Safety and Tolerability of GRF6019 Infusions in Severe Alzheimer’s Disease: A Phase II Double-Blind Placebo-Controlled Trial

Article type: Research Article

Authors: Hannestad, Jonas^a | Duclos, Tiffanie^{a; 1} | Chao, Whitney^a | Koborsi, Katie^a | Klutzaritz, Vicki^a | Beck, Brian^b | Patel, Ashok K.^c | Scott, James^d | Thein, Stephen G.^e | Cummings, Jeffrey L.^f | Kay, Gary^g | Braithwaite, Steven^{a; *} | Nikolich, Karoly^a

Affiliations: [a] Alkahest Inc., San Carlos, CA, USA | [b] CCT Research, Scottsdale, Arizona, USA | [c] Bio Behavioral Health, Toms River, NJ, USA | [d] Riverside Clinical Research, Edgewater, FL, USA | [e] Pacific Research Network –an ERG Portfolio Company, San Diego, CA, USA | [f] Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA | [g] Cognitive Research Corporation, St. Petersburg, FL, USA

Correspondence: [*] Correspondence to: Steven Braithwaite, Chief Scientific Officer, Alkahest, Inc., 125 Shoreway Road, Suite D, San Carlos, CA 94070, USA.Tel.: +1 650 801 0493; Fax: +1 650 801 0480; E-mail: sbraithwaite@alkahest.com.

Note: [1] Present affiliation: Zogenix, Inc., Emeryville, CA, USA

Abstract: Background:The plasma fraction GRF6019 shows multiple benefits on brain aging in mice, including enhanced cognition, neurogenesis, and synaptic density, as well as reduced neuroinflammation. Objective:To evaluate the safety, tolerability, and preliminary efficacy of GRF6019 in patients with severe Alzheimer’s disease (AD). Methods:A phase II, double-blind, placebo-controlled study in patients with severe AD (Mini-Mental State Examination score 0–10). Patients were randomized 2 : 1 to GRF6019 (N = 18) or placebo (N = 8) and received daily 250 mL intravenous infusions over 5 days. The primary endpoints were the rates of adverse events (AEs) and the tolerability of GRF6019 as assessed by the number of patients completing the study. Change from baseline in cognitive and functional assessments was also evaluated. Results:All patients completed 100%of study visits and infusions. The rate of AEs was similar in the GRF6019 (8/18 patients [44.4%]) and placebo (3/8 patients [37.5%]) groups, and there were no deaths or serious AEs. The most common AEs considered related to treatment were mild, transient changes in blood pressure in the GRF6019 group (hypotension: 2 patients [11.1%]; hypertension: 1 patient [5.6%]); there were no related AEs in the placebo group. The trial was not powered to detect statistically significant differences between treatment groups. At the end of the study, patients in both treatment groups remained stable or improved on all cognitive and functional endpoints. Conclusion:GRF6019 demonstrated excellent safety, feasibility, and tolerability. Future trials designed to characterize the potential functional benefits of GRF6019 and related plasma fractions in severe AD are warranted.

Keywords: Aging, Alzheimer’s disease, blood proteins, dementia, plasma, randomized controlled trial

DOI: 10.3233/JAD-210011

Journal: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1649-1662, 2021