KP-1461, also known as SN1461 and SN1212, is a type of medicine called a nucleoside analogue. KP-1461 works by introducing changes to HIV's genetic makeup that eventually kill the viral particles.
HIV/AIDS-Related Uses
KP-1461 is an investigational medicine that is not yet approved by the FDA for use outside of clinical trials. It is being studied for the treatment of HIV-1 infection. This medicine does not cure or prevent HIV infection or AIDS and does not reduce the risk of passing the virus to other people.
Dosage Form/Administration
KP-1461 is taken by mouth.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine.
Possible Side Effects
Along with its desired effects, KP-1461 may cause some unwanted effects. Not all of these effects are known; further study is needed to identify side effects.
Drug and Food Interactions
A doctor should be notified of any other medications being taken, including prescription, nonprescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use KP-1461.
Manufacturer Information
KP-1461
Koronis Pharmaceuticals
12277 134th Court NE, Suite 110
Redmond, WA 98052
Phone: 425-825-0240
Fax: 425-825-7470
Last Updated: April 8, 2009
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]
References
[1] CROI 11th, 2004. Abstract 532.
[2] Koronis Pharmaceuticals Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 04/08/09.
[3] Antiviral Res 2005 Jul;67(1):10-7. Epub 2005 Jan 26.
HIV/AIDS-Related Uses
KP-1461, also known as SN1461, is in Phase IIa trials for the treatment of HIV-1 infection in adults. [1] [2]
References
[1] CROI 11th, 2004. Abstract 532.
[2] Koronis Pharmaceuticals Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 04/08/09.
Dosing Information
Mode of Delivery
Oral. [1]
References
[1] CROI 11th, 2004. Abstract 532.
Pharmacology
KP-1461, also known as SN1212, is the oral prodrug of KP-1212. [1] KP-1461 introduces continual mutations into the HIV genome during viral replication by reverse transcriptase (RT). These mutations decrease virus viability and lead to viral collapse. This mechanism, selective viral mutagenesis or lethal mutagenesis, is novel to the nucleoside analogue class. [2]
Unlike approved nucleoside RT inhibitors (NRTIs) that contain a modified sugar and an unmodified base, KP-1461 contains a natural or unmodified sugar and a modified base, allowing for efficient recognition by the viral polymerase and multiple base pairing. Because KP-1461 pairs with multiple bases, it is able to target all viral proteins rather than a single protein. [3] [4]
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. [5] The active substance, KP-1212, has been shown to inhibit viral activity in tissues after just one pass; accumulation has been shown to eradicate the virus entirely. [6] It has also been found that HIV strains treated with KP-1212 demonstrate increased sensitivity to zidovudine. [7]
KP-1461 has been evaluated in a Phase Ib, randomized, double-blinded, placebo-controlled safety and pharmacology trial. In this trial, approximately 40 HIV-infected subjects failing prior antiretroviral therapy received escalating doses of KP-1461 or placebo in four cohorts. KP-1461 also entered a Phase IIa, open-label trial evaluating safety, efficacy, and tolerability as a monotherapy in 32 treatment-experienced, HIV infected subjects. [8] [9] However, in order to investigate data discrepancy and examine clinical results, this trial was suspended by the drug developers. [10]
In laboratory tests, multiple tissue passes in the prescence of SN1212 failed to induce resistant HIV isolates after several attempts. In addition, cross resistance to SN1212 has not been observed with HIV strains resistant to common nucleoside analogues such as zidovudine, lamivudine, stavudine, and abacavir. [11] [12]
References
[1] CROI 11th, 2004. Abstract 532.
[2] Koronis Pharmaceuticals Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 04/08/09.
[3] Koronis Pharmaceuticals Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 04/08/09.
[4] Antiviral Res 2005 Jul;67(1):10-7
[5] Antiviral Res 2005 Jul;67(1):10-7
[6] CROI 2004. Abstract 532.
[7] Antiviral Res 2005 Jul;67(1):1-9
[8] 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 04/08/09.
[9] 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 04/08/09.
[10] Koronis Pharmaceuticals Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 04/08/09.
[11] CROI 11th, 2004. Abstract 532.
[12] Antiviral Res 2005 Jul;67(1):1-9
Adverse Events/Toxicity
No significant genotoxicity was observed in vitro in Chinese hamster ovary cells or in human B cells. [1] At doses up to 2 g/kg, no toxicity was observed in dogs; lactate levels did not increase, reflecting a lack of mitochondrial toxicity. [2] KP-1461 appears safe and well-tolerated in humans, with no dose-related toxicities observed in Phase I studies. [3] [4] Results from the suspended Phase IIa open-label trial suggest occasional mild to moderate adverse events related to the use of KP-1461. [5]
References
[1] CROI 11th, 2004. Abstract 532.
[2] Antiviral Res 2005 Jul;67(1):1-9
[3] 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 04/08/09.
[4] 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 04/08/09.
[5] Koronis Pharmaceuticals Koronis Pharmaceuticals - Programs: KP-1461 for HIV. Available at: http://www.koronispharma.com/KP1461forHIV.html. Accessed 04/08/09.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use KP-1461.
Chemistry
Further Reading
Novel anti-HIV agent enters Phase IIa clinical trial. Expert Rev Anti Infect Ther. 2007 Aug;5(4):540-1.
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 04/08/09.
Manufacturer Information
KP-1461
Koronis Pharmaceuticals
12277 134th Court NE, Suite 110
Redmond, WA 98052
Phone: 425-825-0240
Fax: 425-825-7470
Last Updated: April 8, 2009