December 5, 2012
S/GSK-1265744 is an integrase inhibitor, similar to dolutegravir. Results from two studies presented at ICAAC 2012 found that 744 had high potency and an exceedingly long half-life. When given orally at once-daily doses of 30 mg, patients showed a median 2.6 log reduction in viral load. More impressive, when using nanotechnology to formulate 744 to be injected subcutaneously or intramuscularly, a single dose showed a half-life between 21 and 50 days. Remarkably, after a single dose, patients still had detectable levels of 744 up to 48 weeks after injection.
Similar to dolutegravir, 744 seems to have a high barrier to drug resistance. According to Gulick, using site-directed molecular clones (molecules created with specific mutations) associated with integrase inhibitor resistance, these mutations showed high levels of resistance to raltegravir and elvitegravir, but remained susceptible to 744 and dolutegravir.
In terms of safety, there were some injection site reactions and nodules associated with subcutaneous dosing. But conceivably, 744 could be taken as infrequently as every three months for treatment, or even as PrEP (pre-exposure prophylaxis). Research is ongoing.
HIV entry inhibitors block HIV at the point at which they attach to CD4 cells. Many of the other classes of drugs, including protease inhibitors, NRTIs and NNRTIs, fight HIV after it has infected a CD4 cell.
Among the entry inhibitors, there are presently three sub-classes. We already have approved drugs in the first two sub-classes: CCR5 antagonists and fusion inhibitors. In the CCR5 antagonist sub-class, we already have maraviroc (Selzentry, Celsentri), and a new drug called cenicriviroc is being investigated. The fusion inhibitor class has long featured only enfuvirtide (Fuzeon), but a new drug called albuvirtide is being studied.
The third sub-class is an investigational one: CD4 attachment inhibitors. These new drugs are being developed to either bind at the location of HIV's gp120 protein (such as BMS-663068) or on the CD4 receptor itself (such as ibalizumab, a once- or twice-a-day drug that's still under investigation for both treatment and prevention).
Gulick offered a closer look at a few of these drugs in his overview.
Cenicriviroc is an investigational CCR5 antagonist. Not only does it antagonize CCR5 binding, it also antagonizes CCR2 binding. CCR2 is a receptor that sits on the surface of macrophages and may be involved in inflammation.
Cenicriviroc showed potent antiretroviral activity in a small study by Jacob Lalezari, M.D., and others. They followed treatment-experienced patients who had not been on treatment for at least six weeks, had a CD4+ cell count above 250 and a viral load above 5,000 copies/mL. They were randomized to receive either 25, 50, 75, 100 or 150 mg of once-daily cenicriviroc. At the highest doses, after 10 days, patients showed a 1.5 log reduction in viral load.
An update on the follow-up study was discussed by David Martin, M.D., at CROI 2012. In Martin et al's phase-2b study, they randomized 150 treatment-naive patients into three groups to receive tenofovir/emtricitabine with either cenicriviroc (at 100 or 200 mg) or efavirenz. Cenicriviroc was administered using a new, 50-mg formulation. In preliminary data from 18 patients, cenicriviroc was found to be well-absorbed and within the expected therapeutic range of potency. Further study will assess the safety, efficacy and effect of CCR2 inhibition on inflammatory biomarkers.
The only approved fusion inhibitor, enfuvirtide, offers a lot of activity against HIV, but the obvious downside is that it requires twice-daily injections. Albuvirtide, on the other hand, is an investigational fusion inhibitor that when given intravenously has a long average half-life of 11 days, warranting weekly dosing.
Albuvirtide has a similar design to enfuvirtide. It is a peptide that is an analogue of gp41, one of the envelope proteins on HIV's surface, and thereby blocks HIV through CD4 membrane fusion.
Two proof-of-concept studies by Dong Xie and others were presented at ICAAC 2012. In the first study, albuvirtide was given to 54 treatment-naive patients in a single dose; doses ranged from 20 to 640 mg. They found that albuvirtide's half-life ranged between 10 and 13 days, and that the drug suppressed plasma viremia for between 6 and 10 days. Albuvirtide was generally well tolerated, with no injection-site reactions and no serious adverse events.
In the second study, albuvirtide was given to 12 treatment-naive patients in multiple doses of either 160 or 320 mg. Doses were given on days 1, 2, 3, 8 and 15. The participants averaged viral load decreases of 0.68 log copies/mL (at 160 mg) and 1.05 log copies/mL (at 320 mg). Similar to the first study, there were no injection-site reactions and no serious adverse events. No anti-albuvirtide antibodies were detected in patients for up to 42 days.
BMS-068 is an HIV attachment inhibitor. It is an oral prodrug that breaks down into the active compound BMS-626529 (a.k.a. BMS-529). It inhibits CD4 binding by specifically binding to gp120, one of HIV's envelope proteins that binds to CD4 cells. Gulick stated BMS-068 could be taken once or twice a day without boosting, but noted, "There is decreased baseline susceptibility in some patients due to envelope polymorphisms."
BMS-068 taken over 8 days with or without ritonavir (Norvir) resulted in substantial declines in plasma HIV RNA levels and was generally well tolerated, according to a study by Richard Nettles, M.D., and others. The study followed 50 patients with a CD4+ cell count above 200 cells/mL and a viral load above 5,000 copies/mL. They were either treatment-naive or not taking any treatment. The median change in viral load ranged from a 1.21 to a 1.73 log reduction, demonstrating that CD4 attachment inhibition can be quite potent and effective.
In terms of resistance, a study presented by Neelanjana Ray, M.D., at CROI 2012, found little resistance after the eight days of monotherapy. Ray and his team analyzed the changes in phenotypic susceptibility and known attachment inhibitor resistance substitutions that may have occurred during the Nettles study. Of the 48 patients that completed the study, 42 had at least a 1 log drop in viral load, showing that BMS-068 was effective. However, the other six (about 12%) had no virologic response, even though their baseline IC50 (a measure of the effectiveness of a compound in inhibiting a biochemical function) levels were quite high.
"When they took a close look and they sequenced gp160, which is broken down into gp120, they showed that a mutation (M426L) was associated with resistance," explained Gulick. "You can see that in patients with virologic response, very few (only 6%) have this mutation, whereas in those without virologic response, 5 of the 6 had this mutation. So it looks like this will be important in screening for activity of this compound as its development moves forward."
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