A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice.
BACKGROUND
Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans.


RESULTS
Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared.


CONCLUSIONS
In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. ulf.neumann@novartis.com.
Ulf
U
Neumann
Global Discover Chemistry, NIBR, Basel, Switzerland. heinrich.rueeger@novartis.com.
Heinrich
H
Rueeger
Global Discover Chemistry, NIBR, Basel, Switzerland. rainer.machauer@novartis.com.
Rainer
R
Machauer
Global Discover Chemistry, NIBR, Basel, Switzerland. siem.veenstra@novartis.com.
Siem Jacob
SJ
Veenstra
Global Discover Chemistry, NIBR, Basel, Switzerland. rainer.lueoend@novartis.com.
Rainer M
RM
Lueoend
Global Discover Chemistry, NIBR, Basel, Switzerland. marina.tintelnot-blomley@novartis.com.
Marina
M
Tintelnot-Blomley
Metabolism and Pharmacokinetics, NIBR, Basel, Switzerland. grit.laue@novartis.com.
Grit
G
Laue
Metabolism and Pharmacokinetics, NIBR, Basel, Switzerland. karen.beltz@novartis.com.
Karen
K
Beltz
DMPK, NIBR, Basel, Switzerland. barbara.vogg@novartis.com.
Barbara
B
Vogg
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. peschmid@aol.com.|Swiss Tropical and Public Health Institute, Basel, Switzerland. peschmid@aol.com.
Peter
P
Schmid
Preclinical Safety, NIBR, Basel, Switzerland. wilfried.frieauff@novartis.com.
Wilfried
W
Frieauff
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. derya.shimshek@novartis.com.
Derya R
DR
Shimshek
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. staufenbiel.m@gmail.com.|Hertie Institute for Clinical Brain Research, Tübingen, Germany. staufenbiel.m@gmail.com.
Matthias
M
Staufenbiel
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. laura.jacobson@florey.edu.au.|The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, Australia. laura.jacobson@florey.edu.au.
Laura H
LH
Jacobson
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006200:Hair Color / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism; D010848:Picolinic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013843:Thiazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; C000605932:NB-360; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010848:Picolinic Acids; D011993:Recombinant Fusion Proteins; D013843:Thiazines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse