A Double-Blind, Randomized, Placebo-Controlled, Single Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of AB-161 Following Oral Administration in Healthy Subjects

Start Date16 Mar 2023

Sponsor / Collaborator

Arbutus Biopharma Corp.

CTR20230241 / SuspendedPhase 1

一项单中心、双盲、安慰剂对照的首次人体研究，用于评估单次和重复剂量给药 AK0706 片的安全性、耐受性、药代动力学特征及食物影响的 Ia 期临床试验

[Translation] A single-center, double-blind, placebo-controlled, first-in-human study to evaluate the safety, tolerability, pharmacokinetic characteristics and food effects of single and repeated doses of AK0706 tablets in a Phase Ia clinical trial

1、研究 AK0706 片在受试者中的安全性和耐受性，初步评估AK0706 对 QT 间期的影响。 2、评估健康受试者单次口服 AK0706 片和 HBsAg 阳性的 ALT 正常的受试者重复口服 AK0706 的 PK 特征。 3、评估食物对健康受试者口服 AK0706 片的 PK 特征的影响。 4、检测 AK0706 可能的代谢产物类型及主要代谢产物的 PK 特征（如适用）。

[Translation]

1. To study the safety and tolerability of AK0706 tablets in subjects and preliminarily evaluate the effect of AK0706 on the QT interval. 2. To evaluate the PK characteristics of healthy subjects who took AK0706 tablets orally once and subjects who were HBsAg positive and had normal ALT after repeated oral administration of AK0706. 3. To evaluate the effect of food on the PK characteristics of healthy subjects who took AK0706 tablets orally. 4. To detect the possible metabolite types of AK0706 and the PK characteristics of the main metabolites (if applicable).

Start Date16 Feb 2023

Sponsor / Collaborator

Xiamen Amoytop Biotech Co. Ltd.

NCT05330455 / RecruitingPhase 2

Four-part, Randomized, Double-blind (Parts 1, 2A, 3 and 4), Multi-center, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK3965193 Monotherapy in Healthy Participants and in Participants Living With Chronic Hepatitis B Infection; and GSK3965193 in Combination With Bepirovirsen in Participants Living With Chronic Hepatitis B Infection

This Phase 1/2a multiple part study is a first time-in-human (FTIH) study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of single (Part 1) and repeat doses (Part 2) of GSK3965193 in healthy participants. Part 3 will evaluate the ability of GSK3965193 to lower hepatitis B virus surface antigen (HBsAg) in participants living with chronic hepatitis B infection (PLWCHB). Part 4 will evaluate the safety and tolerability of combination therapy with GSK3965193 and bepirovirsen and the potential to effect sustained virologic response in PLWCHB.

Start Date14 Apr 2022

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with PAPD7 x PAPD5

100 Translational Medicine associated with PAPD7 x PAPD5

0 Patents (Medical) associated with PAPD7 x PAPD5

Literatures (Medical) associated with PAPD7 x PAPD5

01 Apr 2024·Bioorganic & Medicinal Chemistry Letters

“PROTAC” modified dihydroquinolizinones (DHQs) that cause degradation of PAPD-5 and inhibition of hepatitis A virus and hepatitis B virus, in vitro

Article

Author: Block, Timothy ; Hwang, Nicky ; Lemon, Stanley M ; Clement, Jason A ; Zhou, Tianlun ; Noe, Daisy ; Sun, Liren ; Tang, Liudi ; Du, Yanming ; Li, You ; Snedeker, Andrew

Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit both hepatitis A (HAV) and hepatitis B virus (HBV) in vitro and in vivo. In this report, we describe RG7834-based proteolysis-targeting chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC₅₀ of 277 nM. Although the PROTAC DHQs were also inhibitory to HBV, their activities were substantially less potent against HBV in vitro, being in the 10 to 20 µM range, based on the reduction of HBsAg and HBV mRNA levels. Importantly, unlike RG7834, the incubation of cells in vitro with PROTAC DHQ 12b resulted in the degradation of PAPD5, as expected for a PROTAC compound, but curiously not PAPD7. PAPD5 polypeptide degradation was prevented when a proteasome inhibitor, epoxomicin, was used, indicating that proteasome mediated proteolysis was associated with the observed activities of 12b. Taken together, these data show that 12b is the first example of a PROTAC that suppresses both HAV and HBV that is based on a small molecule warhead. The possibility that it has mechanisms that differ from its parent compound, RG7834, and has clinical value, is discussed.

01 Aug 2023·European Journal of Medicinal Chemistry

Discovery, optimization and biological evaluation of novel HBsAg production inhibitors

Article

Author: Zhang, Yang ; Lu, Dandan ; Wang, Xiaojin ; Xu, Hongjiang ; Chen, Shuo ; Jin, Hui ; Zhang, Yinsheng ; Ao, Wangwei ; Zhang, Li ; Ge, Xingfeng

A series of tetrahydropyridine (THP) derivatives I [R¹ = 6-fluoro-4-(propan-2-yl)pyridin-2-yl, 4-[(cyclopropylmethyl)amino]-6-fluoropyridin-2-yl, 6-fluoro-4-(3-fluoroazetidin-1-yl)pyridin-2-yl, etc.] and II [X = CH ,N; R² = dimethylamino, 3-fluoroazetidin-1-yl, methoxy, etc.] with a bridged ring were synthesized and evaluated for their inhibiting HBsAg production and HBV DNA activity.Among them, compound I [R¹ = 6-fluoro-4-(3-fluoroazetidin-1-yl)pyridin-2-yl (II)] was identified as potent HBsAg production inhibitor with excellent in vitro anti-HBV potency (HBV DNA EC₅₀ = 0.018μM, HBsAg EC₅₀ = 0.044μM) and low toxicity (CC₅₀ > 100μM).Moreover, compound (II) exhibited favorable in vitro/in vivo DMPK properties in mice.Compound (II) could also significantly reduce serum HBsAg and HBV DNA levels (1.08 and 1.04 log units, resp.) in HBV transgenic mice.

01 Jun 2023·Regulatory Toxicology and Pharmacology

Unexpected neurotoxicity in chronic toxicity studies with a HBV viral expression inhibitor

Article

Author: Dinklo, Theo ; Xie, Jianxun ; Kustermann, Stefan ; Funk, Juergen ; Bopst, Martin ; Greiter-Wilke, Andrea ; Jiang, Tianyi ; Lenz, Barbara

The non-clinical safety profile of the small molecule hepatitis B virus viral expression inhibitor RG7834 was studied in a package consisting of safety pharmacology, genotoxicity, repeat dose toxicity and reproductive toxicity studies. The chronic monkey toxicity study identified dose- and time-dependent symptoms of polyneuropathy, with correlating nerve conduction velocity reductions and axonal degeneration in peripheral nerves and spinal cord, in all compound treatment groups with no evidence of reversibility after approximately 3 months of treatment cessation. Similar histopathological findings were observed in the chronic rat toxicity study. Subsequent in vitro neurotoxicity investigations and ion channel electrophysiology did not elucidate a potential mechanism for the late toxicity. However, based on similar findings observed with a structurally different molecule, an inhibition of their common pharmacological targets, PAPD5 & PAPD 7, was considered as a possible mechanism of toxicity. In conclusion, the marked neuropathies, only observed after chronic dosing, did not support further clinical development of RG7834 because of its foreseen clinical treatment duration of up to 48 weeks in chronic HBV patients.

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