[FoRK] KP-1461 for the Treatment of HIV

Tracie K Meyer con10gent_sentience
Sun Oct 16 10:36:20 PDT 2005


KP-1461 for the Treatment of HIV

KP-1461 is an oral prodrug of KP-1212, a nucleoside analog 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.  It is a selective viral
mutagen. In preclinical cell culture studies, KP-1212 demonstrated an
efficacy-dependent increase in random transitional mutations in the HIV
genome without host cell toxicity.   

The metabolism and activation of the prodrug to KP-1212-triphosphate,
the active metabolite and substrate for the viral reverse transcriptase
(RT), is shown in the following figure.

Metabolic Activation of KP-1461
(molecular structure diagrams)

KP-1461 has completed Phase 1a human clinical trials with endpoints of
safety and pharmacokinetics.  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.  Phase 1b safety and PK trials have
just opened for enrollment 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.  Phase IIa efficacy clinical trials will begin at the conclusion
of the Phase 1b studies.

 

Drug Discovery for HCV

The most remarkable and alarming aspects of HCV infection are its high
rate of persistence and its ability to induce chronic liver disease. As
many as 80% of patients have evidence of chronic hepatitis, and 20% to
30% develop cirrhosis. Furthermore, it has become increasingly apparent
that persistent infection with this virus is closely associated with
hepatocellular carcinoma. 

HCV is an RNA virus and its singe-stranded genome has been completely
sequenced.  HCV is a quasi-species with heterogeneity in viral sequences
indicative of a high rate of mutation – exceeding that of HIV. These
mutations are the result of the low fidelity of the HCV-induced RNA
dependent RNA polymerase that replicates the viral genome.  That it is a
quasi-species and has a small, information-dense genome makes it a
viable candidate for SVM drug development. 

Until recently interferon‑a was the only drug approved as a single
therapy for hepatitis C in Europe and North America. In the short term,
about 50% of patients have a response to interferon, but the long-term
results have been disappointing. Recently approved peginterferon-a has
reduced systemic clearance which enables once weekly administration
while maintaining the same side effect profile. Sustained virologic
responses (SVR, defined as undetectable HCV RNA 24 weeks after 48 weeks
of treatment) were 18-25% for peginterferon-a versus 12% for
interferon-a. Among patients with viral genotype 1, the majority of
patients in the U.S., the SVR was 14% while other viral genotype had a
45% response rate. The addition of ribavirin to peginterferon can
increase SVR to 34-42% in patients with viral genotype 1. 

Ribavirin is a synthetic nucleoside analog currently approved for the
treatment of respiratory syncytial virus and for the treatment of HCV in
combination with interferon‑a. Very interestingly, ribavirin’s
predominant mode of action against HCV has been shown to be by Selective
Viral Mutagenesis thus confirming the therapeutic value of Koronis’
technology platform. Combination therapy is becoming the standard of
care for treatment-naive patients and interferon relapsers. However, in
addition to the low SVR rates, interferon therapy is complicated by the
finding that the majority of patients in some care settings are not
candidates for therapy based on such contraindications as psychiatric
illness or ongoing alcohol abuse. 

Because HCV cannot be grown consistently in cell culture, Koronis is
using a combination of model systems to screen its inventory of
potential selective viral mutagens. Bovine viral diarrhea virus and the
synthetic HCV replicon systems allow convenient and relevant screening
for potential efficacy by selective viral mutagens in our inventory.
Potential lead candidates have already been discovered.

http://www.koronispharma.com/pipeline.htm 
Send mail to koronis at koronispharma.com with questions or comments about
this web site.
Copyright © 2005 Koronis Pharmaceuticals
Last modified: 10/14/05  

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-tkm
--
If I could only live at the pitch that is near madness
When everything is as it was in my childhood
Violent,vivid,and of infinite possibility:
That the sun and moon broke over my head.-preface,
'Feast of Snakes'
 

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