Over 20 New Drugs Now in Research Pipeline

雪绒花

Over 20 New Drugs Now in Research Pipeline for Treatment of HBV

By Harvey S. Bartnof, MD

While monotherapy treatment with either Epivir-HBV (lamivudine, 3TC) or Intron A (alfa * interferon, approved for chronic hepatitis B) shows some benefits for chronic hepatitis B, there is a need for additional therapies. Fortunately, there are many agents in the development pipeline. Several of them were described in presentations at the 3rd International Conference on Therapies for Viral Hepatitis (Maui, Hawaii, December 12-16, 1999).

The drugs that are the farthest along in development include those that are owned by Triangle Pharmaceuticals. They include Coviracil (FTC), DAPD and L-FMAU. Another drug that is already in human clinical trials is adefovir dipivoxil (Gilead Sciences). Gilead's tenofovir (PMPA) also has anti-HBV activity. Adefovir, DAPD, L-FMAU, and tenofovir have activity against HBV strains that are resistant to Epivir-HBV (lamivudine, 3TC). All agents in this paragraph also have activity against HIV.

Two drugs under development by Novirio Pharmaceuticals are epavudine (L-dT, NV-02B) and epcitabine (L-dC, NV-02C). They were the topics of six abstracts or 5% of the total. L-dT is beta-L-thymidine, while L-dC is beta-L-deoxycytidine. Both are nucleoside inhibitor drugs. Each of these drugs has significant activity against human HBV, in addition to both duck and woodchuck models of HBV. Studies to determine possible toxicity to human mitochondria (energy producers in cells) reveal none thus far. This included no incorporation into mitochondrial DNA. Also, there was a lack of lactic acid accumulation. This is in contrast to many of the NRTI (nucleoside reverse transcriptase inhibitor) drugs used to treat HIV, that are toxic to mitochondrial DNA and can lead to lactic acid accumulation, sometimes with fatty infiltration of the liver.

In a woodchuck chronic hepatitis B model, each of these two drugs were safe and showed significant dose-dependent potency. Metabolism testing of each was also performed in cynomolgous monkeys. In human liver cells (hepatocytes), the half-life (time for an original amount to be reduced by half) of the active component of each drug (intracellular tri-phosphate forms) is at least 15 hours, suggesting that once daily dosing for humans is possible.

Each drug has no activity against HIV, four different human herpes group viruses tested (herpes simplex, cytomegalovirus, varicella-zoster virus, Epstein-Barr virus), or four respiratory viruses tested (influenza virus, parainfluenza virus, rhinovirus, respiratory syncytial virus). In the laboratory, when the two drugs were combined, synergism occurred (enhanced effects by combining, when compared to the individual effects added together) Human phase I trials will be undertaken.

Another group of anti-hepatitis B virus agents is the fluoro L- and D-nucleosides, according to S. B. Pai, PhD, from Pharmasset Inc. In the L-nucleoside group, the 2'-Fd4N compounds were the most potent. For example, the cytosine and fluorocytosine agents inhibited HBV DNA replication at a very low concentration. Similarly, the D-series (cytosine and fluorocytosine analogues) were quite potent. In selected cell culture tests, neither demonstrated toxicity. Testing of these agents will take place in animal models of HBV.

Other drugs with activity against HBV mentioned or discussed at the Meeting include: lobucavir (activity against Epivir-HBV-resistant HBV); Famvir (penciclovir); entecavir (BMS-200475); racivir; DXG; L-ddA prodrug; HDP-P-acyclovir; LM-019c; CS-1091; PS-019; PS-018; ara-AMP prodrugs; thymosin; Compound A; (-)-Carbovir; HBV/MF59 therapeutic vaccine (see AASLD Conference report); and hammerhead ribozymes. As discussed in a previous Internet Conference Report from this Meeting, glycosidase inhibitors, in addition to "protein folding" inhibitors, show promise against both HBV and hepatitis C virus (HCV).

* Note that all four generic versions use the spelling 'alfa' and not 'alfa.'

12/22/99

References

Block T and others. Glucosidase/protein folding inhibitors as possible mutation-proof anti-hepatitis B and C virus agents. Abstract and oral presentation 16 at the 3rd International Conference on Therapies for Viral Hepatitis. December 12-16, 1999; Maui, USA and Antiviral Therapy 1999; 4 (Supplement 4), 8.

Cretton-Scott E and others. Pharmacokinetics of beta-L-thymidine and beta-L-2'-deoxycytidine in woodchucks and monkeys. Abstract and poster presentation 124 at the 3rd International Conference on Therapies for Viral Hepatitis. December 12-16, 1999; Maui, USA and Antiviral Therapy 1999; 4 (Supplement 4), 50.

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Ono-Nita SK and others. Screening of new antivirals for wild-type hepatitis B virus and three lamivudine-resistant mutants. Abstract and poster presentation 89 at the 3rd International Conference on Therapies for Viral Hepatitis. December 12-16, 1999; Maui, USA and Antiviral Therapy 1999; 4 (Supplement 4), 33.

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