Synonyms: AZD3293 , LY3314814, 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: AstraZeneca, Eli Lilly & Co.
AZD3293 is an inhibitor of BACE1, the β-secretase sheddase that cleaves the APP protein to release APP's C99 fragment. This fragment then becomes a substrate for subsequent γ-secretase cleavage and Aβ peptide generation. 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.
AZD3293 is one of several BACE1/2 inhibitors currently in development. AZD3293 is administered in tablet form. This compound's in-vitro and in-vivo pharmacologic profile in primary cortical neurons, mice, guinea pigs, and dogs, as well as a broader development review, were formally published (Eketjall et al., 2016, Sims et al., 2017).
In December 2012, AstraZeneca started a Phase 1 study that evaluated the safety and pharmacological effects of single doses of oral AZD3293 in 72 healthy volunteers. Doses ranged from 1–1,000 mg.
In 2013 and 2014, six additional Phase 1 studies in the United States and Japan further evaluated safety, tolerability, metabolism, and potential drug interactions of single and multiple ascending doses of a tablet and an oral formulation in both elderly volunteers and Alzheimer's patients. Effects on biomarkers in plasma and CSF were also measured. The results have not yet been published in peer-reviewed journals, but the company has reported at scientific conferences that the inhibitor appeared safe and strongly reduced CSF Aβ levels (see Mar 2014 news story). In October 2016, a peer-reviewed paper on the first two of these Phase 1 trials reported the compound was well-tolerated across the dose range and caused prolonged Aβ reductions in plasma and CSF. Notably, the paper reported blood Aβ reduction even with once-a-week dosing (Cebers et al., 2016). Likewise, the first trial in Japan was published to have shown robust blood and CSF Aβ reduction and no safety concerns (Sakamoto et al., 2017).
In September 2014, AstraZeneca and Eli Lilly announced that they would jointly develop AZD3293, with AstraZeneca handling manufacturing and Eli Lilly leading clinical trials (see company press release). The clinical development program of this compound will largely skip Phase 2. Instead of running medium-size Phase 2 followed by separate, larger confirmatory Phase 3 trials, the sponsors opted for a large, pivotal Phase 2/3 trial. Called AMARANTH, this trial compares AZD3293 to placebo given for two years in 2,202 patients who meet NIA-AA criteria for MCI due to AD or mild AD. Each participant or his or her partner must report worsening in the past six months, and the participant's MMSE must be above 21 at screening. To ascertain that they have brain amyloid accumulation, participants will undergo either an amyloid PET scan or a lumbar puncture and continue in respective substudies monitoring those markers for treatment response. The trial will compare two doses given once daily as a tablet to placebo, and measure success by change from baseline on the clinical dementia rating sum of boxes (CDR-SOB). The ADAS-cog and ADCS-ADL are secondary outcome measures, along with other clinical markers as well as change in CSF markers, functional and amyloid PET, and MRI. This multicenter trial began enrolling in December 2014, and is set to run until 2019.
In 2015 and 2016, four additional Phase 1 trials in a total of 175 healthy volunteers were conducted. They evaluated a new tablet formulation, as well as the interaction of this BACE inhibitor with certain drugs commonly prescribed in the elderly, such as the blood thinners warfarin and dabigatran, the sedative midalozam, as well as simvastatin and donepezil.
In July 2016, a second Phase 3 trial started up. Called DAYBREAK-ALZ and to be conducted in 228 locations worldwide, it enrolls 1,899 patients with mild AD dementia as defined by an NIA-AA diagnosis of probable AD with a biomarker evidence of brain amyloid and an MMSE of 10 to 26. This four-arm trial compares two once-daily doses given for three years to two groups who start out on placebo for 18 months and then switch to their the low or high dose for the second half of the trial. The primary outcome is change on the ADAS-cog13 scale; 16 listed secondary outcomes include clinical, functional, biomarker, and population pharmacokinetic measures. This trial is set to run until 2021.
On August 22, 2016, the FDA fast-tracked AZD3293 for expedited review (Reuters news).
On June 12, 2018, the AMARANTH and DAYBREAK-ALZ trials were discontinued due to lack of efficacy determined at an interim futility analysis (June 2018 news).
For all clinical trials of this compound, see clinicaltrials.gov.
Clinical Trial Timeline
- BACE Inhibitor Heads for Phase 2/3 Trials
- Scratch Lanabecestat: This BACE Inhibitor Doesn’t Work in Symptomatic AD, Either
- Cebers G, Alexander RC, Haeberlein SB, Han D, Goldwater R, Ereshefsky L, Olsson T, Ye N, Rosen L, Russell M, Maltby J, Eketjäll S, Kugler AR. AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. J Alzheimers Dis. 2017;55(3):1039-1053. PubMed.
- Sakamoto K, Matsuki S, Matsuguma K, Yoshihara T, Uchida N, Azuma F, Russell M, Hughes G, Haeberlein SB, Alexander RC, Eketjäll S, Kugler AR. BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides. J Clin Pharmacol. 2017 Nov;57(11):1460-1471. Epub 2017 Jun 15 PubMed.
- Eketjäll S, Janson J, Kaspersson K, Bogstedt A, Jeppsson F, Fälting J, Haeberlein SB, Kugler AR, Alexander RC, Cebers G. AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. J Alzheimers Dis. 2016;50(4):1109-23. PubMed.
- Sims JR, Selzler KJ, Downing AM, Willis BA, Aluise CD, Zimmer J, Bragg S, Andersen S, Ayan-Oshodi M, Liffick E, Eads J, Wessels AM, Monk S, Schumi J, Mullen J. Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814). J Prev Alzheimers Dis. 2017;4(4):247-254. PubMed.
- Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA, Jhee S, Kleijn HJ, Kuvelkar R, Li W, Mattson BA, Mei H, Palcza J, Scott JD, Tanen M, Troyer MD, Tseng JL, Stone JA, Parker EM, Forman MS. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. PubMed.