following restrictive CMS coverage. Patients on prescription could continue treatment through November 1, 2024. ARIA-E rate reported ~35% vs 3% placebo; ARIA-H microhemorrhage 19% vs 7%; ARIA-H superficial siderosis 15% vs 2% (Wikipedia summary of trial data, cross-referenced against alzforum figures of ~one-third ARIA-E and 17% ARIA-H).\n\nlisted price year: 2022\npivotal_n basis: label section 14: Study 1 (EMERGE) 1638 randomised 1:1:1 and Study 2 (ENGAGE) 1647 randomised 1:1:1 = 3285 across the two phase 3 trials; stored 1638 is EMERGE alone while pivotal_trial names both trials\n\nstatus basis: Biogen discontinued development and commercialisation on 2024-01-31 and terminated the confirmatory ENVISION study; accelerated approval was never converted. Drugs@FDA still lists BLA 761178 products with marketing status 'Prescription' and no withdrawal action, so 'accelerated-then-withdrawn' would overstate a formal regulatory withdrawal; the product is no longer on DailyMed.",
  "aria_risk_definition": "ARIA-E 35% (387/1105) at 10 mg/kg vs 3% placebo; ARIA-H 28% vs 9%; any ARIA including asymptomatic 41% vs 10%.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:BLA761178 (ORIG accelerated approval 2021-06-07 priority; labeling supplements 2021-07-07, 2022-04-29, 2023-08-30; efficacy supplement S-007 2023-02-08; last action CMC 2024-03-15; products still 'Prescription')",
    "https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761178s011lbl.pdf (final label, Revised 8/2023)",
    "https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/aduhelm (withdrawn 20 April 2022; Agency had recommended refusal December 2021)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx (Aduhelm EMEA/H/C/005558: Application withdrawn)",
    "https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise (2024-01-31: discontinue development and commercialization of ADUHELM, terminate ENVISION; 'not related to any safety or efficacy concerns'; license terminated, rights revert to Neurimmune)",
    "https://dailymed.nlm.nih.gov/dailymed/services/v2/spls.json?drug_name=Aduhelm (no current SPL)"
   ],
   "note": "Checked 2026-09-27. CORRECT: fda_approval_date 2021-06-07 (Drugs@FDA ORIG, priority, accelerated approval per label 'approved under accelerated approval'); accelerated_approval true; aria_risk_pct 35 matches the label's ARIA-E figure (definition added); primary_endpoint CDR-SB at 78 weeks (label section 14); requires_biomarker_confirmation true; discontinuation date and 'not safety/efficacy' wording confirmed from Biogen's release; $28,200 was the price cut announced December 2021 (stored notes) - year flagged 2022 and product no longer marketed. CORRECTED: status wording, ema_status detail (withdrawal 2022-04-20), pivotal_n (3285 for EMERGE+ENGAGE), MRI schedule (5th/7th/9th/12th). The 'continue through November 1, 2024' patient-access statement in stored notes was not in the Biogen release text loaded (it appears in secondary coverage) - unverified."
  }
 },
 {
  "id": "donepezil",
  "name": "Donepezil",
  "inn_name": "donepezil hydrochloride",
  "brand_name": "Aricept",
  "mechanism": "Reversible acetylcholinesterase inhibitor; increases synaptic acetylcholine availability",
  "target": "acetylcholinesterase",
  "modality": "small-molecule",
  "route": "oral (tablet, orally disintegrating tablet, oral solution); transdermal patch (Adlarity) approved 2022",
  "status": "approved",
  "fda_approval_date": "1996-11-25",
  "ema_status": "not centrally authorised: no EMA EPAR exists for donepezil/Aricept (EMA medicines list of centrally authorised products, generated 27/09/2026, has no single-agent donepezil entry; EPAR URL returns 404). Donepezil is authorised nationally in EU member states, so no EU-wide approval date exists.",
  "accelerated_approval": false,
  "indication_population": {
   "stage": "mild, moderate, and severe AD",
   "biomarker_requirement": "clinical"
  },
  "pivotal_trial": "multiple registration trials (pre-1996); not a single named pivotal trial",
  "pivotal_n": null,
  "primary_endpoint": "ADAS-Cog and CIBIC-plus (varies by trial)",
  "primary_endpoint_result": "Symptomatic cognitive benefit vs placebo across pivotal trials; not disease-modifying",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": false,
  "monitoring_requirements": null,
  "sources": [
   "https://www.alzforum.org/therapeutics/donepezil"
  ],
  "notes": "Symptomatic cholinesterase inhibitor, not a disease-modifying/anti-amyloid therapy. Generic since 2010. Indication expanded to severe AD in 2006/2007. Annual cost not meaningfully comparable given widespread generic availability at low cost; left null rather than citing a potentially outdated generic price. The 1996-11-25 approval date is consistently corroborated across multiple independent secondary sources (alzforum, alzheimersnewstoday, drugs.com) but the underlying FDA approval-letter PDF (accessdata.fda.gov, NDA 20-690) is a scanned image that could not be parsed as text to directly confirm the exact day.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA020690 (Aricept tablets ORIG approved 1996-11-25, priority, Type 1 NME; efficacy supplement S-026 approved 2006-10-13 [severe AD]; products 'Prescription')",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA022568 (Aricept 23 mg ORIG approved 2010-07-23)",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/aricept (HTTP 404)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx"
   ],
   "note": "Checked 2026-09-27. CORRECT: fda_approval_date 1996-11-25 is now confirmed from the machine-readable Drugs@FDA record (stored notes said the scanned letter could not be parsed - that caveat can be dropped); status approved; accelerated_approval false; severe-AD indication supplement 2006-10-13 matches notes' '2006/2007'. CORRECTED: ema_status 'approved (long-standing EU approval, exact original date not verified)' is misleading - there is no EMA (centralised) approval; national authorisations only. Not checked: Adlarity transdermal 2022 approval date; generic-since-2010 statement."
  }
 },
 {
  "id": "rivastigmine",
  "name": "Rivastigmine",
  "inn_name": "rivastigmine tartrate",
  "brand_name": "Exelon",
  "mechanism": "Reversible inhibitor of both acetylcholinesterase and butyrylcholinesterase",
  "target": "acetylcholinesterase and butyrylcholinesterase",
  "modality": "small-molecule",
  "route": "oral (capsule, solution); transdermal patch",
  "status": "approved",
  "fda_approval_date": "2000-04-21",
  "ema_status": "approved centrally: Exelon EU marketing authorisation issued 11/05/1998 (EMEA/H/C/000169, opinion adopted 28/01/1998; indication: symptomatic treatment of mild to moderately severe Alzheimer's dementia and of dementia in idiopathic Parkinson's disease); Prometax (same substance) authorised 04/12/1998 (EMEA/H/C/000255). Stored 'exact original date not verified' can be replaced.",
  "accelerated_approval": false,
  "indication_population": {
   "stage": "mild to moderate AD (also approved for Parkinson's disease dementia)",
   "biomarker_requirement": "clinical"
  },
  "pivotal_trial": "multiple registration trials (pre-2000); not a single named pivotal trial",
  "pivotal_n": null,
  "primary_endpoint": "ADAS-Cog and CIBIC-plus (varies by trial)",
  "primary_endpoint_result": "Symptomatic cognitive benefit vs placebo across pivotal trials; not disease-modifying",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": false,
  "monitoring_requirements": null,
  "sources": [
   "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20823_Exelon_Approv.pdf",
   "https://www.alzforum.org/therapeutics/rivastigmine"
  ],
  "notes": "Symptomatic cholinesterase inhibitor. Also approved for Parkinson's disease dementia. Generic since ~2011 (capsules) / later for patch. The 2000-04-21 approval date is corroborated by the filename/metadata of the FDA approval letter (accessdata.fda.gov, NDA 20-823, '20823_Exelon_Approv.pdf') and multiple secondary sources, but the PDF itself is a scanned image that could not be parsed as text for direct in-document confirmation.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA020823 (Exelon capsules ORIG approved 2000-04-21, Type 1 NME; efficacy supplement S-016 2006-06-27; brand capsules now 'Discontinued' - Federal Register determination not for safety/effectiveness)",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA021025 (Exelon oral solution ORIG 2000-04-21; discontinued)",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA022083 (Exelon Patch ORIG approved 2007-07-06; sponsor Sandoz; 'Prescription')",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/exelon (marketing authorisation issued 11/05/1998)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx (Exelon 11/05/1998; Prometax 04/12/1998)"
   ],
   "note": "Checked 2026-09-27. CORRECT: fda_approval_date 2000-04-21 confirmed from Drugs@FDA ORIG approval (scanned-PDF caveat in stored notes can be dropped); status approved; accelerated_approval false; Parkinson's disease dementia indication (supplement 2006-06-27). CORRECTED: ema_status now has the EMA date. Note: Exelon brand capsules and oral solution are listed Discontinued in Drugs@FDA (generics and the Exelon Patch remain), which the stored route/notes do not mention."
  }
 },
 {
  "id": "galantamine",
  "name": "Galantamine",
  "inn_name": "galantamine hydrobromide",
  "brand_name": "Razadyne",
  "mechanism": "Reversible acetylcholinesterase inhibitor and nicotinic receptor modulator",
  "target": "acetylcholinesterase",
  "modality": "small-molecule",
  "route": "oral (tablet, extended-release capsule, oral solution)",
  "status": "approved",
  "fda_approval_date": "2001-02-28",
  "ema_status": "not centrally authorised: no EMA EPAR for galantamine (Reminyl/Razadyne) - absent from the EMA medicines list generated 27/09/2026 and the EPAR URL returns 404; authorised nationally in EU member states, so no EU-wide date exists",
  "accelerated_approval": false,
  "indication_population": {
   "stage": "mild to moderate AD",
   "biomarker_requirement": "clinical"
  },
  "pivotal_trial": "multiple registration trials (pre-2001); not a single named pivotal trial",
  "pivotal_n": null,
  "primary_endpoint": "ADAS-Cog and CIBIC-plus (varies by trial)",
  "primary_endpoint_result": "Symptomatic cognitive benefit vs placebo across pivotal trials; not disease-modifying",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": false,
  "monitoring_requirements": null,
  "sources": [
   "https://www.alzforum.org/therapeutics/galantamine"
  ],
  "notes": "Originally marketed as Reminyl; renamed Razadyne in 2005 in the US to avoid confusion with the diabetes drug Amaryl. FDA label 'Initial U.S. Approval' field confirms only the year 2001; the exact month/day could not be confirmed from any accessible primary source (accessdata.fda.gov approval letter PDFs for this NDA are scanned images that could not be parsed as text), so fda_approval_date is left null rather than guessing a day.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA021169 (Razadyne [originally Reminyl] tablets ORIG approved 2001-02-28, standard review, Type 1 NME; brand tablets 'Discontinued', Federal Register determination not for safety/effectiveness)",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA021224 (Razadyne oral solution ORIG 2001-06-22; discontinued)",
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA021615 (Razadyne ER capsules ORIG 2005-04-01; discontinued)",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/reminyl (HTTP 404)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx"
   ],
   "note": "Checked 2026-09-27. CORRECTED: fda_approval_date was null because the scanned approval letter could not be parsed; the machine-readable Drugs@FDA record gives 2001-02-28 for NDA 021169 (consistent with the label's 'Initial U.S. Approval: 2001'). CORRECTED: ema_status - no centralised EU approval exists. CORRECT: status approved (as a molecule; note all Razadyne brand products are now listed Discontinued in Drugs@FDA, generics remain); accelerated_approval false."
  }
 },
 {
  "id": "memantine",
  "name": "Memantine",
  "inn_name": "memantine hydrochloride",
  "brand_name": "Namenda",
  "mechanism": "Low-to-moderate affinity NMDA receptor antagonist; reduces excitotoxicity from excess glutamate signaling",
  "target": "NMDA receptor",
  "modality": "small-molecule",
  "route": "oral (tablet, extended-release capsule, oral solution)",
  "status": "approved",
  "fda_approval_date": "2003-10-16",
  "ema_status": "approved 2002 (EU approval preceded US approval)",
  "accelerated_approval": false,
  "indication_population": {
   "stage": "moderate to severe AD",
   "biomarker_requirement": "clinical"
  },
  "pivotal_trial": "multiple registration trials (pre-2003); not a single named pivotal trial",
  "pivotal_n": null,
  "primary_endpoint": "SIB (Severe Impairment Battery) and CIBIC-plus (varies by trial)",
  "primary_endpoint_result": "Symptomatic cognitive/functional benefit vs placebo across pivotal trials; not disease-modifying",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": false,
  "monitoring_requirements": null,
  "sources": [
   "https://www.alzforum.org/therapeutics/memantine"
  ],
  "notes": "NMDA receptor antagonist, mechanistically distinct from cholinesterase inhibitors; often used in combination with donepezil in moderate-severe disease. Namenda XR (extended-release) approved later (2010). The 2003-10-16 approval date is corroborated by the filename/metadata of the FDA approval letter (accessdata.fda.gov, NDA 21-487, '21-487_Namenda_Approv.pdf') and multiple secondary sources, but the PDF itself is a scanned image that could not be parsed as text for direct in-document confirmation.\n\nEMA detail: approved 2002-05-15 (Ebixa, H. Lundbeck, EMEA/H/C/000463) and 2002-05-17 (Axura, Merz, EMEA/H/C/000378) - EU approval preceded US approval, as stored",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA021487 (Namenda tablets ORIG approved 2003-10-16, Type 1 NME; brand tablets now 'Discontinued', Federal Register determination not for safety/effectiveness)",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/ebixa (marketing authorisation issued 15/05/2002)",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/axura (opinion 21/02/2002; authorisation 17/05/2002)",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx"
   ],
   "note": "Checked 2026-09-27. All checked fields correct: fda_approval_date 2003-10-16 confirmed from Drugs@FDA ORIG approval (scanned-PDF caveat in stored notes can be dropped); status approved; accelerated_approval false; ema_status 'approved 2002' correct - exact dates supplied as a refinement. Namenda XR 2010 date not checked."
  }
 },
 {
  "id": "donepezil-memantine",
  "name": "Donepezil/Memantine combination",
  "inn_name": "memantine hydrochloride extended-release and donepezil hydrochloride",
  "brand_name": "Namzaric",
  "mechanism": "Fixed-dose combination of NMDA receptor antagonist (memantine ER) and acetylcholinesterase inhibitor (donepezil)",
  "target": "NMDA receptor and acetylcholinesterase",
  "modality": "small-molecule",
  "route": "oral (extended-release capsule)",
  "status": "approved",
  "fda_approval_date": "2014-12-23",
  "ema_status": "not authorised in the EU: two centrally submitted memantine/donepezil fixed-dose combinations, Acrescent (EMEA/H/C/002424) and Balaxur (EMEA/H/C/002708), carry status 'Refused' in the EMA medicines list; no Namzaric EPAR exists (URL 404). Stored 'not filed / not found' understates this - applications were filed and refused.",
  "accelerated_approval": false,
  "indication_population": {
   "stage": "moderate to severe AD (in patients already stabilized on both individual components)",
   "biomarker_requirement": "clinical"
  },
  "pivotal_trial": "bioequivalence/pharmacokinetic studies supporting combination product; not a de novo efficacy pivotal trial",
  "pivotal_n": null,
  "primary_endpoint": null,
  "primary_endpoint_result": null,
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": false,
  "monitoring_requirements": null,
  "sources": [
   "https://www.prnewswire.com/news-releases/actavis-and-adamas-announce-fda-approval-of-namzaric-a-fixed-dose-combination-of-memantine-extended-release-and-donepezil-hydrochloride-300013883.html"
  ],
  "notes": "Approved as a fixed-dose combination convenience product based on the established efficacy of its two individual components, not a new pivotal efficacy trial. Developed by Adamas/Forest/Actavis.",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://api.fda.gov/drug/drugsfda.json?search=application_number:NDA206439 (Namzaric ORIG approved 2014-12-23, Type 4 new combination, standard review; efficacy supplement S-003 approved 2016-07-18; sponsor AbbVie; products 'Prescription')",
    "https://www.ema.europa.eu/en/documents/report/medicines-output-medicines-report_en.xlsx (Acrescent and Balaxur: 'Refused'; active substance 'memantine hydrochloride;donepezil hydrochloride')",
    "https://www.ema.europa.eu/en/medicines/human/EPAR/namzaric (HTTP 404)"
   ],
   "note": "Checked 2026-09-27. CORRECT: fda_approval_date 2014-12-23 confirmed from Drugs@FDA (stored source was a PR Newswire release); status approved; accelerated_approval false; requires_biomarker_confirmation false. CORRECTED: ema_status. Refusal dates for Acrescent/Balaxur were not extracted from the list columns loaded, so only the status is stated."
  }
 },
 {
  "id": "remternetug",
  "name": "Remternetug",
  "inn_name": "remternetug",
  "brand_name": null,
  "mechanism": "Monoclonal antibody targeting pyroglutamated amyloid-beta aggregated in plaques (next-generation successor to donanemab, engineered for faster plaque clearance and subcutaneous dosing)",
  "target": "amyloid-beta plaque (pyroglutamate Aβ)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion and subcutaneous injection. Subcutaneous self-injection is already in use within TRAILRUNNER-ALZ 1, and TRAILRUNNER-ALZ 3 and the DIAN-TU prevention arm are subcutaneous; a Phase 1 autoinjector-versus-prefilled-syringe PK study (NCT07056309) completed in December 2025.",
  "status": "phase-3",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "TRAILRUNNER-ALZ 1: early symptomatic Alzheimer's disease (MMSE 20-30, ages 60-85). TRAILRUNNER-ALZ 3: early disease with no-to-minimal cognitive or functional impairment (ages 55-80). Also dominantly inherited Alzheimer's disease in the DIAN-TU primary prevention trial (age 18+).",
   "biomarker_requirement": "biomarker-defined: amyloid PET for TRAILRUNNER-ALZ 1; a phosphorylated-tau blood result consistent with amyloid pathology (Alzforum specifies plasma p-tau217) for TRAILRUNNER-ALZ 3"
  },
  "pivotal_trial": "TRAILRUNNER-ALZ 1 (NCT05463731; Phase 3; completed 2026-05-12); TRAILRUNNER-ALZ 3 (NCT06653153; Phase 3; active, not recruiting; estimated primary completion April 2029); plus a remternetug arm in the DIAN-TU primary prevention trial (NCT06647498, n=280 estimated)",
  "pivotal_n": 1667,
  "primary_endpoint": "TRAILRUNNER-ALZ 1: proportion of participants reaching amyloid plaque clearance on amyloid PET at Week 52 (the registered sole primary outcome). TRAILRUNNER-ALZ 3: time to clinically meaningful progression on the Clinical Dementia Rating, up to Week 255.",
  "primary_endpoint_result": "No TRAILRUNNER-ALZ 1 primary-endpoint result is posted on ClinicalTrials.gov and none is reported by Alzforum. The reported amyloid-clearance result is Phase 1 interim data: at 2,800 mg every participant fell below the amyloid-positivity PET threshold within three months.",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": "MRI monitoring for ARIA (protocol-specified; exact schedule not published)",
  "sources": [
   "https://clinicaltrials.gov/study/NCT05463731",
   "https://clinicaltrials.gov/study/NCT06653153",
   "https://clinicaltrials.gov/study/NCT06647498",
   "https://clinicaltrials.gov/study/NCT07056309",
   "https://www.alzforum.org/therapeutics/remternetug"
  ],
  "notes": "Eli Lilly's next-generation anti-amyloid antibody. The 600 previously recorded as TRAILRUNNER-ALZ 1 enrolment was the placebo-controlled cohort only; the registered actual enrolment is 1,667, with an additional open-label safety cohort. TRAILRUNNER-ALZ 3 (estimated 1,400, subcutaneous only, estimated primary completion April 2029) is testing at-home self-administration. Also in the Knight Family DIAN-TU primary prevention trial (estimated n=280). Interim Phase 1 safety data showed 10 ARIA-E and 7 ARIA-H cases in early cohorts, all ARIA-E in APOE4 carriers (not a population-level percentage). No Phase 3 efficacy or amyloid-clearance readout has been reported.",
  "verified": {
   "date": "2026-09-27",
   "against": [
    "ClinicalTrials.gov API v2",
    "Alzforum",
    "NeurologyLive (CTAD 2025)"
   ]
  }
 },
 {
  "id": "trontinemab",
  "name": "Trontinemab",
  "inn_name": "trontinemab",
  "brand_name": null,
  "mechanism": "Anti-amyloid-beta monoclonal antibody fused to a transferrin-receptor-binding Fab fragment (Brainshuttle technology) to enhance blood-brain-barrier penetration, enabling deep plaque clearance at low doses",
  "target": "amyloid-beta plaque",
  "modality": "monoclonal-antibody",
  "route": "IV infusion",
  "status": "phase-3",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early symptomatic AD (also planned for preclinical/secondary prevention)",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "TRONTIER 1 (NCT07169578; phase 3; started 2025-09-17; 1101 enrolled, actual; active, not recruiting; primary completion 2028-02-16) and TRONTIER 2 (NCT07170150; phase 3; started 2025-11-12; 1060 enrolled, actual; active, not recruiting; primary completion 2028-02-16); PrevenTRON (NCT07717411; phase 3 in cognitively unimpaired individuals at risk, ages 55-80; status RECRUITING; estimated enrollment 1600; registry start date 2026-11-30 (estimated); primary completion 2032-09-03)",
  "pivotal_n": 2161,
  "primary_endpoint": "TRONTIER 1 and 2: change from baseline to week 72 in CDR-SB (sole registered primary outcome). PrevenTRON: time to progression, defined as confirmed CDR-Global Score >0, up to about 6 years. Amyloid PET clearance was the primary outcome only of the phase 1b/2a Brainshuttle AD study (NCT04639050, Part 3).",
  "primary_endpoint_result": "In Phase Ib/IIa data, 91% of participants in the 3.6 mg/kg cohort achieved amyloid PET negativity by 28 weeks; 72% achieved deep clearance below 11 centiloids",
  "aria_risk_pct": 1,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": "MRI monitoring for ARIA (protocol-specified)",
  "sources": [
   "https://www.alzforum.org/therapeutics/trontinemab",
   "https://www.roche.com/media/releases/med-cor-2025-04-03"
  ],
  "notes": "Roche/Genentech program; ARIA-E rate reported as low as ~1% at the highest dose in early-phase data, a notable safety advantage cited versus lecanemab (~13%) and donanemab (~24%) in company/conference presentations -- these are early-phase (Ib/IIa), not phase 3, safety figures and may not hold at larger scale. Phase 3 TRONTIER trials (800 patients each) began September 2025; efficacy/safety phase 3 readout not yet available.\n\npivotal_n basis: 1101 + 1060 actual enrolment across TRONTIER 1 and 2 (registry); stored 800 was the planned per-trial figure\nindication basis: TRONTIER 1/2 enrol ages 50-90 with early symptomatic AD; PrevenTRON ages 55-80 cognitively unimpaired. Stored 'PrevenTRON recruitment began September 2026' is not supported by the registry, which lists an estimated start of 2026-11-30 while showing status RECRUITING (record first posted 2026-07-21, updated 2026-09-10).",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://clinicaltrials.gov/api/v2/studies?query.term=trontinemab (NCT07169578, NCT07170150, NCT07717411, NCT04639050; loaded 2026-09-27; last updates 2026-09-25, 2026-09-25, 2026-09-10, 2026-09-14)",
    "https://clinicaltrials.gov/api/v2/studies/NCT07169578",
    "https://clinicaltrials.gov/api/v2/studies/NCT07170150",
    "https://clinicaltrials.gov/api/v2/studies/NCT07717411"
   ],
   "note": "Checked 2026-09-27. CORRECT: status phase-3; no FDA/EMA approval (null fields appropriate); requires_biomarker_confirmation true. CORRECTED: pivotal_trial (NCT ids, enrolment, dates), pivotal_n (2161 actual vs stored 800), primary_endpoint (CDR-SB at week 72; not amyloid PET). NOT VERIFIED: aria_risk_pct 1 and the 91%/72% amyloid-clearance figures - these come from Roche conference/press material (stored sources) and are early-phase data; no phase 3 results are posted (hasResults false for all four records). PrevenTRON's 'September 2026' start is unsupported."
  },
  "aria_risk_definition": "Company-reported ARIA-E figure from early-phase data; no peer-reviewed source states it, so treat as provisional."
 },
 {
  "id": "semaglutide-ad",
  "name": "Semaglutide (Alzheimer's disease program)",
  "inn_name": "semaglutide",
  "brand_name": "Rybelsus / Ozempic / Wegovy (approved brands in other indications; not AD-specific)",
  "mechanism": "GLP-1 receptor agonist; hypothesized neuroprotective/anti-inflammatory effects unrelated to amyloid or tau clearance",
  "target": "GLP-1 receptor",
  "modality": "small-molecule (peptide)",
  "route": "oral",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early-stage symptomatic AD (MCI or mild dementia)",
   "biomarker_requirement": "biomarker-defined (confirmed amyloid positivity)"
  },
  "pivotal_trial": "EVOKE (NCT04777396) and EVOKE+ (NCT04777409)",
  "pivotal_n": 1855,
  "primary_endpoint": "CDR-SB change from baseline at week 104",
  "primary_endpoint_result": "No significant difference vs placebo: mean CDR-SB change 2.3 in both semaglutide and placebo arms in EVOKE; estimated difference -0.08 (95% CI -0.35 to 0.20), p=0.57 -- trial did not meet primary endpoint",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.alz.org/news/2025/alzheimers-association-statement-oral-semaglutide-phase-3-topline-data-release",
   "https://clinicaltrials.gov/study/NCT04777396",
   "https://clinicaltrials.gov/study/NCT04777409"
  ],
  "notes": "Novo Nordisk announced topline failure of both EVOKE and EVOKE+ phase 3 trials on 2025-11-24; combined enrollment across both trials exceeded 3,800 participants. Oral semaglutide 14mg did not slow clinical decline on CDR-SB despite producing statistically significant (~10%) reductions in some neuroinflammation-related biomarkers -- explicitly not disease-modifying at the clinical level. Not an amyloid- or tau-targeted therapy; ARIA not applicable/not reported as this is not an anti-amyloid antibody. Status marked 'discontinued' for the AD indication specifically; semaglutide remains approved for diabetes/obesity under other brand names."
 },
 {
  "id": "e2814-etalanetug",
  "name": "E2814 (etalanetug)",
  "inn_name": "etalanetug",
  "brand_name": null,
  "mechanism": "Anti-tau monoclonal antibody targeting the microtubule-binding region (MTBR) of tau, intended to block cell-to-cell propagation of pathological tau",
  "target": "tau (microtubule-binding region)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion",
  "status": "phase-2/3",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "dominantly inherited Alzheimer's disease (DIAN-TU Tau NexGen, symptomatic and asymptomatic cohorts) AND sporadic early Alzheimer's disease (Eisai phase 2 with concurrent lecanemab, NCT06602258, 105 enrolled actual, started 2024-09-30, active not recruiting, primary completion 2026-12-03) - the stored 'not yet tested in sporadic late-onset AD' is out of date",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "DIAN-TU Tau NexGen (Phase II/III; DIAN-TU-001 extension), administered alone or with lecanemab",
  "pivotal_n": 197,
  "primary_endpoint": "Tau NexGen: change from week 24 to weeks 104 and 208 in tau PET in the symptomatic population (Cohort 1). Sporadic-AD phase 2 (NCT06602258): change from baseline in CSF MTBR-tau243 at 6 months. Phase 1b/2 Study 103 (NCT04971733, n=8, completed 2024-05-24, results posted): primary outcomes were safety (TEAEs, labs, vitals).",
  "primary_endpoint_result": "Phase Ib/II data (presented Dec 2025) showed etalanetug reduced plasma eMTBR-tau243 and stabilized/trended toward decreased tau-PET signal; full clinical efficacy results not yet reported",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.eisai.com/news/2022/news202205.html",
   "https://www.alzforum.org/therapeutics/etalanetug"
  ],
  "notes": "Developed by Eisai/Denali (originally University of Washington/Genentech-licensed). First subject enrolled in the Phase II/III DIAN-TU study Jan 2022. Note this program is being studied specifically in dominantly inherited (autosomal-dominant, early-onset) AD, not yet as a phase 3 program in typical sporadic late-onset AD; labeled here as phase-2 to reflect the biomarker-stage data available, though the DIAN-TU trial is nominally Phase II/III. No clinical (cognitive) efficacy readout located as of this research.\n\nstatus basis: DIAN-TU Tau NexGen (NCT05269394) is registered as Phase 2/Phase 3, 197 enrolled actual, active not recruiting, primary completion April 2028; plus a separate phase 2 in sporadic early AD (NCT06602258).",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://clinicaltrials.gov/api/v2/studies?query.term=E2814 OR etalanetug (NCT05269394 updated 2026-07-27; NCT06602258 updated 2026-02-11; NCT04971733 updated 2025-06-10; NCT04231513; NCT01760005; loaded 2026-09-27)"
   ],
   "note": "Checked 2026-09-27. CORRECT: no approvals (null FDA/EMA fields); requires_biomarker_confirmation true; pivotal_trial correctly names DIAN-TU Tau NexGen. CORRECTED: status/phase (registered Phase 2/3, not phase-2), indication_population (now also tested in sporadic early AD), pivotal_n (197 actual in Tau NexGen), primary_endpoint wording (tau PET change from week 24; plasma eMTBR-tau243 is not the registered primary). NOT VERIFIED: the 'Dec 2025 phase Ib/II data' statement in primary_endpoint_result - no publication or registry result loaded; NCT04971733 has posted results but only safety outcomes were checked."
  }
 },
 {
  "id": "bepranemab",
  "name": "Bepranemab",
  "inn_name": "bepranemab",
  "brand_name": null,
  "mechanism": "Anti-tau monoclonal antibody targeting mid-region tau, intended to block extracellular tau propagation",
  "target": "tau (mid-region)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "mild cognitive impairment / mild-to-moderate AD",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "TOGETHER (Phase 2)",
  "pivotal_n": 466,
  "primary_endpoint": "CDR-SB change from baseline at 80 weeks",
  "primary_endpoint_result": "Primary endpoint not met at either the 45 mg/kg or 90 mg/kg dose; tau-PET showed up to 58% slowing of tau accumulation vs placebo (secondary/exploratory endpoint) and some cognitive benefit signal in ApoE4 non-carriers with low baseline tau",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.fiercebiotech.com/biotech/ucbs-tau-drug-flunks-phase-2-alzheimers-trial-days-after-roches-exit-120m-bet",
   "https://www.alzforum.org/news/conference-coverage/despite-phase-2-strike-out-new-tau-antibodies-step-plate",
   "https://www.alzforum.org/therapeutics/bepranemab"
  ],
  "notes": "Originally partnered between UCB and Roche/Genentech (Roche paid $120M upfront, up to $2B in milestones in 2020); Roche/Genentech terminated the collaboration and returned global rights to UCB around October 2024, shortly before the Phase 2 TOGETHER primary endpoint miss was announced at CTAD (Clinical Trials on Alzheimer's Disease) 2024. Despite the primary endpoint failure, UCB highlighted positive secondary/exploratory tau-PET and subgroup cognitive findings; status marked 'discontinued' reflecting the Roche exit and primary endpoint failure, though UCB indicated it may continue analyzing data."
 },
 {
  "id": "semorinemab",
  "name": "Semorinemab",
  "inn_name": "semorinemab",
  "brand_name": null,
  "mechanism": "Anti-tau monoclonal antibody targeting the N-terminal region of all six tau isoforms",
  "target": "tau (N-terminal, all isoforms)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "prodromal to mild AD (TAURIEL); moderate AD (LAURIET)",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "TAURIEL (Phase 2)",
  "pivotal_n": 457,
  "primary_endpoint": "CDR-SB change from baseline over 73 weeks",
  "primary_endpoint_result": "Primary endpoint not met: no significant slowing of decline on CDR-SB vs placebo; secondary endpoints (ADAS-Cog13, ADCS-ADL) also not met; safety endpoint (adverse event rate similar to placebo) was met",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://alzheimersnewstoday.com/news/semorinemab-fails-to-show-efficacy-phase-2-early-alzheimers-trial/",
   "https://www.neurologyadvisor.com/news/semorinemab-slow-alzheimer-disease-progression-phase-2-tauriel/"
  ],
  "notes": "Developed by AC Immune/Genentech (Roche). TAURIEL (prodromal-to-mild AD) failed its primary endpoint. A second Phase 2 trial in moderate AD (LAURIET) also did not demonstrate clinically meaningful benefit on cognitive measures, though it reportedly showed slowing on some functional/behavioral measures in exploratory analyses; Genentech discontinued further development of semorinemab for AD following these results."
 },
 {
  "id": "alz-801",
  "name": "ALZ-801 / Valiltramiprosate",
  "inn_name": "valiltramiprosate",
  "brand_name": null,
  "mechanism": "Oral small molecule that inhibits amyloid-beta oligomerization/aggregation (prodrug of tramiprosate)",
  "target": "amyloid-beta oligomers",
  "modality": "small-molecule",
  "route": "oral",
  "status": "phase-3-failed",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early AD (MCI or mild dementia), specifically APOE4/4 homozygotes in pivotal trial",
   "biomarker_requirement": "biomarker-defined (APOE4/4 genotype required in pivotal trial)"
  },
  "pivotal_trial": "APOLLOE4 (NCT04770220; phase 3; 325 enrolled actual; completed, primary completion 2024-05-29; results posted). Long-term extension NCT06304883 (163 enrolled) TERMINATED - 'Sponsor business decision' (registry updated 2026-06-25).",
  "pivotal_n": 325,
  "primary_endpoint": "ADAS-Cog13 change from baseline to week 78 (co-primary with safety/TEAEs per registry)",
  "primary_endpoint_result": "Primary endpoint not met: overall APOE4/4 population ADAS-Cog13 LS mean difference -0.51 (ALZ-801 3.89 vs placebo 4.40; MMRM p=0.6058, ClinicalTrials.gov posted results) = 11% slowing, p=0.607 (N=320) in the publication; key secondary A-IADL difference 0.01 (p=0.9966). Hippocampal atrophy slowed 18% vs placebo (p=0.017, N=290) - not '~28% relative to an external ADNI control' as stored. Prespecified MCI stratum (MMSE >26, N=125): ADAS-Cog13 52% slowing (nominal p=0.041), DAD 96% (nominal p=0.016), CDR-SB 102% (nominal p=0.053), hippocampal atrophy slowing 26% (p=0.004); no clinical effect in mild AD (MMSE <=26, N=195). No increased brain edema or microhaemorrhage; nausea, vomiting and decreased appetite more than double placebo.",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": "No increased vasogenic edema/ARIA-type risk reported (oral small molecule, not an anti-amyloid antibody)",
  "sources": [
   "https://alzheon.com/topline-results-from-pivotal-apolloe4-phase-3-trial-of-oral-valiltramiprosate-alz-801-in-patients-with-early-alzheimers-disease-carrying-two-copies-of-apoe4-gene/",
   "https://www.neurologylive.com/view/valiltramiprosate-demonstrates-greater-promise-milder-forms-alzheimer-disease-phase-3-apolloe4-study-shows"
  ],
  "notes": "Alzheon's oral candidate specifically targeting APOE4/4 homozygotes (~15% of AD patients, at highest genetic risk and often excluded from anti-amyloid antibody trials due to ARIA risk). Topline results presented at AD/PD Vienna, April 1, 2025; peer-reviewed publication announced October 2025. Company continues to pursue regulatory discussions based on subgroup/biomarker findings rather than having met the primary endpoint outright; status reflects an ongoing phase-3-stage program without a clean primary endpoint win.\n\nstatus basis: 'phase-3' is defensible only as 'phase 3 completed, primary endpoint not met'; the phase 3 extension was terminated for a sponsor business decision in 2026 and no regulatory submission was verified from any page loaded.\npublication: Abushakra S et al. Drugs 2025;85(11):1455-1472 (PMID 41015981, doi 10.1007/s40265-025-02250-5); plasma biomarker analysis Hey JA et al. Drugs 2026;86(10):1705-1721 (PMID 42678603)",
  "verification": {
   "date": "2026-09-27",
   "against": [
    "https://clinicaltrials.gov/api/v2/studies/NCT04770220 (results section: ADAS-Cog13 LS mean difference -0.51, p=0.6058 MMRM; A-IADL-W difference 0.01, p=0.9966)",
    "https://clinicaltrials.gov/api/v2/studies/NCT06304883 (TERMINATED, why stopped: Sponsor business decision)",
    "https://pubmed.ncbi.nlm.nih.gov/41015981/",
    "https://pubmed.ncbi.nlm.nih.gov/42678603/"
   ],
   "note": "Checked 2026-09-27. CORRECT: pivotal_n 325 (registry actual and publication); APOE4/4 population; oral small molecule with no ARIA-type signal; no FDA/EMA approval. CORRECTED: primary_endpoint (ADAS-Cog13 at week 78, specifically), primary_endpoint_result (the 28%-vs-ADNI hippocampal claim is unsupported by the peer-reviewed paper or registry, which report 18% vs placebo overall and 26% in MCI; the 'cognitive/functional improvement' in MCI is nominal-significance subgroup data), pivotal_trial (NCT id, extension termination). Status flagged: extension terminated 2026 for business reasons."
  }
 },
 {
  "id": "gantenerumab",
  "name": "Gantenerumab",
  "inn_name": "gantenerumab",
  "brand_name": null,
  "mechanism": "Fully human monoclonal antibody targeting aggregated amyloid-beta (both fibrillar and plaque forms)",
  "target": "amyloid-beta plaque",
  "modality": "monoclonal-antibody",
  "route": "subcutaneous injection",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early AD (prodromal to mild)",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "GRADUATE I and GRADUATE II (Phase 3)",
  "pivotal_n": 1965,
  "primary_endpoint": "CDR-SB change from baseline at 116 weeks",
  "primary_endpoint_result": "Neither trial reached statistical significance: GRADUATE I showed an 8% relative reduction in decline (-0.31 points, p=0.0954); GRADUATE II showed a 6% relative reduction (-0.19 points, p=0.2998) -- both trials failed their primary endpoint",
  "aria_risk_pct": 25,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.roche.com/media/releases/med-cor-2022-11-14",
   "https://www.alzforum.org/news/research-news/gantenerumab-falls-short-phase-3-0"
  ],
  "notes": "Roche/Genentech announced negative topline GRADUATE I/II results on 2022-11-14; combined N=1,965 across both trials. Drug removed roughly half the amyloid plaque expected based on earlier-phase data, which was cited as a likely contributor to the efficacy miss. Pooled ARIA-E incidence was 25% (mostly asymptomatic, few discontinuations). Roche subsequently discontinued the gantenerumab clinical development program for sporadic AD (a related trial in dominantly inherited AD, DIAN-TU, also did not show benefit).",
  "aria_risk_definition": "ARIA-E in the SCarlet RoAD / Marguerite RoAD programme; the drug was discontinued and never approved."
 },
 {
  "id": "solanezumab",
  "name": "Solanezumab",
  "inn_name": "solanezumab",
  "brand_name": null,
  "mechanism": "Humanized monoclonal antibody targeting soluble monomeric amyloid-beta",
  "target": "amyloid-beta (soluble monomers)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "mild dementia due to AD",
   "biomarker_requirement": "biomarker-defined (confirmed amyloid accumulation, required in EXPEDITION3)"
  },
  "pivotal_trial": "EXPEDITION3",
  "pivotal_n": 2129,
  "primary_endpoint": "ADAS-Cog14 change from baseline at 80 weeks",
  "primary_endpoint_result": "Did not meet primary endpoint; difference vs placebo not statistically significant (p=0.095); this was the third consecutive Phase 3 failure for solanezumab across EXPEDITION, EXPEDITION2, and EXPEDITION3",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.alzforum.org/news/research-news/lilliputian-effect-size-fells-phase-3-trial-solanezumab-leaving-its-future"
  ],
  "notes": "Eli Lilly discontinued regulatory plans for solanezumab in mild AD dementia following the EXPEDITION3 failure (announced Nov 2016). Targets soluble monomeric amyloid-beta rather than aggregated/plaque forms, a mechanistic distinction from lecanemab/donanemab that may partly explain its lack of efficacy. Also separately tested (and failed) in the DIAN-TU dominantly-inherited AD prevention trial and the A4 preclinical-AD prevention trial."
 },
 {
  "id": "crenezumab",
  "name": "Crenezumab",
  "inn_name": "crenezumab",
  "brand_name": null,
  "mechanism": "Humanized IgG4 monoclonal antibody engineered for reduced effector function, targeting aggregated amyloid-beta oligomers",
  "target": "amyloid-beta oligomers",
  "modality": "monoclonal-antibody",
  "route": "subcutaneous injection / IV infusion",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early/prodromal AD (CREAD); also tested in preclinical autosomal-dominant AD (API-ADAD)",
   "biomarker_requirement": "biomarker-defined (confirmed amyloid pathology)"
  },
  "pivotal_trial": "CREAD 1 and CREAD 2 (Phase 3)",
  "pivotal_n": 1500,
  "primary_endpoint": "CDR-SB change from baseline",
  "primary_endpoint_result": "Trials stopped early (January 2019) after an interim futility analysis found they were unlikely to meet the primary endpoint of slowing decline on CDR-SB; no new safety signals identified",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.gene.com/media/press-releases/14774/2019-01-29/genentech-to-discontinue-phase-iii-cread",
   "https://www.alzforum.org/therapeutics/crenezumab"
  ],
  "notes": "Genentech/Roche and AC Immune program; CREAD 1 (started 2016) and CREAD 2 (started mid-2017) used doses 4x higher than in earlier Phase 2 testing. Terminated for futility, not safety. A related Phase 2 trial in carriers of an autosomal-dominant AD mutation (API-ADAD, in Colombia) also failed to meet its primary endpoint (reported 2022), though some exploratory biomarker signals were later highlighted by AC Immune."
 },
 {
  "id": "bapineuzumab",
  "name": "Bapineuzumab",
  "inn_name": "bapineuzumab",
  "brand_name": null,
  "mechanism": "Humanized monoclonal antibody targeting the N-terminus of aggregated amyloid-beta",
  "target": "amyloid-beta (N-terminus, aggregated forms)",
  "modality": "monoclonal-antibody",
  "route": "IV infusion",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "mild to moderate AD",
   "biomarker_requirement": "clinical, stratified by ApoE4 carrier status"
  },
  "pivotal_trial": "Studies 301 and 302 (Phase 3)",
  "pivotal_n": null,
  "primary_endpoint": "Co-primary endpoints: cognitive (ADAS-Cog) and functional (DAD) change from baseline",
  "primary_endpoint_result": "Co-primary endpoints not met in either the ApoE4 carrier study (301, announced July 2012) or the ApoE4 non-carrier study (302, announced August 2012)",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": false,
  "monitoring_requirements": null,
  "sources": [
   "https://www.jnj.com/media-center/press-releases/johnson-johnson-announces-discontinuation-of-phase-3-development-of-bapineuzumab-intravenous-iv-in-mild-to-moderate-alzheimers-disease",
   "https://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_co_primary_clinical_endpoints_not_met_in_second_phase_3_bapineuzumab_study_in_mild_to_moderate_alzheimer_s_disease_patients_who_do_not_carry_the_apoe4_genotype"
  ],
  "notes": "One of the earliest anti-amyloid monoclonal antibodies tested in AD; developed by Janssen AI (Johnson & Johnson) and Pfizer. Phase 3 IV development in mild-to-moderate AD discontinued August 2012 after both co-primary endpoints were missed in ApoE4 carriers (Study 301) and non-carriers (Study 302). Notable for establishing ARIA (then called vasogenic edema) as a class safety signal for anti-amyloid antibodies, particularly in ApoE4 carriers, that informed the design of all later programs (including lecanemab and donanemab). Exact trial N not found in accessible sources; left null rather than estimating."
 },
 {
  "id": "verubecestat",
  "name": "Verubecestat",
  "inn_name": "verubecestat",
  "brand_name": null,
  "mechanism": "Oral BACE1 (beta-secretase) inhibitor; blocks the enzymatic step that generates amyloid-beta from APP",
  "target": "BACE1 (beta-secretase)",
  "modality": "small-molecule",
  "route": "oral",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "mild-to-moderate AD (EPOCH); prodromal AD (APECS)",
   "biomarker_requirement": "clinical in EPOCH; biomarker-defined in APECS"
  },
  "pivotal_trial": "EPOCH (mild-to-moderate AD, Phase 3); APECS (prodromal AD, Phase 2/3)",
  "pivotal_n": null,
  "primary_endpoint": "ADAS-Cog and CDR-SB (varies by trial)",
  "primary_endpoint_result": "EPOCH stopped February 2017 for futility (unlikely to show positive benefit-risk); APECS stopped early 2018 after showing worsening cognition (worse ADAS-Cog13 and CDR-SB scores) and hippocampal atrophy vs placebo at the 40mg dose",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": null,
  "monitoring_requirements": null,
  "sources": [
   "https://www.merck.com/news/merck-announces-discontinuation-of-apecs-study-evaluating-verubecestat-mk-8931-for-the-treatment-of-people-with-prodromal-alzheimers-disease/",
   "https://alzres.biomedcentral.com/articles/10.1186/s13195-019-0520-1"
  ],
  "notes": "Merck's BACE1 inhibitor. EPOCH trial stopped for futility, not safety; the later APECS trial (prodromal/earlier-stage AD) was stopped after data showed dose-related cognitive worsening and hippocampal atrophy versus placebo -- an unexpected class-level concern for BACE inhibitors (excessive BACE inhibition may impair non-amyloid substrates important for synaptic function). No significant hepatotoxicity was reported for verubecestat specifically (distinguishing it from atabecestat's liver-toxicity-driven discontinuation)."
 },
 {
  "id": "lanabecestat",
  "name": "Lanabecestat",
  "inn_name": "lanabecestat",
  "brand_name": null,
  "mechanism": "Oral BACE1/BACE2 inhibitor; blocks amyloid-beta generation from APP",
  "target": "BACE1/BACE2 (beta-secretase)",
  "modality": "small-molecule",
  "route": "oral",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early AD (AMARANTH); mild AD dementia (DAYBREAK-ALZ)",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "AMARANTH and DAYBREAK-ALZ (Phase 3)",
  "pivotal_n": null,
  "primary_endpoint": "Cognitive/functional composite endpoints (varied by trial)",
  "primary_endpoint_result": "Both trials stopped for futility on recommendation of an independent data monitoring committee (June 12, 2018); neither the 20mg nor 50mg dose moved primary or secondary outcome measures relative to expected placebo decline",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.astrazeneca.com/media-centre/press-releases/2018/update-on-phase-iii-clinical-trials-of-lanabecestat-for-alzheimers-disease-12062018.html",
   "https://investor.lilly.com/news-releases/news-release-details/update-phase-3-clinical-trials-lanabecestat-alzheimers-disease"
  ],
  "notes": "Jointly developed by AstraZeneca and Eli Lilly. Discontinued for futility (lack of efficacy), explicitly not for safety concerns, per the companies' joint statement on 2018-06-12."
 },
 {
  "id": "atabecestat",
  "name": "Atabecestat",
  "inn_name": "atabecestat",
  "brand_name": null,
  "mechanism": "Oral BACE1 inhibitor; blocks amyloid-beta generation from APP",
  "target": "BACE1 (beta-secretase)",
  "modality": "small-molecule",
  "route": "oral",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "preclinical (late-onset) AD",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "EARLY (NCT02569398, Phase 2b/3)",
  "pivotal_n": null,
  "primary_endpoint": "Safety/tolerability (liver enzymes) and cognitive composite",
  "primary_endpoint_result": "Trial halted before efficacy readout due to serious liver enzyme elevations (hepatotoxicity) in a subset of participants; post-hoc analysis of available cognitive data also suggested dose-related cognitive worsening",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://alzheimersnewstoday.com/news/janssen-halts-2-clinical-trials-alzheimers-candidate-atabecestat/",
   "https://www.alzforum.org/news/research-news/liver-tox-ends-janssen-bace-program"
  ],
  "notes": "Janssen (Johnson & Johnson) program. Halted due to hepatotoxicity (serious liver enzyme elevations); later analysis of drug-induced liver injury cases suggested an immune-mediated mechanism (T cells responsive to atabecestat/its metabolites). This is the clearest liver-toxicity-driven BACE inhibitor discontinuation among the four BACE agents in this dataset."
 },
 {
  "id": "elenbecestat",
  "name": "Elenbecestat",
  "inn_name": "elenbecestat",
  "brand_name": null,
  "mechanism": "Oral BACE inhibitor; blocks amyloid-beta generation from APP",
  "target": "BACE (beta-secretase)",
  "modality": "small-molecule",
  "route": "oral",
  "status": "discontinued",
  "fda_approval_date": null,
  "ema_status": null,
  "accelerated_approval": null,
  "indication_population": {
   "stage": "early AD (MCI due to AD and mild AD dementia)",
   "biomarker_requirement": "biomarker-defined"
  },
  "pivotal_trial": "MISSION AD1 (NCT02956486) and MISSION AD2 (NCT03036280), Phase 3",
  "pivotal_n": null,
  "primary_endpoint": "CDR-SB change from baseline (design; trial stopped before readout)",
  "primary_endpoint_result": "Both trials discontinued on 2019-09-13 on recommendation of an independent data monitoring committee, which found an unfavorable overall risk-benefit ratio; efficacy readout was not completed",
  "aria_risk_pct": null,
  "annual_cost_usd_list": null,
  "requires_biomarker_confirmation": true,
  "monitoring_requirements": null,
  "sources": [
   "https://www.eisai.com/news/2019/news201965.html",
   "https://investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-discontinue-phase-iii-clinical-studies-bace"
  ],
  "notes": "Jointly developed by Eisai and Biogen. Discontinued based on an unfavorable risk-benefit assessment by an independent data monitoring committee rather than a specific single adverse event category; the long-term extension of the earlier Phase 2 study (Study 202) was also stopped. Effectively ended the class-wide push for BACE inhibitors in AD alongside verubecestat, lanabecestat, and atabecestat."
 }
]