[Translation] A Phase II, randomized, adaptive, open-label platform trial evaluating the efficacy and safety of multiple combination therapies in subjects with chronic hepatitis B

目的是评估新分子化合物联合治疗在具有肝储备功能且无显著肝纤维化/肝硬化的慢性乙型肝炎受试者中的安全性、耐受性和疗效。

[Translation]

The aim was to evaluate the safety, tolerability and efficacy of combination therapy with new molecular compounds in chronic hepatitis B subjects with hepatic reserve and without significant hepatic fibrosis/cirrhosis.

Start Date10 Jun 2021

Sponsor / Collaborator

F. Hoffmann-La Roche Ltd.

[+1]

CTR20201678

/ CompletedPhase 2

一项在慢性乙型肝炎受试者中评价多种联合治疗的有效性和安全性的II 期、随机、适应性、开放标签平台试验

[Translation] A Phase II, randomized, adaptive, open-label platform trial evaluating the efficacy and safety of multiple combination therapies in subjects with chronic hepatitis B

目的是评估新分子化合物联合治疗在具有肝储备功能且无显著肝纤维化/肝硬化的慢性乙型肝炎受试者中的安全性、耐受性和疗效。

[Translation]

Start Date28 Sep 2020

Sponsor / Collaborator

Roche R & D Center China Co. Ltd.

NCT04225715

/ CompletedPhase 2

A Phase II, Randomised, Adaptive, Open-Label Platform Trial To Evaluate Efficacy And Safety Of Multiple Combination Therapies In Participants With Chronic Hepatitis B

This is a study designed to evaluate the safety, tolerability and efficacy of New Molecular Entity (NME) combination therapies in Chronic Hepatitis B (CHB) participants with preserved liver function and without significant fibrosis/cirrhosis. The platform design allows comparison of multiple NME combination therapies against a common control, and introduction of additional treatment arms at later study time points. Each arm will consist of a screening phase (up to 8 weeks), treatment phase (up to 48 weeks) and post-treatment follow-up phase (48 weeks). The safety and efficacy will be monitored throughout the study.

Start Date05 Jul 2020

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with Ruzotolimod

100 Translational Medicine associated with Ruzotolimod

100 Patents (Medical) associated with Ruzotolimod

Literatures (Medical) associated with Ruzotolimod

05 Dec 2024·NEW ENGLAND JOURNAL OF MEDICINE

Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B

Article

Author: Patil, Avinash ; Xie, Qing ; Peng, Cheng-Yuan ; Kim, Dong Joon ; Triyatni, Miriam ; Asselah, Tarik ; Surujbally, Bernadette ; Chen, Ethan ; Yang, Sheng-Shun ; Leerapun, Apinya ; Glavini, Katerina ; Zhang, Wenhong ; Cheng, Cong ; Kazma, Rémi ; Yuen, Man-Fung ; Hou, Jinlin ; Chuang, Wan-Long ; Kakrana, Priyanka ; Das, Sudip ; Gane, Edward ; Upmanyu, Ruchi ; Kao, Jia-Horng ; Avihingsanon, Anchalee ; Wat, Cynthia ; Tang, Hong ; Bo, Qingyan ; Hua, Rui ; Chughlay, Farouk ; Su, Wei-Wen ; Liang, Xieer ; Catanese, Maria Teresa ; Pavlovic, Vedran ; Morano Amado, Luis Enrique ; Huang, Yan ; Guerreiro, Nelson ; Canducci, Filippo

BACKGROUND:

Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection.

METHODS:

We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed.

RESULTS:

Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level.

CONCLUSIONS:

Among participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon. (Funded by F. Hoffmann-La Roche; Piranga ClinicalTrials.gov number, NCT04225715.).

01 Aug 2024·CTS-Clinical and Translational Science

Using exploratory pharmacokinetic and pharmacodynamic analyses to predict the probability of flu‐like symptoms in healthy volunteers and patients with chronic hepatitis B treated with the toll‐like receptor 7 agonist ruzotolimod

Article

Author: Jin, Yuyan ; Zhu, Yonghong ; Triyatni, Miriam ; Jiang, Qiudi ; Duan, Dan ; Upmanyu, Ruchi ; Grippo, Joseph F. ; Zhang, Yuchen ; Retout, Sylvie ; Glavini, Katerina

Abstract:

Ruzotolimod (Toll‐like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno‐modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug‐related adverse events of flu‐like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu‐like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC‐suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu‐like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu‐like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN‐α, neopterin, IP‐10, and the transcriptional expression of ISG15, OAS‐1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu‐like symptoms occurrence increases with PD responses (IFN‐α and IP‐10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug‐related flu‐like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu‐like symptoms.

01 Apr 2023·The Lancet. Infectious diseases

TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial

Article

Author: Upmanyu, Ruchi ; Balabanska, Rozalina ; Cottreel, Emmanuelle ; Triyatni, Miriam ; Zhu, Yonghong ; Canducci, Filippo ; Yuen, Man-Fung ; Chen, Ethan ; Duan, Dan ; Patil, Avinash ; Gane, Edward J ; Jiang, Qiudi

BACKGROUND:

Toll-like receptor 7 (TLR7) agonists augment immune activity and have potential for the treatment of chronic hepatitis B virus (HBV) infection. We aimed to assess the safety and tolerability of RO7020531 (also called RG7854), a prodrug of the TLR7 agonist RO7011785, in healthy volunteers and patients with chronic HBV infection.

METHODS:

This randomised, observer-blind, placebo-controlled, phase 1 study was done in two parts. Part 1 was done at one site in New Zealand and part 2 was done at 12 sites in Bulgaria, Hong Kong, Italy, New Zealand, the Netherlands, Taiwan, Thailand, and the UK. In part 1, healthy volunteers were randomly assigned (4:1) within one of eight dose cohorts (3 mg, 10 mg, 20 mg, 40 mg, 60 mg, 100 mg, 140 mg, or 170 mg) to receive a single RO7020531 dose or placebo or randomly assigned (4:1) within one of three dose cohorts (100 mg, 140 mg, or 170 mg) to receive either RO7020531 or placebo every other day for 13 days. In part 2, nucleoside or nucleotide analogue-suppressed patients with chronic HBV infection were randomly assigned (4:1) within cohorts 1-3 (150 mg, 150 mg, or 170 mg) to receive either RO7020531 or placebo and treatment-naive patients with chronic HBV infection were randomly assigned (3:1) in cohort 4 to receive either 150 mg of RO7020531 or placebo. Patients were treated every other day for 6 weeks. Study medication was administered orally to participants after they had fasted. Study participants and investigational staff were masked to treatment allocation. The primary outcome was the safety and tolerability of RO7020531, as measured by the incidence and severity of adverse events and the incidence of laboratory, vital sign, and electrocardiogram abnormalities, and was analysed in all participants who received at least one dose of the study medication. This trial is registered with ClinicalTrials.gov, NCT02956850, and the study is complete.

FINDINGS:

Between Dec 12, 2016, and March 21, 2021, 340 healthy volunteers were screened in part 1, of whom 80 were randomly assigned in the single ascending dose study (eight assigned RO7020531 in each cohort and 16 assigned placebo) and 30 were randomly assigned in the multiple ascending dose study (eight assigned RO7020531 in each cohort and six assigned placebo), and 110 patients were screened in part 2, of whom 30 were randomly assigned in cohorts 1-3 (16 assigned RO7020531 150 mg, eight assigned RO7020531 170 mg, and six assigned placebo) and 20 were randomly assigned in cohort 4 (15 assigned RO7020531 and five assigned placebo). All randomly assigned participants received at least one dose of a study drug and were included in the safety analysis. All tested doses of RO7020531 were safe and had acceptable tolerability in healthy volunteers and patients. The most frequent treatment-related adverse events among the total study population were headache (15 [9%] of 160 participants), influenza-like illness (seven [4%] of 160 participants), and pyrexia (ten [6%] of 160 participants). Most adverse events were mild and transient. There were no severe or serious adverse events in healthy volunteers. In the patient cohorts, there was one severe adverse event (influenza-like illness with 170 mg of RO7020531) and one serious adverse event (moderate influenza-like illness with a 3-day hospitalisation in a treatment-naive patient receiving RO7020531). There were no treatment-related deaths.

INTERPRETATION:

Due to acceptable safety and tolerability, RO7020531 should continue to be developed for the treatment of patients with chronic HBV infection.

FUNDING:

F Hoffmann-La Roche.

News (Medical) associated with Ruzotolimod

13 Dec 2024

·www.drugs.com

Combo Treatment With Xalnesiran Shows Promise in Patients With Hep B

FRIDAY, Dec. 13, 2024 -- For patients with chronic hepatitis B virus (HBV) infection with virologic suppression with nucleoside or nucleotide analog (NA) therapy, xalnesiran plus an immunomodulator results in a substantial percentage of patients with hepatitis B surface antigen (HBsAg) loss, according to a study published in the Dec. 5 issue of the New England Journal of Medicine . Jinlin Hou, M.D., from Nanfang Hospital in Guangzhou, China, and colleagues conducted a phase 2 multicenter, randomized, controlled trial involving adult patients with chronic HBV infection with virologic suppression with NA therapy to examine 48 weeks of treatment with xalnesiran 100 mg (group 1; 30 patients), xalnesiran 200 mg (group 2; 30 patients), xalnesiran 200 mg + ruzotolimod (group 3; 34 patients), xalnesiran 200 mg + pegylated interferon alfa-2a 180 µg (group 4; 30 patients), or NA alone (group 5; 35 patients). The primary efficacy end point was HBsAg loss at 24 weeks after the end of treatment. The researchers found that a primary end point event occurred in 7, 3, 12, 23, and 0 percent of patients in groups 1, 2, 3, 4, and 5, respectively. At 24 weeks after the end of treatment, HBsAg seroconversion occurred in 3, 0, 3, 20, and 0 percent of participants, respectively. Only participants with a screening HBsAg level below 1,000 IU/mL had HBsAg loss with or without seroconversion. "Despite the high percentages of participants with HBsAg loss that were observed in the immunomodulatory-therapy groups at the end of treatment, erosion of this response was observed during the follow-up period," the authors write. The study was funded by F. Hoffmann-La Roche, which is developing xalnesiran.

Phase 2Clinical ResultsiRNA

18 Oct 2022

·www.biospace.com

Roche Scraps Mid-Phase Programs in Hepatitis B, Geographic Atrophy

Courtesy Smith Collection/Gado/Getty Images As part of its third-quarter report, Roche announced it has cut two Phase II programs, one for hepatitis B and the other for geographic atrophy, a form of eye disease. Courtesy of Smith Collection/Gado/Getty Images In its third-quarter report Tuesday, Roche announced it has cut two Phase II programs, one for hepatitis B and the other for geographic atrophy, a form of eye disease. RG7907 is a core protein allosteric modulator that was developed for hepatitis B. Early data suggested the drug disrupted hepatitis B viral replication, and a Phase I trial in 2019 led the company to believe it could be part of a combination of drugs that could cure the disease. A Phase I trial was completed in July, and a Phase II trial of the drug in combination with other therapies was ongoing as of August. Roche Diagnostics has several assays to detect hepatitis B and several pipeline drugs, including RG6084, RG6346 and RG7854. RG6147 (galegenimab), an anti-HTRA1 anti-binding fragment, was being developed for geographic atrophy. The Phase II trial launched in June 2019 and as of September, its status was “active, not recruiting.” Roche also has a very active program for ophthalmological conditions, including macular degeneration and geographic atrophy. In a statement, CEO Severin Schwan specifically cited Vabysmo. The drug is the first and only FDA-approved treatment that blocks both VEGF and Ang-2 in wet age-related macular degeneration and diabetic macular edema. It was approved in Europe in the third quarter of this year. Roche’s subsidiary Chugai Pharmaceutical removed a Phase II program of a CHU Oncolytic Type 5 adenovirus for esophageal cancer. These types of viruses are designed to selectively grow in tumor cells, killing them while minimizing disruptions to normal cells. Other Business Updates Roche reported 2% sales growth, despite what Schwan in a press conference called “the expected sharp decline in COVID-19-related products in both divisions in the third quarter. “The demand for our newer medicines for multiple sclerosis, hemophilia, spinal muscular atrophy and cancer remains high,” he said. COVID-19 drug sales dropped by $1 billion (U.S.) in the first nine months of the year. Those included Ronapreve, an antibody treatment, and Actemra, originally developed for arthritis. Roche Diagnostics also reported a 40% decrease in COVID-19-related tests year on year to $604,000. “In spite of increasing incidence rates for COVID-19, we actually don’t see an increase in the demand for COVID-19-related products. It has nothing to do with inventories … there is simply much smaller demand than we have seen in the previous year,” Schwan said. Clinical trial data for Roche’s Alzheimer’s drug gantenerumab is expected to be published by the end of November, the company noted. Since the announcement of positive Phase III data from Eisai and Biogen’s lecanemab for Alzheimer’s disease in late September, analysts and investors have been turning their focus to gantenerumab in a suddenly hopeful market. If anything, Schwan worked to keep expectations low, saying, “It is very dangerous to cross-read on trials. We have to wait for the readout, and then we can take it from there.” Jefferies analysts were pessimistic, writing in a note to investors that they expect the study to fail.

Phase 2Drug ApprovalPhase 3Clinical ResultPhase 1

18 Oct 2022

·www.biospace.com

Roche Scraps Mid-Phase Programs in Hepatitis B, Geographic Atrophy

Courtesy of Smith Collection/Gado/Getty Images In its third-quarter report Tuesday, Roche announced it has cut two Phase II programs, one for hepatitis B and the other for geographic atrophy, a form of eye disease. RG7907 is a core protein allosteric modulator that was developed for hepatitis B. Early data suggested the drug disrupted hepatitis B viral replication, and a Phase I trial in 2019 led the company to believe it could be part of a combination of drugs that could cure the disease. A Phase I trial was completed in July, and a Phase II trial of the drug in combination with other therapies was ongoing as of August. Roche Diagnostics has several assays to detect hepatitis B and several pipeline drugs, including RG6084, RG6346 and RG7854. RG6147 (galegenimab), an anti-HTRA1 anti-binding fragment, was being developed for geographic atrophy. The Phase II trial launched in June 2019 and as of September, its status was “active, not recruiting.” Roche also has a very active program for ophthalmological conditions, including macular degeneration and geographic atrophy. In a statement, CEO Severin Schwan specifically cited Vabysmo. The drug is the first and only FDA-approved treatment that blocks both VEGF and Ang-2 in wet age-related macular degeneration and diabetic macular edema. It was approved in Europe in the third quarter of this year. Roche's subsidiary Chugai Pharmaceutical removed a Phase II program of a CHU Oncolytic Type 5 adenovirus for esophageal cancer. These types of viruses are designed to selectively grow in tumor cells, killing them while minimizing disruptions to normal cells. Other Business Updates Roche reported 2% sales growth, despite what Schwan in a press conference called “the expected sharp decline in COVID-19-related products in both divisions in the third quarter. "The demand for our newer medicines for multiple sclerosis, hemophilia, spinal muscular atrophy and cancer remains high," he said. COVID-19 drug sales dropped by $1 billion (U.S.) in the first nine months of the year. Those included Ronapreve, an antibody treatment, and Actemra, originally developed for arthritis. Roche Diagnostics also reported a 40% decrease in COVID-19-related tests year on year to $604,000. “In spite of increasing incidence rates for COVID-19, we actually don’t see an increase in the demand for COVID-19-related products. It has nothing to do with inventories … there is simply much smaller demand than we have seen in the previous year," Schwan said. Clinical trial data for Roche's Alzheimer’s drug gantenerumab is expected to be published by the end of November, the company noted. Since the announcement of positive Phase III data from Eisai and Biogen’s lecanemab for Alzheimer’s disease in late September, analysts and investors have been turning their focus to gantenerumab in a suddenly hopeful market. If anything, Schwan worked to keep expectations low, saying, “It is very dangerous to cross-read on trials. We have to wait for the readout, and then we can take it from there.” Jefferies analysts were pessimistic, writing in a note to investors that they expect the study to fail.

Antibody

100 Deals associated with Ruzotolimod

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B, Chronic	Phase 2	United States	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	China	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	Bulgaria	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	Canada	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	Chile	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	France	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	Hong Kong	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	New Zealand	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	Romania	Hoffmann-La Roche, Inc.	05 Jul 2020
Hepatitis B, Chronic	Phase 2	South Korea	Hoffmann-La Roche, Inc.	05 Jul 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03530917 (CTgov)	Phase 1	-	70	Placebo (Single Ascending Dose (SAD): Placebo)	bkbeljsorj = zdylrlzwte ryauekxdbk (imtbsytfha, qsqqhbnpem - oarhvrgjag) View more	-	13 Jul 2020
				RO7020531 (SAD: Cohort 1)	bkbeljsorj = lhhxdsslvr ryauekxdbk (imtbsytfha, qvnydqriom - zdgpgjrcgq) View more

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