Preclinical assessment of oral TLR7 agonist SA-5 in a nonhuman primate model
Shokichi Takahama, Takahiro Tomiyama, Sachiyo Yoshio, Yuta Nagatsuka, Hirotomo Murakami, Takuto Nogimori, Mami Kochi, Shoko Ochiai, Hidenori Kimura, Akihisa Fukushima, Tatsuya Kanto, Takuya Yamamoto
Shokichi Takahama, Takahiro Tomiyama, Sachiyo Yoshio, Yuta Nagatsuka, Hirotomo Murakami, Takuto Nogimori, Mami Kochi, Shoko Ochiai, Hidenori Kimura, Akihisa Fukushima, Tatsuya Kanto, Takuya Yamamoto
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Research Article Hepatology Immunology Infectious disease

Preclinical assessment of oral TLR7 agonist SA-5 in a nonhuman primate model

Abstract

TLR7 agonists are promising immunostimulatory agents for the treatment of chronic infections and cancer. However, their systemic toxicity remains a challenge. In this study, SA-5, a potentially novel liver-targeted, orally available TLR7 agonist, was evaluated for pharmacokinetics, safety, and efficacy in young and aged macaques across 1–10 mg/kg repeated doses. Safety was evaluated through hematologic, biochemical, and flow cytometric profiling, while efficacy was assessed via IFN-α production, gene expression of IFN-stimulated genes, and plasmacytoid dendritic cell activation. A principal component analysis–based (PCA-based) composite scoring system was used to integrate multimodal parameters. SA-5 induced dose-dependent type I IFN with limited systemic inflammation, with 3 mg/kg showing optimal balance. SA-5 had comparable immunostimulatory activity to GS-9620 but with reduced adverse biomarker shifts. In aged macaques, efficacy was maintained with modestly increased safety responses. These findings support SA-5 as a safer next-generation TLR7 agonist effective across age groups, highlighting integrated biomarker profiling in preclinical immunomodulatory drug development.

Authors

Shokichi Takahama, Takahiro Tomiyama, Sachiyo Yoshio, Yuta Nagatsuka, Hirotomo Murakami, Takuto Nogimori, Mami Kochi, Shoko Ochiai, Hidenori Kimura, Akihisa Fukushima, Tatsuya Kanto, Takuya Yamamoto

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Figure 5

Integrated analysis of safety and efficacy.

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Integrated analysis of safety and efficacy. (A) Scatter plot indicates P...
(A) Scatter plot indicates PC1 values from 2 principal component analyses (PCAs) for safety and efficacy. Probability ellipses indicate areas encompassing 90% of the distribution. Dashed lines indicate the boundaries of 4 regions defined by the ellipse border at 1 mg/kg. Colors indicate each dose. (B) PC1 safety values in each dose group. (C) PC1 efficacy values in each dose group. (D) Scatter indicates PC1 values for safety and efficacy, as in A, but not separated by dose. Colors indicate each region. (E) Bar plots indicate the frequency of macaques in each region as in D. (F) CRP scores in each dose group. (G) IFN-α scores in each dose group. (H) Scatter plot indicates the correlation between CRP values at Ad.01 and Ad.12. (I) Scatter plot indicates the correlation between IFN-α values at Ad.01 and Ad.12. (B and C) Statistical significance among dose groups was determined using the Wilcoxon rank-sum test stratified by administration (van Elteren), comparing each dose group with the 1 mg/kg group. (F and G) Statistical significance among dose groups based on fold-change values at day 1 (relative to day 0) was determined using the same test. P values were adjusted for multiple comparisons among dose groups using the Benjamini-Hochberg FDR correction; adjusted qvalues are shown. Unless noted otherwise, adjusted qvalues are denoted as: ***q < 0.001, **q < 0.01, *q < 0.05. (H and I) Statistical significance was determined using the Spearman’s rank correlation test. (A–C, F, and G) Colors indicate each dose as in A. (D and E) Colors indicate each region as in D. PCA, principal component analysis; PC1, principal component 1; CRP, C-reactive protein.