Two basic defining characteristics of nucs make them ideal drugs for hepatitis C. First, nucs are prodrugs, which means they're inactive until the body (in this case, the liver) metabolizes the drug into an active form. Having a drug that concentrates and activates in the liver is ideal for viral liver disease like hepatitis C.

Second, nucs, unlike PIs, have a high barrier to viral resistance, meaning the virus has a difficult time mutating or changing into forms that can fight off the drug. Nucs probably can't effectively cure hepatitis C on their own (at least not the current nucs) but Gilead's PSI-7977 (obtained from Pharmasset) may only need to be combined with ribavirin for a short time to be highly effective in treating genotype 2/3 patients -- and perhaps genotype 1 patients as well.

Drawbacks to nucs are that these drugs are generally less potent than PIs (although again, PSI-7977 surprised a lot of people by having PI-like potency) and the risk of serious side effects. Recently, Pharmasset had to shelve another of its nucs due to unacceptable liver toxicity.

Researchers -- and investors -- are so excited about nucs (more so than PIs) these days because the nucs' high barrier to viral resistance means combinations of all-oral drugs can be designed that exclude the need for weekly injections of interferon.

An all-oral therapy against hepatitis C is the golden ticket that every drug company involved in the field is shooting for. At this point, nucs more so than PIs, appear to have the edge as the backbone of future all-oral regimens, and that explains the billions of dollars spent recently to acquire nucs.

Two updates on old friends of the Mailbag who may be nearing their respective ends:

Generex Biotechnology ( GNBT) disclosed in a regulatory filing Tuesday night that it took out second mortgages on company-owned property to raise money to remain in business. I've seen a lot of crazy financing schemes in my days covering biotech, but I've never seen a company resort to real-estate loans (with a 10% annual interest rate, mind you) to keep the lights on.

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