ContraVir is developing Tenofovir Exalidex (TXL™) for Hepatitis B in Phase 2 clinical studies. TXL™ is a novel lipid acyclic nucleoside phosphonate that delivers high intracellular concentrations of the active antiviral agent of tenofovir, marketed by Gilead as Viread®.
TXL™’s novel structure results in decreased circulating levels of tenofovir, lowering systemic exposure and thereby reducing the potential for renal side effects. TXL™ has completed a Phase 1 clinical trial in healthy volunteers, demonstrating a favorable safety, tolerability, and drug distribution profile.
ContraVir believes a potentially best-in-class antiviral like TXL™ can become the cornerstone of a curative combination therapy for hepatitis B. The combination would include multiple drugs that inhibit different points in the viral life cycle, such as ContraVir’s cyclosporine A-derived antiviral TXL™, which is currently in preclinical development. Learn more about TXL™ >>
Potential Advantages of TXL™ over Tenofovir
- Increased efficacy by boosting bioavailability
- Takes advantage of natural lipid uptake mechanisms
- Decreased renal toxicity by reduced circulating TFV
- 97-fold more active against HBV in vitro
Opportunity: TXL™ May Address Limitations of Approved HBV Drugs
Currently there are about 350 million chronic HBV patients worldwide and 786,000 reported HBV-related deaths in 2010. The U.S. is the largest individual market with the highest absolute growth rate of HBV patients at around 15.4% through 2033. The primary goal of treating chronic hepatitis B is to suppress HBV replication and induce liver disease remission prior to the onset of cirrhosis and hepatocellular carcinoma, which are often the result of an HBV infection if not managed. Learn more about chronic hepatitis B >>
The limited efficacy of current antiviral treatments highlights the need for new therapeutic tools for treating chronic HBV. Currently, there are seven FDA-approved drugs for the treatment of chronic HBV, including interferon-alpha, pegylated interferon-alpha, lamivudine, entecavir, telbivudine, adefovir dipivoxil, and tenofovir disporoxil fumarate. No currently approved drug is completely effective at suppressing HBV replication permanently.
Lamivudine often results in resistance development, with a 20% chance after one year, and 70% chance after two years. Adefovir has a much lower rate of resistance development, but has a lower level of potency against HBV. Various combinations of treatment have respective advantages and disadvantages, with none being ideal. Nucleoside analog (“NA”) therapy has advantages over interferon therapy (“IFN”) including fewer side effects and easier administration. However, IFN therapy has the advantage of decreased frequency of resistance, and higher rates of HBeAg loss, but also disadvantages of high cost, limited patient response, and administration by injection with frequent side effects.
Tenofovir so far, in combination with other drugs such as entecavir, is seen as the primary option for treatment, given its low cost, efficacy, and barrier to resistance development. Tenofovir is still is not completely effective in achieving the goals of chronic HBV therapy, which are to reduce the amount of detectible virus in the bloodstream of 95-100% of patients with no emergence of resistance, and the eradication of viral replication in the liver.
Phase I Clinical Study Data
The TXL™ Phase 1 clinical study was a randomized, blinded, dose-escalation trial to evaluate safety, tolerability and pharmacokinetics. Healthy volunteers received a single dose ranging from 25 mg to 400 mg of TXL™ or a standard dose of Viread® for comparison of intracellular levels of the active antiviral, tenofovir diphosphate (“TFV-PP”).
TXL™ was well tolerated and there were no laboratory, vital sign, electrocardiogram changes or adverse event trends attributable to drug. In addition, plasma concentrations of TXL™ increased linearly with dose and target plasma levels were attained. The active antiviral, TFV-PP, was measurable in peripheral blood mononuclear cells (“PBMC”) from all patients after a single 400 mg dose of TXL™.
PBMC levels of TFV-PP remained detectable for six days after the single 400 mg dose of TXL™, suggesting the possibility of a convenient, once-weekly dosing regimen.
Phase 2 Study
ContraVir is developing TXL™ for Hepatitis B in Phase 2 clinical studies.