The protease inhibitor TMC435 was found to be safe and well tolerated in healthy volunteers in a small phase I trial, according to Dr. Henk W. Reesink and colleagues writing in an online article in Gastroenterology.
Moreover, the drug exhibited potent antiviral activity in a subsequently enrolled open-label trial consisting of six chronic hepatitis C patients with genotype 1 who had failed previous interferon treatment.
“The protease inhibitor TMC435 is a promising addition to the growing arsenal of specifically targeted antivirals against HCV undergoing development,” wrote Dr. Reesink, an associate professor in the department of gastroenterology and hepatology at the Academic Medical Center in Amsterdam, and his colleagues (Gastroenterology 2009 Oct. 21 [doi:10.1053/j.gastro.2009.10.033]).
The investigators first looked at 49 healthy volunteers, divided into six panels of 6 to 9 subjects each, who received treatment for 5 days. In the first two panels, which included nine subjects each, “six subjects received active treatment and three received placebo after a standardized breakfast,” wrote the authors. “The doses of the test compound were consecutively escalated, following interim data reviews for safety, tolerability, and pharmacokinetics.”
The highest dose in either group was 600 mg once daily; it was found to be “generally safe and well tolerated,” without any serious adverse events.
Panel 3 received 100 mg once daily; panel 4 received 200 mg once daily; panel 5 received 200 mg twice daily; and panel 6 was given 400 mg once daily, all for 5 days. These subjects had no serious adverse events that were judged to be “very likely related to TMC435 by the investigator.” In panel 5, there was “mild and transient” photosensitivity in three out of the six healthy volunteers taking the drug. Other adverse events (AEs) included diarrhea, abdominal pain, and headache. None of the side effects resulted in patients discontinuing the drug.
Following this, the investigators enrolled a seventh panel of six hepatitis C patients. All of the patients were white males, and they had a median plasma hepatitis C RNA level of 6.75 log10 IU/mL (range 6.47-7.03 log10 IU/mL) at baseline.
Four patients were infected with genotype 1a; two had genotype 1b. Four were previous nonresponders to interferon therapy, and two were “relapsers.” The median age was 56.5 years, with a range from 32 years to 67 years. Two patients had hemophilia A.
“Given the safety profile of TMC435, both for the 200 mg and 400 mg [once daily] regimens in healthy volunteers and anticipating a higher exposure in patients as compared with healthy volunteers, a dose of 200 mg [once daily] was selected for hepatitis C patients” for 5 days, wrote the authors.
“No [significant adverse events] or AEs leading to treatment discontinuation were reported in hepatitis C patients, and no grade 3 or 4 AEs were reported,” the authors wrote.
There was, however, a reduction in hepatitis C RNA levels, with a median drop of 3.46 log 10 IU/ml at day 3 (range, 1.6 log10 to 3.8 log10 IU/mL). The median maximal reduction was 3.9 log10 IU/mL (range 2.9 log10 to 4.1 log10 IU/mL).
“Viral decline appeared similar in patients with genotype 1a and 1b virus, previous nonresponders or relapsers, or between patients presenting with or without hemophilia,” wrote the authors.
Viral RNA levels returned to baseline within 4 weeks after the final dose.
“The potency of TMC435 and in vitro work showing synergy with [pegylated interferon] and additivity with [ribavirin] are consistent with its use in combination with the current standard of care,” wrote the authors. “Additionally, it’s simple dosing schedule and low pill burden may become important attributes in future combination studies with other specifically targeted therapies for hepatitis C.”
The study was fully funded by Tibotec Pharmaceuticals Ltd., the maker of TMC435. Several authors (excluding Dr. Reesink) are employed by the company.
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