Improvements in Neurological Assessments and Decreased Biological Age Seen With Alzheimer Agent Bezisterim
Bezisterim-treated patients showed age deceleration across various DNA methylation clocks, indicating potential anti-aging effects.
Cuong Do
In a randomized, placebo-controlled trial, bezisterim (BioVie), an oral, small molecule, blood-brain permeable compound in development for Alzheimer disease (AD), demonstrated potential to restore homeostasis and decrease biological age in a small per-protocol sample of patients. Formerly known as NE3107, bezisterim appeared to change the monocyte phenotype and DNA methylome, suggesting it may improve probable AD through pathways related to inflammation.1,2
Presented at the 12th Annual Alzheimer’s & Parkinson’s Drug Development Summit, held April 23-25, in Boston, Massachusetts, baseline and completion data were available for 50 subjects (bezisterim: n = 24; placebo: n = 26). DNA samples, analyzed by the Epigenic Clock Development Foundation using the Horvath Skinblood Clock, were available for 33 of this cohort. This group also had DNA methylation data analyzed by Hurdle/Chronomics for PhenoAge, Grim Age, AgeHannoum, and their new InflammAge Clock.
Age deceleration is the difference between a person’s biological age as measured by various DNA methylation clocks and their actual age since birth. All told bezisterim-treated patients displayed –4.77 years advantage on the Inflammation Age Clock (P = .022), –5.0 years advantage on the Hannum Age Clock (P = .006), –1.92 years advantage on the GrimAge Clock (P = .068), and –3.71 years on the PhenoAge Clock (P = .081). In addition, this group had a –3.68-year advantage on SkinBlood Clock (P = .017), a previously published finding.
"We all age and get older – nothing can change that. But these data provide evidence that bezisterim may have the potential to help keep people healthier for a longer time as we age," Cuong Do, president and chief executive officer at BioVie, said in a statement. "BioVie believes that DNA methylation may not need to constantly increase as we age, and thus the progression of age-related disease may not be uni-directional."
Bezisterim, an oral inflammatory and insulin sensitizer, is designed to bind to ERK and inhibit inflammation-specific ERK, NFkB, and TNF signaling, but does not impact their homeostatic functions. The therapy was considered well tolerated, with treatment-emergent adverse events (TEAEs) occurring in 62.5% of treated patients vs 72.7% of those on placebo. Serious AEs occurred in 4 patients (bezisterim: n = 1; placebo: n = 3), although none were treatment-related. In the trial, there was 1 non-treatment-related death in the bezisterim group, a 70-year-old man who died of respiratory arrest.
The study started during the COVID-19 pandemic and enrolled a total of 439 individuals through 39 sites. After the exclusions, the study was no longer powered for end points, but week 30 data suggested bezisterim vs placebo was comparable to results reported by approved medications. Overall, those on the therapy demonstrated a 68% (–0.95) and 26% (–0.94) improvement in Clinical Dementia Rating-Sum of Boxes and Alzheimer’s Disease Assessment-Cognitive subscale 12 (ADAS-Cog12), the two primary end points, vs placebo. In comparison, lecanemab (Leqembi; Eisai) and aducanumab (Aduhelm; Biogen), the 2 previously approved antiamyloid therapies, demonstrated improvements of 27% and 22% on CDR-SB at 1.5 years.
A principal component analysis (PCA), a machine learning method, was performed to reduce data dimensionality for the deacceleration of aging correlations. Overall, decreased age acceleration found in bezisterim was correlated with improvements in neurologic assessments, including CDR-SB (Pearson r = 0.413; P = .099), ADAS-Cog12 (Pearson r = .455; P = .067), Mini-Mental State Exam (MMSE; Pearson r = –0.580; P = .015), Alzheimer’s Disease Assessment Scale (ADCOMS; Pearson r = .469; P = .058), and Alzheimer’s Disease Composite Score-Clinical Global Impression of Change (ADCS-CGIC; Pearson r = .467; P = .059). In comparison, there were no correlations with neurologic assessments for placebo.
Bezisterim’s ability to reduce DNA methylation appeared to target 21 specific genes thus far. Of these, 15 were significant for bezisterim and not for placebo. Investigators reported significant correlations between improvements in the DNA methylation levels for the transmembrane protein 237 (TMEM237) gene, among others, and improvements in various clinical cognitive assessments among bezisterim-treated patients. Decreased TMEM237 promoter methylation has been shown to correlate with improved ADCOMS scores.
"Bezisterim is believed to be the first drug candidate that has shown in clinical trials the ability to modulate the level of DNA methylation, and do so in a manner that’s correlated with disease. But we are only at the beginnings of exploring the full potential of this unique molecule and how it can help modulate the progression of age-related diseases," Do added.
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At week 30, both placebo-treated and beziterim-treated patients demonstrated increased regulation on activation, normal T cell expressed and secreted (RANTES); however, the correlations diverted between groups. For placebo, increased RANTES had significant correlates with CDR-SB (decline), TNF, and triglycerides, as well as trending correlations with baseline WHR, increased c-reactive protein (CRP) & C1q. For bezisterim, increased RANTES was significantly correlated with improved MMSE, CDR-SB, ADCOMS, ADAS-Cog12, and Global Statistical Test (GST). Trending correlations for this group improved ADCS-CGIC, weight, and decreased TNF.
Patients on placebo saw a significant correlation between their Monocyte DNA Methylation Clock and the monocyte levels in their blood samples. No such correlated exited for bezisterim-treated patients, suggesting that bezisterim’s impact on DNA methylation may be changing the monocyte DNA methylome from a pro-inflammatory to an anti-inflammatory state (M1 to M2 transition hypothesis).
On secondary end points, bezisterim-treated patients demonstrated improvements of 40% (+1.02), 47% (+3.08), 139% (–0.43), and 27% (–0.03) on MMSE, ADCS-ADL, ADCS-CGIC, and ADCOMS, respectively. In comparison, available data showed an 18% improvement in MMSE for aducanumab, a 36% improvement in ADCS-ADL for lecanemab, and a 23% improvement in ADCOMS for aducanumab.
