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My journey with KP-1461

| 13 Comments

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 http://projectinform.org/news/2008/061208.shtml, 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.

13 Comments

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Comments on Paul Dalton's blog entry "My journey with KP-1461"

> I hope the company does the right thing,
> invests the resources necessary to figure
> out what went wrong

WHAT WENT WRONG??? That the FDA required Koronis to repeat the serial passage experiments and so it was found out that the previous in vitro results were FALSE, RIGGED!
This is "what went wrong"!

In regards to the previous poster - isn't it also possible that the latter results were the false ones? All we can say for sure is that something curious is going on at Koronis.

This revelation is really depressing indeed.My daughter Amo & I have been following the development process of KP 1461 with extreme hope that finally we might have cure.I hope the company ; Koronis complies with the FDA request to repeat the phase 1 trial & determine what really went wrong.I do not believe this was a scam and I take it that millions of people cant just be duped like that.Somebody needs to explain these issues around Dr Beckers resignition. Isac Molema -South Africa.

It is hard to believe that the first in vitro lab test was not done as per scientific standards . It is hard to believe that FDA did not check deeply as much as possible into any possible datas about this new completely therapeutic approach before any approval in humans clinical trials ( ..of course including hiv control replication..and humans toxic side effects in phase 1a and 1b ). It is hard to believe that Koronispharma team presented any time since the beginning false datas ( for which reasons ? )
NOW IS VERY HARD TO BELIEVE that experiments requested by FDA showed that the drug was having no affect whatsoever on HIV.
May we suspect that they want hide something to us?

To Paul Dalton

I got some news from Koronispharma directly, and it seems they are moving on for an upcoming Phase 2 studies, do you confirm ?
If yes the VDA approach has still the legs.

Thanks a lot Paul

It seems, hopefully, that kp-1461 is not completely gone, anyway until official info from Koronispharma it's better to cross the fingers again.

There's something very weird going on here. It doesn't make any sense that the drug showed so much promise before invitro and they went ahead to phase 2. Then when they went back to repeat the experiment, it has no affect at all. Seriously... are we supposed to believe this? The FDA is probably in bed with companies that manufacture HIV drugs that just suppress the virus, and they know if kp-1461 did eradicate the virus, their fat bankrolls would start getting smaller. This may sound like a conspiracy theory, but what am I suppossed to think? This isn't ok, and someone need's to provide some answers to the public who's been eagerly awaiting some promising results about this drug.

Kp-1461 trial has not been a failure but only suspended, please wait a while, Koronispharma team is planning to go ahead with upcoming humans trial. Give them the time to adjust the chemical formulation and do not worry about Becker's resignation.
It is not true that all the patients had no clinical benefit from kp-1461, few had hiv control replication and few is not like none.
Probably the long lasting viral reservoirs need a longer trial.
Please read - KP-1461 redux -

As an HIV + patient and so young at that it seems to me through my research, that there has always been known cures but are unusable on humans due to Toxicity levels. On the other hand why continue this painful cycle of "Oh we may have found a cure" giving us false hope only to have it crushed. There is a strong need for researchers to honestly come together in one location and work together on finding a cure!

I agree with the opinion posted aug. 6 by Veryfishy.
Actually, an approach (dubbed « viral suicide »), similar in part to the VDA has been advocated by a renowned senior french scientist named Claude Reiss. In an interview broadcasted by a french radio station (« ici et maintenant »), he explained that he has a list of some 100 modified nucleotides of natural origine, allowing to take control over the viral mutation rate, either ridding the virus with errors as vda and kp 1461 does, or cancelling mutations, thereby allowing the immune system to get hold of the stabilized virus.
He also complained that he was bluntly barred from getting support for preclinical trials from the french National Agency for AIDS Research and said that he was told by people from the pharma industry that he « would not be allowed to ruin a $36 billion/year (AIDS) business », as this new therapy would likely achieve full viral clearance.

To JF Vittoz

????...?????

Would be so kind to post some more information?

Vittoz quotes correctly my interview broadcasted some time ago by Ici et Maintenant. Indeed, back in the nineties, my team (I was then research director with the French National Center for Scientific Research, CNRS) investigated the precise mechanism responsible for the high mutation rate of HIV reverse transcription, which is at the root of the deadly viral strategy. As a result, we could establish detailed nucleotide characteristics either enhancing, or reducing the mutation rate. From a therapeutic point of view, increasing the mutation rate will abolish viral infectivity (equivalent to “viral decay accelerator” advocated by Koronis), whilst decreasing this rate will stabilize the virus, thereby allowing the immune system to clear the viral load, just as it does when facing conventional microbial pathogens (immunization against the stabilized HIV strain). Based on the criteria enabling nucleotide analogs to force the virus into one of these “viral suicide” pathways, we found many such analogs in a class of natural nucleic acids present in the biomass, in particular transfer RNAs. We further selected those analogs able to dock into the viral RT, but unable to fit into the cellular, nucleic acid synthesizing enzymes, thereby precluding any genotoxicity of the drug, in particular for mitochondria (for details, see www.vigilentech.com). My employer filed (1999) a patent on this new therapeutic approach (granted by USPO in 2004), but refused to support preclinical studies. I left CNRS and founded a start-up, trying to rise the funding needed for the study ($500k). The many applications I filed with French government agencies (including ANRS, the National Agency for AIDS Research) were systematically rejected. Comments invariably alleged that support was spent for “projects of higher priority”, none even considered or commented the scientific or medical merits of the project, which had of course been carefully considered by CNRS before filing the patent. Someday a member of a board of one of these agencies, who had ties with the pharma industry, told me frankly, of course without a witness, the obvious reason of the systematic rebuttal, as quoted by Vittoz. Understandably then, I watched closely the trials undertaken by Koronis. I was surprised by the failure (revealed by Paul Dalton in ProjectInform) of KP 1461 to reproduce results published earlier, in particular by Karen Anderson’s group of Yale in 2005 dealing with the active moiety of the prodrug, KP 1212. I sent Lawrence Loeb, scientific adviser to Koronis who contributed to the development of the vda concept, a mail in July suggesting possible reasons for the failure. The “passage” test involves two actors mainly: MT-2 cells which had been used for the earlier passage experiment, and KP 1461. May be the MT-2 batch used lostmeanwhile its ability to convert prodrug KP 1461 to KP 1212, or that the KP 1461 tested now is inactive, for instance due to tiny steric differences (depending on the synthesis method) with the earlier version? Loeb did not respond so far. Accordingly, I believe there is only a technical problem which Koronis could rapidly settle.

What you said is terrible....

- immunization against the stabilized HIV strain - , Does it mean that the immune system could clear the remaing hiv or destroy latent hiv reservoirs ?

Now i understand why they have been coerced to stop the trial in that way....THE BIG PHARMA WANT TO MAKE MONEY WITH THE CONVENTIONAL DRUGS AND THEN, AFTER YEARS, TO FIND (or let others to find it ) A CURE, MAKING FURTHER MONEY.

Anyway BIG PHARMA AND FDA go to sleep together, there are no doubts.

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This page contains a single entry by Paul Dalton published on June 27, 2008 10:58 AM.

Farewell to 2 Giants was the previous entry in this blog.

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