GlaxoSmithKline licenses new HIV and HBV drug from Swedish company

Keith Alcorn
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This article is more than 22 years old.

Glaxo Smith Kline announced yesterday that it has obtained a licensing agreement from the Swedish company Medivir for the development and marketing of MIV-210, a nucleoside analogue active against HIV with high level resistance to other nucleoside analogues. If trials prove successful, GSK will market the drug worldwide (except for Scandanavia).

MIV-210 has shown activity against lamivudine-resistant hepatitis B virus, and also in vitro activity against HIV isolates with multi-nucleoside resistance and high level thymidine analogue resistance. The compound is a pro-drug of 3`-fluoro-2`,3``-dideoxyguanosine (FLG).

MIV-210 could prove a useful companion to amdoxovir and elvucitabine (ACH-126,443), the only investigational nucleoside analogues that appear to have activity against both thymidine analogue-resistant viruses and multi-nucleoside-resistant viruses.

Glossary

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

in vitro

Latin term for experiments conducted in artificial environments, e.g. in test-tubes.

thymidine analogue

A type of nucleoside reverse transcriptase inhibitor. Zidovudine (also known as AZT) and stavudine (also known as d4T) are thymidine analogues. Nucleoside reverse transcriptase inhibitors insert a nucleoside into the proviral DNA of HIV, terminating the chain of proviral DNA and preventing the incorporation of proviral DNA into the genome of a host cell. Thymidine analogues insert an altered thymidine nucleoside into the proviral DNA.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 

Phase I studies have already taken place in the UK, according to Medivir, but so far the only publicly available data on MIV-210 relate to in vitro activity against HIV and animal studies of HBV activity.

Data presented by Medivir researchers at last year’s 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy showed little loss of susceptibility to FLG compared to wild-type in viruses with the thymidine analogue mutation complex M41L, D67N, L210W and T215Y, and less than 2.1-fold loss of susceptibility to six isolates with the T69S insertion mutation (associated with substantial resistance to all other NRTIs in this experiment). A 1.5-fold decrease in FLG susceptibility was recorded when isolates with the Q151M mutation were exposed to the compound; in comparison, Q151M resulted in 15 and 19-fold reductions in susceptibility to ddI and d4T respectively (Zhang).

Serial passages selected viruses with reduced susceptibility to FLG and mutations at codons 35 and 133 of reverse transcriptase.

As a fluorinated nucleoside analogue, MIV-210 will be closely scrutinised for signs of the hepatotoxicity that terminated the development of lodenosine and fialuridine, previous fluorinated NRTIs for HIV and hepatitis B that appeared to have promising resistance profiles in vitro.

References

Zhang H et al. Inhibition of multiple drug-resistant (MDR) HIV-1 by 3`-fluoro-2`,3``-dideoxyguanosine (FLG). 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, abstract H-182, 2002.

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