Ibalizumab is a humanized monoclonal antibody that
targets a human protein rather than attacking the virus directly. It binds to
the CD4 receptor on the surface of T-cells and prevents the virus from entering
Ibalizumab (TMB-355) has been in development for more than a decade,
currently by TaiMed Biologics and previously by Tanox (where
it was known as TNX-355).
Early studies showed that ibalizumab was well tolerated and
had antiviral activity against HIV strains that were resistant to other
antiretrovirals. After it demonstrated modest efficacy in a previous phase 2 study, the US Food and Drug
Administration (FDA) gave it orphan drug status and a breakthrough therapy
Brinda Emu of Yale University presented findings from study
TMB-301, a phase 3 trial evaluating the efficacy of ibalizumab for people who are
unable to maintain viral suppression on their current antiretroviral regimen.
The study enrolled 40 heavily treatment-experienced
participants. Most (85%) were men, more than half were white, the mean age was
51 years and they'd had HIV for over 20 years on average. At baseline they had
a mean viral load of approximately 100,000 copies/ml and an average CD4 T-cell
count of just 150 cells/mm3.
About a quarter had used at least ten previous
antiretrovirals and they had documented resistance to at least one drug from three
antiretroviral classes. Half had exhausted all available drugs in at least three
classes and 15% were resistant to all approved antiretrovirals. However, they
needed to have at least one active drug available to construct an optimised
background regimen; to do so 43% had to include the investigational attachment
After a six-day observation period, all participants
in this open-label study received a 2000mg loading dose of ibalizumab as an
intravenous (IV) infusion while remaining on their failing regimen – that is, the
antibody was essentially used as functional monotherapy.
The primary study endpoint was the proportion of people
with at least a 0.5 log10 drop in viral load by day 14. As reported at IDWeek 2016, 83% had at least a 0.5 log10 drop
and 60% had a 1 log10 decrease or more at day 7.
At that point participants switched to an optimised
background regimen determined by resistance testing. They receive another 800mg
ibalizumab IV infusion on day 21 and then every other week until week 24. The
researchers reported 24-weeks data in a late-breaking poster at CROI.
At 24 weeks, 43% of study participants achieved viral
suppression below 50 copies/ml, and half under 200 copies/ml. While 60% of
those with a baseline CD4 count of 50 cells/mm3 or higher achieved
undetectable viral load, this fell to less than 20% for those with lower CD4
Just over half of participants (55%) had at least a 1
log10 decrease and 48% had at least a 2 log10 decrease in
HIV RNA. The average reduction from baseline was 1.6 log10.
The overall average CD4 cell gain was 48 cells/mm3,
but this differed according to baseline level: people who started with at least
50 cells/mm3 saw a mean gain of about 75 cells/mm3, while
those with lower baseline levels gained an average of 9 cells/mm3.
Ibalizumab was generally safe and well tolerated, and
most adverse events were mild or moderate. One person stopped the study due to
a treatment-related serious adverse event (immune reconstitution inflammatory
syndrome), five discontinued for other reasons and four people with advanced
immune suppression died.
"In multidrug-resistant HIV patients with very
limited treatment options due to resistance to approved antiretroviral agents,
bi-weekly ibalizumab plus optimized background regimen maintained virologic
efficacy and was well tolerated through week 24," the researchers
Although ibalizumab is not as potent as many other
antiretrovirals, it may provide the added activity needed to suppress HIV in
people with few or no other treatment options. But having to receive IV
infusions at a healthcare facility every other week would make ibalizumab
difficult to use.
However, as described in another poster presentation
at CROI, researchers are evaluating a new formulation of ibalizumab that is
administered by intramuscular injection. In this phase 1/2 study both tested
doses – 800mg every two weeks and 2000mg every four weeks – were well tolerated
and reduced viral load by up to 0.8 and 1.2 log10, respectively,
when used as monotherapy for seven days.