Mechanism of Action
: NRTI (viral decay accelerator). KP-1461, a deoxycytidine analog, is a non-chain-terminating nucleoside analog described as a viral decay accelerator (VDA). As a VDA, KP-1461 increases HIV base-pairing mutation rates during HIV transcription, which ultimately can lead to viral load reduction.3,4
KP-1461 is an oral prodrug to KP-1212. KP-1212 is intracellularly phosphorylated to its triphosphate form (KP-1212-TP), which acts as a competitive substrate against the natural substrate deoxycytidine triphosphate (dCTP) for reverse transcriptase (RT). During viral transcription, HIV-1 RT incorporates the KP-1212 monophosphate into the viral genome. As a result of its ability to tautomerize, KP-1212 can pair with either guanosine or adenosine and induces primarily G-to-A and A-to-G (and, to a lesser extent, T-to-C and C-to-T) base pairing errors that are incorporated throughout the viral genome.4-7
Unlike other NRTIs that cause viral DNA chain termination, KP-1461 contains an unmodified sugar that allows viral DNA chain elongation by HIV RT to continue. After multiple replication cycles, KP-1212-induced mutations progressively accumulate. The accumulated mutations then exceed the error threshold of the virus, resulting in virus that is no longer viable or infective. HIV can no longer replicate and the viral population diminishes.3-7
: In a study of KP-1461 monotherapy (1600 mg twice daily) in HIV-infected, treatment-experienced participants, the half-life of KP-1461 was 1.5 hours.3
: A Phase IIa study (NCT00504452
) investigated KP-1461 administered as monotherapy over 124 days in HIV-infected, treatment-experienced participants who had received prior non-suppressive ART and/or had documented resistance to multiple ART classes. Resistance data showed no evidence of significant ARV drug resistance evolving over time as a result of KP-1461 administration. Phenotypic resistance tests found changes in drug susceptibility to drugs in the NRTI, NNRTI, and PI classes in 15 out of 23 participants (65%). Most of the drug susceptibility changes that occurred were transient. The changes that persisted were increases in HIV drug susceptibility. There was no evidence that KP-1461 administration caused decreased susceptibility to any ARV agent during or following completion of the study.3,8
: KP-1461-201; NCT00504452
: Koronis Pharmaceuticals
: The purpose of this study was to validate the mechanism of action of KP-1461 by evaluating the safety and efficacy of KP-1461 monotherapy.
- Participants were HIV-infected, treatment-experienced adults who had been off ART for at least 16 weeks prior to screening.
- Participants had received prior nonsuppressive ART and/or had documented resistance to multiple ART classes. Participants had few treatment options available.
- Participants had HIV RNA >2,500 copies/mL at screening and had stable CD4 counts >250 cells/mm3 while off ART at screening.
: KP-1461 1,600 mg was administered as monotherapy orally and twice daily on an empty stomach for 124 days.3,7,8
Selected Study Results
A Phase I safety and pharmacokinetic study (NCT00129194
) of KP-1461 in HIV-infected participants who have previously failed 2 or more ART regimens has also been completed.9
In the Phase IIa study (NCT00504452), 23 out of 24 participants reported at least 1 adverse event (AE), the majority of which were mild to moderate in severity. Overall, the most common AEs reported were upper respiratory tract infection (21%); sinusitis, headache, and pharyngolaryngeal pain (each occurring in 17% of participants); and nausea, fatigue, and dizziness (each occurring in 13% of participants).3
Six Grade 3 or 4 AEs occurred, including 1 (nausea) that was considered probably related to KP-1461. Twelve out of 24 participants experienced at least one AE that was considered possibly related to KP-1461. The most frequently reported KP-1461-related AEs were gastrointestinal (GI) disorders, which occurred in 42% of participants, and nervous system disorders, which occurred in 21% of participants. Nausea was the most common GI disorder; dizziness and dysgeusia were the most common nervous system disorders. Two participants discontinued treatment because of an AE: 1 participant because of headache and nausea, and another participant because of esophagitis. No consistent laboratory abnormalities were noted.3
KP-1461 drug interactions are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/815588-85-3. Last accessed on January 26, 2017.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on January 26, 2017.
- Hicks C, Clay P, Redfield R, et al. Safety, Tolerability, and Efficacy of KP-1461 as Monotherapy for 124 Days in Antiretroviral-Experienced, HIV Type 1-Infected Subjects. AIDS Res Hum Retroviruses. 2013 Feb; 29(2): 250–255. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552433/. Last accessed on January 26, 2017.
- Clay PG, Sweet DE, Osiyemi OO, et al. Safety and tolerability of KP-1461 in phase 1, dose-ranging study in highly ART experienced HIV infected persons. 45th Annual Meeting of the Infectious Diseases Society of America (IDSA); Oct 4-7, 2007; San Diego, CA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2007. Available at: http://www.natap.org/2007/IDSA/IDSA_07.htm. Last accessed on January 26, 2017.
- James JS. New Kind of Antiretroviral, KP-1461; Clinical Trial Recruiting. Interview with Stephen Becker, M.D. AIDS Treat News. 2007 Jul-Sep; 423: 3-7. Available at: http://www.aidsnews.org/2007/10/kp-1461.html. Last accessed on January 26, 2017.
- Murakami E, Basavapathruni A, Bradley W, and Anderson KS. Mechanism of action of a novel viral mutagenic covert nucleotide: Molecular interactions with HIV-1 reverse transcriptase and host cell
DNA polymerases. Antiviral Res. 2005 Jul; 67(1): 10-7. Available at: http://www.vdapharma.com/s/2005-Mechanistic-studies-on-KP-1212.pdf. Last accessed on January 26, 2017.
- Mullins JI, Heath L, Hughes JP, et al. Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461. PLoS One. 2011; 6(1): e15135. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021505/. Last accessed on January 26, 2017.
- Koronis Pharmaceuticals. An Open-Label, Multicenter, Mechanism Validation Study to Evaluate the Safety, Efficacy and Tolerability of KP-1461 as Monotherapy for 124 Days in Antiretroviral-experienced, HIV-1-infected Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 18, 2007. NLM Identifier: NCT00504452. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00504452. Last accessed on January 26, 2017.
- Koronis Pharmaceuticals. A Double-Blind, Placebo-Controlled, Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of KP-1461 in HIV+ Adults Who Have Failed Two or More Highly Active Antiretroviral Regimens (HAART). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 9, 2005. NLM Identifier: NCT00129194. Available at: https://clinicaltrials.gov/show/NCT00129194. Last accessed on January 26, 2017.
Last Reviewed: January 26, 2017