A new non-nucleoside reverse transcriptase inhibitor designed to be active against the most common resistance mutations that develop after failure of efavirenz or nevirapine treatment is entering phase IIa trials, developer Ardea Biosciences announced last week.
RDEA086 was unveiled at last year’s 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Its developers say the drug is highly active in vitro against viruses with common NNRTI resistance mutations that cause the failure of nevirapine or efavirenz-containing regimens. It also performs just as well as the new Tibotec NNRTIs, TMC-125 (etravirine) and TMC-278, against the common NNRTI resistance mutations.
RDEA806 has shown no evidence of rash, central nervous system side-effects or the potential for serious drug interactions in a 92 person study in healthy volunteers.
It does not induce the CYP 3A4 p450 isoenzyme pathway or other major isoenzymes to the same degree as licensed non-nucleosides, and levels of RDEA086 are not increased by ritonavir. (All presentations on RDEA086 are available for download from the Ardea Biosciences website).
Once and twice-daily dosing of RDEA086 will be compared in a phase IIa trial which will test the drug in treatment-naïve patients at treatment centres in Europe, including the United Kingdom.
The study announcement highlights the increasingly competitive efforts among manufacturers to come up with alternatives to the highly successful - and profitable - mainstays of first-line therapy, nevirapine (Viramune) and efavirenz (Sustiva / Stocrin).
Rash, hypersensitivity, liver toxicity, central nervous system side effects and drug interactions are characteristics of the currently licensed NNRTIs nevirapine and efavirenz.
Nevirapine causes rash in around 16-18% of people who take the drug during the first weeks of therapy, and up to 3% of people may need to discontinue treatment as a result of the severity of the rash.
The most problematic aspect of nevirapine’s side-effect profile is its small but potentially life-threatening risk of causing a hypersensitivity reaction that may involve severe liver damage. Analyses of such cases have led to a recommendation that in people starting treatment for the first time, nevirapine should not be given to women with CD4 cell counts over 250 cells/mm3 or to men with CD4 cell counts over 400.
Efavirenz causes central nervous side-effects such as dizziness, insomnia and abnormal dreams in up to 50% during the first months of treatment, and these lead to treatment discontinuation in between 3% and 10% of people in clinical trails. Psychiatric side-effects, such as depression, mania and anxiety may be linked with the drug too, and cause 1% of people to discontinue it.
But a much larger proportion of people who take efavirenz claim that the subtle nervous system side-effects affect their quality of life negatively.
Both drugs are processed by the cytochrome p450 system, and both induce, or rev up, the CYP3A4 enzyme within this system. This causes faster processing of other drugs that are metabolised in the liver by this enzyme, leading to lower than expected levels of these drugs.
For example, nevirapine reduces levels of the TB drug rifampicin, and if used with protease inhibitors, both nevirapine and efavirenz may force increases in the protease inhibitor dose in order to offset the inducer effect. This may not sound too much of a problem, but with drug costs an issue in many countries including the UK, even small increases in dosage can be too expensive.
Tibotec’s rilpivirine (TMC278) has a lower incidence of rash than nevirapine, but safety data presented at conferences last year show that the drug can cause certain types of central nervous system problems.
TMC 278 (rilpivirine) is due to enter phase III studies that will compare the drug to efavirenz in treatment-naïve patients. One study will test the drug alongside a nucleoside analogue backbone of abacavir and 3TC (Kivexa), the other will test the drug alongside tenofovir and FTC (Truvada). By testing the drug with the two most commonly prescribed nucleoside backbones, Tibotec will be able to discover whether there are particular advantages or disadvantages to using the drug with a specific backbone.
TMC278 may be less likely to cause rash, abnormal dreams and dizziness than efavirenz, and also causes less change in cholesterol and triglyceride levels, according to data from the phase IIb study of the drug presented last year at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.
However, the drug scored just as poorly as efavirenz for depression, insomnia and headache.
Those studies are expected to report their first results in 2009 and if the drug performs well, it may be licensed as an additional NNRTI choice by 2010 or 2011. If RDEA086 is successfully developed, it is unlikely to arrive in clinics before 2012.
Etravirine (TMC125), an NNRTI developed for treatment-experienced patients by Tibotec, is likely to be licensed in the United States and Europe during 2008.
UK-453,061, an NNRTI being developed by Pfizer, has undergone a phase IIa study in HIV-positive patients (key data available here). After seven days of monotherapy, viral load was reduced by up to -1.7 log at the highest doses (750mg once daily or 500mg twice daily), with no evidence of central nervous system side-effects emerging during the first week of treatment. A seven day study is probably too short to evaluate the incidence of rash, which tends to emerge after several weeks of NNRTI treatment.
Like the drugs being developed by Ardea Biosciences and Tibotec, Pfizer’s NNRTI does not have a significant effect on CYP 3A4, and is active against the mutations most commonly seen after efavirenz or nevirapine failure. Pfizer says the drug has a relatively high genetic barrier to resistance, unlike the current NNRTIs, which fail after the emergence of one resistance mutation.
A phase IIb study of UK-453,061 is likely to begin in 2008 comparing once-daily and twice-daily dosing.
But for the time being, the currently licensed NNRTIs will continue to dominate prescribing, and for the vast majority of people starting treatment today, that means efavirenz – either as a separate tablet, or as part of a three-in-one pill called Atripla that has now been licensed in Europe and the United States.