CCR5/CCR2 inhibitor cenicriviroc demonstrated good antiviral activity and
tolerability in a phase 2 clinical trial, according to a report at the 14th European AIDS
Conference yesterday in Brussels. The study had many drop-outs, likely to be due to its
complex dosing regimen, but a more user-friendly cenicriviroc formulation has since been developed.
modern antiretroviral therapy is highly safe and effective there is still room
for development of new classes of drugs that work in novel ways. Cenicriviroc (formerly TBR-652),
developed by Tobira Therapeutics, blocks the
CCR5 co-receptor – one of the gateways HIV uses to enter cells – as well as
CCR2, a receptor that plays a role in inflammatory response.
Judith Feinberg from the
University of Cincinnati presented results of a final 48-week analysis from
Study 202, which compared cenicriviroc versus efavirenz (Sustiva or Stocrin) for
previously untreated people with HIV.
The analysis included 143
treatment-naive HIV-positive adults. More than 90% were men, about 60% were
white, about 30% were African-American and the median age was 35 years. At
baseline, the mean CD4 cell count was approximately 400 cells/mm3
and 20% had high viral load (>100,000 copies/ml). Participants were
required to have CCR5-tropic virus, meaning it only uses the CCR5 co-receptor.
Participants were randomly
assigned to receive 100mg or 200mg cenicriviroc or 600mg efavirenz, both in
combination with tenofovir/emtricitabine (the drugs in Truvada). Although all are once-daily drugs, the study used a
complex double-blind/double-dummy design so that everyone took similar looking regimens.
At the time of the study cenicriviroc was only available as a 50mg pill. This
meant participants had to take four pills (either cenicriviroc or placebo) at
breakfast, one pill (either efavirenz or placebo) at bedtime and one Truvada pill whenever they chose.
The primary endpoint was the
proportion of participants with HIV RNA <50 copies/ml at week 24. These results were presented at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) in the spring.
The researchers also looked at viral suppression and CD4 cell changes at week
48, emergence of resistance mutations, changes in viral tropism (switching to
use the CXCR4 co-receptor), side-effects and inflammation biomarkers.
The study had a high drop-out
rate, with 29% in the 100mg cenicriviroc arm, 27% in the 200mg cenicriviroc arm
and 39% in the efavirenz arm stopping prematurely. The efavirenz arm had far
more discontinuations due to adverse events (0, 2 and 21%, respectively), a
majority of which occurred early.
Feinberg speculated that people
who began experiencing well-known central nervous system side effects
associated with efavirenz may have quit the study because if they wanted it they
could get the same regimen – without all the placebos – in the
one-pill/once-daily Atripla coformulation.
"I think the
dosing scheme had an impact on how well patients adhered and their desire to
stick it out," she said.
Despite this difficulty,
cenicriviroc was found to be as effective as efavirenz. In the primary
intent-to-treat 'snapshot' analysis at 24 weeks, 76% of people taking 100mg
cenicriviroc, 73% taking 200mg cenicriviroc and 71% taking efavirenz had
undetectable viral load.
Response rates fell by week 48,
primarily attributable to additional drop-outs, to 68, 64 and 50%,
respectively. Rates of virological failure were 7% with 100mg cenicriviroc, 11%
with 200mg cenicriviroc and 4% with efavirenz, not a significant difference. CD4
cell gains were somewhat higher in the two cenicriviroc arms (211 and 205 cells/mm3)
than in the efavirenz arm (147 cells/mm3).
Seven people taking cenicriviroc,
but none taking efavirenz, showed evidence of nucleoside/nucleotide reverse
transcriptase inhibitor or NNRTI resistance mutations. However, deep sequencing
revealed that the NNRTI mutations were present prior to starting treatment. One
person was found to have virus with dual/mixed tropism (using both CCR5 and
A majority of study participants
experienced some drug-related adverse events: 50% in the 100mg cenicriviroc
arm, 44% in the 200mg cenicriviroc arm and 71% taking efavirenz. However,
serious adverse events were rare (2, 2 and 4%, respectively). The most common
side-effects were the known efavirenz symptoms of abnormal dreams and insomnia
(11% each in the efavirenz arm compared with 0 to 2% amongst cenicriviroc
recipients). Rash and nausea were also reported more often by efavirenz
recipients (7% each vs 0 to 4%).
People taking the 200mg
cenicriviroc dose were more likely to develop grade 3 or 4 laboratory
abnormalities (21%) than those taking 100mg cenicriviroc (12%) or efavirenz
(14%). This was largely attributable to a 16% rate of elevated creatine phosphokinase in the 200mg arm,
which resolved after discontinuation. Looking at lipid changes, total
cholesterol, LDL ('bad' cholesterol) and HDL ('good' cholesterol) all decreased
in the cenicriviroc arms whilst rising in the efavirenz arm.
The researchers also looked at
immune and inflammatory biomarkers. CCR2 is a receptor that binds to monocyte
chemo-attractant protein 1 (MCP-1), a cytokine that promotes monocyte
migration. At CROI it was reported that levels of MCP-1 increased in the cenicriviroc arms, indicating that the
drug was blocking CCR2.
Levels of soluble CD14, a marker of monocyte
activation, decreased in the cenicriviroc arms and rose in the efavirenz arm at
24 weeks. After that point, however, sCD14 levels began rising in the
cenicriviroc arms as well, eventually leveling off slightly above the baseline
level, whilst continuing to rise in the efavirenz arm. Feinberg noted that
higher sCD14 levels
have been associated with mortality amongst people with HIV.
Based on these findings, the investigators
concluded that cenicriviroc is suitable for further development. The 200mg dose
was selected based on pharmacokinetic and safety data. This dose can now be
given as a single pill. A new fixed-dose combination with lamivudine (3TC or Epivir) and single-tablet regimens are
being developed. Phase 3 trials will look at cenicriviroc/lamivudine as a
'backbone' alternative to tenofovir/emtricitabine, to be used with a
guidelines-preferred third drug.