Antiviral agent - celgosivir

Viral diseases such as HIV/AIDS and hepatitis C are a significant healthcare burden, with the incidence rising worldwide.

New antiviral agents are much needed to treat both, because HIV mutates to beat drugs currently used to treat it, leading to resistance, and while hepatitis C can often be cleared by using drugs such as interferons, interleukins and immunomodulators, they do not always work and can cause severe side-effects.

Mirogenix is developing celgosivir as a potential new antiviral agent.¹ First developed to treat hepatitis C, it has also shown activity against a number of other viruses, including HIV, Herpes simplex (HSV) 1 and 2 and bovine viral diarrhoea virus. It inhibits a-glucosidase I, an enzyme that is involved in the biosynthesis of glycoproteins that affect the protein folding that is essential for replication in a number of envelope-coated viruses such as HIV and HSV.

Castanosperimine is an alkaloid iminosugar from the Moreton Bay chestnut tree Castanospermum australe, which has good antiviral effects, but causes diarrhoea because it also inhibits intestinal sucrases. Celgosivir is its 6-O-butanoyl derivative, which has a minimal effect on these sucrases, but is metabolised to castanosperimine in the body.

Initial safety studies have been carried out in patients infected with HIV. In one, 75 asymptomatic HIV positive patients who had received no anti-viral medication for 30 days were given celgosivir as an oral solution in varying doses once or twice a day for 14 days, or 300mg capsules twice a day for eight weeks.² The maximum tolerated dose was pinpointed as 400mg/day for the oral solution; the capsule form was poorly tolerated, possibly because of its bioavailability, but all toxic effects disappeared once dosing stopped.

A multicentre randomised double blind placebo controlled Phase II efficacy and safety trial was carried out in around 400 HIV positive patients who were either asymptomatic or only mildly symptomatic.³ Subjects were given 50, 150, 300 or 400mg doses orally once a day for 24 weeks. Half way through the trial, patients were given open label AZT in addition to their blinded placebo or celgosivir for the remainder of the trial. About one-third of the patients experienced good antiviral activity, a further third experienced stability while poor efficacy was seen in the rest.

It is now also undergoing investigation for its potential in treating hepatitis C.⁴