Overview of Aplaviroc, an Experimental Entry Inhibitor and CCR5 Antagonist

By Ronald Baker, PhD

CCR5 is a major chemokine receptor that HIV uses to enter CD4 cells. A member of the entry (fusion) inhibitor class of anti-HIV drugs, the CCR5 antagonist (inhibitor) aplaviroc, also known as GSK 873140, is an experimental oral agent that binds specifically to CCR5 receptors of human cells. This characteristic of aplaviroc blocks HIV from entering and infecting human cells.

Under development by GlaxoSmithKline, aplaviroc is being studies both to prevent initial HIV infection and to slow HIV disease progression in individuals already infected by HIV.

The results of laboratory studies of aplaviroc suggest that the drug remains bound to the CCR5 receptor of human cells for an extended period of time, with a half-life of greater than 100 hours. Aplaviroc appears to have a longer binding duration than Pfizer’s maraviroc (UK-427,857) and Schering-Plough’s vicriviroc (SCH-D), two other promising CCR5 inhibitors that also are now in clinical trials. These in vitro studies also show that aplaviroc exhibits greater than 97% CCR5 receptor occupancy in the bloodstream after repeat oral administration and maintains viral suppression for 24-48 hours after stopping therapy.

Dosing Studies of Aplaviroc

In clinical trials, aplaviroc has been taken by mouth with moderately fat meals, which appears to facilitate absorption of the drug.

Receptor occupancy and half-life were quantified in a 1-day, dose-ranging study of aplaviroc in 8 HIV uninfected and 31 HIV infected patients (Sparks et al.). After 7 days of 600 mg twice-daily therapy, median CD4 cell CCR5 receptor occupancy was 98%; final post-treatment analysis on Day 13 suggested occupancy half-life was 127 hours after the last administered dose.

HIV infected patients received 10 days of 873140 at doses of 200 or 600 mg twice daily or 200 or 400 mg once daily. After 10 days of therapy, receptor occupancy was greater than 95% in all groups; final post-treatment analysis on Day 24 estimated that occupancy half-life was 122 hours after the last administered dose. Higher doses tended toward longer occupancy duration. After therapy was discontinued and plasma drug levels became undetectable, receptor occupancy remained greater than 50% for approximately 5 days.

In a Phase I/II randomized, double-blind, placebo-controlled, dose-ranging monotherapy study (44^th ICAAC. Ab H-1137b. 2004), GSK-873,140 was given as monotherapy for 10 days to HIV-1 infected antiretroviral-naive and -experienced patients at doses of 200 or 600 mg twice daily and 200 or 400 mg once daily (8 receiving drug, 2 receiving placebo per arm). All doses were given with a moderate fat meal. Antiretroviral-experienced patients abstained from treatment for 12 weeks prior to entry.

All patients had a viral load of 5,000 copies/mL or greater and a CD4 count nadir greater than 200 cells/mm3. All patients were infected with R5-tropic HIV. A greater than 10-fold, dose-dependent, viral load decrease was observed in patients taking 400 mg once daily and 200 or 600 mg twice daily.

The lowest viral load was observed between 24 and 36 hours after therapy discontinuation, suggesting a long CCR5 receptor occupancy. Evidence of viral tropism conversion to dual-tropic virus was seen in one patient on Day 10; virus reverted back to R5-tropic virus on Day 24; analysis is ongoing.

Toxicities and Adverse Events

In early studies of aplaviroc, the drug appeared safe and well tolerated. The most common adverse effects noted in a 10-day monotherapy, dose-ranging study were loose stools, diarrhea, abdominal pain, nausea, and flatulence. Headache, dizziness, and fatigue also occurred. Most adverse effects resolved within three days (44^th ICAAC. Ab H-1137b. 2004). Coadministration of lopinavir/ritonavir (Kaletra) and aplaviroc also resulted in minor, self-limiting gastrointestinal complaints but no significant laboratory abnormalities (K Adkison et al.)

In a surprising development, GlaxoSmithKline (GSK) announced on September 15, 2005 that the company is terminating all clinical trials of aplaviroc in treatment-naïve (no prior therapy) HIV patients due to the observance of severe liver toxicity in patients enrolled in Phase IIb studies. GSK has received reports of elevated ALT and AST in two of the 250 treatment-naïve study participants.

Ongoing Phase III studies of aplaviroc in 40 treatment-experienced patients will continue following implementation of additional safety monitoring requirements, according to GSK.

References and Suggested Reading

C G Barber. CCR5 antagonists for the treatment of HIV. Current Opinion in Investigational Drugs. 5(8):851-861. August 2004.

K Maeda and others. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. Journal of Virology. 78(16): 8654-8662. August 2004.

H Nakata and others. Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602/ONO4128/GW873140, in a novel human peripheral blood mononuclear cell nonobese diabetic-SCID, interleukin-2 receptor gamma-chain-knocked-out AIDS mouse model. Journal of Virology 79(4):2087-96. February 2005.

C Seibert and others. Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs. Current Pharmaceutical Design. 10(17):2041-2062. 2004.

S Sparks and others. Prolonged Duration of CCR5 Occupancy by 873140 in HIV-negative and HIV-positive Subjects. Abstract 77. 12^th CROI. 2005.

H Nakata and others. Greater Synergistic Anti-HIV Effects upon Combinations of a CCR5 inhibitor AK602/ONO4128/GW873140 with CXCR4 Inhibitors than with Other Anti-HIV Drugs Abstract 543. 12^th CROI. 2005.

K Adkison and others. The Pharmacokinetic Interaction between the CCR5 Antagonist 873140 and Lopinavir/Ritonavir in Healthy Subjects. Abstract 664. 12^th CROI. 2005.

Abstract H-1137b. 44^th ICAAC. 2004.

Abstract 139. 11^th CROI. 2004.

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