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Name: Umibecestat
Synonyms: CNP520, 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: Amgen, Inc., Novartis Pharmaceuticals Corporation


CNP520 is an oral, small-molecule inhibitor of the aspartyl protease BACE designed to reduce Aβ production to prevent or treat Alzheimer's disease. BACE1 is the β-secretase enzyme that cleaves the APP protein to release its C99 fragment, which gives rise to various species of Aβ peptide during its cleavage by γ-secretase. The rationale of BACE inhibition is that it represents an upstream interference with the amyloid cascade, regardless of which species or aggregation states of Aβ then exert toxicity in the brain. BACE inhibition is sometimes envisioned as long-term maintenance therapy to limit Aβ production after an initial round of immunotherapy to remove existing amyloid deposits. 

Developed by Novartis, CNP520 is being jointly developed with Amgen (see company press release). CNP520 is formulated to be taken as capsules.

At the 2016 AAIC conference in Toronto, preclinical data presentations reported significant selectivity of CNP520 for BACE1 over BACE2 and other proteases such as renin and cathepsin, as well as absence of skin discoloration seen with some prior BACE inhibitors (see Aug 2016 conference news).


No Phase 1 trials for this compound are listed in; however, at the 2016 AAIC conference, Novartis scientists presented safety, tolerability, and pharmacodynamic data from three Phase 1 trials in a total of 113 healthy volunteers. The presentation also included data on dose-dependent lowering of CSF Aβ40 by up to 95 percent (see Aug 2016 conference news).

From August 2015 to March 2016, Novartis ran a multisite Phase 2a dose-ranging trial in the Netherlands, Belgium, Germany, the United Kingdom, and the United States. It evaluated safety and tolerability, as well as plasma and CSF pharmacokinetics and pharmacodynamics of 2 mg, 10 mg, 35 mg, and 85 mg of CNP520 or placebo taken once daily for 13 weeks by 124 healthy men and women between 60 and 80 years of age. The trial measured change in CSF Aβ38, 40, and 42. Results are posted on Structural features of CNP52, extensive preclinical data in rodents and dogs, as well as data from four Phase 1 trials and this Phase 2a trial were published in a peer-reviewed journal (Neumann et al., 2018).

In November 2015, a secondary prevention study called GENERATION 1 started enrolling 1,340 cognitively normal, homozygous ApoE4 carriers age 60 to 75. Part of the Alzheimer's Prevention Initiative (API) in partnership with Banner Alzheimer's Institute, this Phase 2/3 study is set to run until 2024 (Lopez Lopez et al., 2017Lopez Lopez et al., 2019). The treatment period is five years. This study will randomize half of participants to compare once-daily 50 mg CNP520 to matching placebo, the other half to compare quarterly injections of the investigational active immunotherapy CAD106 to placebo. The trial will measure the agents' ability to delay diagnosis to MCI or AD dementia and change on the APICC cognitive composite (Langbaum et al., 2015). An extensive list of secondary outcomes includes change on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) and other cognitive/functional scales, fluid biomarkers including CSF Aβ and tau, brain imaging including volumetric MRI plus amyloid PET and tau PET measurement of brain amyloid and tangle deposition, respectively, as well as safety measures and Aβ titers (see Jul 2014 conference news).

In August 2017, Novartis and API/Banner Alzheimer’s Institute began an additional Phase 2/3 prevention study. GENERATION 2 is aiming to enroll 2,000 cognitively normal homozygous ApoE4 carriers, or heterozygous carriers with evidence of brain amyloid, age 65 to 70. Participants are to be randomized to one capsule of 15 or 50 mg CNP520 or placebo daily, for at least 60 months, and up to a maximum of 84 months. Like in GENERATION 1, the primary outcome is time to a diagnosis of MCI or dementia due to AD or change on the APICC cognitive composite. Ten secondary outcomes include change on the CDR-SB, RBANS, and other cognitive/functional scales, fluid biomarkers including CSF Aβ and tau, brain imaging including volumetric MRI and measures of cerebral amyloid angiopathy, plus amyloid PET and tau PET measurement of brain amyloid and tangle deposition, respectively, as well as safety measures. This trial is set to run until 2025.

GENERATON trial participation requires disclosure of ApoE genotype to participants and, in the case of GENERATION 2, of brain amyloid status, as well.

On July 11, 2019, the trial sponsors announced a premature end to CNP520 dosing in both GENERATION trials, citing cognitive worsening in the treatment groups measured during a preplanned interim analysis (July 2019 conference news). Participants taking CNP520 subtly declined on the RBANS cognitive composite, had more brain atrophy and lost more weight than people on placebo (Dec 2019 conference news). The results were similar to those of other BACE inhibitors, verubecestat and atabecestat). Researchers continued to monitor cognition and brain volume after treatment was stopped, and reported that cognitive deficits and brain volume loss were reversible (Aug 2020 conference news).

For all trials of this compound, see and EU Clinical Trials Register.

Clinical Trial Timeline

  • Phase 2
  • Phase 2/3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Novartis Pharmaceuticals Corporation NCT02576639
Novartis Pharmaceuticals Corporation NCT02565511
Novartis Pharmaceuticals Corporation NCT03131453

Last Updated: 21 Jan 2021


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News Citations

  1. New Ways to Target Aβ and BACE Show Promising Phase 1 Data
  2. Novartis to Partner with Banner Health on ApoE4 Prevention Trial
  3. Cognitive Decline Trips Up API Trials of BACE Inhibitor
  4. Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors
  5. Umibecestat-Driven Cognitive Decline Is Reversible

Therapeutics Citations

  1. Verubecestat
  2. Atabecestat

Paper Citations

  1. . The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease. EMBO Mol Med. 2018 Nov;10(11) PubMed.
  2. . The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease. J Prev Alzheimers Dis. 2017;4(4):242-246. PubMed.
  3. . The Alzheimer's Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease. Alzheimers Dement (N Y). 2019;5:216-227. Epub 2019 Jun 12 PubMed.
  4. . Establishing Composite Cognitive Endpoints for Use in Preclinical Alzheimer's Disease Trials. J Prev Alzheimers Dis. 2015 Mar;2(1):2-3. PubMed.

Other Citations

  1. CAD106

External Citations

  3. EU Clinical Trials Register
  4. company press release

Further Reading


  1. . The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease. EMBO Mol Med. 2018 Nov;10(11) PubMed.
  2. . The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease. J Prev Alzheimers Dis. 2017;4(4):242-246. PubMed.
  3. . BACE inhibitors in clinical development for the treatment of Alzheimer's disease. Expert Rev Neurother. 2018 Nov;18(11):847-857. Epub 2018 Oct 24 PubMed.
  4. . A promising, novel, and unique BACE1 inhibitor emerges in the quest to prevent Alzheimer's disease. EMBO Mol Med. 2018 Nov;10(11) PubMed.
  5. . Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission. Alzheimers Res Ther. 2020 May 26;12(1):63. PubMed.
  6. . A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat. Clin Transl Sci. 2020 Nov;13(6):1316-1326. Epub 2020 Jul 23 PubMed.
  7. . Unravelling the molecular basis of AM-6494 high potency at BACE1 in Alzheimer's disease: an integrated dynamic interaction investigation. J Biomol Struct Dyn. 2021 Jan 7;:1-13. PubMed.
  8. . Computational modelling of potent β-secretase (BACE1) inhibitors towards Alzheimer's disease treatment. Biophys Chem. 2021 Mar;270:106536. Epub 2020 Dec 26 PubMed.