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. 2024 Aug 17;10(16):e36483.
doi: 10.1016/j.heliyon.2024.e36483. eCollection 2024 Aug 30.

Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Edward F Greenberg  1 , Martin J Voorbach  1 , Alexandra Smith  1 , David R Reuter  1 , Yuchuan Zhuang  1 , Ji-Quan Wang  1 , Dustin W Wooten  1 , Elizabeth Asque  1 , Min Hu  1 , Carolin Hoft  2 , Ryan Duggan  1 , Matthew Townsend  3 , Karin Orsi  4 , Karen Dalecki  5 , Willi Amberg  2 , Lori Duggan  4 , Heather Knight  4 , Joseph S Spina  4 , Yupeng He  1 , Kennan Marsh  1 , Vivian Zhao  6 , Suzanne Ybarra  6 , Jennifer Mollon  7 , Yuni Fang  6 , Aparna Vasanthakumar  1 , Susan Westmoreland  4 , Mathias Droescher  2 , Sjoerd J Finnema  1 , Hana Florian  1
Affiliations

Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Edward F Greenberg et al. Heliyon. .

Abstract

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Edward Greenberg, MD reports financial support was provided by AbbVie Inc. Edward Greenberg MD reports a relationship with AbbVie Inc that includes: employment, equity or stocks, and funding grants. EFG, MV, AS, DRR, YZ, JQW, DWW, EA, MH, CH, RD, MT, KO, WA, LD, HK, JSS, YH, KM, VZ, SY, JM, YF, AV, SW, MD, SJF, and HF are employees of AbbVie and may hold stock. KD was an employee of AbbVie at the time of the study and may hold stock. The design, study conduct, and all funding for this research was provided by AbbVie, the maker of navitoclax (ABT-263). AbbVie participated in the interpretation of data, review, and approval of the publication. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Navitoclax reaches senolytic-relevant concentrations in the rodent CNS. A. Navitoclax (50 mg/kg/day x 5 days) was administered to C57BL/6 mice (n = 3). Navitoclax concentrations in the brain and plasma were assessed 24 h following the last dose of navitoclax. B. [14C]Navitoclax (10 mg/kg/day x 1 day) was administered to male rats. Tissue concentrations of radioactivity were then assessed at 1–120 h following navitoclax administration.
Fig. 2
Fig. 2
Navitoclax in NHP study schema.
Fig. 3
Fig. 3
Navitoclax has on-target thrombocytopenia, BBB penetration, and senolysis in aged NHP. A. Effect of navitoclax on aged NHP platelet levels. Drug was administered Days 1–5 of each cycle. Shown: 2 aged NHP (A2, A4). B. Average 24h post-navitoclax CSF and plasma concentrations from aged NHP (A1, A2, A5 x 2, A6). Left: 24h CSF navitoclax = 0.56 ± 0.29 nM. Right: 24h plasma navitoclax = 190 ± 64 nM. C. Effect of age and navitoclax on mRNA markers of whole-blood senescence (p16) and SASP (IL-8, MCP-1, IL-1β, IL-6). Left: Baseline bulk blood mRNA. Right: Navitoclax effect. D. Effect of age on mRNA markers of PBMC senescence (p16, p21) and SASP (IL1b, TNFa, MCP1, IL6, IL8) in a second cohort of young (N = 21) and aged (N = 12). Statistical comparisons performed using Welch's t-test (p16, p21, IL1b, TNFa) or Mann-Whitney test (MCP1, IL6, IL8). E. Effect of navitoclax on cell surface senescence marker β2M+ in circulating PBMC. Top left: CD20+ B lymphocytes/Bottom left: CD14+ monocytes. Top Right: CD3+ T lymphocytes. Bottom right: CD56+ NK cells. PRE: Baseline, samples collected after 1 cycle of low dose navitoclax lead-in (1.44 mg/kg). POST: post-navitoclax, samples collected 16 days after the last dose of navitoclax cycle 6. F. Effect of age and navitoclax on markers of NHP skin senescence. Left: Effect of age and navitoclax on NHP bulk skin p21 mRNA. Top right: Effect of age and navitoclax on epidermal LMNB1 skin IHC. Results presented as % positive cells for LMNB1 vs total # non-cornified epidermal cells present. Bottom right: Effect of age and navitoclax on epidermal HMGB1. Results presented as % positive cells for HMGB1 vs total # non-cornified epidermal cells present. All PBMC and whole blood mRNA results presented as ΔΔCt = ΔCt (gene of interest mRNA)/–ΔCt (β-actin mRNA). Error bars: ±1 SE. *p < 0.05, **p < 0.01, ***p < 0.001. Abbreviations: NAV, navitoclax; β2M, beta-2 microglobulin. IHC, Immunohistochemistry; SC, senescent cells; SASP, Senescence Associated Secretory Phenotype; b-actin, beta-actin; SE, standard error; LMNB1, lamin B1; HMGB1, High mobility group box protein 1.
Fig. 4
Fig. 4
Effect of age and Navitoclax on CSF biomarkers of SASP and neurodegeneration. A.-D. Effect of age and navitoclax on CSF biomarkers. A. MCP-1. B. YKL-40. C. NF-L. D. GAP-43. Left: Baseline young (n = 12–13). Right: Effect of navitoclax on CSF biomarkers among individual aged NHP (n = 2–4). PRE: Baseline, samples collected after 1 cycle of low dose navitoclax lead-in (1.44 mg/kg). POST: post-navitoclax, samples collected 16 days after the last dose of navitoclax cycle 6. E., F. Baseline protein biomarkers of SASP and neurodegeneration in the CSF (E.) and plasma (F.) from a second cohort of young (N = 21) vs aged (N = 12). From left to right: MCP-1, YKL-40, NF-L, GAP-43 (a pre-synaptic protein biomarker to monitor synaptic health/synaptic damage). Error bars: ±1 SE. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.001. All statistical comparisons performed using Mann-Whitney test.
Fig. 5
Fig. 5
Navitoclax effect on TSPO PET tracer binding in aged NHP. TSPO-PET distribution volume ratios (DVR) for six aged NHPs before (closed symbol) and after navitoclax treatment (open symbol).
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