Koronis: KP-1461

Un farmaco su cui si hanno molte speranze il KP-1461.
Sono stati pubblicati studi preliminari sul KP-1461 della Koronis in cui sembra riesca a produrre mutazioni letali nell'hiv, tanto da ucciderlo e quindi abbassare la carica virale.
Il grosso problema sarebbe la tossicita' pero'.
La Koronis intende continuare con gli studi di fase 2.

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January 19, 2011 01:00 PM Eastern Time
Clinical Trial Results Demonstrate Promise for First Non-suppressive HIV Drug

SEATTLE--(BUSINESS WIRE)--Recently published Phase 2a clinical trial results (accessible by clicking here) show that the frequency of specific, drug-induced mutations in the HIV genome can be significantly increased by administering KP-1461, a drug being developed by Koronis Pharmaceuticals based on its novel Viral Decay Acceleration (VDA) drug mechanism. Koronis is planning a follow-on Phase 2 trial to determine the treatment duration required to achieve a clinically meaningful decrease in a patient’s viral load.

“These clinical findings confirm that KP-1461 causes extra mutations to occur in the HIV genome in HIV-infected patients. We believe the accumulation of extra mutations will eventually cause a critical loss of fitness in a patient’s HIV population. If clinical results from a longer trial confirm that loss of fitness can reduce a patient’s viral load to a clinically meaningful degree, then we believe VDA will become a viable mechanism for an entirely new class of non-suppressive HIV therapeutics”, said lead author James Mullins, Ph.D., Professor of Microbiology and Medicine at the University of Washington.

All approved HIV therapeutics employ suppressive drug mechanisms that inhibit viral enzymatic functions, or block the entry of the virus into uninfected cells. Currently, these suppressive drugs must be administered in a multi-drug cocktail to minimize emergence of drug-resistant HIV strains, and require lifelong administration to ensure continuous suppression of viral replication.

If durable reductions in patient viral populations can be demonstrated in future trials, VDA would become the first clinically-demonstrated non-suppressive drug mechanism against HIV. The possibility of using a non-suppressive drug mechanism such as VDA in HIV treatment would have significant implications for treatment paradigms and could lead to a much wider distribution of anti-HIV drugs throughout the world.

“These results indicate that KP-1461 can increase the frequency of mutations in HIV-1 populations. Importantly, it also appears to be generally safe and well tolerated based on results from the more than 80 patients who have received the drug. While larger studies are obviously needed, the conclusions from this paper certainly underscore the potential for positive clinical effects. This should encourage further development of the VDA mechanism as a new approach for the treatment of HIV-1 infection,” said Charles Hicks, MD, Professor of Medicine at Duke University Medical Center, who is also Director of the Duke University Interdisciplinary Research Training Program in AIDS.

The recently published paper (accessible by clicking here) appears in the January 14, 2011 PLoS One Journal, an international, peer-reviewed publication produced by the Public Library of Science, and presents an analysis of HIV-1 gene sequences from heavily treatment-experienced HIV-infected volunteers treated with KP-1461 for a 4-month period.

About Koronis

Koronis Pharmaceuticals, Inc. was formed in 1998 to develop anti-viral therapeutics based on Viral Decay Acceleration (referred to by some as lethal mutagenesis or selective viral mutagenesis). The Company also has products in development for the treatment of hepatitis C. For more information on Koronis, please visit [Devi essere iscritto e connesso per vedere questo link]

Contacts

Rathbun Communications, Inc.
Julie Rathbun, 206-769-9219
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Gex, credevo ti fossi sbagliato e avessi riportato un articolo vecchio. Infatti della 2afase del trial del KP-1461 se ne parlava gia' nel maggio del 2009.
In realta' si basa su una teoria affascinante quella della "catastrofe da errore" dove praticamente a furia di mutare il virus si suicida.
Mi fa piacere vedere che l'idea non e' stata abbandonata.
Viene spiegata bene qui:
Viral Decay Acceleration
La tecnologia della Viral Decay Acceleration (VDA) della Koronis e’ evoluta inizialmente dal lavoro originale di Manfred Eigen, Nobel laureato al Max Planck Institute di Gottingen, Gemania.
Egli ha sviluppato il concetto di “quasispecie”, l’immensamente grande numero di varianti scoperto nelle popolazioni di virus , specialmente i virus a RNA (Scientific American Luglio 1993).
Una quasispecie virale e’ una popolazione di virus costantemente in evoluzione altamente strutturata e interrelazionata la cui stabilita’ viene definita dalla sua percentuale di errore di replicazione genomica.
Intrinseco in questa definizione sta il concetto di una critica “soglia di errore” che limita la percentuale di errore permesso e la risultante diversita’ dentro la popolazione, e la “catastrofe da errore”, il collasso della popolazione quando la percentuale di errore viene oltrepassata.
La estensione della diversita’ permessa della popolazione virale e’ ulteriormente costretta dall’ambiente circostante. Per esempio, il sistema inmunitario intatto e la attuale terapia farmacologica applicano una constante pressione alla diversita’ permessa.
L’adattiva, alta naturale percentuale di mutazione permette che il virus sviluppi rapidamente la resistenza farmacologica come risposta all’intensa pressione selettiva terapeutica indotta dal farmaco.

Nel caso dell’HIV, la quasispecie risulta dall’altamente prona all’errore trascriptasi inversa virale. I dottori Larry Loeb e Jim Mullins dell’Universita’ di Washington e john Essigmann del Massachusetts Institute of Technology , fondatori della scientifica Koronis, hanno ipotizzato che presentando l’HIV con un substrato di nucleósido trifosfato inducente l’errore, la mutazione del genoma potrebbe essere spinta oltre il limite permesso di diversita’ quindi estinguendo la popolazione.
Questo e’ stato dimostrato in colture cellulari usando un analogo nucleósido che normalmente si basa su una coppi di Guanina ma anche frequentemente su una coppia di Adenina.
Questo accoppiamiento non complementario ha aumentato le mutazioni di G ad A e A a G, nel corso di numerosi cicli di replicazione virale, dando luogo ad un’ablazione virale.
Questo nuovo approccio alla terapia farmacologica antivirale chiamata Viral Decay Acceleration viene applicata a numerosi patogeni umani includendo HIV e HCV.
Uno studio che stanno facendo dei ricercatori israeliani ricorda molto questo della Koronis.
Gli israeliani hanno scoperto che aumentano l'integrazione del cDNA dell'HIV-1 si ottiene la morte per apoptosi delle cellule infette e SOLO delle cellule infette. Senza danni per quelle sane.
A me sembra una ricerca che ha delle prospettive particolarmente buone.
Peccato che sia solo, ancora, alla fase in vitro.

Si Raf anch'io credevo fosse un articolo vecchio, invece sembra che si stia sperimentando di nuovo questo farmaco, molto promettente ma che io ricordi molto tossico..
Dati sulla tossicita lo confermano o sbaglio?

Mah, mi sembra di no. Secondo quanto riportato dalla stessa Koronis non viene riportata nessuna tossicita' genetica sulle cellule ovariche dei criceti ne' sulle cellule B umane.
E' stato testato anche sui cani alle dosi (da cavallo!)di 2 grammi per chilo senza rilevare aumento dei livelli di lattato, che indica una mancanza di tossicita' mitocondriale.
Inoltre sembra sia sicuro e ben tollerato negli umani senza tossicita' in relazione alla dose.

Speriamo allora, l-approccio mi sembra innovativo e interessante..

Ancora un aggiornamento su questo farmaco:

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Clinical Trial Results Demonstrate Promise For First Non-Suppressive HIV Drug

Main Category: HIV / AIDS
Also Included In: Clinical Trials / Drug Trials
Article Date: 21 Jan 2011 - 4:00 PST


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Recently published Phase 2a clinical trial results (accessible by clicking here) show that the frequency of specific, drug-induced mutations in the HIV genome can be significantly increased by administering KP-1461, a drug being developed by Koronis Pharmaceuticals based on its novel Viral Decay Acceleration (VDA) drug mechanism. Koronis is planning a follow-on Phase 2 trial to determine the treatment duration required to achieve a clinically meaningful decrease in a patient's viral load.

"These clinical findings confirm that KP-1461 causes extra mutations to occur in the HIV genome in HIV-infected patients. We believe the accumulation of extra mutations will eventually cause a critical loss of fitness in a patient's HIV population. If clinical results from a longer trial confirm that loss of fitness can reduce a patient's viral load to a clinically meaningful degree, then we believe VDA will become a viable mechanism for an entirely new class of non-suppressive HIV therapeutics", said lead author James Mullins, Ph.D., Professor of Microbiology and Medicine at the University of Washington.

All approved HIV therapeutics employ suppressive drug mechanisms that inhibit viral enzymatic functions, or block the entry of the virus into uninfected cells. Currently, these suppressive drugs must be administered in a multi-drug cocktail to minimize emergence of drug-resistant HIV strains, and require lifelong administration to ensure continuous suppression of viral replication.

If durable reductions in patient viral populations can be demonstrated in future trials, VDA would become the first clinically-demonstrated non-suppressive drug mechanism against HIV. The possibility of using a non-suppressive drug mechanism such as VDA in HIV treatment would have significant implications for treatment paradigms and could lead to a much wider distribution of anti-HIV drugs throughout the world.

"These results indicate that KP-1461 can increase the frequency of mutations in HIV-1 populations. Importantly, it also appears to be generally safe and well tolerated based on results from the more than 80 patients who have received the drug. While larger studies are obviously needed, the conclusions from this paper certainly underscore the potential for positive clinical effects. This should encourage further development of the VDA mechanism as a new approach for the treatment of HIV-1 infection," said Charles Hicks, MD, Professor of Medicine at Duke University Medical Center, who is also Director of the Duke University Interdisciplinary Research Training Program in AIDS.

The recently published paper (accessible by clicking here) appears in the January 14, 2011 PLoS One Journal, an international, peer-reviewed publication produced by the Public Library of Science, and presents an analysis of HIV-1 gene sequences from heavily treatment-experienced HIV-infected volunteers treated with KP-1461 for a 4-month period.

Source:
Koronis Pharmaceuticals, Inc.