作者: Nakashima, Kenji ; Narumi, Tetsuo ; Suzuki, Tetsuro ; Mase, Nobuyuki ; Kawahara, Kazutoshi ; Takeo, Sayuri ; Yokoyama, Masaru ; Fujimoto, Junko ; Takeda, Kazuma ; Sato, Kohei

In this study, we have identified two novel peptides, 19Ac (comprising residues 91-105) and 20Ac (encompassing residues 96-110), from a systematically designed peptide library based on the Hepatitis B virus (HBV) core protein, that inhibit the assembly of HBV capsid. Peptide 20Ac exhibited about twofold the inhibitory potency of 19Ac and proved effective against both standard and morphothiadin (GLS4)-resistant HBV strains. Molecular dynamics simulations revealed that despite their overlapping sequence, 19Ac and 20Ac bonded to different regions of the core protein, thereby inhibiting capsid assembly through distinct mechanisms. These peptides could serve as valuable seed compounds for the further development of HBV capsid inhibitors, including GLS4-resistant strains.

2022-05-12·NEW ENGLAND JOURNAL OF MEDICINE

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection

Article

作者: Berhe, Mezgebe ; Molina, Jean-Michel ; DeJesus, Edwin ; Wang, Hui ; Siripassorn, Krittaecho ; Segal-Maurer, Sorana ; Rhee, Martin S ; Brainard, Diana M ; Baeten, Jared M ; Hyland, Robert H ; Stellbrink, Hans-Jurgen ; Castagna, Antonella ; Ruane, Peter J ; Dvory-Sobol, Hadas ; Sinclair, Gary I ; Richmond, Gary J ; Margot, Nicolas A

BACKGROUND:

Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study.

METHODS:

In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log₁₀ copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26.

RESULTS:

A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log₁₀ copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions).

CONCLUSIONS:

In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Viruses-Basel

Efficacy of Integrase Strand Transfer Inhibitors and the Capsid Inhibitor Lenacapavir against HIV-2, and Exploring the Effect of Raltegravir on the Activity of SARS-CoV-2

Article

作者: Hoffka, Gyula ; Leyssen, Pieter ; Mahdi, Mohamed ; Neyts, Johan ; Kiarie, Irene Wanjiru ; Tőzsér, József ; Laporte, Manon

Retroviruses perpetuate their survival by incorporating a copy of their genome into the host cell, a critical step catalyzed by the virally encoded integrase. The viral capsid plays an important role during the viral life cycle, including nuclear importation in the case of lentiviruses and integration targeting events; hence, targeting the integrase and the viral capsid is a favorable therapeutic strategy. While integrase strand transfer inhibitors (INSTIs) are recommended as first-line regimens given their high efficacy and tolerability, lenacapavir is the first capsid inhibitor and the newest addition to the HIV treatment arsenal. These inhibitors are however designed for treatment of HIV-1 infection, and their efficacy against HIV-2 remains widely understudied and inconclusive, supported only by a few limited phenotypic susceptibility studies. We therefore carried out inhibition profiling of a panel of second-generation INSTIs and lenacapavir against HIV-2 in cell culture, utilizing pseudovirion inhibition profiling assays. Our results show that the tested INSTIs and lenacapavir exerted excellent efficacy against ROD-based HIV-2 integrase. We further evaluated the efficacy of raltegravir and other INSTIs against different variants of SARS-CoV-2; however, contrary to previous in silico findings, the inhibitors did not demonstrate significant antiviral activity.

项与 HBV capsid inhibitor (Bluejay Therapeutics) 相关的新闻（医药）

2023-10-20

·BioSpace

Zhimeng Biopharma CB03 Received Orphan Drug Designation from the US FDA - A Potassium Ion Channel Opener for Amyotrophic Lateral Sclerosis

SHANGHAI, Oct. 20, 2023 /PRNewswire/ -- Shanghai Zhimeng Biopharma Inc. ("Zhimeng"), announced that one of its innovative small-molecule KCNQ2/3 selective opener compounds (CB03), developed for the treatment of amyotrophic lateral sclerosis (ALS), received orphan drug designation (ODD) from US FDA. CB03 is also being developed for other central nervous diseases, such as refractory epilepsy, major depressive disorders (MDD), etc. CB03 is a candidate drug for the treatment of ALS and other central nerve system (CNS) diseases independently developed by Zhimeng. A phase 1 study for the evaluation of the safety, tolerability, and pharmacokinetics of CB03 in healthy subjects is currently ongoing in Australia and US. The phase 1 study is expected to complete the dosing phase (both single dose and multiple dose) before the end of 2023. "The orphan drug designation by US FDA for CB03 is an important milestone in its global clinical development for ALS and other central nervous system diseases," said Dr. Huanming Chen, President and CEO of Zhimeng. "Since ALS is a very serious disease without adequate treatment options, we hope our dedicated efforts will allow us to bring a safer and more effective medicine to ALS patients worldwide as the first indication for CB03." About CB03 Studies on neurons indicate that the hyperexcitability of neurons is the one of the important underlying causes associated with neurodegenerative and neuropsychic CNS diseases, including ALS, epilepsy, MDD, neuropathic pain, among others. As the most widely distributed and the most diverse group of ion channels, potassium (K+) channels are mainly involved in the modulation of neuronal excitability and the frequency and amplitude of action potential discharges. CB03 as a KCNQ2/3 potassium ion channel opener thus has its potential for become a safe and effective treatment option for ALS and other CNS diseases. As a new generation of selective KCNQ2/3 potassium channel opener, CB03 showed better chemical and metabolic stability, higher biological/pharmacological activities in in vitro and ALS animal disease models, and more druggable pharmacokinetic properties. Thus, CB03 is unlikely to present the same safety concerns as other channel openers and warrant further clinical development to demonstrate potential benefits in the ALS patient population. About Amyotrophic lateral sclerosis (ALS) ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord. ALS causes loss of muscle control and the disease gets worse over time. The exact causes of ALS are still not known, but neuron hyperexcitability causing neuron damage may play an important role in disease initiation and progression. A small number (about 10%) of ALS cases are inherited. ALS often begins with muscle twitching and weakness in an arm or leg, trouble swallowing or slurred speech. Eventually ALS affects control of the muscles needed to move, speak, eat, and breathe. A large percentage of ALS patients may only survive for 3-5 years after diagnosis of the disease. There are a few drugs approved for treating the symptoms of ALS or slowing down the disease progression, but currently no cure for this fatal disease. About Zhimeng Zhimeng is a clinical-stage biopharmaceutical company committed to developing innovative drugs for the treatment of chronic hepatitis B (CHB) and severe neurological diseases with significant unmet medical needs. The company has recently announced the successful completion of the phase Ib clinical trial on its novel HBV capsid inhibitor, Canocapavir (ZM-H1505R), and has started the phase II study in June 2022. In addition, the clinical trial application of the company's TLR8 agonist (CB06) was approved by the FDA in December 2021, and the phase I study was launched in the United States in March 2022. Disclaimer This press release contains forward-looking statements. While Zhimeng considers the projections to be based on reasonable assumptions, these forward-looking statements may be called into question by a number of hazards and uncertainties, so that actual results may differ materially from those anticipated in such forward-looking statements. For more information, please visit: com

临床1期临床2期孤儿药

2022-06-14

·PRNewswire

Zhimeng Biopharma will report positive phase 1b trial results on its HBV capsid inhibitor ZM-H1505R in the upcoming International Liver Congress

SHANGHAI, June 14, 2022 /PRNewswire/ -- Shanghai Zhimeng Biopharma announces that it will report the positive results obtained from a phase 1b study on its HBV capsid inhibitor ZM-H1505R in the International Liver Congress in June 22-26, 2022 (the EASL meeting). The recently completed phase 1b study was to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antiviral activity of ZM-H1505R in a double-blind, randomized, placebo-controlled, dose escalating study in treatment-naïve chronic hepatitis B (CHB) patients. Patients were divided into three cohorts (10 patients each) and randomized within each cohort in a ratio of 4:1 to receive an ascending dose of 50, 100, or 200 mg of ZM-H1505R, or placebo once a day for 28 consecutive days. ZM-H1505R was safe and well tolerated within this dose range, with most AEs being mild to moderate in severity. No SAE was observed and there was no withdrawal due to AE. A proportional relationship was observed between dose and plasma exposure of ZM-H1505R. At day 28, the mean plasma Cmin were 2.73, 7.05, and 14.56 folds of its protein-binding adjusted HBV DNA EC50 for 50, 100, and 200 mg doses, respectively. Serum levels of HBV DNA and HBV pgRNA were significantly reduced from baselines after 28 days of treatment with ZM-H1505R. The mean maximal reductions from baselines in HBV DNA were -1.54, -2.50 and -2.75 log10 IU/mL, and in HBV pgRNA were -1.53, -2.35 and -2.34 log10 IU/mL in the 50, 100 and 200 mg cohorts, respectively. The mean maximal declines from baseline in HBcrAg were -0.61 and -0.51 log10 IU/mL in the 100 and 200 mg cohorts, respectively. "We are pleased to see the positive safety and preliminary efficacy results of ZM-H1505R from this phase 1b study." Commented Dr. Huanming Chen, CEO of Zhimeng Biopharma. "We believe that HBV capsid inhibitors such as ZM-H1505R will play an important role in further reducing the viruses in patients who have been treated with a NA for a long time but still have low levels of viremia. We are also confident that ZM-H1505R may become a component of a combination therapy for functional cure of CHB. With such promising results of ZM-H1505R, we will initiate a phase 2 trial in Q3 of 2022 to further evaluate its safety and efficacy". About ZM-H1505R ZM-H1505R is a small-molecule HBV capsid assembly modulator with a novel pyrazole structure currently being evaluated for the treatment of chronic hepatitis B (CHB). It is active against most HBV variants that show resistance to other HBV capsid modulators. About Zhimeng Biopharma Zhimeng Biopharma is a clinical-stage biopharmaceutical company committed to developing innovative drugs for the treatment of chronic hepatitis B (CHB) and severe neurological diseases with significant unmet medical needs. The company has recently announced the launch of the first-in-human phase I study of its novel TLR8 agonist, developed for CHB, in the US in March 2022; and the first-in-human phase I study of its novel small molecule, KCNQ2/3 selective opener, developed for the treatment of refractory epilepsy, in the US in May 2022. For more information, please visit: SOURCE Shanghai Zhimeng Biopharma, Inc.

合作抗体创新药小分子药物

2022-04-02

·core-biopharma

Zhimeng Biopharma Announces Dosing of First Subject in First-in-Human Phase I Clinical Trial of CB06

Shanghai, China. March 31, 2022. Shanghai Zhimeng Biopharma, Inc. (“Zhimeng”), an innovation-driven biopharmaceutical company focused on the development of innovative drugs for the treatment of chronic hepatitis B and central nervous system diseases, announced dosing of the first participant in the US Phase I study of its novel TLR8 agonist (CB06), which is being developed for the treatment of chronic hepatitis B virus infection. The Phase I clinical trial, a randomized, double-blind and placebo-controlled study, is to evaluate the safety, pharmacokinetics and pharmacodynamics of single escalating doses of CB06 in healthy adult subjects. “We are pleased to have received FDA approval for the clinical trial and are now moving forward with the first human dosing of CB06, which is a testament to our capabilities in global clinical development.” Said Dr. Huanming Chen, President and Chief Executive Officer of Zhimeng, “Zhimeng plans to submit a clinical trial application to the National Medical Products Administration (NMPA) following the U.S. Phase I clinical trial to fast-track the clinical study of CB06 in chronic hepatitis B patients in China, fulfilling the urgent clinical need to achieve a cure for chronic hepatitis B.” About CB06 CB06 is a small molecule, oral TLR8 agonist independently developed by Zhimeng, and it is the second candidate with exclusive intellectual property that successfully enters the clinical development stage, within Zhimeng’s innovative pipelines. Activating Toll-like receptor 8 (TLR8) triggers innate and adaptive immune responses via recognizing pathogen-derived single-stranded RNA fragments. Since chronic hepatitis B is associated with a dysfunctional immune response, a selective TLR8 agonist may be an effective treatment option. Preclinical studies have shown that CB06 can induce cytokines in human peripheral blood mononuclear cells, which will activate antiviral effector functions by multiple immune mediators. Preclinical studies also show that CB06 has a good liver targeting activity. About Chronic Hepatitis B About 250 million people worldwide are infected with chronic hepatitis B virus (HBV), and about 650,000 people die each year from HBV-related liver failure, cirrhosis, and hepatocellular carcinoma. In China, about 90 million people are infected with chronic HBV, among them about 30 million have developed chronic hepatitis B and need treatment. The underlying pathogenic mechanism of HBV is complex, and current therapeutic drugs (including nucleoside/nucleotide analogs and immunomodulators) have apparent limitations and are inadequate to address the clinical needs for HBV therapeutics. About Zhimeng Biopharma Zhimeng Biopharma is a clinical-stage biopharmaceutical company committed to developing innovative drugs to treat chronic hepatitis B virus infection and neurological diseases. Zhimeng has recently announced the successful completion of the Phase Ib clinical trial of its novel HBV capsid inhibitor, Canocapavir (ZM-H1505R), with an upcoming Phase II study to begin shortly. In addition, the company has successfully filed IND application in US for its KCNQ2/3 potassium channel opener for the treatment of epilepsy in December 2021, and the clinical phase I study will be launched soon in the US. Disclaimer This press release contains forward-looking statements. While Zhimeng considers the projections to be based on reasonable assumptions, these forward-looking statements may be called into question by a number of hazards and uncertainties, so that actual results may differ materially from those anticipated in such forward-looking statements.

临床2期临床1期临床申请

100 项与 HBV capsid inhibitor (Bluejay Therapeutics) 相关的药物交易

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