Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease: A Randomized Clinical Trial

Christopher H van Dyck, Haakon B Nygaard, Kewei Chen, Michael C Donohue, Rema Raman, Robert A Rissman, James B Brewer, Robert A Koeppe, Tiffany W Chow, Michael S Rafii, Devon Gessert, Jiyoon Choi, R Scott Turner, Jeffrey A Kaye, Seth A Gale, Eric M Reiman, Paul S Aisen, Stephen M Strittmatter, Christopher H van Dyck, Haakon B Nygaard, Kewei Chen, Michael C Donohue, Rema Raman, Robert A Rissman, James B Brewer, Robert A Koeppe, Tiffany W Chow, Michael S Rafii, Devon Gessert, Jiyoon Choi, R Scott Turner, Jeffrey A Kaye, Seth A Gale, Eric M Reiman, Paul S Aisen, Stephen M Strittmatter

Abstract

Importance: Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease.

Objective: To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated.

Design, setting, and participants: This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018.

Interventions: AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks.

Main outcomes and measures: Primary outcome was the reduction in relative CMRgl, as measured by 18F-fluorodeoxyglucose (18F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers.

Results: Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: -0.006 units/y; 95% CI, -0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness.

Conclusions and relevance: Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures.

Trial registration: ClinicalTrials.gov identifier: NCT02167256.

Conflict of interest statement

Conflict of Interest Disclosures: Dr van Dyck reported receiving consulting fees from Roche, Eisai, Kyowa Kirin, Merck, Eli Lilly, and Janssen as well as grants for clinical trials from Biogen, Novartis, Eli Lilly, Merck, Eisai, Janssen, Roche, Genentech, Biohaven, Toyama, and TauRx outside of the submitted work. Dr Nygaard reported receiving 18F-Florbetapir from Avid Radiopharmaceuticals for the Canadian site (University of British Columbia). Dr Donohue reported personal fees from Eli Lilly and Neurotrack and other from Janssen outside the submitted work. Dr Chen reported current full-time employment at Green Valley Pharmaceuticals, Shanghai, China, and past employment at Banner Alzheimer’s Institute during the conduct of the study. Dr Raman reported receiving grants from Eli Lilly, Janssen, and the National Institute on Aging through the Alzheimer’s Therapeutic Research Institute. Dr Brewer reported receiving consulting fees from Elan, Bristol-Myers Squibb, Avanir, Novartis, Genentech, and Eli Lilly as well as stock options in CorTechs Labs Inc and Human Longevity Inc. Dr Koeppe reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Kaye reported receiving grants from Alzheimer's Therapeutic Research Institute during the conduct of the study. Dr Turner reported receiving consulting fees from Eli Lilly and grants for clinical trials from Acadia, Biogen, Novartis, Eli Lilly, Merck, Eisai, Janssen, Roche, Genentech, and Toyama. Dr Gale reported receiving consulting fees from Phillips and grants for clinical trials from Eisai, Roche, Eli Lilly, Novartis, and Genentech. Dr Reiman reported receiving fees as a scientific advisor to Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Roche (expenses only), United Neuroscience, and Zinfandel and grants for clinical trials from Genentech/Roche, Novartis/Amgen, and Avid/Lilly. Dr Aisen reported receiving consulting fees from Proclara, Merck, Biogen, Roche, Eisai, Storz, and ImmunobrainCheckpoint as well as grants for clinical trials from Eli Lilly and Janssen. Dr Strittmatter reported receiving founder shares and consulting fees from ReNetX Bio as well as being an inventor on Yale patents and patent applications related to Alzheimer treatment. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram
Figure 1.. CONSORT Diagram
Figure 2.. Primary Outcome
Figure 2.. Primary Outcome
A, A 52-week cerebral metabolic rate for glucose (CMRgl) decline statistical region of interest (sROI; in the red-to-yellow color scale) and a spared sROI (in the blue-to-green color scale) were generated using baseline and follow-up. Shown are 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images acquired in an Alzheimer’s Disease Neuroimaging Initiative study and updated for amyloid-positive participants with Alzheimer disease, as previously described., B. The y-axis represents relative CMRgl-derived 18F-FDG PET in the Alzheimer disease–associated sROI normalized to the spared sROI. The treatment groups did not differ in the 52-week decline in CMRgl (difference, −0.006 units/y; 95% CI, −0.017 to 0.006; P = .34). The mean (SD) 12-month decrease in 18F-FDG PET CMRgl was .0525 (.0340) in the placebo (control) group (n = 72), which was close to the pilot estimates used in the power analysis, and 0.0569 (0.0303) in the AZD0530 group (n = 59). Blue represents the placebo group; orange, the AZD0530 group.
Figure 3.. Secondary Outcomes
Figure 3.. Secondary Outcomes
A, Analyses of clinical variables used a mixed model of repeated measures to estimate the mean group difference at each follow-up time, with change from baseline as the outcome, controlling for baseline score, age, and apolipoprotein E (APOE) ε4 status. B. Analyses of magnetic resonance imaging (MRI) variables used an analysis of covariance model with percentage of deformation per year from baseline as the outcome, adjusted for mean baseline volume or thickness of brain region, age, and APOE ε4 status. Blue represents the placebo group; orange, the AZD0530 group. aAlzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) score range: 0 (indicating best) to 70 (worst). bAlzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score range: 0 (worst) to 78 (best). cClinical Dementia Rating–Sum of Boxes (CDR-SB) score range: 0 (best) to 18 (worst). dNeuropsychiatric Inventory score range: 0 (best) to 144 (worst).

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