Back to the Top


Name: LY3202626
Synonyms: BACE Inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Eli Lilly & Co.


LY3202626 is a potent small-molecule inhibitor of BACE1, the β-secretase enzyme that cleaves the APP protein to release its C99 fragment. C99 gives rise to various species of Aβ peptide during its subsequent cleavage by γ-secretase. The rationale of BACE inhibition is that it represents an upstream interference with the amyloid cascade. This treatment approach is sometimes envisioned as long-term maintenance therapy to limit Aβ production after an initial round of immunotherapy to remove existing amyloid deposits. 

The potential advantage of LY3202626 over earlier compounds is its high potency. At the 2016 AAIC conference, Lilly reported that 1 mg/day of LY3202626 reduced CSF Aβ40 by half after two weeks (Aug 2016 conference news). It is formulated in capsule form.


Between December 2014 and February 216, Eli Lilly conducted a Phase 1 trial in four sequential parts. Parts A to C enrolled healthy people, part D enrolled people with AD, for a combined 136 participants. In part A, participants received placebo or 0.1 to 45 mg of the drug as a single dose and were monitored for safety. In part B, volunteers received 1.6 to 26 mg or placebo as a single dose, and serial plasma and CSF samples were taken for pharmacokinetic and pharmacodynamic analysis. Part C entailed multiple dosing up to 26 mg or placebo for two weeks. Part D administered 6 mg/day for two weeks. CSF was sampled at baseline in parts C and D, and again 24 hours after the final dose. At AAIC 2016, Lilly reported that LY3202626 was well-tolerated at all doses, without adverse events up to 42 days after the last dose. The compound’s half-life in plasma was 21 hours; it readily crossed the blood-brain barrier and dose-dependently reduced Aβ40 and Aβ42 in plasma and CSF. At 1, 6, and 26 mg/day over two weeks, LY3202626 reduced Aβ40 in CSF by 50, 75, and 90 percent, respectively (Aug 2016 conference newsWillis et al. 2016).

In September 2015, a second Phase 1 trial evaluated pharmacokinetic parameters of labeled LY3202626 in eight healthy volunteers, and from January to April 2017, a third Phase 1 trial in 30 healthy volunteers compared two different formulations and evaluated food effects on the pharmacokinetics of LY3202626.

In June 2016, Lilly started a Phase 2 trial called NAVIGATE-AD. Initially listed as aiming for 500 participants, this trial was cut back to 380 in August 2017, and terminated following an interim analysis in August 2018, when enrollment stood at 316. Enrollees had mild AD dementia as diagnosed by NIA/AA criteria, a positive florbetapir scan, and an MMSE between 20 and 26. They took either of two doses of LY3202626 or placebo once daily for a year, and were evaluated primarily with tau PET for their neurofibrillar pathology burden at baseline and one year. Secondary outcomes included safety measures of ARIA, pharmacokinetics of drug and Aβ in blood—but not CSF—as well as various efficacy measures such as the ADAS-cog13, the ADCS-iADL, and the integrated Alzheimer's Disease rating scale (iADRS). The trial was to take place at 76 centers in North America, Japan, and Australia, and to run through summer 2018. At the 2018 CTAD conference, Lilly reported that participants in this trial who had the longest exposure to LY3202626 showed hints of a cognitive deficit on the MMSE and ADAS-Cog13 (Nov 2018 conference news). Trial results have been published (Lo et al., 2021). The full analysis revealed no differences in tau PET, amyloid deposition, or measures of cognition and function in treated groups compared to placebo. Treatment was associated with brain volume loss in the hippocampus and other regions. A significant increase in psychiatric adverse events was noted for both doses compared to placebo, consistent with findings from trials of other BACE inhibitors, e.g. verubecestat.

In December 2017, Lilly began TRAILBLAZER, a combination trial of two investigational drugs targeting different points in the amyloid cascade. This Phase 2 was to evaluate safety, tolerability, and efficacy of an 18-month course of this BACE inhibitor in combination with donanemab, a monoclonal antibody against a pyroglutamate form of Aβ aggregated in plaques. It was to enroll 375 participants whose memory had been worsening for at least six months, and who met a cutoff on the CogState Brief Battery and had a positive tau PET scan. Because the antibody requires an infusion and the BACE inhibitor comes as a capsule, the three treatment arms in this blinded, placebo-controlled trial were to be as follows: One group to receive intravenous antibody plus placebo administered orally; the second group to receive intravenous antibody plus BACE inhibitor orally; the third group to receive both an intravenous and an oral placebo. Hence the trial was to evaluate the antibody alone and the antibody in combination with this BACE inhibitor, but not LY3202626 alone. The primary outcome is change on the Integrated Alzheimer's Disease Rating Scale (iADRS), a combined cognitive/functional measure for early stage AD developed by Lilly (Wessels et al., 2015). Secondary measures include the ADAS-Cog13, CDR-Sum of Boxes, MMSE, ADCS-iADL, as well as amyloid and tau PET and volumetric MRI. To ease the logistical burden of trial participation, this study offers rides to and from study sites via a partnership between GAP and the ridesharing company Lyft (press release). The study takes place at 69 sites in North America and is set to run until March 2020.

In October 2018, Lilly discontinued the BACE inhibitor arm of this trial; evaluation of the antibody remains ongoing, with a revised enrollment estimate of 266 participants. 

For all trials on this drug, see

Clinical Trial Timeline

  • Phase 2
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Eli Lilly & Co. NCT02791191

Last Updated: 30 Jul 2021


No Available Comments

Make a Comment

To make a comment you must login or register.


News Citations

  1. New Ways to Target Aβ and BACE Show Promising Phase 1 Data
  2. Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition

Therapeutics Citations

  1. Verubecestat
  2. Donanemab

Paper Citations

  1. . Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of LY3202626, a Novel Bace1 Inhibitor, in Healthy Subjects and Patients with Alzheimer’s Disease. Alzheimer's & Dementia, 01 July 2016
  2. . Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer's Disease Dementia. J Alzheimers Dis Rep. 2021 Apr 29;5(1):321-336. PubMed.
  3. . A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS). J Prev Alzheimers Dis. 2015 Dec 1;2(4):227-241. PubMed.

External Citations

  1. press release

Further Reading


  1. . Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor. J Med Chem. 2021 Jun 24;64(12):8076-8100. Epub 2021 Jun 3 PubMed.
  2. . Excretion, Mass Balance, and Metabolism of [14C]LY3202626 in Humans: An Interplay of Microbial Reduction, Reabsorption, and Aldehyde Oxidase Oxidation That Leads to an Extended Excretion Profile. Drug Metab Dispos. 2020 Aug;48(8):698-707. Epub 2020 Jun 4 PubMed.