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GW873140, New HIV Drug, Novel CCR5 Inhibitor
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Reported by Jules Levin
"Single and Multiple Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Receptor Binding of GW873140, a Novel CCR5 Receptor Antagonist, in Healthy Subjects"
J Demarest1, K Adkison1, S Sparks1, A Shachoy-Clark1, K Schell1,2, S Reddy1, L Fang1, K O'Mara1, S Shibayama3, and S Piscitelli*11GlaxoSmithKline, Research Triangle Park, NC, USA; 2Univ. of Wisconsin, Madison, USA; and 3ONO Pharm. Ltd., Osaka, Japan
GW873140 is a novel CCR5 receptor antagonist that binds specifically to human CCR5 and demonstrates potent in vitro anti-HIV activity: IC50 1-5 nM. GW873140 binds to human CCR5 with a unique profile as evidenced by the selective inhibition of monoclonal antibody binding, and the drug is orally bioavailable. Following this report on the oral presentation by GSK on this new initiative in developing their CCR5 inhibitor is a report below of the poster presentation suggesting that GW873140 has a unique binding site suggesting successful combination therapy with other CCR5 inhibitors in development; as well, CCR5 inhibitors may be combined with fusion and BMS' attachment inhibitor in new HIV treatment regimens that may also include drugs from the currently available classes of drugs. The presentations at this 11th CROI show advancement in developing this new class of drugs—entry inhibitors. CCR5 inhibitors from Pfizer, Schering, and GSK are in various stages of early clinical development, and BMS' attachment inhibitor program is also moving along in early clinical development, BMS has several candidates behind the current one presented at this conference.
Commentary from Jules Levin: One of the many ways in which CCR5 inhibitors differ from the currently available classes of HIV drugs is that they bind to the host (CCR5 receptor), the cell, target rather than to the viral enzymes in cells like the CD4 cell. One of the questions about CCR5 inhibitors is their effectiveness against dual tropic viruses, CCR5 & X4 viruses. We don't know the answer to this question but studies will explore this. Another question surrounds viruses switchng to X4 receptors: do they switch, when do they switch, what causes the switch, and how this effects HIV progression & response to HIV drugs, such as CCR5 inhibitors. We don't know answers to these questions yet, but these studies will explore these questions. There is a notion that switching to an X4 virus is bad, but we are not certain of this yet. It appears from some available data, but there isn't much, that 50% of patients switch from CCR5 to X4 and 50% don't switch. Switching to X4 may be an effect, not a cause, we don't know yet. We do know, that studying this new class of drugs will examine these questions and we are likely to emerge with a better understanding of these questions, and hopefully new treatment regimens and concepts.
Steve Piscatelli from GlaxoSmithKline reported on an early study of this drug at the 11th Retrovirus Conference. The study is a double blind, randomized, placebo-controlled single (n=30) and multiple oral dose (n=40) escalation study was conducted in 70 fasted subjects (57 males, 13 females), healthy adult volunteers.
During single dose escalation, 3 cohorts of 10 subjects (8 active / 2 placebo) received doses of 50, 200, 400, 800, 1200 mg, or 400 mg + standard breakfast in an alternating panel design.
During multiple dose escalation, 4 cohorts (8 active / 2 placebo) received doses of 200, 400, 600, or 800 mg as a single dose on day 1 and then twice daily for 7 days. In vivo CCR5 occupancy was evaluated during the multiple dose phase and analyzed directly using samples of whole blood collected at baseline and at timepoints following single or multiple doses.
Flow cytometric analysis was used to determine percentage CCR5 occupancy using 3 CCR5 monoclonal antibodies, each with unique binding specificity. Laboratory safety tests, vital signs, serial ECGs, and serial pharmacokinetic sampling were performed at regular intervals.
Preliminary data indicated that GW873140 was well tolerated with no serious adverse events and no grade 3 or 4 adverse events. Adverse events were reportedly generally mild & self-limiting; primarly GI in nature: mild to moderate side effects included abdominal cramping, nausea, loose stools, and diarrhea. There were no serious adverse events. One subject discontinued due to grade 2 LFT increase on placebo. There were no grade 2/3 AST/ALT lab abnormalities in the patients receiving GW873140. There were several instances of geade 2/3 lipase and CPK. No specific trends in laboratory parameters and no clinically significant ECG changes were noted, no QTc prolongation, no dose related abnormalities.
Piscatelli said that steady state PK was approximately dose proportional in exposure; steady state trough concentrations achieved within 7 days; there were no obvious gender differences. Median GW873140 AUC ranged from 130 ng*h/mL for the 200mg q12h dose to 246 ng*h/mL (n=8) for the 400 mg twice daily (q12h) dose (n=7) to 302 ng*h/mL (n=8) for the 600mg q12h dose (n=8) and 479 ng*h/mL at 800 mg BID, respectively. Other PK measures reported also appeared dose proportional.
Food increased the AUC and Cmax by a mean of 1.7- (range 1.2 to 2.2 fold) and 2.2-fold (range 1.1 to 3.6 fold), respectively. In vivo CCR5 binding analyses showed 0% receptor occupancy at baseline for all subjects and at all time points for subjects receiving placebo. Median receptor occupancy at 24 hours post single doses ranged from 68% to 88% despite GW873140 plasma concentrations being below or near assay limits (1 ng/ml). CCR5 occupancy was >97% at 2 and 12 hours after multiple dosing with GW873140 for all dose regimens.
The authors concluded that GW873140 was safe and well-tolerated in healthy volunteers following single doses and multiple doses administered twice daily. Food increases exposure by mean 1.7 fold. There was no QTc prolongation observed. The prolonged CCR5 occupancy in vivo suggests a long half-life for GW873140 binding to the receptor, suggesting QD or BID dosing. These data support further evaluation of GW873140 in HIV-infected individuals. Future studies are planned in HIV+ individuals.
Determination of Binding Sites of a Unique CCR5 Inhibitor AK602 (GW873140) on Human CCR5
K Maeda*1, H Ogata1, S Harada1, Y Tojo1, T Miyakawa1, H Nakata1, Y Takaoka2, S Shibayama2, K Sagawa2, F Daikichi2, J Moravek3, E Arnold4, and H Mitsuya1,51Kumamoto Univ. Sch. of Med., Japan; 2ONO Pharm. Co. Ltd., Osaka, Japan; 3Moravek Biochemicals, Inc., Brea, CA; 4Rutgers Univ., Piscataway, NJ, USA; and 5NCI, NIH, DHHS, Bethesda, MD, USA
A novel spirodiketopiperazine derivative, AK602/ONO4128/GW873140 exerts potent activity against R5 HIV-1 in vitro. We characterized the CCR5 binding profile of AK602 and its interactions with HIV-1 gp120, CC-chemokines, and CCR5 in comparison with those of other previously published CCR5 inhibitors.
A variety of mutant CCR5 were expressed on various cell lines and assays for CCR5 binding of CC-chemokines, cytosolic Ca2+ mobilization, and susceptibility to HIV-1 were conducted. Effects of various CCR5 inhibitors on CCR5/gp120 interactions were also examined. Using selected 3H-labeled CCR5 inhibitors and cells expressing a variety of mutated CCR5, the binding sites of CCR5 inhibitors were determined.
Three selected CCR5 inhibitors (AK602, SCH-C, and TAK-779) exerted potent activity against R5 HIV (IC50; 0.2, 1, and 4 nM) and had high affinity to CCR5 with KD values of 3, 16, and 30 nM, respectively. AK602, unlike SCH-C and TAK-779, completely blocked the binding of an extracellular loop (ECL) 2-specific monoclonal antibodies (45531), suggesting AK602 directly interacts with ECL2. When mutations were introduced in the interface of ECL2 (G163A/R and K191A), the affinity of AK602 to CCR5 was totally nullified. Several mutations (e.g., Y108A and E283A) also decreased AK602's affinity to CCR5, a common feature to the binding profiles of TAK-779 and/or SCH-C. We also determined the effects of CCR5 mutations on CC-chemokine binding/functions and gp120 binding to CCR5. A variety of mutations in the transmembrane domain of CCR5 and the K191A mutation decreased the affinity of CC-chemokines and/or gp120 binding, indicating that these mutations induce structural/conformational changes in the helices and/or ECL domains. Taken together, the data suggest that unlike SCH-C and TAK-779 whose binding sites are reportedly located in the transmembrane domains, the binding sites of AK602 are clustered around the interface of ECL2.
The present data suggest that the binding sites of AK602 on CCR5 are substantilly differennt from those of previously published CCR5 inhibitors. The data also might help to construct the optimal combination regimens of CCR5 inhibitors.
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