A new type of drug which is based on a completely different approach to treating HIV than those currently on the market began enrollment in late June for a Phase 2a proof-of-concept study.

The drug, KP-1461, is a mutagen, or a drug that causes mutations. This can be a scary term for some people because you want to make sure that the drug selects for the virus and does not promote mutations in other types of cells, but tests so far have shown it to be safe and generally well tolerated in humans.

This is a small, open-label study of 32 HIV-positive individuals to see whether the drug has activity against the virus in humans. Each study participant will receive the same amount of drug (the dose being studied is 1,600 mg, currently four pills twice-daily). Individuals who are already triple-class resistant and have more than 250 T-cells will receive KP-1461 monotherapy for four months. People interested in joining the study should not go off their therapy, but rather they are looking for those who have already decided for whatever reason to be off drug for at least 16 weeks.

KP-1461 works through a process called Viral Decay Acceleration (VDA), which in the test tube increases the mutation rate of the virus, leading to impaired viral function and eventual collapse of the viral population. VDA has been trademarked by the company developing the drug, Koronis. Stephen Becker, M.D., Chief Medical Officer for Koronis, explains that resistance mutations usually occur in response to drug therapy which inhibits reverse transcriptase or protease, or to the selective pressure of the immune system on the virus.

“It’s almost counter-intuitive, because in the HIV world we’ve lived in up until now, mutations are ‘bad’ things, and now we are talking about a drug that induces mutations, and ‘hyper-mutates’ the virus. So it’s a completely different phenomenon, but when you understand that HIV, like other viruses such as hepatitis B and C, sort of teeters on the brink, if you give it too many mutations it doesn’t survive, then this makes sense. When you take a viral load measurement, most of what we’re measuring is dead virus. HIV has got a lot of dead virus, it’s amazing how much damage it does with so little fully infective progeny. It wreaks havoc with a relatively small volume of live virus. It probably doesn’t take many mutations to collapse HIV or other viral populations that live on the edge.

“If you think of the success of the viral population as being more live births than deaths, just like any other population, if we create a viral population where fitness is impaired to non-viability, and we have a population that is no longer able to produce more infective virions than those that are ineffective, or dead, then that population will collapse. And what that could mean for the HIV-infected patient is that the viral population could collapse, and that the virus could be eradicated.”

Of course we’ve heard the term eradication before, and you’re not going to hear Dr. Becker say that this can cure HIV, because in his words that would be “unfair and far overreaching to say that.” But in vitro (in cell cultures) the drug extinguishes the virus in 14 serial passages, and this could translate to 4-8 weeks of therapy in humans. “If it works in HIV-infected individuals the way it works in the test tube, we think it could eradicate infection. That would distinguish it markedly from other anti-HIV therapies, which as you well know inhibit a viral protein or a viral enzyme, or they inhibit entry into the cell. But those drugs are just inhibitors, they don’t extinguish virus. So the shift in the paradigm would be huge if this in fact works in vivo the way it works in vitro. And I don’t know the answer to that yet, but that’s the purpose of the Phase 2 proof-of-concept study that we’ve just begun.”

While it’s still too early to tell, if this drug is ultimately proven to work in humans, whether or not it would be best used in combination with other drugs, as monotherapy, or even as a “pulsed” therapy remains to be seen. Theoretically it could even be used in someone who has a high CD4+ T-cell count who doesn’t need to start therapy, but could possibly delay the time to when that person would ultimately have to begin therapy.

If you are interested in joining this trial or would like to learn more about KP-1461, contact Jeff Parkins, Koronis Director of Operations at (425) 825-0240, ext. 214, or visit www.clinicaltrials.gov. If you are in Chicago, contact Northstar Healthcare at (773) 296-2400.