LY2062430 · program

Solanezumab for Alzheimer's disease

DiscontinuedDiscontinuedEli Lilly and Company (LLY)

Eli Lilly's solanezumab (LY2062430) Alzheimer's disease program — one of the largest negative franchises in CNS drug development, spanning ~14 years of Phase 3 across every stage of the disease. Generation 1: EXPEDITION (NCT00905372) and EXPEDITION2 (NCT00904683), 400 mg IV q4w in mild-to-moderate AD, both missed their cognitive and functional co-primary endpoints (topline 2012-08-24), though pre-specified pooled secondary analyses suggested slowing of cognitive decline in the mild subgroup — the signal that justified generation 2. Generation 2: EXPEDITION3 (NCT01900665, n=2,129, mild AD dementia with amyloid confirmation; primary endpoint changed to ADAS-Cog14 alone before unblinding) missed (p=0.095, topline 2016-11-23); Lilly announced it would not pursue regulatory submission, and the prodromal-AD EXPEDITION-PRO (NCT02760602) was terminated at n=26 while the open-label extension EXPEDITION-EXT (NCT01127633) was wound down. Generation 3 — prevention: the solanezumab arm of the academic DIAN-TU-001 platform trial (NCT01760005, Washington University-sponsored) in dominantly inherited AD missed its primary endpoint (topline 2020-02-10; Salloway et al. Nat Med 2021), and the NIA/Lilly-partnered A4 study (NCT02008357, n=1,169, amyloid-positive asymptomatic older adults, up to ~7.5 years of treatment with escalation to 1600 mg) showed no slowing of cognitive decline, no reduction in progression risk, and no plaque clearance (topline 2023-03-08; Sperling et al. NEJM 2023). Lilly ended solanezumab development for Alzheimer's disease with the A4 announcement.

Data current as of

Development timeline

DiscontinuedMar 2023 – Sept 2023
  1. missedFull A4 results published: no effect of solanezumab on cognitive decline or amyloid accumulation in preclinical Alzheimer's disease (Sperling et al., NEJM 2023).↗
  2. missedA4 study: solanezumab does not slow cognitive decline in preclinical (asymptomatic, amyloid-positive) Alzheimer's disease and does not clear brain amyloid plaque; Lilly ends solanezumab development for AD.↗
Phase 3May 2009 – Feb 2020
  1. missedSolanezumab arm of the DIAN-TU platform trial misses its cognitive primary endpoint in dominantly inherited Alzheimer's disease; Lilly will not pursue a submission in this population.↗
  2. missedFull EXPEDITION3 results published: solanezumab 400 mg q4w did not significantly affect cognitive decline in mild Alzheimer's dementia (Honig et al., NEJM 2018;378:321-330).↗
  3. Trial terminatedEXPEDITION-PRO (prodromal AD) terminated after the EXPEDITION3 miss
  4. Trial terminatedEXPEDITION-EXT open-label extension terminated
  5. missedEXPEDITION3 misses its primary endpoint in mild Alzheimer's dementia (ADAS-Cog14, p=0.095); Lilly will not pursue regulatory submission for solanezumab in mild AD dementia.↗
  6. missedFull EXPEDITION/EXPEDITION2 Phase 3 results published: solanezumab failed to improve cognition or functional ability in mild-to-moderate Alzheimer's disease (Doody et al., NEJM 2014;370:311-321).↗
  7. missedEXPEDITION and EXPEDITION2 both miss their co-primary cognitive and functional endpoints in mild-to-moderate Alzheimer's disease; pre-specified pooled secondary analyses suggest slowing of cognitive decline in mild AD only.↗
  8. Phase 3 EXPEDITION (NCT00905372) and EXPEDITION2 (NCT00904683) both started May 2009 per ClinicalTrials.gov (400 mg IV q4w vs placebo in mild-to-moderate AD; ~1,000 patients each). Day-of-month not registered — CT.gov gives '2009-05' only, so the anchor is the first of the month.

Readouts

  • 2023-09-21ReportedFull resultsmissedNCT02008357

    Full A4 results published: no effect of solanezumab on cognitive decline or amyloid accumulation in preclinical Alzheimer's disease (Sperling et al., NEJM 2023). ↗

  • 2023-03-08ReportedTopline datamissedNCT02008357

    A4 study: solanezumab does not slow cognitive decline in preclinical (asymptomatic, amyloid-positive) Alzheimer's disease and does not clear brain amyloid plaque; Lilly ends solanezumab development for AD. ↗

  • 2020-02-10ReportedTopline datamissedNCT01760005

    Solanezumab arm of the DIAN-TU platform trial misses its cognitive primary endpoint in dominantly inherited Alzheimer's disease; Lilly will not pursue a submission in this population. ↗

  • 2018-01-25ReportedFull resultsmissedNCT01900665

    Full EXPEDITION3 results published: solanezumab 400 mg q4w did not significantly affect cognitive decline in mild Alzheimer's dementia (Honig et al., NEJM 2018;378:321-330). ↗

  • 2016-11-23ReportedTopline datamissedNCT01900665

    EXPEDITION3 misses its primary endpoint in mild Alzheimer's dementia (ADAS-Cog14, p=0.095); Lilly will not pursue regulatory submission for solanezumab in mild AD dementia. ↗

  • 2014-01-23ReportedFull resultsmissedNCT00905372

    Full EXPEDITION/EXPEDITION2 Phase 3 results published: solanezumab failed to improve cognition or functional ability in mild-to-moderate Alzheimer's disease (Doody et al., NEJM 2014;370:311-321). ↗

  • 2012-08-24ReportedTopline datamissedNCT00905372

    EXPEDITION and EXPEDITION2 both miss their co-primary cognitive and functional endpoints in mild-to-moderate Alzheimer's disease; pre-specified pooled secondary analyses suggest slowing of cognitive decline in mild AD only. ↗

Clinical trials in Alzheimer's disease

NCT02760602H8A-MC-LZBC (EXPEDITION-PRO)Phase 3Discontinuedn=26

A Study of Solanezumab (LY2062430) in Participants With Prodromal Alzheimer's Disease (EXPEDITION-PRO)

Started Jun 2016· Primary completion May 2017· 📍 193 sites across 13 countries (United States, Japan, Spain, France)

NCT02008357H8A-MC-LZAZ (A4)Phase 3Completedn=1169

Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4)

Started Feb 2014· Primary completion Dec 2022· 📍 68 sites across 4 countries (United States, Canada, Australia, Japan)

missedprimaryChange from baseline in Preclinical Alzheimer Cognitive Composite (PACC) at 240 weeks (amyloid-positive, cognitively unimpaired adults 65-85)

Solanezumab did not slow cognitive decline versus placebo in preclinical AD, did not reduce the risk of progression to symptomatic AD, and did not clear brain amyloid plaque. Run in partnership with NIA/ATRI (public-private A4 collaboration); dose escalated from 400 mg to up to 1600 mg IV q4w mid-study. Full results: Sperling et al. NEJM 2023;389:1096-1107 (PMID 37458272).

NCT01900665H8A-MC-LZAX (EXPEDITION3)Phase 3Discontinuedn=2129

Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo (EXPEDITION3)

Started Jul 2013· Primary completion Oct 2016· 📍 198 sites across 11 countries (United States, France, Japan, United Kingdom)

missedprimaryChange from baseline in ADAS-Cog14 at 80 weeks (mild AD dementia, amyloid-confirmed) (0.095)

Primary endpoint not met (p=0.095); secondary endpoints directionally favored solanezumab but treatment differences were small; no new safety signals. The primary endpoint had been changed from cognitive+functional co-primaries to cognition-only (ADAS-Cog14) before unblinding. Lilly announced it would not pursue regulatory submission. Full results: Honig et al. NEJM 2018;378:321-330.

NCT01760005DIAN-TU-001Phase 2/3Activen=490

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia (DIAN-TU-001 master protocol)

Started Dec 2012· Primary completion Apr 2028· 📍 38 sites across 15 countries (United States, France, Canada, Australia)

missedprimaryDIAN Multivariate Cognitive Endpoint over 4 years (solanezumab arm; dominantly inherited AD mutation carriers)

The solanezumab arm did not meet its cognitive primary endpoint in the Washington University-sponsored DIAN-TU platform trial (topline 2020-02-10); Lilly did not pursue a submission in dominantly inherited AD. Full results: Salloway et al. Nat Med 2021;27:1187-1196 (PMID 34155411). The master protocol remains active for other drug arms; the solanezumab arm is closed.

NCT01127633H8A-MC-LZAO (EXPEDITION-EXT)Phase 3Discontinuedn=1457

Continued Safety Monitoring of Solanezumab (LY2062430) in Alzheimer's Disease (EXPEDITION-EXT)

Started Dec 2010· Primary completion Jul 2014· 📍 147 sites across 16 countries (United States, Japan, Australia, Canada)

NCT00905372H8A-MC-LZAM (EXPEDITION)Phase 3Completedn=1000

Effect of LY2062430 on the Progression of Alzheimer's Disease (EXPEDITION)

Started May 2009· Primary completion Apr 2012· 📍 85 sites across 5 countries (United States, Japan, Canada, Argentina)

missedprimaryCo-primary: change from baseline in ADAS-Cog11 and ADCS-ADL at 18 months (mild-to-moderate AD)

Neither the cognitive nor the functional co-primary endpoint was met (topline 2012-08-24). Pre-specified pooled secondary analyses across EXPEDITION and EXPEDITION2 showed statistically significant slowing of cognitive decline in the mild subgroup but not the moderate subgroup. Full results: Doody et al. NEJM 2014;370:311-321.

NCT00904683H8A-MC-LZAN (EXPEDITION2)Phase 3Completedn=1040

Effect of LY2062430 on the Progression of Alzheimer's Disease (EXPEDITION2)

Started May 2009· Primary completion Jun 2012· 📍 95 sites across 13 countries (United States, Australia, Germany, Italy)

missedprimaryCo-primary: change from baseline in ADAS-Cog11 and ADCS-ADL at 18 months (mild-to-moderate AD)

Primary endpoints not met (topline 2012-08-24, announced jointly with EXPEDITION). Full results: Doody et al. NEJM 2014;370:311-321.

Formulations

FormulationRouteRegimenPharmacokinetics
Solanezumab intravenous infusion
Intravenous infusion every 4 weeks. EXPEDITION, EXPEDITION2 and EXPEDITION3: 400 mg IV q4w. A4: initiated at 400 mg IV q4w, dose-escalated up to 1600 mg IV q4w by protocol amendment mid-study as evidence mounted that 400 mg was subtherapeutic. First-in-human single doses ranged 0.5-10 mg/kg.
IntravenousOther—

Mechanism of action (compound-wide)

Humanized IgG1 monoclonal antibody that binds the mid-domain of soluble, monomeric amyloid-beta peptide — it does not appreciably bind deposited fibrillar plaque, the inverse selectivity of gantenerumab, aducanumab, lecanemab and donanemab. The therapeutic hypothesis was the 'peripheral sink': sequestering soluble Abeta in plasma and CSF to shift the equilibrium away from aggregation and deposition. Single-dose administration produced dose-dependent, dramatic increases in total (bound) plasma and CSF Abeta without acute cognitive change, consistent with target engagement of the soluble pool. Across four Phase 3 disease-stage populations the mechanism failed to produce significant clinical benefit, and in the A4 prevention study solanezumab did not reduce brain amyloid plaque burden — together the strongest clinical evidence that engaging soluble monomeric Abeta alone is insufficient to modify Alzheimer's disease.

TargetActionAffinity
Amyloid-beta (aggregated)primaryAPPInhibitor—ⓘ

← Full LY2062430 compound page (identity, identifiers, all indications)

Sources

  1. Doody RS, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370(4):311-321 — The New England Journal of Medicine / PubMed
  2. Eli Lilly and Company Announces Top-Line Results on Solanezumab Phase 3 Clinical Trials in Patients with Alzheimer's Disease (2012-08-24) — Eli Lilly and Company
  3. Honig LS, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease [EXPEDITION3]. N Engl J Med. 2018;378(4):321-330 — The New England Journal of Medicine / PubMed
  4. Lilly Announces Top-Line Results of Solanezumab Phase 3 Clinical Trial [EXPEDITION3] (2016-11-23) — Eli Lilly and Company
  5. Lilly Announces Topline Results for Solanezumab from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Study (2020-02-10) — Eli Lilly and Company
  6. Lilly Provides Update on A4 Study of Solanezumab for Preclinical Alzheimer's Disease (2023-03-08) — Eli Lilly and Company
  7. NCT00904683 (EXPEDITION2) — Effect of LY2062430 on the Progression of Alzheimer's Disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT00905372 (EXPEDITION) — Effect of LY2062430 on the Progression of Alzheimer's Disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT01127633 (EXPEDITION-EXT) — Continued Safety Monitoring of Solanezumab (LY2062430) in Alzheimer's Disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT01760005 (DIAN-TU-001) — Dominantly Inherited Alzheimer Network Trial master protocol (Washington University School of Medicine, sponsor; Eli Lilly, collaborator) — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. NCT01900665 (EXPEDITION3) — Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo — ClinicalTrials.gov (U.S. National Library of Medicine)
  12. NCT02008357 (A4) — Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss — ClinicalTrials.gov (U.S. National Library of Medicine)
  13. NCT02760602 (EXPEDITION-PRO) — A Study of Solanezumab (LY2062430) in Participants With Prodromal Alzheimer's Disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  14. Siemers ER, et al. Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol. 2010;33(2):67-73 — Clinical Neuropharmacology / PubMed
  15. Sperling RA, et al. Trial of Solanezumab in Preclinical Alzheimer's Disease [A4]. N Engl J Med. 2023 (print 2023-09-21) — The New England Journal of Medicine / PubMed