 |
|
|
| |
New Drugs for HCV; Viramidine: 24 week study results
|
| |
| |
Reported by Jules Levin
In today's oral session on Hepatitis C researchers presented early research results for several potential drugs for HCV including Viramidine, a potential substitute for ribavirin that may not cause anemia but show the same efficacy. All the results are from studies very early in the process of development, so although promising it is too early to attach high expectations on the drugs. An interesting study presented in this session found that daily pot smoking accelerated HCV disease progression.
IN-VITRO AND IN-VIVO EVALUATION OF HCV POLYMERASE INHIBITORS AS POTENTIAL DRUG CANDIDATES FOR TREATMENT OF CHRONIC HEPATITIS C INFECTION
Researchers from Israel (S Dagan, XTL Biopharmaceuticals Ltd., Rehovot, Israel) and Korea (W Suh, Myong Ji University Gyunggido, Korea) reported on the development of two new drugs for HCV, 2 polymerase inhibitors in early stages of development. They reported on their laboratory testing methods and mouse model they used to evaluate drugs against HCV. They have utilized a unique HCV cell-based assay and their HCV-Trimera mouse model to evaluate drug candidates (HCV polymerase inhibitors) as a potential therapy against chronic hepatitis C.They screened over 1,000 compounds, and narrowed it down to two molecules, BC 2125 and BC 2329, possessing good oral bioavailability properties, which they further evaluated in vitro (cell-based assay) and in vivo (HCV-Trimera model).
Two different molecules were designed, synthesized, and tested for their ability to inhibit the activity of the HCV polymerase. In a biochemical assay, they both showed good inhibition activity.
The first molecule, BC2125 is water soluble with a good rodent oral PK profile. This molecule was proved to have low cytotoxicity and inhibits HCV replication at concentrations of 2-10 micro grams/ml using our cell-based assay for both Huh7 and FLC4 cells. In vivo, BC2125 was able to reduce viral loads and percentages of HCV-positive mice in HCV-Trimera mice at 100, 50, and 30 mg/kg/day. These reductions were in a dose dependent manner. At higher doses toxicities were observed in mice and rats but investigators said BC2125 has good chances to pass toxicological tests for advancing to clinical development. BC2329 also reduced HCV RNA in HCV+ mice after oral administration. The authors said these two compounds had acceptable early stage toxicity profiles and good oral bioavailility and PK parameters suggesting acceptable oral clinical treatment. The authors concluded that good in vitro and in vivo toxicity profiles and PK data together with antiviral inhibitory activity in both assay systems indicate the potential of BC2125 as oral drug candidates for treatment of chronic hepatitis C. Further in vitro and in vivo evaluation of these two compounds is underway. Additional metabolism, toxicity and pharmacology studies are planned. Other molecules are still under evaluation. The authors also concluded they developed valuable in vitro cell culture system to test efficacy of potential therapeutics and a powerful in vivo model to select drugs
CLINICAL EVALUATION OF A HUMAN MONOCLONAL ANTIBODY AGAINST THE ENVELOPE PROTEIN (E2) OF HCV FOR PREVENTION OF HCV INFECTION
The same Israel research group (Dagan, XTL Biopharmaceuticals Ltd., Rehovot, Israel) reported on the development of a therapy to prevent reoccurrence of HCV after liver transplantation.
Hepatitis C virus infection after liver transplantation occurs in 100% of cases. The researchers wanted to develop an effective therapy to prevent HCV after liver transplantation, human monoclonal antibodies directed against the envelope protein of the virus were generated. The antibodies having high affinity and broader activity against different viral genotypes were selected based on their neutralizing activity in vitro in a cell-based infection assay and in vivo in the HCV-Trimera mouse model.
They reported on two antibodies and both reduced HCV RNA in mice. In a phase 1a study, single doses ranging from 0.25 to 40 mg of HCV-AB 68 were administered to a total of 15 chronic HCV patients. HepeX-C was well tolerated with no serious adverse events. In 8 out of 15 patients, HCV-RNA levels were reduced at least by half immediately following a single IV infusion and then returned to initial levels. Reductions in HCV RNA ranged from 2 to 100 fold. There were no major adverse side effects.
A multidose phase 1b study of 10, 20, 40, 80, and 120 mg of HCV-AB 68) in 25 HCV chronic patients was conducted. Doses were administered weekly for 3 weeks and then 3 times a week during the fourth week. Multiple doses were well tolerated. 8 out of 25 (32%) patients had at least 1-log reduction and 18 out of 25 patients (72%) had at least 0.75-log reduction in HCV-RNA from pre-treatment baseline at one or more time points following administration.Further analysis is underway.
The good safety and efficacy data from this trial provided a basis for a phase 2a study. Two antibodies will be combined for study for safety and efficacy. Phase 2/3 clinical study will be followed bu a pivotal study in liver transplant patients. I asked if they would study in nonresponders and they said they are prioritizing liver transplantation. A multicenter, blinded, placebo controlled study is currently underway: 24 patients; Sites: Mt Sinai, Mayo Clinic, University of Virginia, INOVA Fairfax Hospital, Hadassah, Rabin Medical Center; 6 cohorts: 20, 40, 80, 120, 240, 480 mg doses of HCV-AB 68. The first 3 cohorts (20, 40, 80 mg):
--1 infusion at anhepatic phase
--daily for 7 days
--weekly for 3 weeks
--monthly for 2 months
Amended protocol (120, 240, 480 mg):
--1 infusion at anhepatic phase
--3 infusions during first 24 hrs
--daily for 7 days
--weekly for 3 weeks
--bi-monthly for 2 months
ORAL IDN-6556, AN ANTI-APOPTOTIC CASPASE INHIBITOR, LOWERS AMINOTRANSFERASES IN HCV PATIENTS
E.R. Schiff from the University of Miami reported on this potential therapy in early development.
Increased rates of apoptosis (programmed cell death) have been implicated in hepatic disease including HCV, NASH, HBV and PBC. IDN-6556 is a potent inhibitor of caspases, the proteases that execute apoptosisThis study is a multicenter, double-blind, placebo-controlled, dose-ranging study.
The study they reported included 44 patients with chronic hepatitis C and 1 with NASH (ALT or AST: 1.5-10 x ULN) randomized to receive placebo or once daily dosing of 5, 25, 100, or 200 mg
All doses of drug significantly lowered ALT and AST. The decrease of ALT from baseline at day 14 for each dose was: -40% (25 mg QD), -33% (100mg QD), -35% (200mg QD), -49% (5 mg BID), -42% (50 mg BID) and -56% (100 mg BID). The 100mg BID dose normalized ALT or AST in all 6 patients. Placebo patients did not change significantly (+2%). AST changes were similar.
Adverse Experiences were generally mild and brief; no discontinuations from adverse events; no serious adverse events. Patients reported abdominal pain (10%), dyspepsia (10%), fatigue (10%), headache (10%), not obviously different from placebo; no clear AE-dose response relationship.
47/48 HCV patients had no changes in HCV RNA titers >1 log unit; one patient (IDN-6556, 100mg BID) showed complete viral clearance at the end of follow up. There were no other clinically meaningful changes in laboratory parameters.
They studies 100mg twice daily in HBV+ patients: 7 placebo, 7 drug. 4/7 patients had negative HBV DNA, 3/4 were confirmed, 1 patient not confirmed. ALT was also reduced by average of 50% in HBV.
The authors concluded oral IDN-6556, given once or twice daily for 14 days, significantly lowered aminotransferases and appeared well tolerated. The trial is still ongoing. Further groups will include additional dose levels in HCV patients and 100mg BID doses in HBV, PBC and NASH patients.
SMOKING POT: a study was presented finding a strong link between daily pot use and fibrosis progression rate in patients with HCV. The authors recommended daily pot consumption should be avoided in patients with HCV. Details to follow in next report.
SAFETY AND EFFICACY OF VIRAMIDINE IN COMBINATION WITH PEGYLATED INTERFERON ALFA-2A FOR TREATMENT OF HEPATITIS C IN THERAPY-NAÏVE PATIENTS
R. Gish (Department of Hepatology, California Pacific Medical Center, San Francisco CA, USA) reported early study results for this ribavirin substitute which is now in larger studies.
Ribavirin combined with pegylated interferon alfa is effective in achieving sustained viral responses in some hepatitis C patients, but is associated with dose-limiting hemolytic anemia. This is a dose-ranging study to examine whether viramidine, a liver-targeting prodrug of ribavirin, is a safer substitute for ribavirin.
180 patients were randomized to receive Pegasys 180 _g/wk SQ in combination with viramidine 400 (N=47), 600 (N=43), 800 (N=45) mg oral BID or ribavirin 1000/1200 mg/daily (N=45).
Patients were predominately male (71%), Caucasian (84%), genotype 1 (76%), with a median age of 49 years (23 to 68), and median HCV RNA 6.5 log10 copies/mL (range 4.0 to 7.5); treatment-naïve; compensated HCV-related liver disease; elevated ALT/AST at screening. Median hemoglobin: 14-16. g/dL. BMI 18-35 kg/m2. 73% had >2 million copies/ml. Weight: 78 kg.
A 24-week interim analysis assessed HCV RNA levels and the occurrence of anemia (hemoglobin < 10 g/dL).
Following 24 weeks of treatment, there was no significant difference between viramidine (800-1600 mg/day) versus ribavirin in the proportion of patients with undetectable HCV RNA or a log decrease in viral load of 2 or more (83% versus 83%, respectively).
There were significantly fewer patients in the viramidine groups with anemia when compared with the ribavirin arm (2% versus 24%; p< 0.001). Among patients receiving the 400 mg BID and 600 mg BID doses of viramidine, there were no cases of defined anemia.7% of patients receiving 800mg dose of Viramidine experienced anemia. Patients receiving 800 mg dose had more incidence of hemoglobin drop of 2.5 g/dL or more and/or <10 g/dL during 24 weeks. There was no difference between 400 and 600 mg doses. Other adverse events were similar among treatment groups. Rates of reported depression and fatigue by patients were the same in RBV and Viramidine groups. As well, side effects profile were similar. Investigators said the 600 mg dose is chosen as the dose for phase III with the best balance of safety and efficacy. Phase III study will examine impact of genotype, baseline viral load, race, and gender on Viramidine safety and efficacy.
The authors concluded that Viramidine demonstrated antiviral activity comparable to that of ribavirin when used in combination with peginterferon alfa-2a but with a significantly lower incidence of hemolytic anemia.
|
| |
|
|
|
|
|
