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KP-1461
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Drug Class: Nucleoside Reverse Transcriptase Inhibitors
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Drug Description |
| KP-1461 is a potent, non--chain-terminating, mutagenic deoxyribonucleoside analogue. Designated a DNA covert nucleoside, the drug consists of a modified base that incorporates randomly into HIV and pairs with multiple bases.[1][2][3] |
HIV/AIDS-Related Uses |
| KP-1461, also known as SN1461, is in Phase Ia and IIa trials for the treatment of HIV-1 infection in adults.[4][5] |
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Dosing Information |
Mode of Delivery |
| Oral.[6] |
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Pharmacology |
KP-1461 is the oral prodrug of KP-1212. KP-1461 is also known as SN1212.[7] KP-1461 introduces continual mutations into HIV during viral replication by reverse transcriptase (RT). These mutations decrease virus viability and are eventually lethal. This mechanism, selective viral mutagenesis or lethal mutagenesis, is novel to the nucleoside analogue class.[8]
Unlike approved nucleoside RT inhibitors (NRTIs) that contain a modified sugar and unmodified base, KP-1461 has a modified base that allows multiple base pairing. Because KP-1461 pairs with multiple bases, it is able to target all viral proteins rather than a single protein.[9][10]
KP-1461, after conversion to KP-1212, is metabolized to a triphosphate and incorporated into the HIV-1 genome by RT. The drug is similarly incorporated into human mitochondrial DNA polymerase.[11] The active substance KP-1212 has been shown to inhibit antiviral activity in tissues after just one pass; accumulation has been shown to eradicate the virus entirely.[12] HIV strains treated with KP-1212 also showed increased sensitivity to zidovudine.[13]
KP-1461 is being evaluated in an ongoing Phase Ib, randomized trial. In this trial, 40 HIV infected people who have failed prior antiretroviral therapy are receiving escalating doses of KP-1461 or placebo in four cohorts. KP-1461 also is entering a Phase IIa, open-label trial to evaluate its safety, efficacy, and tolerability as monotherapy in 32 treatment-experienced, HIV infected people.[14][15]
In laboratory tests, multiple tissue passes failed to induce resistant HIV isolates after several attempts.[16] No cross resistance has been observed with HIV strains resistant to common nucleoside analogues such as zidovudine, lamivudine, stavudine, and abacavir.[17] |
Adverse Events/Toxicity |
| No significant genotoxicity was observed in vitro in Chinese hamster ovary cells or in human B cells.[18] At doses up to 2 g/kg, no toxicity was observed in dogs; lactate levels did not increase, reflecting a lack of mitochondrial toxicity.[19] KP-1461 appears safe and well tolerated in humans in Phase I studies, and no dose-related toxicities were observed in a completed Phase I study.[20][21] |
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Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use KP-1461. |
Chemistry |
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Other Names |
SN1461[22]
SN1212 [metabolized drug][23]
KP-1212 [metabolized drug][24]
KP-1212/1461[25]
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Further Reading |
PMID/17678417 Novel anti-HIV agent enters Phase IIa clinical trial. Expert Rev Anti Infect Ther. 2007 Aug;5(4):540-1.
PMID/15890415 Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res. 2005 Jul;67(1):1-9. PMID: 15890415
Harris K, Brabant B, Li L, Styrchak S, Gall A, Daifuku R. SN1212/1461 a Novel Mutagenic Deoxyribonucleoside Analog with Activity Against HIV. San Francisco, Abstract 532, 2004.
ClinicalTrials.Gov - Safety and Efficacy Study of KP-1461 to Treat ART-Experienced HIV+ Patients. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00504452. Accessed 02/13/08.
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Manufacturer Information |
KP-1461
Koronis Pharmaceuticals
12277 134th Court NE, Suite 110
Redmond, WA 98052
(425) 825-0240
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References |
[1] CROI - 11th, 2004. Abstract 532.
[2] Koronis Pharmaceuticals - Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 02/13/08.
[3] Antiviral Res - 2005 Jul;67(1):10-7. Epub 2005 Jan 26.
[4] CROI - 11th, 2004. Abstract 532.
[5] Koronis Pharmaceuticals - Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 02/13/08.
[6] CROI - 11th, 2004. Abstract 532.
[7] CROI - 11th, 2004. Abstract 532.
[8] Koronis Pharmaceuticals - Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 02/13/08.
[9] Koronis Pharmaceuticals - Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 02/13/08.
[10] Antiviral Res - 2005 Jul;67(1):10-7
[11] Antiviral Res - 2005 Jul;67(1):10-7
[12] CROI - 2004. Abstract 532.
[13] Antiviral Res - 2005 Jul;67(1):1-9
[14] Koronis Pharmaceuticals - Koronis Newsroom: News and Events. Koronis Pharmaceuticals Begins Phase 1b Clinical Trial of Novel Anti-Viral HIV/AIDS Therapeutic in HIV-Positive Patients [Press Release], October 12, 2005. Available at: http://www.koronispharma.com/News-2005-10-12.Html. Accessed 02/13/08.
[15] Koronis Pharmaceuticals - Koronis Newsroom: News and Events. Koronis Pharmaceuticals Begins Phase 2a Proof of Concept Study of KP-1461, a Novel, Viral Decay Acceleration Agent for HIV Infection [Press Release], June 26, 2007. Available at: http://www.koronispharma.com/news-2007-06-26.html. Accessed 02/13/08.
[16] CROI - 11th, 2004. Abstract 532.
[17] Antiviral Res - 2005 Jul;67(1):1-9
[18] CROI - 11th, 2004. Abstract 532.
[19] Antiviral Res - 2005 Jul;67(1):1-9
[20] Koronis Pharmaceuticals - Koronis Newsroom: Older Releases. Koronis Pharmaceuticals Begins Phase 1b Clinical Trial of Novel Anti-Viral HIV/AIDS Therapeutic in HIV-Positive Patients [Press Release], October 12, 2005. Available at: http://www.koronispharma.com/News-2005-10-12.Html. Accessed 02/13/08.
[21] Koronis Pharmaceuticals - Koronis Newsroom: News and Events. Koronis Pharmaceuticals Begins Phase 2a Proof of Concept Study of KP-1461, a Novel, Viral Decay Acceleration Agent for HIV Infection [Press Release], June 26, 2007. Available at: http://www.koronispharma.com/news-2007-06-26.html. Accessed 02/13/08.
[22] CROI - 11th, 2004. Abstract 532.
[23] CROI - 11th, 2004. Abstract 532.
[24] Antiviral Res - Jul;67(1):10-7
[25] Antiviral Res - 2005 Jul;67(1):1-9
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Updated February 13, 2008
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