POZ Community Forums
Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: Central79 on June 27, 2007, 04:56:07 am
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This drug is moving ahead, and is a different approach to treating HIV. Basically it increases the mutation rate of HIV, which reduces the bug's fitness and causes a collapse in the population of the virus.
http://www.medicalnewstoday.com/medicalnews.php?newsid=75325
I'm not sure quite how it works with existing anti-retrovirals - you'd think it might induce resistance. But they're giving it a go as monotherapy, to see how well it works.
I guess the other drawback is that it relies on the virus replicating, and so doesn't touch on the issues of latency. I don't know which body compartments it does/does not penetrate.
Still, one to watch.
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What a great concept. Let the virus mutate itself into oblivion. I'm keeping my fingers crossed for this one.
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I read about this one some time ago and am glad to hear it's moving into phase 2. I haven't read up on all the specifics, but it sounds at least somewhat promising. Also great that it's expected to work for (and is being tested on) drug-resistant patients.
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thier team seems to be brilliant from all top univsities, and have tons of money behind them
looks like a great method
is this trial in Washington state???
where the company is located or
san diego where the lead Lead Principal Investigator for the trial?????
"KP-1461 is an investigational compound that is a truly different approach to the treatment of HIV," said Robert Schooley, M.D., Head, Division of Infectious Diseases at the University of California, San Diego, School of Medicine and the Lead Principal Investigator for the trial. "The preclinical data for KP-1461 demonstrates that HIV can be extinguished. Whether this same effect will be seen in humans is the subject of this clinical trial. While currently approved HIV treatments are designed to inhibit the growth of HIV, KP-1461 induc
http://www.koronispharma.com/about_us.htm
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this is cool...
basically they throw a wrench in the
viral reverse transcriptase (RT)
with the following 3D compound
The metabolism and activation of the prodrug to KP-1212-triphosphate, the active metabolite and substrate for viral reverse transcriptase (RT), is shown in the following figure.
http://www.koronispharma.com/pipeline.htm
this is cool too........
The Phase 1a trial was a single dose, dose escalation, placebo controlled study of KP-1461 in healthy volunteers. It was shown to be well tolerated at each dose through the highest dose level tested.
also if it only attacks
viral reverse transcriptase (RT)
well the human body doesnt do that so inhibiting it wont hurt us so much
the body does use protease enzyme for example
wow this is based on some major science breakthrus!!!
Koronis' technology evolved initially from the original work of Manfred Eigen, Nobel Laureate at the Max Planck Institute in Gottingen, Germany. He originated the concept of a “quasispecies” - the immensely large number of variants found in populations of virus, especially the RNA viruses (Scientific American July, 1993)
http://www.koronispharma.com/technology.htm
the concept of a critical “error threshold” that sets the bounds for the allowed error rate and resultant diversity within the population and “error catastrophe”, the collapse of the population when that error rate is exceeded.
Drs. Larry Loeb and Jim Mullins of the University of Washington and John Essigmann of the Massachusetts Institute of Technology, Koronis’ scientific founders, hypothesized that by presenting HIV with an error-inducing nucleoside triphosphate substrate, the viral genome mutation rate could be pushed beyond the allowable range of diversity thus extinguishing the population (Proceedings National Academy of Sciences. USA (1999) 96:1492-1497).
one of the advisors seems really smart and created a retrovirus vaccine!!!
http://www.koronispharma.com/AdvisoryBoard.htm
James I. Mullins, Ph.D., Dr. James Mullins has been actively involved in the study of lentiviruses since 1980 and is a world authority in the study of HIV evolution during the course of infection. Dr. Mullins discovered the successful vaccine to protect against the feline leukemia retrovirus FeLV. His lab developed the heteroduplex mobility assay (HMA) that has been used worldwide to track the molecular epidemiology of HIV.
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Full extinction could occur "somewhere in the range of 40 or 50 days," Elmer says.
The clinical study will evaluate whether the product -- known as KP-1461-201 -- is safe and effective in patients who have become resistant to conventional HIV treatments. Up to 32 patients will receive two daily 1600mg doses of the therapy for 124 days.
http://blog.seattletimes.nwsource.com/techtracks/
Privately held Koronis expects to have preliminary results as early as the third quarter, but the drug still has many a hoop to jump through. If all clinical trials are successful and the Food and Drug Administration gives its blessing, the product could hit the market sometime in late 2010 or 2011, Elmer says.
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It's an interesting concept. Problem is that patients will have to stop HAART for 6 weeks, so that's a bit scary, but I'm sure they will find 40 volunteers. Also, they don't know if the body itself may not become overwhelmed with all those different strains. The cells do not know if a strain is virulent or not, they just try to destroy it, and if the virus multiplies like crazy with different shapes, the immune system may suffer. I hope it all goes well!
Milker.
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Sounds promising?
in one article i hear full estingushing.
another article not a cure.
Does that mean it just gets the replicating virus? i did not here it might get the latent cells or how would it get into the latent cells???anymody know :-\
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The major issue of this concept is not stopping the Harrt, but the mutation not only happen in HIV but also your body cells.
Human body have sooooo many DNA and RNA, how can they promise the mutation only happen in HIV, but not elsewhere?
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Human body have sooooo many DNA and RNA, how can they promise the mutation only happen in HIV, but not elsewhere?
Got to agree with this point of concern. All of the other meds screw with the human body's function in one manner or other -- mmm, going from "Bear" to hairless one morning after four months of Crixivan was no joy! -- so the implications of this med could be quite chilling. Our cells may not proliferate in the same manner of HIV, but unintended consequences.....
Cheers,
David
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How i understood this: The idea is to let HIV infect as many T-cells as possible with unfit strain of handicapped HI-viruses. As the time goes on more and more of the the infected T-cells will be producing more handicapped viruses, and fewer and fewer infected T-cells will be producing effective HIV. The most severely handicapped viruses are not able to infect, or are not able to replicate. In the long run, all viruses that are left are not able to infect or are not able to replicate which leads to collapse of virus population.
In the begining all HIV-viruses are high quality good-fitness virus. But in the presence of the drug next generation will seriously impaired. The HIV will be thinking: "How in the hell my children look like this?". Next generation will be even more genetically handicapped and it must be worrisome to HIV when it sees the seriously handicapped mutant generation being brought forward. HIV ask himself "How in the hell my beautiful children turned into these horrible no-good mutants?"
http://en.wikipedia.org/wiki/HIV
HIV differs from many other viruses as it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 10^9 to 10^10 virions every day, coupled with a high mutation rate of approximately 3 x 10-5 per nucleotide base per cycle of replication and recombinogenic properties of reverse transcriptase.[55] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[55]
http://www.medscape.com/viewarticle/421048_3
It is estimated that up to 10 billion (10^10) particles of HIV-1 are produced and cleared daily in an infected individual.[35] This dynamic equilibrium results in continuous turnover of the virus population, with approximately one half of the circulating virus being replaced with newly produced virions each day.[36,37] Thus, the half-life of HIV-1 in the plasma appears to be only 1 to 2 days; the half-life of infectious virions is on the order of minutes.[38] ... . Therefore, given the short half-life of HIV, most of the virus detected in the blood has been produced recently. The cells that produce the virus are also short lived, with a half-life of approximately 1.2 days .. Mathematical modeling suggests that the decay of long-lived infected cells, which have an average half-life of 14 days, is the major determinant of the second-phase decay... In one study, the half-life of latently infected resting memory CD4+ cells was estimated to be as long as 43 months, whereas a second study documented a half-life of only 6 months.[45,46] .
The fact that virus-producing cells have a half-life of approximately 1.2 days means that the viruses must copy themselves (replicate) and infect new cells in order to survive another 1.2 days. But in precense of this new drug the virus is not able to copy itself accurately enough. Each 1.2 days the infectious virus population is cut in half. In a week less than one percent is remaing. Etc
The big question is, how does one ensure that the drug "only attacks viral reverse transcriptase (RT)"?
I wonder if this drug could be effective in those patients having very low T-cell-CD4 count? I mean the fever T-cells one has, the less chances the new-born short-lived infectious viruses have to infect. I suppose when using this drug, low CD4-level is acceptable, maybe even desired for a period of time.
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All of the other meds screw with the human body's function in one manner or other -- mmm, going from "Bear" to hairless one morning after four months of Crixivan was no joy! -- so the implications of this med could be quite chilling. Our cells may not proliferate in the same manner of HIV, but unintended consequences.....
This "mutation acceleration" sounds worse than it is: this med is not about nuclear or radiation experiment. Your sperm/eggs will be OK. Mutation here refers to viral replication mechanisms. Mutation is one of the greatest weapons HIV has, but as it turned out, it is also HIV's weak point, because reverse transcriptae procedure lacks error-control. If this medicide is truly HIV-genome integrated, as they claim, then it only concerns HIV-infected T-cells. This medicine probably does not mean any problems for normal cellular multiplication. The phase 1 trials indicated good safety. I would take it.
This is speacial type of medicine also in the sense that HIV cannot develop a resistant strain against it.
http://www.koronispharma.com/drugdevelopment.html
KP-1461 is an oral prodrug of KP-1212, a nucleoside shown to be effective in cell culture against HIV-1 and HIV-2. It is also effective against virus with mutations conferring resistance to many of the drugs currently approved for treatment of HIV/AIDS. In preclinical cell culture studies, KP-1212 demonstrated an efficacy-dependent increase in random transitional mutations in the HIV genome without host cell toxicity.
Now, lets hope two things:
1) lets hope this medicine works
2) lets hope that if it works, Koronis should obtain a great financial compensation for this smart idea that exceeds the work of big pharmaceutical companies. We need this kind of innovations.
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I felt compelled to write and share with you all my thoughts after having read and researched this thread., especially with regards to the Quasispecies Model and its author...1967 Nobel Prize in Chemistry ....Manfred Eigen.
What a Grande Finale this would be indeed....especially in regards to concepts such as Darwins evolution of the species ...
The analogy and irony whereby the HIV virus would essentially be given a dose of "its own stupidity" ...... is outstanding.
Unfortunately, HIV virus has no concept of condoms....and would essentially die of the same fate it nearly gave humanity.
For those not yet seeing the analogy, here it is;
HIV is essentially ..well like us....in its stupidity. Before it procreates it doesn`t ask its mate for if he or she is a true HIV Positive (as opposed to an imperfect one...the KP1212 mutated one). Its too busy to replicate for that ...plus it does not have a conscience like us.
Manfred Eigen (1967 Nobel Prize in Chemistry) proved that, with time (generational time - HIV is a procreating rabbit in that sense), if you mutate ONE with imperfection (KP1212 effect), you mutate them all.
Manfred Eigen (1967 Noble Prize) proved that eventually, a species with a flaw, but which can still reproduce, will eventually transmit (via reproduction) that flaw to its whole species.
The folks at KoronisPharma have engineered a means of introducing this ¨flaw¨ to its gene pool. Manfred is telling us....let it loose...and you`ll prove my point.
Here is a simple example to Manfred Eigen`s theory.
http://en.wikipedia.org/wiki/Quasispecies_model#A_simple_example (http://en.wikipedia.org/wiki/Quasispecies_model#A_simple_example)
Above all....here is the man behind it.
http://nobelprize.org/nobel_prizes/chemistry/laureates/1967/eigen-bio.html (http://nobelprize.org/nobel_prizes/chemistry/laureates/1967/eigen-bio.html)
Especially interesting are the interview section. Especially the one entitled ¨On Explaining evolution - 7 min¨
http://nobelprize.org/nobel_prizes/chemistry/laureates/1967/eigen-interview.html
(http://nobelprize.org/nobel_prizes/chemistry/laureates/1967/eigen-interview.html)
Keep listening to it to the end ...his thoughts on how he he reconciles theories on creationism verus evolutionism....are simply...divine :)
I know that nothing is proven yet....but there is hope. A whole lot of hope.
I can't wait for Phase II results scheduled sometimes in June 2008.
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I don't want to be too negative about this because any new research is good news, but we have to remember that cancer tumors are often the result of cells replicating themselves to oblivion with bad DNA, and this particular experience is at high risk for generating tumoral cells. I think this is still an experience and unless amazing results are found I don't see this "multiply to death" new way of thinking happening as a way to cure diseases before at least 10 or 20 years. I certainly will not participate in a study that uses that method.
Milker.
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This is one of the most promising medicines in the pipeline. When i read about this drug first time, i was thinking "just another class of HAART". But this is more than that. From scientific-philosophical perspective, and as a method of attack, this drug far exceeds all other forms of HAART. Ofcourse safety is an issue, and it is being studied. Phase 1 showed green flag. I well understand that the term "mutation" rises fear of cancer, but remember that HIV is constantly mutating whether you take this drug or not. HIV is mutating as we speak, whether you like it or not. And your common NNRTI and NRTI's could be far more cancerous than this.
If this drug integrates to HIV RNA only and does not interfere other transscripting activities, then it is safe to use. So i suppose. This is what they say:
The use of a natural sugar in Koronis’ nucleoside drugs allows efficient recognition by the viral polymerase facilitating incorporation of the drug into the viral nucleic acid.
After integrating into the HIV RNA everything else in the cell works as normal.
All subsequent DNA copying prcesses inside the infected T-cell are performed as normal:
Normal transportation to cell nucleus
Normal integration to cell host genome
Normal assembly of proteins
Normal release (budding)
Everything will ne normal, save the fact that viral RNA was distorted in the first place. Does not sound so dangerous to me.
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Questions:
1Does it mentioned about how to deal with dormant HIV?
2.If the not mutant one wake up in a morning and start to produce "healthy" HIV, will it then re-infect the already infected T-cell?
3.If the "dormant HIV" in T cell has not yet been cleaned up, does it means that we always have chance to get sick again?
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I read that some of HIV will be hiding in the gut, and stay there dormant for months (years?).
In test tube, they were able to destroy HIV-population completely. I doubt that this will happe in humans, simply because some of the hiding HIV is already integrated to host DNA long before the drug enters the body. Should the host become active and start budding new HIV:s, this new HIV will have the orginal wild strain genome and it is able to re-infect. So you would not be able to stop using HAART.
However, because of mutating effect, i believe this drug cleans up the body more completely than traditional HAART. None of the active HIV will be spared from the effect of this drug because this drugs operates in a progressive way, from generation to generation. If a particular HIV virus did not meet this drug in one T-cell, it's children will surely meet this drug in another generation and another T-cell. It is more efficient to destroy HIV gradually than attempting to do that in one step. Ultimately all active HIV in the body will be completely destroyed, but latent/silent HIV will survive untouched.
So this is not a "cure", but an effective drug (if it works as planned).
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I read that some of HIV will be hiding in the gut, and stay there dormant for months (years?).
Can someone give us a reference as to this fact? What i am particularly interested in knowing is whether it has been proven that we are talking about one virus ¨life cycle¨ or perhaps many occurring withing these latency reservoirs. essentailly does science know what the ¨tunrover rate¨ is?. I think this is a very important concept with regards to the number of ¨n¨ (Generations - ie. treatment period). Whether it is the same virus that is dormant or whether it is ¨flushed out¨ and re-introduced with a new generation is quite different from a Quasispecies Model and KoronisPharma efficacy point of view.
From your posts under ref #10, it seemed clear, that these little bugs do die off (regardless of where they hide - quite rapidly indeed). What I would like to know is whether it is their reproducing ability that gives them this latency ability. My thought was that its the ¨bunker¨ not the ¨bunkee¨ ability of this virus that keeps it latent.
Please someone enlighten us with regards to latency and specifically with regards known studies on ¨turnover rate¨ withiin these reservoirs.
Seems to me that KP1212 ¨flawed viruses¨ would eventually fill up these reservoirs.
mny thx
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Sorry, I missed it in your quote. My mistake.
Indeed your posts does state that studies point to anywhere from 6 months to potentially 43 months ¨tunrover rate¨ within these latent reservoirs.
Having said so, as per the QuasiSpecies Model, the virus would be out after that. Personnally, I think it would not be on the extreme side....it couldn`t..........power of exponentials.....:). Even if it did, you would be ¨undetectable¨ for all that time with possibly no NRTI..NNRTI...PMI metabolic side effects.
As to the cancer theories.......as Manfred said....RNA is much simpler than DNA. RNA is the root cause.....not our DNA..
I`ll stop here and keep our hopes up.
Looking for Next Gen.
thx
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I don't think this link was cited above - very interesting interview with one of the lead researchers, including extensive discussion of the phase II trial:
http://www.aidsnews.org/2007/09/kp-1461.html
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NYCguy:s linked article. Pay special attention to the statement he made:
You and I both know that none of the HIV drugs currently marketed have been able to extinguish the virus in laboratory cultures, and certainly not in humans. They may be very potent inhibitors, but when the drug is taken away, the virus re-grows. That did not happen with KP-1461. It's a distinguishing feature, from a therapeutic perspective, is that it is capable of viral eradication in vitro.
And after an average 15 serial passages, that virus was irreversibly extinguished -- repeatedly. Repeated, published experiments have demonstrated that you can collapse the viral population with KP-1461.
So in test tube this drug was able to completely eradicate HIV from blood. But only in test tubes...
If the half-life of latent HIV is 43 months, you can count that you need a time of 20 half-lifes to eradicate HIV from the "latent reservoirs", whereever they may be. That would be 70 years. If the half-life of latent HIV is 6 months, the time needed would be reduced to 10 years.
Should this drug be successful, this drug maybe potential for intermittent treatment, or cyclic treatment with normal HAART. You use KP1212 for 6 months, then you switch to normal HAART... Always when you have viral rebound, you challenge it with KP1212... or something...
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Let's speculate a litte bit more about the prospects of destroying HIV...
http://forums.poz.com/index.php?topic=2501.0
A University of California research team has discovered that HIV is able to survive the antiviral effects of treatment by hiding out in the mucosal tissues of the intestine. Even when blood tests show that viral load is undetectable and T-cell counts are responding well to HIV treatment, there is likely ongoing viral replication and immune system damage occurring in the gut.
http://forums.poz.com/index.php?topic=2310.0
The virus replicates in the lining of the gut and does much of its damage to the immune system there, Satya Dandekar, chairwoman of the Department of Medical Microbiology and Immunology at the University of California Davis Health System, and colleagues reported.
The good news here is that the virus is not silent in the gut. HIV is replicating in the gut. This means that in presence of KP1212 virus RNA would be rendered useless in a few generations. If KP1212 is present in the gut, it will destroy HIV there. The question is, can enough drug be delivered to the gut?
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I don`t think the virus within these reservoirs would be in any way protected or shielded. By the drug yes, but remember, the mutated KP1212 is like a trojan horse. Reservoir Virus are not a `Closed System` barring entry into their little sub-population party.
The beauty of this new approach is that KP1212 (the drug) doesn`t need to permeate these reservoirs. HIV will do that by itself. Remember, all you need is one KP1212 mutated virus to go join his fellow mates in there and boom.....this sub-population is doomed (again, according to Manfred Eigen` QuasiSpecies Model`).
I think that is the real beauty of this novel approach. Its the exponential power of the virus replication that is at work not the ability of the drugs to perform one time holocaust.
It lets the virus do what it does best.
Replicate.
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I don`t think the virus within these reservoirs would be in any way protected or shielded. By the drug yes, but remember, the mutated KP1212 is like a trojan horse. Reservoir Virus are not a `Closed System` barring entry into their little sub-population party. The beauty of this new approach is that KP1212 (the drug) doesn`t need to permeate these reservoirs. HIV will do that by itself. Remember, all you need is one KP1212 mutated virus to go join his fellow mates in there and boom.....this sub-population is doomed
One unfit virus entering the sub-population party will not be sufficient. It would multiply and infect T-cells in the gut, but there will be a balance between good fit and unfit viruses. And remember, in absence of the drug (in the gut), evolutionary forces favour the good-fit viruses, because they are more prone to infect. For this drug to work, there needs to be a small flow of mutated unfit viruses entering the gut all the time. That would ultimately result to a change in the genetic makeup of gut viral population (isolated sub-population), marking the dawn of its collapse. So it is not necessary for the drug the permeate everywhere, but sufficient viral exchange is necessary. We do not know yet if there is such a sufficient viral exchange, nor do we know whether this drug will permeate the gut to some degree. However it is clear there is a way for the main-strain viruses to enter to the gut, because thats how they got there in the first place. A lot more is known after phase II trial. But yes, this is a promising drug. Having all that said, it is possible that the optimal strategy with this drug is not "hit-hard", but preferrably "increase slowly", which allows more extensive change in the genotype of viral population allover the body.
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Think about the following scenario:
step 1) You introduce a culture of HIV-resistant T-cells to your body, by genetic engineering, as i mentioned in http://forums.poz.com/index.php?topic=16089.0. These T-cells pass on their HIV resistance to their daughters upon cell division.
step 2) After some months from step 1 you bring about a viral collapse with KP1212. Almost total collapse of HIV would be accomplished, but not in the gut.
In order to survive HIV needs to find a new host within days from entering a T-cell. However, the last remaining HIV viruses in the gut would not be able to reproduce due to the HIV resistant T-cells in the gut. So combining KP1212 to T-cell engineering could in theory accopmlish the dream of eradication. Am i just dreaming?
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well my two cents and I have thought about this alot, i also went to lecture by top ucla dr. re. quasi species is this...
we already have a perfect model to look at this...
the model of two separate individuals, one poz one neg...
one is infected with an managery of quasi species of hiv, this is true all the time, there are always different species in each infected person, then this person infects another neg person
ok now the newly infected depending on his own unique immune system is able to suppress certain species and others are able to get thru, this is determined by APC and peptides and epitopes and the individual properites of each persons immune system, ok now we know that if this individual is average he will have hiv infection for 7 -9 years before cd4 t cells drop to 200 or so
now same thing with this new drug, if it does indeed result in a complete collapse of the active virus, then
after the collapse even if the new virus came out of the latent reservoir
we would have a 7-9 year period where our cd4 cells would slowly get worn down by the virus that escapes from latent reservoirs.
then say at year 5 you could get the treatment again or even after 1 year or once every 6 months or so
by that time they will learn alot about reservoirs and such
the replication rate is extensively studied oxford had a computer model and i read many math articles about this rate
basically i think that this could work brilliantly, and i disagree with milker in his analogy and negative comment that a tumor is mutated that takes over
that is not relavant here why because
this mutation med they have and are giving to humans already!!! that is fantastic in the first place that the time from invention and idea to having a drug to test seems amazingly short
well this drug supposedly only mutates the virus by putting a wrentch in dna
the thing about these dna, and molecules and meds, and shapes of drug molecules is that a molecule is absolutely perfect and cannot be well what i am trying to say is that its behavior is based on electro magnetic physics laws, that i studied extensively in univ. that was my major and for example a nuke or non nuke it has to go to the site of the enzyme because of electro magnetic forces, like two magnets joining together, it is not like they have a choice, these molecules, this molecule world have very very rigid laws
they can be calculated by computers and 2 plus two always is four
the shapes of these molecules is based on electromagnetic properties
so putting that mutation wrentch in the dna of hiv and getting it to reproduce is a major thing
it is so powerful
remember that when say a nuke or a non nuke stops working it is not because the nuke or non nuke that particlular molecule stops working it is because the perfect shape that fit the space in the enzyme, the enzyme was a perfect shape and it changed and evolved a slight different shape so the nuke doesnt magnate or fit in the space anymore
that is why it stops working
a tiny change in one part of molecule changes the shape and the electromagnetic forces do not allow the key to fit
in fact it is much much much more of a tight fit than a key and a lock
it is on the nuclear level and level of the electrons as they zoom around
electrons are as hard as metal, in fact when you see silvery metal you are basically seeing raw exposed electrons in a way
there are very strong and powerful
this is all about 3d shapes and very strong perfect forces of physics law
the math part of the collapse of hte quise species population is another topic
yes
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i just had a major exciting realization
the guy Eigen
when i went to the wiki post by pepino
i realized that this is the same Eigen as Eigen values that I studied extensively in univ. in math, physics, and engineering
eigen values were incredibly interesting though i do not remember too much
i did not even know at the time that eigen was a last name of a person
27 years ago when i studied this ... i thought it was just the name of a math concept like
exponent http://en.wikipedia.org/wiki/Eigenvalue
this is a great way to look at this...
what eigen says is that all things in nature and world
here is an interesting sentance from the new approach paper
http://www.aidsnews.org/2007/09/kp-1461.html
The conventional approach to this problem is to use combinations of different drugs, hoping to suppress HIV to such a low level that little mutation and evolution can take place. This may suppress the virus for years
when they say, "suppress HIV to such a low level that little mutation and evolution can take place"
what they really mean is that the nukes, non nukes and protease, bind to the nuke, non nuke, and protease enzyme and because almost all the enzymes have a drug molecule in them the number of sites of replication of hiv goes from trillions of trillions to ten in the entire body. So with only ten copy machines working, then the detection of only ten copies means under 50 copies means undetectable. but really it is not stopping replication it is just slowing it way way down, so still a few get copied and mistakes get made cause hiv is not good at copying, and then a mutation happens, then virus is immune to the med
now then the problem because how to rebuild the immune system, both CD4 and CD8 and the new discovery that even on successful HAART that there is something some protein or something inside the cd4 cells that causes the ctla receptor to never get turned back on so that cd4 can rebound
so if you collapse all the viral populaiton
and find a way to turn the cd4 back on and cd8 back on then
you are well on the way to rebuilding the immune system
now some think it is hard to find a molecule that can turn the cd4 back on and cd8 back on
i did alot of searching for this in last 12 months and i think one great candidate is a retinoid.
a drug based on retinoid, they already have the monoclonal antibody that fits into the receptor on cd4 and cd8 and that is great but it is far easier to find a molecule that goes into the cell and effects the receptors on cd4 and cd8 FROM THE INSIDE, because remember the cell wall is like a porous membraine and these receptors have part on outside of cell where the anitbody or monoclonal antibody fits and the receptor penetrates thru to the interior of the cell, where molecules can be designed that slow or change the function of the receptor
this is very exciting words on this....
We've gone through phase I studies; phase IA study in healthy volunteers, and a phase I B study in 50 HIV-infected individuals, similar in description to the current phase IIA subjects. They were triple-class-experienced individuals; the drug was given in the 1B study for 14 days, because that is all the animal safety data there was at that time. The bottom line for the phase I studies is that the drug appears safe and quite well tolerated.
this means it is very well tolerated and that they did not see any horrible mutations in the triple-class-experienced individuals.
this is all very very good
What cities is this trial!!!
can we encourage people who are over 250 t cells to try this?
"we actually have one individual who was infected with triple-class resistant virus. Even though they are not treatment experienced, I provided a waiver for that patient, because they had a terribly ugly genotype of triple-class resistant virus, though by transmission, not prior therapy."
anyone who has triple-class resistant virus should try to get in this study!
here is list of dozen of cities!!!!
http://www.clinicaltrials.gov/ct/show/NCT00504452?order=1
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basically i think that this could work brilliantly, and i disagree with milker in his analogy and negative comment that a tumor is mutated that takes over
that is not relavant here why because
this mutation med they have and are giving to humans already!!! that is fantastic in the first place that the time from invention and idea to having a drug to test seems amazingly short
Well I'm sorry but a tumor an abnormal mass of tissue that results when cells divide like crazy or do not die as scheduled. Any genetic mutation due to differences in cell protein expressions can result in oncogenes which then would increase the risk of creating tumoral tissue. All I'm saying is that we do not know yet if this exercise can result in loss of cell regulation.
It is relevant because i'm not taking about the meds, i'm taking about the cell life. We already know about cell exhaustion, this could also be another side effect. And i'm not even going to talk about the brain, where studies on the effect of HIV on the brain are sparse.
It is exciting new science, I agree, but I wouldn't jump on it as being the next best treatment for now.
Milker.
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Here are the safety facts:
http://www.koronispharma.com/drugdevelopment.html
The Phase 1a trial was a single dose, dose escalation, placebo controlled study of KP-1461 in healthy volunteers. It was shown to be well tolerated at each dose through the highest dose level tested. There were no SAE’s (Serious adverse events).
Phase 1b safety and PK trials are underway in HIV-positive patients not receiving other drugs but having experienced multiple classes of currently approved drugs and with demonstrated resistance development to the approved drugs. Based on preliminary Phase 1b data, KP-1461 appears to be generally safe and well tolerated.
http://www.koronispharma.com/KP1461forHIV.html
Phase 1b Trial Confirms Safety & Efficacy of KP-1461 in HIV-positive patients
Preliminary results from a Phase 1b multi-center, randomized, double-blinded, placebo-controlled safety and pharmacology trial in therapy-experienced HIV-infected patients have demonstrated KP-1461 to be generally safe and well tolerated. The trial involves approximately 40 HIV positive patients.
About cancer:
http://www.aidsnews.org/2007/09/kp-1461.html
Genotoxicity depends on how much of the drug is incorporated by human DNA polymerase, and how much of it is excised [cut out]. In the case of human DNA in the nucleus of cells, KP-1461 is very poorly incorporated (by human DNA polymerase) -- a log [about 10 fold] than any of the other nucleoside analogs. But it is incorporated to a modest degree, about as much as 3TC or tenofovir, by gamma polymerase in human mitochondrial DNA. However, it is very quickly proofread and excised. We have done those experiments, and we and the FDA are satisfied with them for dosing, at least this far in our development program.
Cancer is almost always result of years of use of HAART, and this trial is only 4 months. They also mentioned that animal testing warranted 4 months use in human trial, and test tube experiments indicate no host cell toxicity.
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Cancer is almost always result of years of use of HAART, and this trial is only 4 months. They also mentioned that animal testing warranted 4 months use in human trial, and test tube experiments indicate no host cell toxicity.
Whiskey Tango Foxtrot? Cancer is almost always the result of the use of HAART? Would you care to produce some evidence to that effect?
And no, a link from Wikipedia will not do.
MtD
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All right, time to conlude on this thread before we get into too narrow.
Overall, there is no doubt that this new drug is not only different but also full of promises.
Having said so their are risks, and no, you can¨t get assurance from wikipidia.com on that. As a matter of fact, neither could you get such assurance on lypodystrophy, metabolic changes and cancer incidences cause by tri-therapy when the current regime of drugs came out orignally. You can¨t even get that on most of the drugs currently on the market.
So...
If you are within the 3 categories of patients discussed as potential candidates for this study, you can either wait for a wikipidia.com re-assurance or ....well......re-read this thread in its entirety and make up your own mind as to what your risk and benefits are.
The rest of us, are only going to encourage you whatever decision you make.....and support you.
Big Pharma better pick up on this science.....or any other alternative genetic based cures (yes I said cure). If they don¨t, they will be overtaken....and shamed.
Big Kiss to everyone.
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All right, time to conlude on this thread before we get into too narrow.
Oh really? When were you empowered to decide when debates and discussions begin and end?
MtD
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Pepino2 -- your post are very good very factual and scientific -- keep up the good work. Do not feel bad if the gallery of guys say things critical, there are many many individuals with all kinds of painful experiences they have gone thru.
you are completely right on on the post -- esp. about the proofreading out of the mitochondria and the fact that it is factor of ten less toxic for cancer etc than current meds -- this is a miracle, just the concept of it is amazing.
the fact that they are trying it in the best best univ. where they have detailed gene amplification to watch the progress
keep posting man
you are a great reader and great with science
you are not afraid of defining terms - keep using wikipedia
try google scholar and use advanced search and constrain search to 2007 or 2006 so you get the latest papers
my concern with this med -- because i think hope it will work is that --
the great thing about big pharma and the research companies and there are thousands of them and the actual functioning of capitalism (i do have my complaints) is that a totally new thing like this could completely displace everything and make tons of things obsolite... they are finding new uses for haart type meds for cancer which a great thing
but my point is that the system is somewhat functioning cause even any new things that works will be used and you dont see big pharma crying... they will be rejoicing because of a cure or new less toxic treatment
the stock market will price the loss very quickly out of the system...
but i am still very very big on this
i studied Eigen Values when i was in undergrad and it is amazing science
Eigen is a god of a mind and if he thought this up it is a miracle in itself
best way to understand eigen values is --- take a painting of mona lisa -- it can be thought of as millions of points or small rays of different colors -- think of rays not points with different directions, those can be represented mathematically ... now turn the painting so it is not visible you only see the side of the painting
this is a transformation of the rays but suddenly all the rays collapse into one edge and become nothing
-- so then the analogy of the mona lisa and the painting to hiv infection
ok -- all the hiv viruses are like points on a painting, actuallly 3d because 3rd dim. is time, so each different version of quasi species of virus is like one color of the mona lisa painting and then it changes into another color etc, each history of evolution of each species of mutation of each virus in a persons body is a different color and over time paints a picture, that is not too hard to imagine, now
if you can figure out a way to make those mutate faster so that you are turning the family tree of all the viruses perpendicular to the viewer all the evolution collapses because there is no rays no points no colors that can make things continue,
and you do not have to turn the painting completely on it side when you get very very close to on its side, say 99% the virus populaiton collapses just like the painting becomes with out any informaiton content
this is all information content and info theory http://en.wikipedia.org/wiki/Eigenvector
it is wierd to me that what i studied years before 81 and learned is now or could be now the salvation of my life
or at least i am hoping it will be...
the family tree of each viral species or queasi species as eigen calls them is like a vector or ray or point of color on a mona lisa painting
when you turn the matrix far enough all info content collapses
if you like the matrix (i didnt much) it is like that
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When quoting it's usually better to quote the good, but also the bad:
The other key question that people rapidly come up with is, could you create a supervirus?
This needs to be considered. It is a concept that most of us are not familiar with. In HIV therapeutics we are trying to avoid mutations and avoid viral diversity. KP-1461 is a drug intended to create mutations and increase viral diversity. The question of whether you could create a supervirus is one that, at this time, has much less data than the viral vs host DNA selectivity question.
And the unknown:
We can only speak in terms of virology, HIV virology, and evolution. And these studies suggest that of 100 mutations, 49 of them are non-coding; they don't result in an altered protein in any way. These mutation do not change viral enzymes. So they are basically silent.
Fifty of the 100 mutations will reduce viral fitness. We see this all the time with HIV. A mutation in response to a drug impairs the fitness of the virus. Sometimes that fitness hit is greater (as with K65R or 184V mutations), and sometimes less; but they all impair viral fitness.
One percent of mutations are believed to increase viral fitness. So could we create a supervirus? On theoretic grounds it is possible but not likely at all. HIV has evolved to become the supervirus. Mother nature has been testing billions of mutations for decades. For example, compared to Ebola, HIV is successful because it does not kill its host in days. Evolution has selected against the most pathogenic strains that would kill the host too quickly before the virus could be transmitted throughout a human population, which is of course exactly what the virus from its perspective is trying to do. So one could argue that mother nature has in some ways already created this supervirus. The most efficient and effective virus already exists. And 99 of 100 mutations are going to reduce the viruses fitness, not increase it.
I never said I didn't believe it would work, I said it will need more data and that because it's a new approach that has never been tested on other species, I, personally, will not adopt it for now.
Milker.
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Do not feel bad if the gallery of guys say things critical, there are many many individuals with all kinds of painful experiences they have gone thru.
Huh? You mean when someone corrects your repeated assertions that poppers cause Kaposi's Sarcoma it's because we're just bitter old cows with lower t-cells than you?
Surely you jest my good friend. I'd appreciate some clarification on that commentary regarding this web board you've just offered a new member.
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I might not be "new" to the scene, but I've been around long enough to empathize with Biz's statement.
Don't become discouraged Pep-
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Maybe we should get back to talking about this potential treatment and not bashing each other and trying to decide who deserves more pity...
This was just in Thebody.com. Not much new info but some interesting background:
http://www.thebody.com/content/art43529.html?mtrk=3420277
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milker: " The question of whether you could create a supervirus is ..."
Milker. I think originally you were worried about KP1461 mutating host genome DNA. Now you are worried about virus mutating to super virus. Carcinogenicity to host, and super-virus mutation are separate threats. If were you worried about super-virus mutation, and not carcinogenity, why did you not tell it to us in the first place?
I bet within 10 years, you will be taking KP1461 (or it derivatives)... Oh yes, you will be popping these pills like candy.
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I was quoting the link you gave.
Milker.
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Is there anyway this could actually cure hiv infection, it sounds really promising I think this is the best thing I've heard about let's all pray it works. God Bless Everyone
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http://www.physlink.com/Education/AskExperts/ae520.cfm
this is most simple version of a taste of eigen values
i like this stretch metaphor, this shows it in only two dimensions but we live in a four dimensional world, where time is a dimension so this simple example become very much more complex, when you think of a family tree of different offspring of a virus all producing millions of babies and some of those reproducing you have a big structure of a family tree, this can be stretched and deformed and when the mutations of the individuals is so great then the entire structure collapses, that is the theory at least. You see it does not matter how many generations on the family tree the thing is still all one family still all a dog or a virus or an hiv virus, if there are tons of mutations then that acts as a deformation or a stretch of the structure of the family tree (if each node on the tree is a different 3D individual made up of the gene structure of that individual)
see end of this post and i will translate the above link into hiv biology... before your very eyes...
this is what i studied for four years in university, math of eigen, this all made sense to me back then, spent thousands of hours on this... 26 years ago it was very new
http://mathworld.wolfram.com/Eigenvalue.html
this is one trial in so calif. if you live close and meet criteria try it, esp. if meds are failing...
The UCSD Antiviral Research Center is currently seeking participants for a research study of an experimental HIV medication designed to affect the "fitness" of the virus and make it hard for the virus to replicate.
Qualified participants must:
---currently be off HIV medication for at least 16 weeks (don’t go off your drugs for the study)
--have resistance to three classes of HIV medications
--have an HIV RNA greater than 2500
--have a CD4 count greater than 250
You will be compensated up to $750 for your time and the study is for four months.
There is an article in Positively Aware about the study and drug. If you can't follow the link, copy and paste it into your browser :
http://positivelyaw are.com/2007/ 07_04/kp_ 1641.html
Those interested should contact Jack Degnan at the AVRC at 619-543-8080.
What are Eigen Values as applied to hiv drug treatment?
Answer
Place a picture of the family tree of a virus on it and set it spinning. Take something thin and spread it over that picture of the family tree of the virus - all future mutations are on the family tree, even ones that come after the host is destroyed. Pick up an elastic band and stretch it. In each of these cases we do something that affects the shape or orientation of the object or picture in question. The elastic band and butter have been deformed and the picture has been rotated.
When we investigate transformations mathematically we find that there are directions that remain the same after the deformation (forced mutation) has occurred. In the case of the stretching of the elastic band, if you had drawn an arrow on the band before you stretched it, would it point in the same direction afterwards ?
The preserved direction is called an EIGENVECTOR --- this i interpret as the inevitable direction of mutation of virus over time
of the transformation and the associated amount by which it has been stretched is an EIGENVALUE... the value i interpret as the break point after which too many mutations destroy the very possibility of the family tree having any life ... the virus population is terminated.
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http://scholar.google.com/scholar?hl=en&lr=&q=+%22KP+1461%22&as_ylo=2004&as_yhi=2005&btnG=Search
First time this med was ever written about in science was 2005 only one article
then in 2006 only five articles
http://scholar.google.com/scholar?hl=en&lr=&q=+%22KP+1461%22&as_ylo=2006&as_yhi=2006&btnG=Search
then 2007 only one article.. and now we are already in clinical trials...
http://scholar.google.com/scholar?hl=en&lr=&q=+%22KP+1461%22&as_ylo=2007&as_yhi=2007&btnG=Search
2005 article!!!!
Koronis Pharmaceuticals Inc., 12277 134th Ct. N.E. Redmond, WA 98052, USA
Received 9 August 2004; accepted 14 March 2005. Available online 28 April 2005.
Abstract
We report the activities of a novel nucleoside analog against HIV. This nucleoside (KP-1212) is not a chain terminator but exerts its antiviral effects via mutagenesis of the viral genome. Serial passaging of HIV in the presence of KP-1212 causes an increase in the mutation rate of the virus leading to viral ablation. HIV strains resistant to KP-1212 have not yet been isolated. Quite to the contrary, virus treated with KP-1212 exhibited an increased sensitivity not only to KP-1212 but also to another nucleoside reverse transcriptase inhibitor (NRTI), zidovudine. HIV strains resistant to other NRTIs (e.g. zidovudine, lamivudine, stavudine, abacavir, etc.) exhibited no cross-resistance towards KP-1212. Multiple assays confirmed that KP-1212 has a favorable (low) genotoxicity profile when compared to some approved antiviral nucleosides. In addition, KP-1212 is not toxic to mitochondria nor does it exhibit any inhibitory effects on mitochondrial DNA synthesis.
redmond washington... where bill gates and many microsoft billionaires live...
http://koronispharma.com/
Koronis Pharmaceuticals develops anti-viral therapeutics based on Viral Decay Acceleration™ (VDA). The Company's lead product candidate, KP-1461, is currently in clinical trials for HIV..
see this koronis link there are many links and an ANIMATION of KP-1212 -- you have to click the play button like ten times to see the entire video i did at least...
http://koronispharma.com/
http://www.kcumb.edu/NewsDetail.asp?id=11
Location Information
United States, Florida
Bach and Godofsky, Bradenton, Florida, 34205, United States
University of Miami, Miami, Florida, 33146, United States
Triple O Medical Services, West Palm Beach, Florida, 33401, United States
United States, Kansas
Research Centers of Via Christi, Wichita, Kansas, 67214, United States
United States, Maryland
Institute of Human Virology, University of Maryland, Baltimore, Maryland, 21201, United States
United States, Missouri
Dybedal Center for Clinical Research, Kansas City University of Medicine and Biosciences, Kansas City, Missouri, 64106-1453, United States
United States, New Jersey
St. Michael's Medical Center, Newark, New Jersey, 07102, United States
United States, New York
AIDS Community Research Initiative of America, New York, New York, 10018, United States
United States, South Carolina
Greenville Hospital System, Greenville, South Carolina, 29605, United States
More Information
Study ID Numbers: KP-1461-102
Last Updated: July 17, 2007
Record first received: August 9, 2005
ClinicalTrials.gov Identifier: NCT00129194
as an aside...
this was found on an eigen value search
http://civs.stat.ucla.edu/Segmentation/DDMCMC/DDMCMC_segmentation.htm
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http://koronispharma.com/KP1461forHIV.html
see this for more science papers on thier new discovery
http://koronispharma.com/viraldecayacceleration.html
also here the info on quasi species
Drs. Larry Loeb and Jim Mullins of the University of Washington and John Essigmann of the Massachusetts Institute of Technology, Koronis’ scientific founders, hypothesized that by presenting HIV with an error-inducing nucleoside triphosphate substrate, the viral genome mutation rate could be pushed beyond the allowable range of diversity thus extinguishing the population (Proceedings National Academy of Sciences. USA (1999) 96:1492-1497).
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next day..
i have had time to read the abstracts of the above science papers and I am even more excited by this new therapy
the optimistic view is the worse case senario is that the new med would be
- extremely powerful med to add to HAART -- studies linked above show this new med works with some first line therapys --- so that would be a great god send
- use as one of 3 in a triple cocktail or even be able to use as one of two in a dual cocktail
- use as a monotherapy in a once a week, once a day for a few months then off for a few months or a even year
the dosing could be very interesting and less toxic in alternatives
- use as a 4th med in a haart combo for persons with failing reg., this could be like a major power for these people (kind of like noravir is used now)
- use as a monotherapy at normal once a day one pill one med regiem with low side effects
(reason this has low low side effects is shown in the links above)
some of this is guesses and hopeful thinking but i truly believe from all i have read about this now that worst case we have something very very good and exciting on our hands
look how fast it got into clinical trials
best case -- you take it for 6 mo or a year or two years --- and then can go off meds and have undetectable and good t cells that do not fall for years... heck i am seeing that already with a friend on haart, he was on haart right after exposer for 5 years -- now they took him off and for one year his numbers stayed and are still undetectable and 800 tcells
so i think that is what we are looking at some very very good possibilities
low low toxicity
strong potentator for exisiting or resistant
good dosing
the reasons i feel so optimistic is the molecular biology and the ingeneous way this med changes one base pair amino acid and sometimes presents one amino othertimes presents another amino -- see animation link above -- this is a wonderful trojan horse type model
if the list of cities is not one of your cities then please go to clinical trials. gov website and type in the clinical trial code above and see if there are other cities near you
esp. if you have failing or problems with meds
this one in my humble opinion will be as big as protease inhibitors, a revolution on the treatment of this disease
and the finest achievement of a nobel prize math physics wiz
Mr Eigen
from germany i think or usa
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there is a talk tonight on this in san diego by Dr. Susan Little
they are doing a trial on this at ucsd
but most big cities in usa are doing trial
try to get in if you are
1. on failing regiment
or
2. have some big resistance
3 have over 250 t cels
4 have been off meds for 1 or 2 months
this is a big deal
most all gay hubs in USA have this trial
this could be a major breakthru and with low side effects
worth a try
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There is now a Flash animation (http://www.koronispharma.com/flash/video.html) available which illustrates exactly how KP-1461 works. It is an utterly fascinating drug and, whether or not it ultimately makes viral eradication possible, I think it looks very likely it will revolutionise the world of HAART.
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There is now a Flash animation (http://www.koronispharma.com/flash/video.html) available which illustrates exactly how KP-1461 works. It is an utterly fascinating drug and, whether or not it ultimately makes viral eradication possible, I think it looks very likely it will revolutionise the world of HAART.
Wow, that's one kick ass animation....anyone that hasn't seen it check it out.
http://www.koronispharma.com/flash/video.html
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The expected completion date of the trial is july 2008. Only then we will able to see is this drug has "in vivo" antiviral activity.
http://clinicaltrials.gov/ct2/show/NCT00504452?term=kp+1461&rank=1
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Excellent...look forward to the results of this!
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The expected completion date of the trial is july 2008. Only then we will able to see is this drug has "in vivo" antiviral activity.
http://clinicaltrials.gov/ct2/show/NCT00504452?term=kp+1461&rank=1
If they are still recruiting people, and the med shall be taken for 124 days, then it may be a bit difficult to complete the trial in July.
I am very willing to put myself on trial, but I do not fit in the criteria. Wondering if any reader here fall in that category, and would like to give a try?
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fantastic animation thanks for posting, i spent an hour on thier website and some how missed it or perhaps it is very new, i suspect the later
the perfection of this great man Eigen getting nobel prize in math at young age and then at 70 years old thinking of applying his math theory to biology and possibly solving the hiv treatment puzzle is a elegant thing, for his intellect,
it is kind of like putting a mistake into the pattern your grandma was knitting or crocheting in fact after watching so many dna and rna animations i was thinking recently it reminds me so so much of knitting or crocheting
if there is enough errors added to the pattern (the hiv dna) eventually the pattern is not recognizable
in latin the word for net or mesh or lace is labyrinth and the women in portugal and its colonies still weave these amazing labyrinths of white thread ...
and in the texts of greece they said these women were actually weaving the actual universe together
kind of a myth
now we have kp 1212 which weaves a different color thread into the dna of hiv and makes it unviable
i have so much hope
but then i worry that it will not succed
they are doing this at the top universities in the usa
the clinical trial
if you know anyone who is highly resistant or having alot of troubles with meds
or been on meds along time
let them know about this
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Excepting a description on how it work, can't found anything about the outcome of the phase I.
I do understand that these information are confidential, and that probably the results of the Phase I were encouraging (as the Phase II has started), but short comments such as "outstanding result" will have been most appreciated.
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Wow that animation is so cool it got me as excited as kid on Christmas morning. Let's hope and pray this 'present' really gets delivered. I just love it when great thinkers use their gifts creatively to solve problems in novel ways - especially when one of those problems is mine!
Ok, on the pragmatic side, I considered trying to figure out how to invest in this company, but I suspect there is no way without being an institution or very wealthy and going through their VC underwriter. If anyone has any experience or idea about this, would appreciate sharing.
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Excepting a description on how it work, can't found anything about the outcome of the phase I.
Yes, Phase 1 showed the drug to be safe and quite well tolerated. However, it was only based on participants receiving the drug for 14 days (because this was all that could be supported given animal safety data). Apparently it also suggested a positive effect on viral load (although this finding obviously wasn't the subject of this phase).
Phase 2 is ongoing and is based on four months of therapy (because there now is animal safety data to warrant this length).
This and more is outlined in this interview with the doctor behind the trial :
http://www.thebodypro.com/content/treat/art43529.html
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This and more is outlined in this interview with the doctor behind the trial :
http://www.thebodypro.com/content/treat/art43529.html
That interview was very instructive, thanks. Even before results of phase II are published, if a big pharma company makes a bid for, or buys Koronis, that will be a very very strong sign that this new drug will really work. From the interview, we can see that Koronis is not interested in atracting small private investors, they want a single huge investor to associate with them. The same thing happened with Tibotec, when it was acquired by J&J in 2002. Now, if no big pharma company gest interested in Koronis, that is a bad omen.
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anyone who is part of this trial in one of the thirty universities and big research and med. hiv centers in the usa
if you have taken the new medicine
please post your experiences
do you have side effects?
how does it feel to be on a monotherapy?
do you feel the viremia -- the malaise caused by hiv virus - being held off by the meds or returning?
Please post your experiences
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Outcome of the KP-1461 Phase I
The main conclusion can be summarized as follow:
There is little change in the viral load during this 14 days study but authors think it should take 8-12 weeks to see a viral load response.
In others words: no results yest..
Source: http://www.natap.org/2007/IDSA/IDSA_07.htm
Safety and tolerability of KP-1461 in phase 1, dose-ranging study in highly ART experienced HIV infected persons
Reported by Jules Levin
IDSA Oct 2007
SUMMARY
KP-1461 is a novel antiretroviral agent that works as a selective viral mutagen through a process called Viral Decay Acceleration. Unlike conventional ART, KP-1461 demonstrates irreversible viral extinction in vitro. This phase I-b study shows that treatment with KP-1461 is generally safe and well tolerated when administered over 14 days at doses of 400, 800, and 1600 mg every 12 hours to HIV-infected subjects. Whether the notable effect seen in the in vitro studies is replicated in vivo is the subject of an ongoing phase 2 study.
Background
KP-1461 is a novel, first-in-class, therapeutic agent for the treatment of human immunodeficiency virus (HIV) infection. KP-1461 is an oral prodrug of KP-1212, which in vitro irreversibly extinguishes HIV through the process of Viral Decay Acceleration (Harris).
KP-1461 is a deoxycytidine analog that acts as a selective viral mutagen. As a result of its flexible structure, KP-1461 induces base pairing errors. This accumulation of errors leads to a progressive reduction of viral fitness and eventual error catastrophe and population collapse. The naturally high error rate in the incorporation of bases during HIV transcription and the information dense genome allow the virus to escape immune system responses and to develop resistance to antiviral drugs. As a result, HIV exists as a quasispecies containing related variants with differing degrees of fitness, virulence and pathogenicity. The high inherent error rate, lack of RT proofreading capability, and no known ability to repair a DNA-RNA heteroduplex make HIV and other viruses particularly vulnerable to additional errors that could adversely affect viral population survival (Overbaugh; Eigen; Anderson).
KP-1461 contains an unmodified sugar, allowing continual chain elongation by RT, with a modified base that appears ambiguous to the complementary base. Through a tautomeric process, KP-1461 can pair with either guanosine or adenosine, thus creating G-to-A and C-to-T errors (Loeb). Base pairing errors are incorporated randomly throughout the viral genome and persist through subsequent replication cycles. Based on in vitro data where HIV was ablated, modeling suggests that at least 8 to 12 weeks of treatment may be required before a significant antiviral effect in humans is noted.
Consequent to its mechanism of action, KP-1461 does not appear to exert the same type of selective pressure on the virus as conventional antiretrovirals. This may reduce, or even preclude, the development of KP-1461-resistant variants. The ability to irreversibly extinguish virus in vitro, a feature that distinguishes KP-1461 from all approved antiretroviral agents, and extensive pre-clinical evaluation conditioned the conduct of the phase I-b study performed in HIV-infected individuals reported here.
Additional Findings
Combining all subjects treated with KP-1461 to evaluate the system organ classes with the highest incidence of events, the most frequently reported adverse events were: Gastrointestinal Disorders (13 subjects, 41%), Investigations (11 subjects, 34%), Blood and Lymphatic Disorders (8 subjects, 25%), Nervous System Disorders (7 subjects, 22%), Infections and Infestations (7 subjects, 22%), and Metabolism and Nutrition Disorders (7 subjects, 22%).
When individual adverse events were evaluated, headache, nausea, neutropenia and fatigue (or increased fatigue) were the most frequent, with 5 events. Other events were thrombocytopenia and diarrhea, each with 4 events, and dizziness, with 3 reported events for the total KP-1461 group.
Discussion
Safety & Tolerability:
These data demonstrate that KP-1461 is generally safe and well tolerated when administered at multiple doses, thus warranting phase 2 efficacy studies.
--Most adverse events were mild to moderate in intensity
--There were no dose-dependency findings to AEs
-- Gradable values for laboratory abnormalities were generally mild to moderate and showed no dose-dependency
--Further evaluation of hematologic findings in longer-term studies is warranted --No clinically significant changes noted in serial ECG
A total of 3 subjects experienced SAEs. None were attributed to KP-1461
- Thrombocytopenia
- Muscle spasm
- Catheter-related infection
Efficacy:
Despite the expectation that a longer period of dosing would be required, trends are suggestive of antiviral effect by HIV RNA and RT assay at higher doses. (Formal efficacy analysis was not planned as part of this assessment. Descriptive data only is provided.)
Pharmacokinetics:
Findings are supportive of pursuing twice daily dosing. (Full PK data will be presented at European AIDS Conference, Madrid, October 2007.)
Purpose:
The purposes of study KP-1461-102 are to determine the safety, tolerability, and pharmacokinetic activity of multiple oral doses of KP-1461 in HIV+ men and women, and to assess any effect of KP-1461 on plasma HIV RNA.
Objectives:
To assess the safety and tolerability of oral KP-1461 administered every 12 hours for 14 days (28 doses) to cohorts of HIV+ subjects
To determine the PK profiles of KP-1461 (the inactive prodrug) and KP-1212 (the active drug)
To assess the effects of twice-daily KP-1461 over 14 days on plasma HIV RNA copy number and HIV Reverse Transcriptase activity
STUDY DESIGN
Methods
This was a phase 1-b multi-site, randomized, double-blind, placebo-controlled dose-escalation study. Study population included:
• Men and women 18 to 60 years of age
• CD4+ cell counts >100cells/mm3
• HIV RNA 2,500 to 200,000 copies/mL
• Documented exposure to at least two different HAART regimens containing NRTI(s), NNRTI(s), and at least two (2) PIs, excluding low dose Ritonavir, for a minimum of four months each OR documented three class resistance by genotype and/or phenotype AND in the opinion of the investigator, have few if any effective treatment options available.
Four cohorts of 10 subjects each were randomized in a ratio of 4:1 to KP-1461 or placebo, respectively. Successive dose cohorts received 400 mg, 800 mg and 1600 mg of KP-1461 every 12 hours. An additional 10 subjects were enrolled at the 1600-mg dose for a total of 20 subjects at the 1600-mg dose. A fifth cohort of 5 subjects was randomized in a ratio of 4:1 to KP-1461 or placebo, respectively, at a KP-1461 dose of 3200 mg every 12 hours. Data on this cohort is not yet complete.
Subjects were off antiretroviral drugs for at least two weeks prior to the first dose of study drug. Each dose was taken on an empty stomach. Subjects in each cohort were treated for 14 days with an additional 14 days of follow-up. Entry into the next higher dose cohort began when the previous cohort completed enrollment and ≥ 80% of subjects completed dosing plus 1 week of observation. Approval to dose escalate was provided by a Safety Review Committee (SRC). If two or more subjects in a cohort experienced a Grade 3 or 4 toxicity, the SRC reviewed the event to determine whether further dose escalation was safe. If the SRC halted escalation, the previous dose level would be considered the maximum tolerated dose (MTD). Blood was collected for a 12-hour PK profile after the first dose and a 24-hour PK profile after the last dose of KP-1461 (Day 14) and at Days 8, 16, 21 and 28 to determine trough drug concentrations. Routine safety assessments were measured at baseline and on Days 4, 6, 8, 10, 12, 14, 16, 21, and 28. Follow-up safety evaluations occurred at Days 16, 18, 21 and 28. Subjects were able to restart antiretroviral medications after the Day 28 visit. If restarted within 2 weeks of the Day 28 visit, blood was to be collected for viral load and CD4+ count 84 days afterward, if subject agreed to do so.
This study was conducted in accordance with the clinical research guidelines defined in the U.S. 21 CFR Parts 50, 56, and 312, the principles enunciated in the World Assembly Declaration of Helsinki and its most recent amendments, and the principles defined by the International Conference on Harmonization.
(http://www.natap.org/2007/images/101107/Results-1.gif)
(http://www.natap.org/2007/images/101107/organ-2.gif)
(http://www.natap.org/2007/images/101107/cohorm-3.gif)
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I have read with interest and -I'll confess- hope this thread and all the links.
I have a question though.
This med has wiped out the virus completely in cell culture and it's now being tested in humans.
My question is, what happens with the HIV reservoirs such as lymph nodes, brain, liver, ...? even if HIV is extinct in the blood won't the virus in other organs kick in at that point and just keep on replicating itself? I thought that current HAARTS regimens was unable to reach the reservoirs and even though this new med is different I thought it still affected the blood.
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Newbie
I don't think anyone knows the answer to this question, including the people developing the drug. The issue is mentioned in the interview:
It is up to creative scientists, chemist and virologists, to create drugs that can eradicate HIV. We have many things to contend with -- sanctuary sites, and latent resting reservoirs -- but who is to say that the next generation of drugs should not have eradication as its goal?
And I suspect they are viewing this issue with as much hope as you are. Who knows if perhaps this drug can penetrate beyond the circulatory system - the fact that there were neurological adverse events reported in the first study implies that it might cross the blood-brain barrier. But I think the short answer is: no one knows and there won't be anymore answers until the next study is done. If I've missed something anyone, please feel free to correct me!
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This is someones post I read on Thebody.com, but I'm far from a computer genius and for some reason I can't get the link to work so if someone could find out what this is about I would be very thankful.
KP-1461 is doing so well, that koronispharma will start phase 3 within december 2008.
They do not care about any FDA approval..
Here is a link of pacific horizon
http://www.pacifichorizon.com/news/1360635644December2007InVivoEncouragingMutationsVentureModel.pdf
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I read through the whole article but I didn't see this:
"KP-1461 is doing so well, that ..... " Where is that? I only saw one patient has to get an extension meaning the virus wasn't eradicated.
They do not care about any FDA approval.. " -- I only see they are trying to do 202 study, on drug naive poz, in some other coutries because FDA doesn't allow that in the US.
Somebody misinterpreted something.
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Short video discussing to what extend is the mutagenesis for the virus and not the host DNA
http://www.youtube.com/watch?v=5wt5ghBCIjk
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I read something else that said one person will get an extension because they didn't achieve an undetectable viral load during the 124 day's of treatment but they didn't say any thing about all the other people in the study. I had very high hopes for this drug and I would love to know what happened to everyone else during the 124 day's of treatment, I'm sure if someone was eradicated of the virus it would be all over the news and I don't see that, so If anyone else has any new information about this please let us know.
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I second that datdude- id love to hear more about this one.
In my humble opinion this is one of the 2 or 3 most interesting pieces of research that might lead to a possible cure or at least a far superior treatment option.
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I think that good or bad news this company must be very careful how and when it announces so not hearing anything yet means nothing. Sometimes a scientist in a univ. announces a basic science breakthru in press but almost always this is first presented at science conferences to peers. They always tell thier collegues first to get kudos and because these are the people who would understand it the most. a company has more strict requirements to how and when it announces info if it wants to be respected and get investors. many times a year their are private med tech conferences where the bio tech companies present either alone or in groups to the wall street investment world, hoping to get more investment in hopeful new therapies,
i think that the number of breakthrus in last year or two or three is huge and we can all be hopeful and i know i am.
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Your right Bimazek, i guess they have to keep info quiet as not to affect share price, investor interest or even give their ideas to competitors.
However it is hard having to wait several months after 1 piece of good news to see if there were good or bad results.......
Are you looking at anything interesting at the moment?
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interesting, we need to stay on this topic, it should be stickied, sounds very interesting.
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This paper, very interesting even if months old:
interview with Stephen Becker, M.D
http://findarticles.com/p/articles/mi_m0HSW/is_/ai_n21055143
More recently (April 2008)
Safety, Tolerability and Activity of KP-1461
http://www.natap.org/2008/Pharm/Pharm_24.htm
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Author Conclusion
Sufficient evidence to complete all cohorts
Phase 2 studies ongoing at this time:
An Open-Label, Multicenter, Mechanism Validation Study to Evaluate the Safety, Efficacy and Tolerability of KP-1461 as Monotherapy for 124 Days in Antiretroviral-Experienced, HIV-1-Infected Subjects (NCT00504452) (n=32) --26 subjects enrolled,
--9 completed
--1 underwent FDA-compassionate use (beyond 124 days)
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More recently (April 2008)
Safety, Tolerability and Activity of KP-1461
http://www.natap.org/2008/Pharm/Pharm_24.htm
(((((( Can someone explain this in english)))))
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More recently (April 2008)
Safety, Tolerability and Activity of KP-1461
http://www.natap.org/2008/Pharm/Pharm_24.htm
(((((( Can someone explain this in english)))))
Well, I am not sure if I see the diagram correctly, but it seems that, after 14 weeks taking monotherapy KP-1416, the p24 antigen has drop 3 log to almost undectable.
But that is not the major focus. All HAART med can do that. The most important issue here is: after ceasing KP-1212, how would the patient's viral load and CD4 goes?
This medicine is focus on either 1.eradication of the virus, or 2. If not eradicate, patient may cease the med without viral load bouce back "quickly" or CD4 go down to nadir point "quickly".
Therefore, upon ceasing KP-1416, if patient can keep the viral load low for a while (longer than ususal HAART) or they can help patient to keep CD4 dropping slower than HAART), I would say, it is 60% sucessful.
Moreover, they also need to prove, if not eradicate, that patient can cease taking Monotherapy KP-1416 for, say, a year, and then, when go back to the therapy again, the result is still the same. It means that, patients can take the medicine on and off again and again. This is to prevent patient having long term drug toxcity issues caused by Haart. If they can prove this, I would say, it is 80% successful.
If, they can prove that, after cease taking KP-1416 and the viral load will always be undectable, then I'll say, it is 100% successful. (Although, frankly speaking, I kinda doubt this will happen...I still would cross my finger and wish this miracle become true......)
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If this new medicine can maintain viral load undetectable with no serious side effects and with no resistance issues, that would already be a miracle, in my point of view.
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thanks for trying hahaha, but theres alot of graphs and I'm wondering if anyone can explain what they mean and why would they only let one person keep taking kp-1461 if it works. More recently (April 2008)
Safety, Tolerability and Activity of KP-1461
http://www.natap.org/2008/Pharm/Pharm_24.htm
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More recently (April 2008)
Safety, Tolerability and Activity of KP-1461
http://www.natap.org/2008/Pharm/Pharm_24.htm
(((((( Can someone explain this in english)))))
Guys,
In looking more closely at this article and charts, I believe this data is from one of the much earlier phase 1 studies assessing tolerability and basic pharmacology, which was used to justify the current phase 2. This was a 14 day study and I don't think any data at all has been released on the ongoing phase 2, except that it's not over and one person is doing compassionate continuation. And I wouldn't read too much into that - it could mean that it worked so well that the others don't need it anymore and this one person just needed a few more weeks (this is the hopeful reading...) Or it could mean something totally different, but the data's not out yet.
If I'm wrong on this, please correct.
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I agree... this looks like a phase I study results... showing drug concentration in the bloodstream. Because the trial period is short, I think we should be hearing about some phase II data before the end of 2008.
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Guys,
In looking more closely at this article and charts, I believe this data is from one of the much earlier phase 1 studies assessing tolerability and basic pharmacology, which was used to justify the current phase 2. This was a 14 day study and I don't think any data at all has been released on the ongoing phase 2, except that it's not over and one person is doing compassionate continuation. And I wouldn't read too much into that - it could mean that it worked so well that the others don't need it anymore and this one person just needed a few more weeks (this is the hopeful reading...) Or it could mean something totally different, but the data's not out yet.
If I'm wrong on this, please correct.
I think you are right. The data seem to be from this the phase 1b trial, (NCT00129194 in the clinical trials site):
http://clinicaltrials.gov/ct2/show/NCT00129194?term=kp+1461&rank=2
The phase 1b trial was a study of safety, tolerability and pharmokineticc (PK) of kp 1461, and all tables, graphs and charts seem to be about safety, tolerability and PK, except fot a table with the title DRUG ACTIVITY: HIV RNA ( since the study was not designed to study the efficacy of the drug, i did not understand the meaning of this table, maybe someone could explain).
The trial that will give results on the antiretroviral efficacy of KP 1461is the phase 2a trials:
http://clinicaltrials.gov/ct2/show/NCT00504452?term=kp+1461&rank=1
According to the link above, the Estimated Study Completion Date to evaluate the antiviral activity of KP 1461 is december 2008.
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i dont have any questions....just give me some of this stuff!
a pill fatigued fiercenbed
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It is frustrating though, because at this point obviously someone knows something but not one is talking and there's really no way to interpret that unless someone here happens to be in touch with one of the study participants. But it's looking like we'll just have to wait until Dec.
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It seems that:
- Koronis might present a poster next August at AIDS Mexico 2008 (http://www.aids2008.org/)
- Some argues that:
i) as all the 9 participants of the phase I were multi-resistants
ii) that 1 underwent FDA-compassionate use
then: the 8 others have got good results, otherwise they will probably have underwent FDA-compassionate use as well
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i just got emailed this from a recruiter looking for poz guys... this is going on now!!!!!!
I'm on here to help recruit possible subjects for an experimental HIV eradication drug, KP-1461.
The drug is intended to mutate HIV so much that virus population extinguishes itself due to error catastrophe. The drug is in Phase 2 clinical trials and is sponsored by Koronis Pharmaceuticals. Learn more at www.koronispharma.com
To participate you have to have been on antiviral medication THEN DISCONTINUED treatment for 16 weeks or more.
To find a local facility, go to www.clinicaltrials.gov and type KP-1461 in the search field. All information related to the study, including points of contact will be available.
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John:
I read an interview some time back w/the drug investigators and the single compassionate use case was a favor to a guy w/no options left. Otherwise, the study is quite picky about who gets in. I looked at the Clinical Trials site again and nothing has changed... still have very specific requirements to get into this one.
Let hope for a welcome Christmas present this year.
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My ID Dr . ( Nick Bellos) is one of the people conducting a study of this drug..I talked briefly with the person ( J Rice) he has conducting the interviews but couldn't get any thing specific except they are seeing some promise here......very narrow focus for participation as already mentioned....said I would not be considered since my ongoing regimen has been overall successful.....I will check with him each time I go for an appointment..( 3 months) would be nice to see a "cure" instead of a "treatment"
Nick
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There's a huge recruiting ad in "IN MAGAZINE", page 27, here in Los Angeles for this study. The ad doesn't specifically mention the drug's name, but it's obvious from the eligibility requirements. It's a 22 week study.
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http://www.projectinform.org/news/2008/061208.shtml
is this the end of KP 1461???
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In a stunning setback, Project Inform has learned Koronis Pharmaceuticals has stopped two studies of their experimental drug, KP-1461. This decision was based on unexpected results from lab tests and not on safety concerns. Those participating in these studies have been told of these developments.
The lab tests that led to this decision were required by the FDA and were essentially repeats of earlier work done by the company. The tests, called serial passage experiments, exposed HIV to different concentrations of the drug to try and force HIV to grow resistant to it. This helps doctors and researchers understand what changes HIV creates to become resistant. Earlier tests failed to force resistance to KP-1461, so the FDA required Koronis to repeat them until resistance emerged.
The experiments were done by the same team who performed the earlier work. Surprisingly, they found that KP-1461 didn’t show measurable anti-HIV activity, which conflicts with what was seen in earlier lab study. The company then looked at the results from the ongoing studies and found similar results: few people experienced significant reductions in their HIV levels.
Only two people were taking KP-1461 at the time of this discovery. The company informed them of the findings, stopped the KP-1461, and recommended they start a full HIV regimen.
Stephen Becker MD, the lead investigator for Koronis, told Project Inform that the company is, “committed to understanding these discordant results and will attempt to validate the original 2002 research,” on KP-1461. Dr. Becker estimated that it would take at least two months to fully investigate this setback.
KP-1461 is a novel HIV treatment that is supposed to work by speeding up the mutation rate of HIV. In theory, this would lead HIV to mutate so much that it becomes unable to infect cells and replicate. This approach, called terminal mutagenesis,was supported by lab experiments which showed that when HIV was exposed to KP-1461 it eventually mutated itself to death. Many people were skeptical and questioned the wisdom of encouraging HIV to mutate — something every other HIV drug seeks to avoid. Even those who support its development, including Project Inform, have acknowledged the unique hurdles faced by KP-1461 and Koronis.
This setback comes at a time when the pipeline of experimental HIV treatments is drying up. While the past few years have marked an impressive period for new HIV drugs, the next few look thin at best. These disappointing and unexplained results make this situation worse. Project Inform hopes that Koronis can get to the bottom of this vexing mystery and refocus its efforts on developing new treatments against HIV/AIDS.
are you kidding me, talk about losing hope I really thought this was gonna work, this was the only thing I was looking forward to, what if you need to take it for a longer period, I honestly thought it would take a couple years to work completely I never thought you would take this drug for a couple months and you would magically be cured I was thinking 2 years or something like that, why would they just stop it and where am I supposed to go from here. http://www.projectinform.org/news/2008/061208.shtml
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F*CK!
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F..RAUD
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F*CK!
To say the least.
F..RAUD
Also in my opinion.
I THINK ACTIVISTS MUST DO SOMETHING TO SHED LIGHT ON THIS INCREDIBLE STORY.
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Nobody cares about your opinion.
Activists are more concerned about access to health care for poor people, not the views of insane crazy people. For years I wondered why the loony shouting guy who thought he was Jesus and who lives under the railway bridge near my place was homeless.
Then I met you.
So take your capital letters and shove them up your relevant campaign.
MtD
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Matty, chill.
Leit, Paul Dalton of Project Inform who wrote the piece above IS an activist and IS attempting to "shed light" on this story. But the fact is, it's not so incredible. If I had a dime for every agent that entered the drug development pipeline that looked positively amazing in early studies, only to pan out to be a big dud, I'd be a wealthy man. Something obviously went wrong here -- and that's unfortunate. Problem here is that the hype surrounding this compound was always much greater than the actual data supporting it -- and you can thank company-hired publicists and lazy mainstream media for this. Nobody was actually hurt -- aside from a venture capitalist or two -- in the process of this lackluster discovery, so I don't think this really deserves to be chalked up as anything more than it really is... another failed compound.
Tim Horn
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Sorry Tim.
Matty the Damned is like totally chilled, but you're right he should have known better.
And Leit,
Sorry to you to as well. You didn't deserve to be spoken to like that. I offer appropriate apologies.
But honey, if you want to be accepted into this community you've gotta step out into the light. Lurking here in the Research forum just makes you seem like a weirdo.
Drop me a PM sometime. We'll work it out, :)
MtD
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Thank you very much for your reply, Tim!
Paul Dalton of Project Inform who wrote the piece above IS an activist and IS attempting to "shed light" on this story.
Yes, I'm following his valuable work but, if I may venture a remark, he is perhaps a bit "too kind", in the circumstances.
If I had a dime for every agent that entered the drug development pipeline that looked positively amazing in early studies, only to pan out to be a big dud, I'd be a wealthy man.
:) Same here! BUT... if you had a billion for every agent that
- "proved" to irreversibly estinguish the virus after 15 serial passages in vitro
- reached a phase II clinical trial
- THEN, retested in vitro (as required by the FDA) the same way as above, turned out to be completely inactive
would you be a billionaire???
This, IMHO, is the big difference between the KP-1461 story and "normal failures"!
Something obviously went wrong here -- and that's unfortunate.
I strongly hope that Paul Dalton finds out what this "something" is. And, very frankly, I suspect it is not a "scientific something"...
Nobody was actually hurt
I was, Tim. Maybe I'm credulous but I was actually hurt. As you know, KP-1461 approach was completely different from those of all the drugs we have (and VERY intriguing, to say the least); that's why I found this story so depressing both scientifically and in itself.