Delving into the Latest Updates on RO7049389 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

CpAM

Target

Capsid

Mechanism

Capsid inhibitors(Capsid protein inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication

Hepatitis B, Chronic

Inactive Indication-

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization

F. Hoffmann-La Roche Ltd.

Roche Diagnostics (Shanghai) Co., Ltd.Hoffmann-La Roche, Inc.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (CN)

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AIMSRO7049389 (linvencorvir) is a developmental oral treatment for chronic hepatitis B virus infection. The aim of this work was to conduct mass balance (MB) and absolute bioavailability (BA) analyses in healthy volunteers, alongside in vitro evaluations of the metabolism of RO7049389 and a major circulating active metabolite M5 in human hepatocytes, and physiologically based pharmacokinetic (PBPK) modelling to refine the underlying drug disposition paradigm.METHODSParticipants in the clinical study (MB: Caucasian, male, n = 6; BA: Caucasian and Asian, male and female, n = 16, 8 in each ethnic groups) received oral [¹⁴ C] or unlabelled RO7049389 (600/1000 mg) followed by 100 μg intravenous [¹³ C]RO7049389. Metabolic pathways with fractions metabolized-obtained from the in vitro incubation results of 10 μM [¹⁴ C]RO7049389 and 1 μM M5 with (long-term cocultured) human hepatocytes in the absence and presence of the cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole-were used to complement the PBPK models, alongside the clinical MB and BA data.RESULTSThe model performance in predicting the pharmacokinetic profiles of RO7049389 and M5 aligned with clinical observations in Caucasians and was also successfully applied to Asians. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P-glycoprotein (~41%), direct glucuronidation via uridine 5'-diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%).CONCLUSIONThese results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development.

01 Jan 2022·Clinical and Translational ScienceQ3 · MEDICINE

Evaluation of the safety, tolerability, and pharmacokinetics of RO7049389 in healthy Chinese volunteers

Q3 · MEDICINE

ArticleOA

Author: Zhang, Jing ; Zhang, Wenhong ; Jin, Yuyan ; Feng, Sheng ; Zhao, Na ; Bo, Qingyan ; Zhu, Mingfen ; Wu, Xiaojie ; Triyatni, Miriam ; Zhang, Yuchen

AbstractThe objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first‐in‐human study (in which most of the HVs were non‐Asian). HVs randomly received a single dose of 200–600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200–400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well‐tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half‐life ranged from 3.66 to 14.6 h. A single dose of 200–600 mg and multiple doses of 200–400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non‐Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.

01 Sep 2021·The Lancet Gastroenterology & HepatologyQ1 · MEDICINE

Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial

Q1 · MEDICINE

Article

Author: Zhou, Xue ; Feng, Sheng ; Tanwandee, Tawesak ; Kazma, Remi ; Cosson, Valerie ; Schwabe, Christian ; Lemenuel-Diot, Annabelle ; Triyatni, Miriam ; Xue, Zenghui ; Jin, Yuyan ; Gane, Edward ; Yuen, Man-Fung ; Bo, Qingyan

BACKGROUNDRO7049389, a hepatitis B virus (HBV) core protein allosteric modulator being developed for the treatment of chronic HBV infection, was found to be safe and well tolerated in healthy participants (part 1 of this study). The objective of this proof-of-mechanism study (part 2) was to evaluate the safety, pharmacokinetics, and antiviral activity of RO7049389 in patients with chronic HBV infection.METHODSThis was a multicentre, randomised, placebo-controlled, phase 1 study. Patients with chronic HBV infection who were not currently on anti-HBV therapy were enrolled at 11 liver disease centres in Hong Kong, New Zealand, Singapore, Taiwan, and Thailand. Seven patients per dose cohort were randomly assigned (6:1) to receive oral administration of RO7049389 at 200 mg or 400 mg twice a day, or 200 mg, 600 mg, or 1000 mg once a day, for 4 weeks, or matching placebo. Randomisation was via interactive voice web response system-generated numbers, with study participants, investigators, and site personnel masked to treatment allocation. The primary endpoint of the study was safety of RO7049389 and its antiviral effect on HBV DNA concentration at the end of treatment, assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02952924.FINDINGSBetween May 21, 2017, and April 3, 2019, 62 patients were screened for eligibility, and 37 eligible patients were enrolled in five dose cohorts sequentially. All adverse events were of mild or moderate intensity. Among the 31 patients who received RO7049389, the most common adverse events were headache (in five [16%] of 31 patients), increased alanine aminotransferase (ALT; five [16%]), increased aspartate aminotransferase (AST; four [13%]), upper respiratory tract infection (four [13%]), and diarrhoea (three [10%]). The most common moderate adverse events were ALT increase (three [10%]) and AST increase (two [6%]), and there were no serious adverse events. At the end of 4 weeks treatment, mean HBV DNA declines from baseline in RO7049389-treated patients were 2·44 log₁₀ IU/mL (SD 0·98) in the 200 mg twice a day group, 3·33 log₁₀ IU/mL (1·14) in the 400 mg twice a day group, 3·00 log₁₀ IU/mL (0·54) in the 200 mg once a day group, 2·86 log₁₀ IU/mL (0·79) in the 600 mg once a day group, and 3·19 log₁₀ IU/mL (0·33) in the 1000 mg once a day group versus 0·34 log₁₀ IU/mL (0·54) in the pooled placebo patients.INTERPRETATIONRO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks of treatment in patients with chronic HBV infection. These findings support further clinical development of RO7049389 as a component of novel combination treatment regimens for patients with chronic HBV infection.FUNDINGF Hoffmann-La Roche.

100 Deals associated with RO7049389

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B, Chronic	Phase 2	CN	Roche Diagnostics (Shanghai) Co., Ltd.	13 Apr 2020
Hepatitis B	Discovery	CN	Hoffmann-La Roche, Inc.	24 Aug 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04729309 (CTgov)	Phase 1	-	22	[13C] RO7049389 (Mass Balance (MB) Cohort)	emgzvktyjn(idyrgytqsd) = pakmhmdput tzdoifmhne (xihfzbfskm, wfgxgqcfbm - dbtabmnasq) View more	-	15 Jul 2024
				[13C] RO7049389 (Absolute Bioavailability (BA) Cohort)	fxsfdekhld(chqdzyjeae) = rqtxuimlqi yisydklztr (ysfjkilqqg, affudwdqyi - dvchotovdd) View more
NCT02952924 (EASL2022)	Phase 1	Hepatitis B, Chronic	-	RO7049389+NUC	xqfzggxmnt(rjudvesfno) = ALT elevations resolved spontaneously and were not accompanied by significant changes in liver function btjvvycnce (obnyysfgtp ) View more	-	25 Jun 2022
				RO7049389+NUC+Peg-IFN-alpha
NCT03717064 (CTgov)	Phase 1	-	18	RO7049389+Pitavastatin	ogmtvalioy(fvtjebpemy) = cxincqzduv fqhlmtzymq (dxtzhqiczs, uvhtwcxvrj - ldketztpus) View more	-	10 Jan 2020
Phase I study (EASL2019)	Phase 1	Hepatitis B	-	RO7049389 200mg BID	taazhxxfdk(ikzvpgcysg) = A total of 39 adverse events (AEs) were reported in 14 of 22 HBV patients, 3 patients had treatment emergent Grade 3 ALT/AST increase which resolved without treatment in follow-up. One pre- dose SAE was reported and the patient was replaced. No AEs leading to drug discontinuation were reported and no clinically significant changes in any safety parameters tested were observed. sclxnibksa (wkkezchbau )	Positive	12 Apr 2019
				RO7049389 400mg BID