The moment I saw the email, I knew something was amiss. It was from Stephen Becker, MD- the medical director for Koronis Pharmaceuticals, a Seattle-based company developing a new HIV drug. The email was addressed to all of the members of their advisory board, which I am a community member, and implored each of us to speak with Stephen (he hates it when I call him Dr. Becker) the next day.

Emails like this are the industry equivalent of your girlfriend or boyfriend saying, ?we need to talk,?- often a sign of trouble ahead. It was.

As I wrote about here, Becker was letting us know about a stunning setback for their drug- called KP-1461. The short version is laboratory studies called in to question the drug?s viability. Worse still, a look at the results from the ongoing study confirmed these concerns.

Within a few days, the one ongoing study of KP-1461 was halted, I broke the story on our website, and Stephen announced his resignation from Koronis. The future of this product looks bleak at best.

Setbacks are part of the drug development process. The road from discovery to commercialization is indeed fraught with pitfalls, scientific, logistical and economic. In just the past few years, we have seen aplaviroc, T-1249, PL-100, brecanavir and others fail for reasons ranging from formulation problems, to liver toxicity.

Is this just another bump in the road, or something more? I don?t know, but it feels significant to me.

My relationship with KP-1461 goes back to my earliest days working on drug development with Project Inform. I was in the office one day, when Marty walked in. Marty works from home, so there is always a reason when he appears at the office. When I asked him why he was in, he told me to meet with a new pharmaceutical company, and I should sit it the meeting.

We sat in our conference room looking with a couple of folks from this Seattle company, I had never heard of. They had a drug they thought held promise for HIV, which worked in a radically new way. It was the radical new way that caught my attention, and piqued my imagination.

KP-1461 was supposed to work in a very count-intuitive way- by encouraging HIV mutation. All other HIV drugs seek to prevent HIV from mutating- a difficult task for sure, but one crucial to the success of ARVs. This drug turned that on its head and proposed that you could actually mutate HIV to death.

I have seen several names for this approach. Koronis? website calls it Viral Decay Acceleration. My favorite term is terminal mutigenesis, which I probably like in part because it sounds like a heavy metal band name.

Why in the world would you ever want to encourage HIV to mutate? Doesn?t it do that enough on its own? Isn?t mutation a bad thing?

In the HIV world we do talk about HIV mutation as a bad thing- and it usually is. HIV is very prone to mutation, making it very adaptable to changing environments. This leads many people to think HIV is clever or wily. Not really.

HIV is sloppy, sometimes to its advantage. It reminds me of the story of Dock Ellis. In 1970, Ellis was a starting pitcher for the Pittsburgh Pirates. Unaware that he was scheduled to start against the San Diego Padres later that day, Ellis and his girlfriend took LSD. Ellis learned later in the day that he was the starting pitcher.

Ellis pitched anyway, throwing what would be the defining game of his career. He allowed no hits, while walking 8 batters and hit one batter. In baseball they call this ?effectively wild.?

HIV is effectively wild. That is, it makes many, many mistakes while replicating. Most of those mistakes are either harmful or neutral. If a person is not taking HIV drugs, the vast majority of mutations go away. When a person is taking HIV drugs, certain mistakes give the virus an advantage- allowing the virus to evade drugs.

We often think of viruses in a science fiction manner, particularly when it comes to mutation. The word itself conjures up images of extra terrestrials and shape shifters, growing ever stronger with each change.

The truth is quite different. Mutation rarely makes a virus stronger. It may provide a survival benefit when one is taking drugs, but is likely to make the virus somewhat weaker on its own. For example, one very common drug resistance associated mutation is called M184V, which often happens when a person is taking either Epivir (3TC) or Emtriva (FTC). While M184V allows HIV to evade these drugs, it also makes it less fit- or able to infect cells and replicate.

(This is why a person might stay on these drugs despite harboring the mutation. If you go off the drug the mutation will sort of go away. It doesn?t fully go away, but it will cease to become the dominant viral strain in the body.)

Koronis sought to exploit the reduction in viral fitness by accelerating the rate of mutation. The goal was to make HIV accumulate so many mutations that it would no long be viable- that is it could no longer infect cells and replicate.

Back to the conference room: Marty and I were meeting with Koronis folks to review their pre-clinical data and their development plan. It is fair to say that both Marty and I were fascinated by this idea. At the same time we saw a rocky road ahead. How would such a drug be studied? In whom? How would it be evaluated? What would the FDA have to say about it? Would people with HIV take such a drug?

The drug went ahead. The FDA had concerns, but saw the drugs potential. I was asked by the company to join their scientific advisory committee, to review the research and advise the company on its plans.

The early research was promising. The drug appeared well tolerated- which is the most important factor in early human research. There were signs that the drug was working, but the research was far too preliminary to know with any certainty.

The company received approval to do a phase II trail in the US, and one in Argentina. The US trail was for treatment experienced people and the Argentine for people taking HIV drugs for the first time. Although it was slow to recruit, the US trial was up and running. The Argentine study faced regulatory hurdles, but was recently approved.

I talked with Stephen the day after I got the ?we should talk? email, I expected bad news. I didn?t expect his to say what he did.

He explained that the FDA had asked them to repeat a set of tests called, serial passage experiments where HIV is exposed to varying concentrations of a drug in order to force drug resistance to develop. This is a normal part of the drug development process. The FDA required Koronis to repeat their earlier serial passage experiment, because drug resistance did not emerge in the earlier experiments. The idea was to keep the experiment going until resistance did emerge.

It never emerged, because the experiments showed that the drug was having no affect whatsoever on HIV. They went and looked at the results from the US study, and found little to no evidence that the drug was working. Had the clinical data shown the drug working, it would have likely trumped the lab results.

I am both a activist and a journalist. I sat on the story for a few days to make sure that all of the study participants heard from the study, rather than our website. Once I was confident that the information was publically available, I posted the story to the web.

As quoted in our story, Becker said the company was committed to understanding what went wrong. He estimated it would take 2 months to figure it out.

A week ago today, Stephen sent out an email announcing his resignation from Koronis. I was saddened if not surprised. It casts a pall on the future for this drug- most likely it is DOA.

I don?t know what led him to resign. Whatever led him to leave Koronis, Stephen?s acted in a highly ethical and straightforward manner throughout the process. I hope he doesn?t stray far from HIV, we need folks like him on our side.
Before writing this entry, I went to Koronis? website, and there is no mention of either the setback of Becker?s resignation. I hope the company does the right thing, invests the resources necessary to figure out what went wrong and continue to follow Stephen?s example of transparency and forthrightness with community.

This setback feels bigger to me than losing aplaviroc or Becker?s last company?s CXCR4 inhibitor. The pipeline is both thin and unimpressive. The mechanism of accelerated viral decay is precisely the kind of thing that could lead to true breakthroughs in treatment. We need this kind of creative thinking to move to the next level in HIV.