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Author Topic: the return of kp1461 in 2010  (Read 15322 times)

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Offline brazilianman

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Offline mecch

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  • red pill? or blue pill?
Re: the return of kp1461 in 2010
« Reply #1 on: September 26, 2009, 09:36:08 PM »
cool concept. but how would this lead to a cure? how would it do anything about dormant HIV that is not replicating.
“From each, according to his ability; to each, according to his need” 1875 K Marx

Offline freewillie99

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Re: the return of kp1461 in 2010
« Reply #2 on: September 27, 2009, 06:03:20 PM »
Such a confusing drug.  It's in, it's out, it's in again. 
Beware Romanians bearing strange gifts

Offline NYCguy

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  • Posts: 180
Re: the return of kp1461 in 2010
« Reply #3 on: October 15, 2009, 05:21:02 PM »
So are they testing it again or what?  I'm confused. 
11/9/06 = #$%^&!
sometime early Dec 2006:
CD4 530 20%/VL >250,000 (&*$$%!!)
started Reyataz300mg/Norvir/Truvada 12-27-06.
1/30/07 CD4 540 30%/VL <400
4/07 CD4 600+ 33%/VL <50
6/9/07 CD4 720 37%/VL <50
10/15/07 CD4 891 (!) %? VL <50
1/2010 CD4 599 (37%) VL<50 (drop due to acute HCV)
9/2010 - looks like HCV is gone for good! And I'm finally drinking again, thank GOD
2013 - considering a switch to Stribild. but I love my Kidneys (but I hate farting all the time!)...
June 2013 - switched to Stribild.  so far so good...

Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #4 on: October 15, 2009, 05:53:00 PM »
So are they testing it again or what?  I'm confused.  

Koronis Pharmaceuticals' Scientific Advisory Board Confirms KP-1461 Clinical Drug Activity, HIV Ablation

Seattle, WA -- May 19, 2009 -- Koronis Pharmaceuticals, Inc., a biotechnology company focused on the development of antiviral therapeutics, today announced that its Scientific Advisory Board (SAB) completed a comprehensive review of the current in vitro and in vivo data for its lead HIV drug, KP-1461. The SAB concluded that recently completed in vitro serial passage studies corroborated the original published data, demonstrating that KP-1212, the active form of the oral prodrug KP-1461, ablated HIV in equivalent laboratory experiments. Additional studies are underway to assess ablation with greater sensitivity.

The SAB also reviewed statistical analyses of in vivo data from clinical trials of KP-1461. They concluded that KP-1461 demonstrated a statistically significant decrease in HIV RNA at the highest dose level as compared to placebo in the Phase 1b study. Decreases in HIV RNA were seen in some patients in Koronis' Phase 2a study, though the results were not statistically significant. Each clinical study met its primary endpoint of demonstrating that KP-1461 was generally safe and well tolerated.

"The current data confirms that the drug results in a substantial loss of HIV in tissue culture, demonstrates antiviral activity in HIV-positive patients and supports the continued development of KP-1461 and Viral Decay Acceleration," stated James Mullins, PhD, Professor of Microbiology and Medicine at University of Washington and Koronis SAB Chair.

According to Dr. Mullins, "Koronis has shown that in a repeat of previous work KP-1461 reduces HIV titer to below detectable levels without noting the drug resistance that is seen with currently approved HIV drugs. This demonstration of the VDA mechanism, if confirmed by further clinical studies, will dramatically alter the treatment paradigm for HIV patients."

Koronis is in the process of completing formulation refinement and designing the next clinical studies of KP-1461
.


LINK:

http://www.hivandhepatitis.com/recent/2009/052209_d.html

What's exciting about this compound, if they can ever turn it into a safe and effective drug, is that,  since it makes HIV mutate to a point that it's powerless, it appears not to have resistance issues.

cool concept. but how would this lead to a cure? how would it do anything about dormant HIV that is not replicating.

If it ends up working, which is a big "IF," I think the idea would be that this would be one medication without issues of resistance, that would replace existing ARVs.
« Last Edit: October 15, 2009, 06:07:05 PM by Inchlingblue »

Offline veritas

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Re: the return of kp1461 in 2010
« Reply #5 on: October 16, 2009, 06:06:54 AM »

Inch,

This drug, KP 1461, encourages the virus to mutate itself to the point of viral decay. True, the virus seems to not be able to find a mutation to outsmart KP 1461, but my question is if viral decay isn't reached, will the virus now have enough mutations to render ART useless? I know the trials were stopped prematurely do to safety ( I believe animal  safety trials went for 120 days and the clinical trials were going beyond that time limit with little viral decrease so the trial was stopped).
The other question is how long does one have to be dosed to reach viral decay?

A lot of questions to be answered. I don't know if I would enter a clinical trial with KP 1461. It will be interesting to watch.

v


Offline NYCguy

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Re: the return of kp1461 in 2010
« Reply #6 on: October 19, 2009, 01:19:25 PM »
The original theory was that if the virus were forced to mutate fast enough the populaton would collapse and they were even hinting at eradication.  If my memory serves, however, the trials were stopped because followup in vitro tests showed no antiviral activity. I don't think it was due to safety issues altiough I believe there was not enough animal data to allow them to test past a short period, which did not prove to have any effectiveness.

I just wonder what has suddenly changed now...
11/9/06 = #$%^&!
sometime early Dec 2006:
CD4 530 20%/VL >250,000 (&*$$%!!)
started Reyataz300mg/Norvir/Truvada 12-27-06.
1/30/07 CD4 540 30%/VL <400
4/07 CD4 600+ 33%/VL <50
6/9/07 CD4 720 37%/VL <50
10/15/07 CD4 891 (!) %? VL <50
1/2010 CD4 599 (37%) VL<50 (drop due to acute HCV)
9/2010 - looks like HCV is gone for good! And I'm finally drinking again, thank GOD
2013 - considering a switch to Stribild. but I love my Kidneys (but I hate farting all the time!)...
June 2013 - switched to Stribild.  so far so good...

Offline veritas

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Re: the return of kp1461 in 2010
« Reply #7 on: October 19, 2009, 01:33:39 PM »

NYCguy,

I understand the premis for freeflowing virus to collapse, but would that mean that dosing would have to continue until all the latent cells bud? I don't think KP 1461 can get at the latent reservoirs. I believe the safety issue was the fact that they did not have enough animal data so they had to stop the trial. What has changed is a good question. Perhaps they did more animal trials or came up with a statistacal method to determine if the time should be extended for humans to reach viral collapse. Does anyone have any clues?
I still think I'll watch from the sidelines.

v

Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #8 on: October 19, 2009, 06:15:17 PM »
I came across this very interesting description of the MOA of KP-1461. They explain here that it can, theoretically, get to the reservoirs. Existing HAART kills individual viruses, KP-1461 (theoretically) promotes the growth of an entire new quasispecies of virus wherever the virus exists in the body, including the reservoirs. This new quasispecies is rendered impotent due to the accelerated mutations. Part of what the clinical trials must determine is for how long the drug must be taken in order for this to (hopefully) happen. Here is what Dr. Becker estimates as far as that: The serial passage data showed extinction of the virus after 15 serial passages in the laboratory. . . we think it will take a couple months to bring about an effect in humans. So the four months was chosen in part reflective of this couple months of dosing, and the fact that there is animal safety data that will permit a study of four months.

Background: The scientific story began when Mansfeld Eigen (who had already won a Nobel Prize in chemistry for other work) applied his chemistry and mathematics background to problems in biology, and with Peter Schuster and others developed the concept of quasispecies. Standard Darwinian evolution predicts that the fittest strain of an organism, the one that reproduces fastest in a given environment, will displace the other strains there. But a virus like HIV is different; it is always mutating, and can mutate back and forth between different strains. The result is that HIV, in a patient with advanced infection or AIDS, exists as millions of related strains within the same patient (usually only one was transmitted, and then it evolved within that individual into countless slightly different variants).

This makes HIV hard to treat, because some members of the quasispecies probably already have resistance mutations to a new drug even by chance alone, and these resistant viruses are ready to be selected and become much more prevalent when the drug is started. 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, but has never succeeded in eradicating it, so patients usually have to stay on treatment for life.

Quasispecies follow different rules than Darwinian evolution. For example, it is possible at least in theory for the strain that reproduces fastest to be replaced entirely by strains that individually reproduce more slowly, but are more fit as a quasispecies. Eigen and Schuster also wrote a well-known book, The Hypercycle: A Principle of Natural Self-Organization, published in 1979 on quasispecies and related concepts.

A way to attack a quasispecies as a whole is to increase the already-high mutation rate, leading to an "error catastrophe" and collapse of the population. This approach was used to design the drug now in a phase II trial, KP-1461. KP-1461 is a nucleoside analog, like AZT, 3TC, and the others; once inside the cell it is chemically modified (triphosphorylated) into its active form (called KP-1212), which can replace one of the four bases used to make DNA. (The four bases are adenosine, cytodine, thymidine, and guanosine -- some say that the initials 'ACTG' for the government AIDS clinical-trials network were not just coincidence.) In DNA the bases are paired, forming the famous double helix; cytidine always pairs with guanosine, and thymidine always pairs with adenosine.

KP-1212 can replace cytidine when the viral enzyme reverse transcriptase is building a new copy of HIV, and pair normally with guanosine. It does not terminate the DNA chain. But KP-1212 was chemically designed to be a flexible molecule, such that it can also look like thymidine and then pair with adenosine. This introduces an error that then is locked into the viral DNA.

These errors happen at random, anywhere in the virus; and when they do not kill the virus outright, they accumulate over generations in the DNA of the viral population. The result is eventually an error catastrophe that can wipe out the entire quasispecies, at least in laboratory tests. If you then take the drug away, the virus does not come back. And the cells on which the virus grew are still alive -- cured of the infection.

AZT and the other approved nucleoside analogs terminate the growth of the DNA chain, killing the copy of virus being built. But that copy is easily replaced by other copies that do not have an abnormal error accumulation, so the population as a whole is not damaged. In contrast, KP-1212 continues to add new errors to the population, in addition to the errors that are already there due to the very high normal mutation rate of HIV.


Continued...

LINK:

http://www.aidsnews.org/2007/10/kp-1461.html
« Last Edit: October 19, 2009, 07:59:42 PM by Inchlingblue »

Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #9 on: October 19, 2009, 06:25:36 PM »
More from the above link:

Several series of in vitro experiments were done in cell cultures, using a very nasty strain of HIV, a homogeneous, highly fit virus. 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.

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 distinguishing feature, from a therapeutic perspective, is that it is capable of viral eradication in vitro. We don't know if that will happen in humans; this is exactly what the current phase II clinical trial is designed to determine.

Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #10 on: October 19, 2009, 06:49:41 PM »
 True, the virus seems to not be able to find a mutation to outsmart KP 1461, but my question is if viral decay isn't reached, will the virus now have enough mutations to render ART useless?

Within 2 weeks after completing Day 28 visit, 18 subjects receiving KP-1461 restarted antiretroviral therapy (ART) and returned for repeat viral load and CD4+ counts at Day 84 (+14 days). Viral load reductions after the restart of ART suggests that treatment with KP-1461 did not cause subjects to become resistant to ART.


LINK (Sections VI, VII, IX & X):

http://www.koronispharma.com/koroniscompendium.html
« Last Edit: October 19, 2009, 06:55:28 PM by Inchlingblue »

Offline xman

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Re: the return of kp1461 in 2010
« Reply #11 on: October 19, 2009, 06:55:44 PM »
They are also claiming the intention to start another phase II trial by EO 2010. What means EO? Perhaps EO is end of?
« Last Edit: October 19, 2009, 06:58:17 PM by xman »
sign the petition launched by the aids policy project addressed to the nih aimed to increase the money needed to find the cure:

http://www.aidspolicyproject.org/petition_for_the_nih

we can make a difference and we need to fight. please support them! it doesn't cost you anything. they need it now more than ever!

Offline veritas

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Re: the return of kp1461 in 2010
« Reply #12 on: October 20, 2009, 05:32:33 AM »

Inch,

Thanks for the further clarifications. I'm still not totally comfortable with KP1461. Some questions that still must be answered and of course further research will have to be done to answer these questions:

Did the eradication that occured in-vitro include virus enclosed in latent cells?
Is 14 days long enough for mutated virus to appear after re-start of ART?
Did they do a genotype or phenotype to determine what mutations are present in post KP1461 virus?
If not (the above) why not?

My gut is telling me they are not being totally up-front with results just like the Thai vaccine. What are your thoughts?  Of course time will tell.

xman,
Yes, EO 2010 means end of year 2010.

v



Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #13 on: October 20, 2009, 11:09:16 AM »

Did the eradication that occured in-vitro include virus enclosed in latent cells?
Is 14 days long enough for mutated virus to appear after re-start of ART?
Did they do a genotype or phenotype to determine what mutations are present in post KP1461 virus?
If not (the above) why not?

 

1) I don't think the in vitro eradication included latent cells, although now that Robert Siciliano has been able to simulate latency in the lab, they should probably test it that way. The reason they say it is the only compound that has achieved eradication in vitro is because when in vitro tests are done with existing ARVs, if the meds are stopped the virus comes back. With KP-1461 when it was stopped, the virus remained inactive. The way I understand how this works, KP-1461 promotes an entirely new quasispecies of the virus in the body, at least theoretically, and this would include reservoirs. IOW the new (and impotent) quasispecies takes over or replaces the existing viral population throughout the body, including the reservoirs. Once medication is stopped, the virus is still there but it is now in a form that cannot do damage. Of course, there's no way to know absolutely if this will happen unless and until clinical trials proceed.

2) He did not say 14 days, he said from 2 to 4 months is what they estimate, but he admits this is just an estimate and there's no way to know for sure. As far as toxicity, up to 4 months was fine in animal models.

3) Yes, they discuss all of that in that first link posted by Brazilianman. This is one part that jumped out at me:

Because KP-1212 is incorporated randomly and not targeted to specific codons, the vast majority of mutations (98%) should occur at sites in the genome that are not known to be involved in drug resistance.

I agree that much remains to be answered. For me, one of the biggest concerns is will it cause mutation in human DNA, which can lead to cancers and other pathologies. Apparently, according to their studies, it is not absorbed by human DNA at levels that are significant enough to do much damage.

I do find this approach a very "elegant" one from a purely theoretical point of view. Viruses in general and HIV in particular are able to evade us precisely because of their ability to mutate and this takes that very fact and turns it on its head.
« Last Edit: October 20, 2009, 11:23:25 AM by Inchlingblue »

Offline NYCguy

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  • Posts: 180
Re: the return of kp1461 in 2010
« Reply #14 on: October 20, 2009, 05:50:25 PM »
I agree that it is not clear how the latency issue will be resolved, but that quote about eradication in-vitro was thrown around quite a bit in the first go-round of this.  Everyone was quite excited and then mid-trial, some FDA-required retesting showed no in-vitro anti-viral activity, so the trial was immediately halted.  Great disappointment abounded, as a lot of us had high hopes for this novel treatment.  Understandably, the company is not pointing this out, but I still wonder what has changed?  Did they re-do the re-do's and find out it actually does work?

And yes, the lack of animal data prevented them from running the trials long enough to reach the theoretical breaking point, but the brief trial showed basically nothing except that it did not induce resistance, which doesn't really prove anything unfortunately.

I'm not holding my breath this time, but I would love to see it work.
11/9/06 = #$%^&!
sometime early Dec 2006:
CD4 530 20%/VL >250,000 (&*$$%!!)
started Reyataz300mg/Norvir/Truvada 12-27-06.
1/30/07 CD4 540 30%/VL <400
4/07 CD4 600+ 33%/VL <50
6/9/07 CD4 720 37%/VL <50
10/15/07 CD4 891 (!) %? VL <50
1/2010 CD4 599 (37%) VL<50 (drop due to acute HCV)
9/2010 - looks like HCV is gone for good! And I'm finally drinking again, thank GOD
2013 - considering a switch to Stribild. but I love my Kidneys (but I hate farting all the time!)...
June 2013 - switched to Stribild.  so far so good...

Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #15 on: October 20, 2009, 08:02:38 PM »
  Everyone was quite excited and then mid-trial, some FDA-required retesting showed no in-vitro anti-viral activity, so the trial was immediately halted.  

According to their website the trial closure was not due to any requirements (or even requests) from the FDA:

Koronis stopped this trial prior to complete enrollment in order to conduct in vitro serial passage studies, which have confirmed HIV ablation consistent with original preclinical results. The trial closure was not requested or required by the FDA and was not related to any safety concerns or adverse events during the trial. Results also demonstrated drug activity as subjects treated with KP-1461 had an increased frequency of HIV mutations that were statistically significant as compared to a separate control group.

LINK:

http://www.koronispharma.com/clinicaltrials.html
« Last Edit: October 20, 2009, 08:07:58 PM by Inchlingblue »

Offline loneranger

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Re: the return of kp1461 in 2010
« Reply #16 on: October 20, 2009, 08:35:26 PM »
I recently emailed Koronis the following:

Dear Sir/Madam

I am writing to you regarding the investigational drug kp 1461 for the treatment of hiv infection. I am a hiv patient based in the UK. Can you give me any details of plans for further clinical trials for kp 1461? I am aware that the phase 2a trial has been completed - I assume phase 2b is the next step and is dependent on funding? Would this trial be global or in US sites only? I am very keen to participate in clinical trials, thus the interest!

Thank you for taking the time to answer my questions.



Here's the reply:

Thank you for your inquiry.

Koronis has very recently updated its website with the Koronis Compendium.
Please visit www.koronispharma.com to review this information.

We are currently refining the drug’s formulation to improve effectiveness
and planning for the next clinical studies to begin in 2010. We are also
looking for additional funding sources for the next clinical trials. If
anyone you know is interested in supporting further clinical trials of
KP-1461, please let me know.

Also, please do let me know if you'd like to be added to our distribution
list for receipt of future news alerts from Koronis.

Looks like funding might be an obstacle at the moment?

Offline veritas

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Re: the return of kp1461 in 2010
« Reply #17 on: October 21, 2009, 05:49:10 AM »

Inch and loneranger,

Just a thought, if Koronis stopped the trial to do more in-vitro studies (pre-clinicals) to confirm ablation then why was the trial started in the first place before these studies were done? The followup by loneranger's email states they have reformulated KP1461 to improve efficacy. What did they see in the trial (or not see) that made them reformulate. Couple the aforementioned with funding problems, when HIV funding seems to be abundant, gives me pause concerning this therapy.

v

Offline NYCguy

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Re: the return of kp1461 in 2010
« Reply #18 on: October 21, 2009, 02:27:29 PM »
Ok, just so we're all very clear on why the original trial was stopped (and so I can stop talking out my ass and use it for what it's supposed to be used for...any volunteers?  :o) I'm going to re-print this entire article from the original thread from 2007.  It's true that Koronis was not required to stop the trial by the FDA (or that they stopped before the FDA could step in) and that it was not due to safety concerns, but rather that FDA-required re-testing did NOT show any anti-hiv activity.  Again, I have serious concerns and I think Koronis is mincing words a bit...

June 12, 2008
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
                                                   

http://www.projectinform.org/news/2008/061208.shtml
« Last Edit: October 21, 2009, 02:30:51 PM by NYCguy »
11/9/06 = #$%^&!
sometime early Dec 2006:
CD4 530 20%/VL >250,000 (&*$$%!!)
started Reyataz300mg/Norvir/Truvada 12-27-06.
1/30/07 CD4 540 30%/VL <400
4/07 CD4 600+ 33%/VL <50
6/9/07 CD4 720 37%/VL <50
10/15/07 CD4 891 (!) %? VL <50
1/2010 CD4 599 (37%) VL<50 (drop due to acute HCV)
9/2010 - looks like HCV is gone for good! And I'm finally drinking again, thank GOD
2013 - considering a switch to Stribild. but I love my Kidneys (but I hate farting all the time!)...
June 2013 - switched to Stribild.  so far so good...

Offline Inchlingblue

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  • Chad Ochocinco PETA Ad
Re: the return of kp1461 in 2010
« Reply #19 on: April 28, 2010, 05:35:26 PM »
Koronis Appoints Rondaxe To Secure Commercialization Partner For KP-1461, Possible Cure For HIV

(Syracuse, NY. – April 28, 2010) – Rondaxe Enterprises, LLC, announced today that it has entered into an agreement with Koronis Pharmaceuticals to secure a commercialization partner to advance an HIV drug known as KP-1461. KP-1461 is currently in phase II clinical trials and is demonstrating remarkable potential to alter the treatment paradigm for HIV.

“If approved, KP-1461 could significantly advance the treatment of HIV over currently available agents, and lead to a cure, rather than today’s chronic treatment of the disease,” said Rondaxe’s James Bergey, Ph.D., who is leading the project.

“We are excited to be working with Rondaxe as we believe their vast network and extensive industry knowledge will help us to identify a sophisticated commercial partner to complete late-stage development and commercialize the product globally” said Donald Elmer, Managing General Partner of Pacific Horizon Ventures, and CEO of Koronis.


Continued . . .

LINK:

http://pharmalive.com/News/index.cfm?articleid=700722&categoryid=54

Offline georgep77

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Re: the return of kp1461 in 2010
« Reply #20 on: April 28, 2010, 09:24:17 PM »
Awesome !
Big pharma must be very, very scared of kp1461.

                   :)
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
+ 2008

Offline Hellraiser

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Re: the return of kp1461 in 2010
« Reply #21 on: April 28, 2010, 09:25:02 PM »
Awesome !
Big pharma must be very, very scared of kp1461.

                   :)


From the way it sounds I'm kinda of scared of it.

Offline veritas

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Re: the return of kp1461 in 2010
« Reply #22 on: April 29, 2010, 05:43:23 AM »

Not only am I leery about it, I don't like the way the original trial and results were reported. I'll wait for phase 3. I doubt big pharma is afraid of this one. Unless they were able to tweak it, to allow for the virus to reach the point of extinction through mutations a lot quicker, I don't like this approach.

Just my humble opinion.

v

Offline hahaha

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Re: the return of kp1461 in 2010
« Reply #23 on: April 29, 2010, 11:43:56 PM »
I used to be the "fan" of kp-1461, but not now,
My new target is the immuntoxin.  My point is, why don't you just kill the virus (infected CD4) instead of expediting its mutation?   If liver toxicity is not an issue, I will give immuntoxin a try.

Nevertheless, with the best of my wishes, I still hope KP-1461 works.  Finger cross.
Aug 9, 2006 Get infected in Japan #$%^*
Oct 2006 CD4 239
Nov 2006 CD4 299 VL 60,000
Dec 1, Sustiva, Ziagan and 3TC
Jan 07, CD4 400

Offline Pepino2

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Re: the return of kp1461 in 2010
« Reply #24 on: May 05, 2010, 08:34:24 AM »
Sounds like a garage sale to me. ??? 

Problem is no one really knows what they are selling.  Similar to hahaha, I too had great hopes for KP1461.  In my humble opinion though, they are either selliong air or they royally screwed up in terms of public disclosures.  Either way, there is lack of transparency, which is usually not a good sign.

Offline geobee

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Re: the return of kp1461 in 2010
« Reply #25 on: May 05, 2010, 06:48:54 PM »
I was skeptical until they started talking about Ribavirin and HCV.  He explained that they didn't know how it worked and now think that it probably works with the same mechanism -- mucking up the HCV genome during replication and causing viral population collapse since it loses the ability to replicate itself.

Offline hello

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Re: the return of kp1461 in 2010
« Reply #26 on: June 08, 2010, 07:07:07 PM »
Inch,

This drug, KP 1461, encourages the virus to mutate itself to the point of viral decay. True, the virus seems to not be able to find a mutation to outsmart KP 1461, but my question is if viral decay isn't reached, will the virus now have enough mutations to render ART useless? I know the trials were stopped prematurely do to safety ( I believe animal  safety trials went for 120 days and the clinical trials were going beyond that time limit with little viral decrease so the trial was stopped).
The other question is how long does one have to be dosed to reach viral decay?

A lot of questions to be answered. I don't know if I would enter a clinical trial with KP 1461. It will be interesting to watch.

v


From what Koronis says, the mutations this drug induces are 1) permanent and crippling, and 2) decrease viral fitness rather than increase it.  I suppose its theoretically possible for an ARV-resistant strain to emerge, but assuming Koronis' scientists know their stuff it isn't gonna happen.  According to Koronis, the drug works by fooling HIV into thinking it is one of the base pairs it needs and the virus incorporates it into its RNA, so not only does the drug induces debilitating mutations, it makes whatever part of HIV's genome it ends up in useless and irreparable since HIV doesn't know it used a false building block to build its genetic structure with.  Also, since the drug exerts no selective pressure (ie targeting a certain HIV function or area of its genome) and induces random errors throughout the entire genome, HIV cannot evolve around it.  HIV evolves around drugs like AZT cause they always target the same spot so HIV is able to "see it coming" so to speak.  Just like if I never threw anything but right hooks at you, you'd eventually predict it and outsmart me.  But if I have absolutely no discernable fighting style or pattern then you can't predict it and thus won't be able to outsmart me.

Sorry if I rambled for too long; I was just trying to convey what I had read in layman's terms.  This one looks promising so far, but then so has just about every other failed miracle drug or vaccine thus far...
PS Only the first paragraph was actually quoted from someone else; the rest is mine.  Could someone tell me how to separate a quote from the rest of the message??
« Last Edit: June 08, 2010, 07:11:41 PM by hello »
peace

Offline Assurbanipal

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Re: the return of kp1461 in 2010
« Reply #27 on: June 08, 2010, 08:22:10 PM »
PS Only the first paragraph was actually quoted from someone else; the rest is mine.  Could someone tell me how to separate a quote from the rest of the message??

Put your cursor all the way at the bottom of the page before you type (So it is underneath the text that reads bracket backslash quote bracket)
5/06 VL 1M+, CD4 22, 5% , pneumonia, thrush -- O2 support 2 months, 6/06 +Kaletra/Truvada
9/06 VL 3959 CD4 297 13.5% 12/06 VL <400 CD4 350 15.2% +Pravachol
2007 VL<400, 70, 50 CD4 408-729 16.0% -19.7%
2008 VL UD CD4 468 - 538 16.7% - 24.6% Osteoporosis 11/08 doubled Pravachol, +Calcium/D
02/09 VL 100 CD4 616 23.7% 03/09 VL 130 5/09 VL 100 CD4 540 28.4% +Actonel (osteoporosis) 7/09 VL 130
8/09  new regimen Isentress/Epzicom 9/09 VL UD CD4 621 32.7% 11/09 VL UD CD4 607 26.4% swap Isentress for Prezista/Norvir 12/09 (liver and muscle issues) VL 50
2010 VL UD CD4 573-680 26.1% - 30.9% 12/10 VL 20
2011 VL UD-20 CD4 568-673 24.7%-30.6%
2012 VL UD swap Prezista/Norvir for Reyataz drop statin CD4 768-828 26.7%-30.7%

Offline Hellraiser

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Re: the return of kp1461 in 2010
« Reply #28 on: June 08, 2010, 08:27:34 PM »
Put your cursor all the way at the bottom of the page before you type (So it is underneath the text that reads bracket backslash quote bracket)

it will look like [ / quote ]  but without the spaces it means it's the end of the other party's quote.

Offline veritas

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Re: the return of kp1461 in 2010
« Reply #29 on: June 09, 2010, 05:12:00 AM »

hello,

I read that paragraph before and believed as you did with the first go round. It didn't work out that way and Koronis has not given a complete answer as to why the first trial was stopped. This type of action sends a red flag up for me. I simply don't trust what they have to say.  Sure, other drugs fail to meet expectations, but with this one there are too many un-answered questions. Also, where are the peer reviews? For me , I will not enter a clinical trial for this drug period. Perhaps, after phase 3  , if proven to be safe and effective.

v

Offline zadex

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Re: the return of kp1461 in 2010
« Reply #30 on: September 09, 2010, 01:16:51 PM »
http://www.businesswire.com/news/home/20100909005539/en

Koronis Pharmaceuticals Announces Late-Breaker Oral Presentation on HIV Therapeutic Candidate KP-1461 at 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Offline newt

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Re: the return of kp1461 in 2010
« Reply #31 on: September 10, 2010, 04:25:32 PM »
If your income depends on sommat that works in a test tube you's gonna ressurect a dead horse n flog it.

Deckchair please

- matt
"The object is to be a well patient, not a good patient"

Offline zadex

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Re: the return of kp1461 in 2010
« Reply #32 on: September 10, 2010, 08:00:44 PM »
This announcement seems to be claiming that there will be a presentation about a First-in-man study and translational science.

I guess we'll see on Monday.

Offline mousey

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Re: the return of kp1461 in 2010
« Reply #33 on: September 28, 2010, 10:05:38 AM »
hi all...any updates on this?  :)
:: Believe in a cure ::

Offline zadex

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Re: the return of kp1461 in 2010
« Reply #34 on: January 15, 2011, 06:10:31 PM »
This report on the Phase II trials was published yesterday:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015135?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plosone%2FPLoSONE+(PLoS+ONE+Alerts%3A+New+Articles)

Not very impressive.
 
But they do believe that "These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach."


Offline Inchlingblue

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Re: the return of kp1461 in 2010
« Reply #35 on: January 16, 2011, 10:30:59 AM »
This report on the Phase II trials was published yesterday:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015135?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+plosone%2FPLoSONE+(PLoS+ONE+Alerts%3A+New+Articles)

Not very impressive.
 
But they do believe that "These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach."


I think it sounds very impressive, actually. The aim of the study was to "determine if there were evidence for an early, subclinical effect of KP1461, prior to the hypothesized ablation of the viral population."

And they found that there was, which is very good news.

As an aside, even though it's common knowledge that HIV replicates very fast, I thought this bit was interesting:

Evolution of HIV-1 proceeds about 1 million times faster than that of the human genome, with approximately one error incorporated into the viral genome each time the virus is replicated.

Based on the level of mutations they were able to quantify, they conclude:

The data revealed an excess of mechanistically anticipated mutations in subjects treated with the drug, suggesting that VDA is applicable to human treatment.

Offline zadex

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Re: the return of kp1461 in 2010
« Reply #36 on: January 19, 2011, 01:25:39 PM »
Here is the press release from Koronis:

http://www.koronispharma.com/news-2011-01-19.html


Offline buginme2

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Re: the return of kp1461 in 2010
« Reply #37 on: January 19, 2011, 09:27:26 PM »
Question...If this compound causes HIV to mutate itself..Could it theoretically cause the virus to mutate into something even more destructive than what it already is?  Who's to assume that it will mutate into something less harmful?
Don't be fancy, just get dancey

Offline zadex

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Re: the return of kp1461 in 2010
« Reply #38 on: January 19, 2011, 11:29:25 PM »
Buginme:
Dr. Stephenecker addressed that concern in a 2007 interview. Here is his answer to that question:

"Dr. Becker: 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.

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 mutations 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 virus's fitness, not increase it."

The whole interview:
http://findarticles.com/p/articles/mi_m0HSW/is_423/ai_n21055143/?tag=content;col1

Offline zadex

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Re: the return of kp1461 in 2010
« Reply #39 on: January 19, 2011, 11:30:31 PM »
*That's Dr. Stephen Becker

Offline buginme2

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Re: the return of kp1461 in 2010
« Reply #40 on: January 19, 2011, 11:38:56 PM »
Thanks Zadex!
Don't be fancy, just get dancey

 


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