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NEW HCV DRUGS IN EARLY DEVELOPMENT
Reported by Jules Levin
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Posters on 4 new drugs for HCV in very early stages of development were presented today at the poster session at AASLD: BILN 2061, ISIS 14803, HCV-AB68 (human monoclonal antibody), Albuferon (a recombinant human albumin-interferon fusion protein). BILN 2061 is the first HCV protease inhibitor. There are 4 abstracts at this meeting on BILN 2061 including phase 1 study results in HCV-infected individuals receiving single doses of the drug. This will be presented later in the meeting. Below are the abstracts from the AASLD program book and additional observations from viewing the posters and talking with researchers.
TREATMENT OF CHRONIC HEPATITIS C WITH ISIS 14803, AN ANTISENSE OLIGONUCLEOTIDE INHIBITOR OF HCV. EFFECT OF TARGET REGION SEQUENCE ON ANTIVIRAL EFFICACY (abstract 469)
28 HCV chronically infected patients received dose escalation of drug for 4 weeks with either intravenous or subcutaneous injection administration. Of the 28 patients 3/10 treated with 2 mg/kg had significant viral load reductions of 1.3 to 2.1 log. The duration of response ranged from 44 to 83+ days. Some patients experienced ALT flares. 5 patients had <1 log viral load reductions. The other patients had no viral load reductions.
BACKGROUND. ISIS 14803 is a 20-base phosphorothioate oligodeoxynucleotide that inhibits HCV replication and protein expression in cell culture and mouse models through an antisense mechanism, i.e., binding to and inducing the cleavage of the viral RNA. The ISIS 14803 target sequence is located within the 5 prime noncoding (5NC) region of the viral genome, in a conserved region of the internal ribosome entry segment (IRES), upstream to the open reading frame initiation codon. AIM. Our aim was to determine whether or not variations in the target sequence and/or neighboring regions could influence ISIS 14803 antiviral efficacy. METHODS. 16 patients with chronic HCV genotype 1 infection included in a dose-escalation trial received ISIS 14803, 0.5, 1, or 2 mg/kg tiw for 4 weeks intravenously. A 5NC region fragment spanning the full IRES, including the first 30 nucleotides of the core coding sequence, was PCR-amplified before treatment started. Amplified fragments were directly sequenced in all patients before treatment and, in 4 of them, extensive quasispecies analysis was performed by sequencing 30 clones per sample. Overall, 136 full-length IRES sequences were analyzed and compared with treatment efficacy. RESULTS. 2 of 16 patients, both receiving 2 mg/kg, had HCV RNA reductions of approximately 1.5 log, whereas HCV RNA reductions less than 1 log were seen in 7 other patients. This effect was delayed by several days to weeks relative to treatment initiation and lasted up to 30 days. The remaining patients experienced no effect on viral replication or minor fluctuations. IRES direct sequencing showed full conservation of ISIS 14803 target sequence and neighboring regions in all patients. Quasispecies analysis in 4 of them revealed the presence of minor variant sequences bearing mutations at various IRES positions. ISIS 14803 target sequence was fully conserved among the quasispecies variants of 3 patients, whereas the remaining patient harbored a minor population with a single nucleotide substitution in the target region. Based on the predicted IRES secondary structure, this mutation was unlikely to alter the stability of the corresponding stem-loop. CONCLUSIONS. The ISIS 14803 target sequence is conserved among different HCV genotype 1 strains and within individual patient quasispecies, regardless of ISIS 14803 antiviral efficacy in the patients studied to date. This result excludes a role for primary resistance due to mutations in ISIS 14803 target sequence. Selection of target sequence mutations during therapy is currently under analysis in the same patients.
A PHASE 1 STUDY TO EVALUATE THE PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF ESCALATING DOSES OF A NOVEL RECOMBINANT HUMAN ALBUMIN-INTERFERON FUSION PROTEIN (ALBUFERONTM) IN SUBJECTS WITH CHRONIC HEPATITIS C (abstract 490), Human Genome Sciences, Inc., Rockville, MD
This study looked mainly at PK, safety, and tolerability. Patients received only 1 or 2 doses of drug, but limited efficacy data was reported. 6 patients experienced transient 0.5 log reductions in viral load. A number of patients experienced improvements in ALT. Exploration of increased dosing amounts will be considered.
Background: Interferons (IFNs) are the foundation of antiviral therapy for chronic hepatitis C. Pegylated interferons (PEG) have improved efficacy compared to standard IFN because of longer half-lives and decreased clearance. AlbuferonTM is a novel, 85.7 kD protein consisting of recombinant INF-alpha genetically fused to recombinant human serum albumin. Like PEG, this fusion protein was designed to delay clearance and extend the half-life compared to IFN-alpha. Preclinical studies in monkeys found Albuferon clearance was 140-fold less than IFN while IFN-induced 2'5'OAS mRNA was increased for 10 days after a single dose warranting the administration of Albuferon in the clinic every 14 days. This phase 1, open-label, dose escalation study was done to evaluate the pharmacokinetics, safety, tolerability, and immunogenicity of Albuferon in subjects with hepatitis C virus (HCV) who previously failed IFN-alpha therapy. Methods: Subjects are enrolled in 4 sequential dose groups (10-12 subjects per each group at 7 ug, 20 ug, 40 ug, and 80 ug). Within each dose group a minimum of 5 and a maximum of 6 subjects per cohort are enrolled sequentially to receive 1 or 2 subcutaneous (SC) doses of Albuferon administered 14 days apart. Dose escalation beyond 80 ug may continue until the maximum tolerated dose is reached. Plasma Albuferon concentrations and antibody to Albuferon were measured by ELISA. Results: Preliminary results are available for 15 subjects in the single dose cohorts up to 40 ug (5 subjects each) and for 5 subjects dosed twice 14 days apart (7 ug). Only preliminary safety results are available for the single injection 80 ug cohort. Genotype 1 HCV was present in 90% of the subjects. Albuferon plasma concentrations were detectable at the 7 ug dose level, but there were too few data points for PK modeling. At the higher doses (20 and 40 ug), mean clearance of Albuferon was 389 ±108 mL/hr and 498 _ 95 mL/hr, respectively. The average volume of distribution was 17 ± 5 L at 20 ug and 23 ± 7 L at 40 ug. Cmax (0.6 ± 0.1 and 1.1 ± 0.2 ng/mL) was linear, and the AUClast (52 ± 11 and 85 ± 14 hr*ng/mL) was dose related, but not dose proportional. The mean terminal half-life was 29 ± 3 hours at 40 ug but was more variable (64 ± 31 hours) at 20 _g. The mean residence time ranged from 77 ± 4 to 118 ± 39 hours. In addition, the 20 ug and 40 ug doses resulted in nearly a one log10 increase in 2'5' OAS mRNA within 24 hours of the dose. Levels peaked within the first week and remained elevated through days 10 and 21 in the 20 and 40 ug cohorts, respectively. Albuferon was well tolerated. Most adverse events were mild and transient flu-like symptoms or injection site erythema. Moderate neutropenia (ANC 1000-1499) usually lasting 3-4 days occurred in 20% of subjects at the 7 ug (both single and double injection cohorts), 20 ug and 80 ug cohorts, and in 60% of those who received the 40 ug single dose of Albuferon. The incidence of neutropenia was not related to drug exposure, as measured by AUC, or to the maximal plasma concentration. No subjects developed anti-Albuferon antibodies.Conclusions: Albuferon is a novel recombinant human albumin-INF alpha fusion protein that is well tolerated, has an extended half-life with low clearance and results in a sustained elevation in the mRNA for an INF-inducible antiviral protein, 2'5'OAS after a single SC injection. The sustained circulating half-life of Albuferon is expected to result in a decreased dosage and/or frequency of injections to achieve a similar or improved therapeutic effect compared with current IFN-alpha therapy.
DEVELOPMENT AND CLINICAL EVALUATION OF HUMAN MONOCLONAL ANTIBODIES FOR TREATING HCV INFECTION (abstract 498)
XTL Biopharmaceuticals Ltd, Rehovot, Israel
There are urgent needs to develop effective therapies for managing HCV infection. Antibodies may be useful to prevent infection following liver transplantation or accidental exposure. They could also be used for treatment of patients with chronic infection possibly in combination therapies. Human monoclonal antibodies (HMAbs) to the HCV envelope protein (E2) were generated from peripheral B cells isolated from individuals infected with HCV genotype 1b. The HMAbs were tested in vitro for their binding, affinity and their ability to immunoprecipitate viral particles from sera of patients infected with HCV from different genotypes. HMAbs having high affinities to E2 and broad immunoprecipitation ability were selected and further evaluated in the HCV-Trimera mouse model that was developed to permit practical in vivo screening of anti-HCV agents. They were capable to inhibit HCV infection of human liver fragments as measured by reductions in mean viral load and in the percentage of HCV positive mice. Their possible role in treatment was demonstrated by their ability to significantly reduce mean viral load when administered to HCV-Trimera mice with established viremia. A HMAb, HCV-AB68, was chosen as a clinical candidate. A phase IA clinical study was designed to test safety, tolerability and efficacy of a single infusion of HCV-AB68 in 15 chronic HCV patients. HCV-AB68 was safe and well tolerated. Significant reduction in HCV viral RNA levels, ranging from 2 to 100 fold, was demonstrated in 8 out of 15 patients following HCV-AB68 administration. A phase I/II multiple infusions, dose escalating clinical study is currently underway.
THE DISCOVERY OF BILN 2061 - AN ORALLY BIOAVAILABLE SMALL MOLECULE INHIBITOR OF THE HCV SERINE PROTEASE AND A PROMISING ANTIVIRAL FOR TREATMENT OF HEPATITIS C. (abstract 464)
Boehringer Ingelheim (Canada) Ltd, Research and Development, Laval, PQ, Canada
Introduction: The inadequate efficacy and tolerability of current therapies for the emerging and devastating infectious liver disease caused by Hepatitis C Virus (HCV) worldwide have warranted significant efforts in the development of new therapeutics. With the insights gained in the design of HIV protease inhibitors for the treatment of AIDS, a similar substrate-based approach was undertaken to design active site inhibitors of the NS3 serine protease with promise in blocking viral replication in HCV-infected patients. Results: We have reported competitive peptide inhibitors based on N-terminal cleavage products (Llinas-Brunet et al 1998). Optimization studies on these peptide inhibitors led to the discovery of BILN 2061, a small, selective and potent inhibitor of the NS3 serine protease. BILN 2061 was selected from an optimized series of inhibitors with potent in vitro activity and adequate pharmacokinetics in various animal species. A distinguishing feature of the BILN 2061 inhibitor series is the presence of a C-terminal carboxylic acid functionality. This provides exquisite selectivity with respect to other proteases, a property not easily attained with more conventional classes of covalent, reversible serine protease inhibitors. Inhibitor constant (Ki) values of 0.30 nM and 0.66 nM with a non-covalent, competitive mode of inhibition were obtained for BILN 2061 from steady state velocity analysis using the NS3 serine proteases of HCV genotypes 1a and 1b respectively. BILN 2061 retains its inhibitory efficacy in human cells and showed low nanomolar inhibition of HCV RNA replication using the replicon cell model system. Mechanism of action studies further demonstrated the ability of BILN 2061 to block NS3 protease-dependent polyprotein processing in HCV replicon-containing cells. BILN 2061 is orally bioavailable in various animal species. Conclusion: In view of the potent activity in vitro, good PK data in animal models and adequate pre-clinical safety profile, BILN 2061 was selected for in-depth clinical evaluation in man as a novel antiviral compound class with great therapeutic potential for HCV infection.
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