Levovir (clevudine) / Bukwang Pharma, Eisai - LARVOL DELTA

DFT/TDDFT calculations of geometry optimization, electronic structure and spectral properties of clevudine and telbivudine for treatment of chronic hepatitis B. (PubMed, Sci Rep) - "Calculations for this study were carried out using the Gaussian 09 program package coupled with the DFT/TDDFT technique. The hybrid B3LYP functional method and the 6-311++G(d, p) basis set were used for the calculations."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

PET/CT in Evaluating Response to Chemotherapy in Patients With Breast Cancer (clinicaltrials.gov) - P=N/A | N=12 | Terminated | Sponsor: University of Southern California | N=25 ➔ 12 | Trial completion date: Nov 2024 ➔ Nov 2022 | Recruiting ➔ Terminated | Trial primary completion date: Nov 2023 ➔ Nov 2022; Insufficient accrual

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens. (PubMed, Antivir Chem Chemother) - "Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection."

Journal • Review • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Myositis

Protecting-group-free synthesis of clevudine (L-FMAU), a treatment of the hepatitis B virus. (PubMed, Org Biomol Chem) - "Starting from 2-deoxy-2-fluoro-D-galactopyranose, we developed the shortest and highest yield synthesis of this unnatural L-nucleoside. Key steps involve an iodine-promoted cyclization and oxidative cleavage to access the L-arabinofuranosyl scaffold."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

A Randomized Phase 1b Trial of the Active Site Polymerase Inhibitor Nucleotide ATI-2173 in Patients With Chronic Hepatitis B Virus Infection. (PubMed, J Viral Hepat) - P1 | "In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies."

Clinical • Journal • P1 data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Pain

PET/CT in Evaluating Response to Chemotherapy in Patients With Breast Cancer (clinicaltrials.gov) - P=N/A | N=25 | Recruiting | Sponsor: University of Southern California | Trial completion date: Nov 2022 ➔ Nov 2024 | Trial primary completion date: Nov 2021 ➔ Nov 2023 | Suspended ➔ Recruiting

Enrollment open • Preclinical • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

The Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Moderate COVID-19 (clinicaltrials.gov) - P2 | N=64 | Completed | Sponsor: Bukwang Pharmaceutical | Recruiting ➔ Completed

Trial completion • Infectious Disease • Novel Coronavirus Disease

The Proof of Concept Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Mild and Moderate COVID-19 (clinicaltrials.gov) - P2 | N=104 | Completed | Sponsor: Bukwang Pharmaceutical | Recruiting ➔ Completed | N=80 ➔ 104

Enrollment change • Trial completion • Infectious Disease • Novel Coronavirus Disease • CRP

Sustained 12 week off treatment antiviral efficacy of ATI-2173, a novel active site polymerase inhibitor nucleotide, combined with tenofovir disoproxil fumarate in chronic hepatitis B patients, a phase 2a clinical trial (EASL-ILC 2022) - P2a | "Background and aims: ATI-2173 is a novel phosphoramidate livertargeted prodrug of clevudine that functions as an active site polymerase inhibitor nucleotide (ASPIN). Similar on- and off-treatment HBV DNA antiviral activity was observed between 25 mg and 50 mg cohorts of ATI-2173 + TDF. In the off-treatment period, ATI-2173 + TDF provided prolonged HBV DNA suppression, longer time to rebound, and absence of ALT flares compared toTDFalone. 24-week off-treatment data will be presented at the conference."

Clinical • P2a data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Non-alcoholic Fatty Liver Disease

R&D Milestone: HebaBiz Biotech's application for phase III clinical trial in China for Clevudine (L-FMAU), an anti-hepatitis B virus drug candidate under development has been approved (PRNewswire) - "HebaBiz Biotech is pleased to announce that in November 2021, the Center for Drug Evaluation (CDE) of The National Medical Products Administration (NMPA) of China has approved the application for phase III clinical study of Clevudine (L-FMAU), a drug candidate under development for chronic hepatitis B virus (HBV), the application of which was made by HebaBiz Biotech on August 18, 2021, marking another major milestone on its achievement on advancing the clinical study for liver diseases."

Non-US regulatory • Hepatitis B • Infectious Disease

Clevudine attenuates bleomycin-induced early pulmonary fibrosis via regulating M2 macrophage polarization. (PubMed, Int Immunopharmacol) - "Less infiltration of M2 macrophages between α-SMA + cells was also found in clevudine treated mice. Our findings indicate a potential anti-fibrotic effect of clevudine by regulating macrophage polarization and might be meaningful in clinical settings."

Journal • Fibrosis • Hepatitis B • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Infectious Disease • Inflammation • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • CD86 • IL10 • IL6 • MRC1

[VIRTUAL] EARLY ON-TREATMENT HBV RNA AND HBCRAG PROFILES PREDICT FAVOURABLE HBsAg SUPPRESSION OR SEROCLEARANCE UPON LONG-TERM NUCLEOS(T)IDE ANALOGUE THERAPY IN CHRONIC HEPATITIS B INFECTION (AASLD 2021) - " 64 CHB patients (19 received lamivudine, 8 received adefovir, 16 received entecavir, 5 received telbivudine, and 16 received clevudine) were included... Early on-treatment changes of serum HBV RNA and HBcrAg as early as 4 weeks predict HBsAg seroclearance or ≤100 IU/mL in CHB patients put on NAs upon long term FU."

Hepatitis B • Hepatology • Infectious Disease • Inflammation

[VIRTUAL] Phase 1 results for ATI-2173, a novel active site polymerase inhibitor nucleotide, in HBV-infected subjects (EASL-ILC 2021) - "Background and aims: ATI-2173 is a novel phosphoramidate liver- targeted prodrug of clevudine-5′-triphosphate that functions as an active site polymerase inhibitor nucleoside (ASPIN). ATI-2173 is a novel ASPINwith potent activity (−2.7 log10 IU/ml) against HBV at 28 days of treatment. 65% of ATI-2173 treated subjects were BLQ at EOT. Sustained off-treatment responses were noted 1- to 6-months post ATI-2173 discontinuation."

Clinical • P1 data • Hepatitis B • Pain

[VIRTUAL] Pharmacokinetics of ATI-2173, a novel active site polymerase inhibitor nucleotide, in a Phase 1b clinical trial (EASL-ILC 2021) - "ATI-2173 is a novel ASPIN to treat chronic HBV infection. ATI-2173 at doses of 10 to 50 mg orally per day had potent antiviral activity against chronic HBV with greatly decreased systemic exposure to the active nucleoside clevudine. The 25 and 50 mg doses of ATI-2173 have been advanced into a phase 2a study in combination with tenofovir in both HBV mono-infected and HBV/ HDV co-infected populations."

Clinical • P1 data • PK/PD data • Hepatitis B • Infectious Disease

How far have Korean pharmaceutical companies come in developing a treatment for COVID-19? [Google translation] (Women's Consumer Newspaper) - "...Daewoong Pharmaceutical registered the first patient in a phase 3 preventive clinical trial of 'DWJ1248 (trade name: Coviblock)', which is being developed as a treatment for COVID-19....Daewoong Pharm is recruiting a group of patients, starting with the first patient registration for phase 3 clinical trial on the 7th of this month....Shinpoong Pharmaceutical, which is developing a treatment for COVID-19 based on 'Pyramax'...is known to announce the results of phase 2 clinical trials within this year. Bukwang Pharmaceutical, which is developing levovir...has recently completed the recruitment of 104 patients for phase 2 clinical trials."

Enrollment status • P2 data • Trial status • Infectious Disease • Novel Coronavirus Disease

The Proof of Concept Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Mild and Moderate COVID-19 (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: Bukwang Pharmaceutical

Clinical • New P2 trial • Infectious Disease • Novel Coronavirus Disease • CRP

PET/CT in Evaluating Response to Chemotherapy in Patients With Breast Cancer (clinicaltrials.gov) - P=N/A; N=25; Suspended; Sponsor: University of Southern California; Trial completion date: Nov 2021 ➔ Nov 2022; Trial primary completion date: Nov 2020 ➔ Nov 2021

Clinical • Preclinical • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Bukwang's COVID-19 treatment wins FDA approve to go ahead with second-phase clinical trials (Ajunews Buisness Daily) - "Bukwang Pharm based in South Korea has won approval from the U.S. Food and Drug Administration to go ahead with second-phase clinical trials to check if its antiviral drug Levovir is effective and safe in treating COVID-19 patients....Except for severe symptoms, 40 patients will be injected with Levovir and placebo."

New P2 trial • Infectious Disease • Novel Coronavirus Disease

The Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Moderate COVID-19 (clinicaltrials.gov) - P2; N=60; Recruiting; Sponsor: Bukwang Pharmaceutical; Trial completion date: Dec 2020 ➔ Mar 2021; Trial primary completion date: Sep 2020 ➔ Jan 2021

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

Biogenesis and molecular characteristics of serum hepatitis B virus RNA. (PubMed, PLoS Pathog) - "Furthermore, pgRNA-virion collected from cells treated with a reversible HBV priming inhibitor L-FMAU was unable to establish infection in HepG2-NTCP cells. In summary, serum HBV RNA is secreted in noninfectious virion-like particle as spliced and poly(A)-free pgRNA. Our study will shed light on the molecular biology of serum HBV RNA in HBV life cycle, and aid the development of serum HBV RNA as a novel biomarker for CHB diagnosis and treatment prognosis."

Journal • Hepatitis B • Hepatology • Infectious Disease

[VIRTUAL] ATI-2173, a novel phosphoramidate nucleoside prodrug for HBV cure regimens (EASL-ILC-I 2020) - "In vitro combination studies of ATI-2173 activity against HBV in primary human hepatocytes demonstrated additive antiviral activity with TDF, lamivudine, and GLS4 (CAM inhibitor); and synergistic activity with entecavir (ETV), adefovir and interferon. In vitro drug resistance studies confirm mutational cross resistance with lamivudine, telbivudine, and ETV but not HBV capsid inhibitors or TDF... ATI-2173 is a potent liver-targeted molecule that delivers the 5’-monophosphate of clevudine, enhancing the anti-HBV activity while significantly reducing systemic exposure to clevudine in the rat and monkey. ATI-2173 combined with TDF, ETV or other direct acting antivirals, could become an integral part of combination HBV cure regimens."

Myositis

ATI-2173, A Novel Liver-Targeted Non-Chain Terminating Nucleotide for HBV Cure Regimens. (PubMed, Antimicrob Agents Chemother) - "ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. Despite reduced plasma clevudine exposure, liver concentrations of the 5'-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5'-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5'-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy."

Journal • Hepatitis B • Infectious Disease • Myositis

The Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Moderate COVID-19 (clinicaltrials.gov) - P2; N=60; Recruiting; Sponsor: Bukwang Pharmaceutical; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Infectious Disease • Novel Coronavirus Disease

The Phase 2 Study to Evaluate the Safety and Efficacy of Clevudine in Patients With Moderate COVID-19 (clinicaltrials.gov) - P2; N=60; Not yet recruiting; Sponsor: Bukwang Pharmaceutical

Clinical • New P2 trial • Infectious Disease • Novel Coronavirus Disease