Lersivirine

Lersivirine (UK-453061) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI)for human immunodeficincy virus (HIV) infection with IC50 value of 119 nM [1].

HIV is a retro virus that causes HIV infection and acquired immunodeficiency syndrome (AIDS). It may infect vital cells of human immune system such as helper T cells and dendritic cells. HIV transcriptase plays an important role in the infection process. HIV carries a reverse transcriptase which can transcript single-stranded virus RNA into double-stranded DNA. When the virus anchor to the target cell surface, the reverse transcriptase will be injected into host cell, there it may complete the transcription. And the transcribed DNA is able to integrate into host genome to complete infection and viral replication.

Lersivirine (UK-453061) is a NNRTI with a unique resistance profile that exhibits potent antiretroviral activity against wild-type HIV and clinically relevant NNRTI-resistant strains. When lersivirine was tested with a panel of isolated wild-type and drug-resistant HIV reverse transcriptase, it exhibited excellent inhibitory activity, which confirmed the high potency of it as the next-generation anti-HIV NNRTI. The compound also has good aqueous solubility and formulation characteristics which enable further in vivo evaluation [2].

Mated Crl:CD1 mice were administered 0, 150, 350, and 500 mg/kg lersivirine once daily by oral gavage on gestation days 6 to 17, followed by cesarean section on gestation day 18. The first 2 days of dosing for the high-dose group were done at 250 mg/kg to allow induction of hepatic metabolizing enzymes, after which the dose was increased to 500 mg/kg/day. Exposure of lersivirine did not cause any increases in external, visceral, or skeletal malformation, which demonstrated lersivirine is not teratogenic in mice [3].

References:
[1] Mowbray C E et al. , Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate. Bioorg Med Chem Lett. 2009, 19(20):5857-60.
[2] Davis J et al. , The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects. Eur J Clin Pharmacol. 2012, 68(11):1567-1572.
[3] Cappon G D et al. , Developmental toxicity study of lersivirine in mice. Birth Defects Res B Dev Reprod Toxicol. 2012, 95(3):225-30.

Effects of lersivirine on canine and rodent thyroid function.[Pubmed:24135463]

Toxicol Pathol. 2014 Jul;42(5):897-912.

Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) being developed for the treatment of HIV-1 infection. Like other NNRTIs, Lersivirine is a potent enzyme inducer in rodents capable of inducing a number of hepatic enzymes including those involved in its own metabolism. Preclinically Lersivirine has been associated with hepatocellular hypertrophy and thyroid gland follicular cell hypertrophy in rats, mice, and dogs. In rodents, we show that development of thyroid hypertrophy is related to the classic mechanism, namely increased thyroxine (T4) clearance secondary to induction of uridine-diphosphoglucuronosyltransferase (UDPGT) in the liver and a resulting increase in thyroid-stimulating hormone. Similarly, Lersivirine-exposed dogs exhibit a significant increase in hepatic UDPGT enzyme activity along with increased T4 clearance although clear effects on serum thyroid hormone levels were less apparent. These effects on thyroid hormonal clearance in the dog suggest that thyroid gland hypertrophy in this species is due to the same mechanism shown to occur in rodents although, as expected, dogs better adapt to these effects and therefore maintain relatively normal thyroid hormonal balance. It is also notable that the minimal thyroid follicular hypertrophy that occurs in dogs does not progress as is seen in rodents. As is the case with rodents, these adaptive changes in the dog are not considered indicative of a human health risk.

Efficacy and safety of lersivirine versus etravirine for the treatment of HIV-1 infection in patients with prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance: a randomized phase 2B trial.[Pubmed:25350959]

HIV Clin Trials. 2014 Sep-Oct;15(5):209-17.

OBJECTIVE: To assess the efficacy and safety of Lersivirine versus etravirine in patients with HIV-1 and prior non-nucleoside reverse transcriptase inhibitor (NNRTI) use and evidence of NNRTI resistance. METHODS: In this 96-week, phase 2b study, 97 patients were randomized and treated with Lersivirine 750 mg qd (n = 31), Lersivirine 1,000 mg qd (n = 32), and etravirine 200 mg bid (n = 34), plus one optimized nucleoside reverse transcriptase inhibitor and darunavir/ritonavir 600/100 mg bid. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/mL at week 24. RESULTS: At week 24, HIV-1 RNA <50 copies/mL was achieved by fewer patients receiving Lersivirine 750 mg (48.4%) and 1,000 mg (43.8%) qd compared with etravirine 200 mg qd (67.7%) (intention to treat [ITT], missing/switch/discontinuation equals failure [MSDF]). At week 48, HIV-1 RNA <50 copies/mL and <400 copies/mL were also achieved by fewer patients receiving Lersivirine 750 mg (41.9% and 41.9%, respectively) and 1,000 mg (31.3% and 34.4%, respectively) qd compared with etravirine 200 mg bid (61.8% and 70.6%, respectively) (ITT, MSDF). Least squares means (SE) change from baseline in log transformed HIV-1 RNA at week 48 was -1.42 (0.27) and -0.95 (0.28) copies/mL for Lersivirine 750 mg and 1,000 mg qd, respectively, versus -2.02 (0.26) copies/mL for etravirine 200 mg bid (ITT). Lersivirine and etravirine were generally safe and well-tolerated. CONCLUSIONS: Lersivirine 750 mg and 1,000 mg qd was associated with lower rates of viral suppression at week 24 and week 48 versus etravirine in patients with prior NNRTI use and evidence of NNRTI resistance. No new safety signals were detected.

Lersivirine - a new drug for HIV infection therapy.[Pubmed:24128277]

Expert Opin Investig Drugs. 2013 Dec;22(12):1687-94.

INTRODUCTION: Lersivirine (UK-453,061) is a novel second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). It binds reverse transcriptase in a distinct way leading to a unique resistance profile. The development of Lersivirine was recently stopped in Phase IIb clinical development. AREAS COVERED: This article describes the background of Lersivirine, its pharmacodynamic and pharmacokinetic profile and its clinical efficacy in HIV-infected patients. Moreover, the authors review its resistance profile in addition to its possible interactions with coadministered drugs and safety and tolerability. The authors' evaluation is based on the articles retrieved from a Medline in addition to abstracts from major HIV conferences and workshops addressing Lersivirine. EXPERT OPINION: The authors believe that Lersivirine has therapeutic potential for HIV-infected individuals with viral strains resistant against first-line NNRTIs. However, no large, well-powered studies have been conducted so far, which assess noninferiority against established antiretroviral agents. In February 2013, the developing company behind Lersivirine halted further development as it was decided that it would not provide an improvement over existing therapies; perhaps this is an opportunity missed.

Lersivirine(UK-453061) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI, IC50=119 nM) with a unique resistance profile that exhibits potent antiretroviral activity against wild-type human immunodeficiency virus and clinically relevant NNRTI-resistant strains.

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