New ART KP-1461 Safety/tolerability
Brian Mailman
reported, but just about everything has "gastric events" anyway.
B/
> *Safety and tolerability of KP-1461 in phase 1, dose-ranging study in
> highly ART-experienced HIV infected persons
>
> *Reported by Jules Levin IDSA Oct 2007
>
> P. G. Clay1, D. E. Sweet2, O. O. Osiyemi3, E. Godofsky4, R.
> Redfield5, S. E. Smith6, R. Campo7, J. H. Shrank8, J. Parkins9, J.
> Reno9, S. Becker9 1Kansas City University of Medicine and
> Biosciences, Kansas City, MO, 2University of Kansas School of
> Medicine, Wichita, KS, 3Triple O Medical Services, West Palm Beach,
> FL, 4Bach and Godofsky, MD, PC, Sarasota, FL, 5University of
> Maryland, Baltimore, MD, 6New Jersey Medical School, Newark, NJ,
> 7University of Miami, Miami, FL, 8Greenville Hospital System,
> Greenville, SC, 9Koronis Pharmaceuticals, Inc., Redmond, WA.
>
> *SUMMARY *KP-1461 is a novel antiretroviral agent that works as a
> selective viral mutagen through a process called Viral Decay
> Acceleration. Unlike conventional ART, KP-1461 demonstrates
> irreversible viral extinction /in vitro/. This phase I-b study shows
> that treatment with KP-1461 is generally safe and well tolerated when
> administered over 14 days at doses of 400, 800, and 1600 mg every 12
> hours to HIV-infected subjects. Whether the notable effect seen in
> the /in vitro /studies is replicated /in vivo /is the subject of an
> ongoing phase 2 study.
>
> *Background *KP-1461 is a novel, first-in-class, therapeutic agent
> for the treatment of human immunodeficiency virus (HIV) infection.
> KP-1461 is an oral prodrug of KP-1212, which /in vitro /irreversibly
> extinguishes HIV through the process of Viral Decay Acceleration™
> (Harris).
>
> KP-1461 is a deoxycytidine analog that acts as a selective viral
> mutagen. As a result of its flexible structure, KP-1461 induces base
> pairing errors. This accumulation of errors leads to a progressive
> reduction of viral fitness and eventual error catastrophe and
> population collapse. The naturally high error rate in the
> incorporation of bases during HIV transcription and the information
> dense genome allow the virus to escape immune system responses and to
> develop resistance to antiviral drugs. As a result, HIV exists as a
> quasispecies containing related variants with differing degrees of
> fitness, virulence and pathogenicity. The high inherent error rate,
> lack of RT proofreading capability, and no known ability to repair a
> DNA-RNA heteroduplex make HIV and other viruses particularly
> vulnerable to additional errors that could adversely affect viral
> population survival (Overbaugh; Eigen; Anderson).
>
> KP-1461 contains an unmodified sugar, allowing continual chain
> elongation by RT, with a modified base that appears ambiguous to the
> complementary base. Through a tautomeric process, KP-1461 can pair
> with either guanosine or adenosine, thus creating G-to-A and C-to-T
> errors (Loeb). Base pairing errors are incorporated randomly
> throughout the viral genome and persist through subsequent
> replication cycles. /*Based on in vitro data where HIV was ablated,
> modeling suggests that at least 8 to 12 weeks of treatment may be
> required before a significant antiviral effect in humans is noted.
>
> */Consequent to its mechanism of action, KP-1461 does not appear to
> exert the same type of selective pressure on the virus as
> conventional antiretrovirals. This may reduce, or even preclude, the
> development of KP-1461-resistant variants. The ability to
> irreversibly extinguish virus /in vitro/, a feature that
> distinguishes KP-1461 from all approved antiretroviral agents, and
> extensive pre-clinical evaluation conditioned the conduct of the
> phase I-b study performed in HIV-infected individuals reported here.
>
> *Additional Findings *Combining all subjects treated with KP-1461 to
> evaluate the system organ classes with the highest incidence of
> events, the most frequently reported adverse events were:
> Gastrointestinal Disorders (13 subjects, 41%), Investigations (11
> subjects, 34%), Blood and Lymphatic Disorders (8 subjects, 25%),
> Nervous System Disorders (7 subjects, 22%), Infections and
> Infestations (7 subjects, 22%), and Metabolism and Nutrition
> Disorders (7 subjects, 22%).
>
> When individual adverse events were evaluated, headache, nausea,
> neutropenia and fatigue (or increased fatigue) were the most
> frequent, with 5 events. Other events were thrombocytopenia and
> diarrhea, each with 4 events, and dizziness, with 3 reported events
> for the total KP-1461 group.
>
> *Discussion Safety & Tolerability: *These data demonstrate that
> KP-1461 is generally safe and well tolerated when administered at
> multiple doses, thus warranting phase 2 efficacy studies. --Most
> adverse events were mild to moderate in intensity --There were no
> dose-dependency findings to AEs -- Gradable values for laboratory
> abnormalities were generally mild to moderate and showed no
> dose-dependency --Further evaluation of hematologic findings in
> longer-term studies is warranted --No clinically significant changes
> noted in serial ECG
>
> A total of 3 subjects experienced SAEs. None were attributed to
> KP-1461 - Thrombocytopenia - Muscle spasm - Catheter-related
> infection
>
> *Efficacy: *Despite the expectation that a longer period of dosing
> would be required, trends are suggestive of antiviral effect by HIV
> RNA and RT assay at higher doses. (Formal efficacy analysis was not
> planned as part of this assessment. Descriptive data only is
> provided.)
>
> *Pharmacokinetics: *Findings are supportive of pursuing twice daily
> dosing. (Full PK data will be presented at European AIDS Conference,
> Madrid, October 2007.)
>
>
> *Purpose *The purposes of study KP-1461-102 are to determine the
> safety, tolerability, and pharmacokinetic activity of multiple oral
> doses of KP-1461 in HIV+ men and women, and to assess any effect of
> KP-1461 on plasma HIV RNA.
>
> *Objectives *To assess the safety and tolerability of oral KP-1461
> administered every 12 hours for 14 days (28 doses) to cohorts of HIV+
> subjects
>
> To determine the PK profiles of KP-1461 (the inactive prodrug) and
> KP-1212 (the active drug)
>
> To assess the effects of twice-daily KP-1461 over 14 days on plasma
> HIV RNA copy number and HIV Reverse Transcriptase activity
>
> *STUDY DESIGN Methods *This was a phase 1-b multi-site, randomized,
> double-blind, placebo-controlled dose-escalation study. Study
> population included: o Men and women 18 to 60 years of age o CD4+
> cell counts >100cells/mm3 o HIV RNA 2,500 to 200,000 copies/mL o
> Documented exposure to at least two different HAART regimens
> containing NRTI(s), NNRTI(s), and at least two (2) PIs, excluding low
> dose Ritonavir®, for a minimum of four months each OR documented
> three class resistance by genotype and/or phenotype AND in the
> opinion of the investigator, have few if any effective treatment
> options available.
>
> Four cohorts of 10 subjects each were randomized in a ratio of 4:1 to
> KP-1461 or placebo, respectively. Successive dose cohorts received
> 400 mg, 800 mg and 1600 mg of KP-1461 every 12 hours. An additional
> 10 subjects were enrolled at the 1600-mg dose for a total of 20
> subjects at the 1600-mg dose. A fifth cohort of 5 subjects was
> randomized in a ratio of 4:1 to KP-1461 or placebo, respectively, at
> a KP-1461 dose of 3200 mg every 12 hours. Data on this cohort is not
> yet complete.
>
> Subjects were off antiretroviral drugs for at least two weeks prior
> to the first dose of study drug. Each dose was taken on an empty
> stomach. Subjects in each cohort were treated for 14 days with an
> additional 14 days of follow-up. Entry into the next higher dose
> cohort began when the previous cohort completed enrollment and ≥ 80%
> of subjects completed dosing plus 1 week of observation. Approval to
> dose escalate was provided by a Safety Review Committee (SRC). If two
> or more subjects in a cohort experienced a Grade 3 or 4 toxicity, the
> SRC reviewed the event to determine whether further dose escalation
> was safe. If the SRC halted escalation, the previous dose level would
> be considered the maximum tolerated dose (MTD). Blood was collected
> for a 12-hour PK profile after the first dose and a 24-hour PK
> profile after the last dose of KP-1461 (Day 14) and at Days 8, 16, 21
> and 28 to determine trough drug concentrations. Routine safety
> assessments were measured at baseline and on Days 4, 6, 8, 10, 12,
> 14, 16, 21, and 28. Follow-up safety evaluations occurred at Days 16,
> 18, 21 and 28. Subjects were able to restart antiretroviral
> medications after the Day 28 visit. If restarted within 2 weeks of
> the Day 28 visit, blood was to be collected for viral load and CD4+
> count 84 days afterward, if subject agreed to do so.
>
> This study was conducted in accordance with the clinical research
> guidelines defined in the U.S. 21 CFR Parts 50, 56, and 312, the
> principles enunciated in the World Assembly Declaration of Helsinki
> and its most recent amendments, and the principles defined by the
> International Conference on Harmonization.
>
> *References *Overbaugh J and Bangham CR. Selection Forces and
> Constraints on Retroviral Sequence Variation. Science 2001;
> 292(5519):1106-1109.
>
> Eigen M. Error Catastrophe and Antiviral Strategy. Proc Natl Acad Sci
> USA 2002; 99(21):13374-6.
>
> Anderson JP, Daifuku R, and Loeb LA. Viral Error Catastrophe by
> Mutagenic Nucleosides. Annu Rev Microbiol 2004; 58:183-205.
>
> Loeb LA, Essigmann JM, Kazazi F, Zhang J, Rose KD, and Mullins JI.
> Lethal Mutagenesis of HIV with Mutagenic Nucleoside Analogs. Proc
> Natl Acad Sci USA 1999; 96(4):1492-1497.
>
> 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 Research 2005;67:1-9.
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