More doubts were cast on the viability of vicriviroc, Schering Plough’s investigational anti-HIV drug, a member of a new drug class called CCR5 antagonists, after the company announced on Friday that a Study Monitoring Committee of an AIDS Clinical Trials Group study in 118 treatment-experienced patients had found no less than four cases of lymphoma and one case of stomach cancer in a phase II randomised study of vicriviroc.
The ACTG has concluded that a causal association between vicriviroc and the lymphoma cases could not be established at this time, and that all those who developed cancers had very advanced HIV disease, but says that it will put in place more intensive monitoring procedures in the study, which is comparing two doses of vicriviroc with an optimized background regimen plus placebo (for further information on the study, ACTG 5211, click here. The ACTG says that all participants in the study will undergo monitoring for three to five years after the study is completed in order to determine whether there are any harmful long-term effects of vicriviroc treatment.
Schering Plough was unable to comment further on the findings; vicriviroc development lead Dr Wayne Greaves told aidsmap that the company was waiting for more detailed communication from the ACTG. However he reiterated the ACTG’s statement that all patients who developed a malignancy had 'severely advanced HIV disease', and confirmed that all the cases of malignancy occurred in patients who were receiving vicriviroc in the study.
Background on malignancies and CCR5 inhibition
Paradoxically a study published in the journal Cancer Research in 1999 showed that HIV-positive individuals heterozygous for the CCR5 delta 32 polymorphism (persons with a single copy of the CCR5 delta 32 allele) had a reduced risk of AIDS lymphoma when compared to individuals without the polymorphism. When discussing the potential long-term effects of CCR5 inhibition by CCR5 antagonists, researchers have frequently cited studies such as the 1999 publication showing almost no evidence of increased incidence of serious conditions in individuals who carry the CCR5 delta 32 polymorphism, on the grounds that this population are likely to reflect the long-term consequences of carrying this polymorphism in the HIV-negative population, and therefore should reflect the long-term consequences of CCR5 inhibition using CCR5 antagonists.
However, a study published in the Journal of Experimental Medicine in November 2003 showed that in women with breast cancer that was wild-type for p53, those who were heterozygous for CCR5 delta 32 had shorter disease-free survival, suggesting that in at least one type of cancer, the CCR5 delta 32 polymorphism influences the risk of disease progression and survival in a negative manner.
Vicriviroc: a troubled development history
Vicriviroc has a troubled development history. A phase II study in treatment-naive individuals was halted after it became evident that individuals who initially experienced viral suppression when taking the drug quickly experienced viral rebound, especially at lower doses.
Presenting findings from the study at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver last month, Wayne Greaves told delegates that very high rates of viral rebound were seen at two lower doses of vicriviroc, and that a further dose finding study was now being planned to define the optimal dose of vicriviroc in treatment-naive patients.
The study randomized 92 patients to receive one of three doses of vicriviroc (25, 50 or 75mg qd) or a placebo for 14 days as monotherapy, after which the vicriviroc group added Combivir (AZT/3TC) and the placebo group initiated Combivir/efavirenz.
The median age of participants was 37, the median CD4 cell count was 290 cells/mm3 and median viral load 4.79log.
| VL reduction at day 14 (log copies/ml) | Viral rebounds at study termination (%) | ||
| placebo | - 0.07 | 4% | |
| 25mg qd | - 0.83 | 56% | Vs pl: p=0.001 Vs 75mg: p=0.003 |
| 50mg qd | - 1.18 | 41% | Vs pl: p=0.003 |
| 75mg qd | - 1.34 | 17% | Vs pl: p=0.188 |
Further analysis showed that viral load reduction at day 14 was strongly correlated with the risk of viral rebound. After adjusting for baseline viral load above 100,000 copies/ml, a viral load reduction of more than 1.5 log at day 14 was associated with a 6.5-fold greater likelihood of sustained viral suppression (P=0.01).
Dean M et al. Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-D32 mutation. Cancer Research 59: 3561-3564, 1999.
Mañes S et al. CCR5 expression influences the progression of human breast cancer in a p53-dependent manner. The Journal of Experimental Medicine 198 (9): 1381-1389, 2003.
Greaves W et al. Late virologic breakthrough in treatment-naïve patients on a regimen of Combivir + vicriviroc. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 161LB, 2006.