Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial - 02/01/25

Doi : 10.1016/j.tjpad.2024.100016 
Stephen Macfarlane a, Timo Grimmer b, Ken Teo a, Terence J O'Brien c, Michael Woodward d, Jennifer Grunfeld e, Alastair Mander f, Amy Brodtmann g, Bruce J. Brew h, Philip Morris i, Cathy Short j, Susan Kurrle k, Rosalyn Lai l, Sneha Bharadwaj m, Peter Drysdale n, Jonathan Sturm o, Simon J.G. Lewis p, David Barton q, Chris Kalafatis r, Saif Sharif s, Richard Perry t, Nicholas Mannering u, J.Emer MacSweeney v, Stephen Pearson w, Craig Evans x, Vivek Krishna y, Alex Thompson z, Malathy Munisamy aa, Neel Bhatt bb, Aliya Asher cc, Sandra Connell dd, Jennifer Lynch ee, Sterre Malou Rutgers ff, Paul LJ Dautzenberg gg, Niels Prins hh, Patrick Oschmann ii, Lutz Frölich jj, Pawel Tacik kk, Oliver Peters ll, Jens Wiltfang mm, Alexandre Henri-Bhargava nn, Eric Smith oo, Stephen Pasternak pp, Andrew Frank qq, Howard Chertkow rr, Jennifer Ingram ss, Ging-Yuek Robin Hsiung tt, Rodney Brittain uu, Carmela Tartaglia vv, Sharon Cohen ww, Luca M Villa xx, Elizabeth Gordon xx, Thomas Jubault yy, Nicolas Guizard yy, Amanda Tucker zz, Walter E Kaufmann zz, Kun Jin zz, William R Chezem zz, Christopher U Missling zz, Marwan N Sabbagh ab,
a The Dementia Centre, HammondCare, Melbourne, Victoria, Australia 
b Technical University of Munich, School of Medicine and Health, Klinikum rechts der Isar, Munich, Germany 
c The Department of Neuroscience, The School of Translational Medicine, Alfred Hospital, Monash University, Melbourne, Victoria, Australia 
d University of Melbourne and Austin Health, Ivanhoe, Victoria, Australia 
e Peninsula Therapeutic & Research Group Pty Ltd, Frankston, Victoria, Australia 
f Geelong Private Medical Centre, Geelong, Victoria, Australia 
g Royal Melbourne (RMH) Parkville, Victoria (Australia) and Eastern Clinical Research Unit, Monash University, Box Hill, Victoria, Australia 
h St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia 
i Gold Coast Memory Disorders Clinic, Southport, Queensland, Australia 
j The Queen Elizabeth Hospital, Woodville South, South Australia, Australia 
k Hornsby Ku-ring-gai Hospital, Hornsby, New South Wales, Australia 
l KaRa MINDS, Macquarie Park, New South Wales, Australia 
m Australian Alzheimer's Research Organization, Nedlands, Western Australia, Australia 
n Delmont Private Hospital, Glen Iris, Victoria, Australia 
o Central Coast Neurosciences Research, Tumbi Umbi, New South Wales, Australia 
p Brain and Mind Centre, University of Sydney, Camperdown, New South Wales, Australia 
q NeuroCentrix, Noble Park, Victoria, Australia 
r King's College London, London, United Kingdom 
s Southern Health NHS Foundation Trust Memory Assessment & Research Centre, Southampton, United Kingdom 
t Imperial College Healthcare NHS Trust, London, United Kingdom 
u Re:Cognition Health, Guildford, United Kingdom 
v Re:Cognition Health, London, United Kingdom 
w Re:Cognition Health, Plymouth, United Kingdom 
x MAC Clinical Research, Barnsley, United Kingdom 
y MAC Clinical Research, Blackpool, United Kingdom 
z MAC Clinical Research, Cannock, United Kingdom 
aa MAC Clinical Research, Leeds, United Kingdom 
bb MAC Clinical Research, Liverpool, United Kingdom 
cc MAC Clinical Research, Manchester, United Kingdom 
dd MAC Clinical Research, Stockton-on-Tees, United Kingdom 
ee Glasgow Memory Clinic, Motherwell, United Kingdom 
ff Brain Research Center, Amsterdam, the Netherlands 
gg Brain Research Center, Den Bosch, the Netherlands 
hh Brain Research Centre, Zwolle, the Netherlands 
ii Klinikum Bayreuth, Bayreuth, Germany 
jj Central Institute of Mental Health (CIMH), Mannheim, Germany 
kk University Hospital Bonn, Bonn, Germany 
ll Charité University Medicine, Berlin, Germany 
mm Clinic for Psychiatry and Psychotherapy, Göttingen, Germany 
nn Vancouver Island Health Authority, Victoria, British Columbia, Canada 
oo Healthy Brain Aging Laboratories, University of Calgary, Calgary, Alberta, Canada 
pp Parkwood Institute/Western University, London, Ontario, Canada 
qq Bruyere Continuing Care, Ottawa, Ontario, Canada 
rr BayCrest Health Sciences, Toronto, Ontario, Canada 
ss Kawartha Centre - Healthy Aging Redefined, Peterborough, Ontario, Canada 
tt University of British Columbia Hospital, Vancouver, British Columbia, Canada 
uu True North Clinical Research, Halifax, Nova Scotia, Canada 
vv Toronto Western Hospital, Toronto, Ontario, Canada 
ww Toronto Memory Program, Toronto, Ontario, Canada 
xx QYNAPSE SAS, Paris, France 
yy QYNAPSE Canada Inc. Montréal, Canada 
zz Anavex Life Sciences, New York, NY, USA 
ab Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA 

Corresponding author at: Barrow Neurological Institute, St. Joseph's Hospital and Medical Center 240 W. Thomas Rd.; Phoenix, AZ 85013, USA.Barrow Neurological InstituteSt. Joseph's Hospital and Medical Center 240WThomas Rd.PhoenixAZ85013USA

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Abstract

Background

There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).

Objectives

The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.

Design

ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.

Setting

Multicenter - 52 medical research centers/hospitals in 5 countries.

Intervention

508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934.

Measurements

The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model.

Results

Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related.

Conclusions

Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.

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Keywords : Blarcamesine, Autophagy, Sigma-1 receptor, Randomized clinical trial


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