TBR-652
Inhibits HIV, May Dampen Inflammation
SUMMARY
TBR-652, a drug that blocks both CCR5 and CCR2 cell receptors,
showed potent antiviral activity against HIV, but did
not change most inflammation biomarkers. |
By
Liz Highleyman
HIV
uses 2 different surface co-receptors -- CCR5 and CXCR4 --
along with the CD4 receptor to enter T-cells. CCR5 antagonists
such as maraviroc
(Selzentry) prevent HIV from entering cells by blocking
this co-receptor.
Tobira's
investigational drug TBR-652 blocks both CCR5 and CCR2, a
receptor that binds to monocyte chemoattractant protein 1
(MCP-1, also known as CCL2), a chemical messenger that promotes
migration of monocytes and macrophages.
Though
not fully understood, CCR2 plays a role in inflammation and
has been studied in inflammatory conditions such as atherosclerosis
and metabolic syndrome. A growing body of evidence indicates
that ongoing immune activation and persistent inflammation
may contribute to a range of non-AIDS conditions in people
with HIV.
In
2010, researchers presented
data from a proof-of-concept study of TBR-652 in HIV positive
people at CROI and at the International AIDS Conference in
Vienna. Their findings have now been published in the June
1, 2011, Journal of Acquired Immune Deficiency Syndromes.
This
double-blind Phase 2 study included 52 participants in the
U.S. and 2 in Argentina with confirmed CCR5-tropic (using
the CCR5 co-receptor) HIV. Most were men, the average age
was about 40 years, and the mean CD4 T-cell count was about
450 cells/mm3. They were treatment-experienced but had never
used CCR5 antagonists and had been off all ART for at least
6 weeks at study entry.
Participants
were randomly assigned to receive TBR-652 monotherapy at oral
doses of 25, 50, 75, 100, or 150 mg per day, or else placebo,
once-daily for 10 days. The 100 mg dose group used a different
formulation that was later discontinued; these patients --
which included the 2 in Argentina -- were excluded from the
efficacy analysis but included in the safety analysis.
At
days 1 and 10 the researchers measured HIV RNA and biomarkers
associated with inflammation, including MCP-1, high-sensitivity
C-reactive protein (hs-CRP), and interleukin 6 (IL-6). Elevated
MCP-1 was used as an indicator of effective CCR2 blocking.
Results
 |
TBR-652
demonstrated potent anti-HIV activity, significantly greater
than that of placebo. |
|
Maximum
median decreases in HIV RNA from baseline were -0.7, -1.6,
-1.8, and -1.7 in the 25, 50, 75, and 150 mg dose groups,
respectively, compared with -0.3 in the placebo group. |
|
33%,
71%, 100%, and 75% of patients in respective TBR-652 dose
groups achieved viral load reductions of at least 1 log.
|
|
Participants
reached a nadir or lowest HIV viral load after a median
of 10-11 days, or just after the last dose. |
|
At
10 days levels of MCP-1 increased significantly in the
50 mg and 150 mg dose groups, by about 100 and 300 pg/mL,
respectively. |
|
The
average CRP level decreased, but this was mainly attributable
to a single participant with a high baseline level due
to acute inflammation. |
|
Effects
on other immune or inflammation markers including hs-CRP
and IL-6 levels were "negligible." |
|
CD4
cell count also did not change significantly during the
short dosing period. |
|
TBR-652
was generally safe and well-tolerated at all doses studied. |
|
No
severe adverse events or laboratory abnormalities were
observed in any TBR-652 dose group, and no participants
withdrew due to side effects. |
Based
on these results, the study authors concluded, "TBR-652
caused significant reductions in HIV-1 RNA at all doses. Significant
increases in MCP-1 levels suggested strong CCR2 blockade."
"TBR-652
was generally well tolerated with no dose-limiting adverse
events," they continued. "[Pharmacodynamic characteristics]
indicate that TBR-652 warrants further investigation as an
unboosted, once-daily, oral CCR5 antagonist with potentially
important CCR2-mediated anti-inflammatory effects."
In
their discussion they noted that since the lowest viral loads
were observed on average on days 10-11, as treatment was ending,
"a true nadir may not have been reached in the 10-day
treatment," suggesting viral levels might decline further
with longer therapy.
Tobira
is now conducted a Phase 2b clinical trial with various substudies
to evaluate immunological, cardiovascular, and metabolic parameters,
"with the hopes of clarifying their usefulness in predicting
inflammatory processes and reducing the risk of inflammatory
disease with TBR-652 therapy." Drug interaction studies
are also underway to enable construction of a combination
regimen with an appropriate TBR-652 dose.
Investigator affiliations: Quest Clinical Research, San
Francisco, CA; Private Practice, Houston, TX; Central Texas
Clinical Research, Austin, TX; AIDS Research Consortium of
Atlanta, Atlanta, GA; Community Research Initiative of New
England, Boston, MA; Orlando Immunology Center, Orlando, FL;
CIBIC, Rosario, Argentina; AIDS Community Research Initiative
of America, Inc.; Tobira Therapeutics, Inc., Princeton, NJ.
5/31/11
Reference
J
Lalezari, J Gathe, C Brinson, et al. Safety, Efficacy, and
Pharmacokinetics of TBR-652, a CCR5/CCR2 Antagonist, in HIV-1-Infected,
Treatment-Experienced, CCR5 Antagonist-Naive Subjects. Journal
of Acquired Immune Deficiency Syndromes 57(2): 118-125
(abstract).
June 1, 2011.
