Clinical relevance of immunogenicity to biologics

Clinical relevance of immunogenicity to biologics


One of the greatest challenges in treating
psoriasis is maintaining the efficacy of therapies over long periods of time. Currently we get innumerable studies that
show our biologic therapies work really well for the first 12, 16, or 24 weeks, but the
real question is how well are they doing at Weeks 48, 96, and so on? Many times we find patients do very well and
then lose response …and loss of response can come in many flavors. It could be rapid, whereby the patient loses
their control of psoriasis over say 6–8 weeks, or slow and inexorable, where loss
of response is dragged out over 26, 52 weeks, longer periods of time. Regardless, there are many mechanisms that
might explain this and one prominent mechanism that we always talk about is immunogenicity. Biologic therapies, by definition, are foreign
molecules, and when given to patients there is the tendency of a patient to “quote-unquote”
reject the drug as foreign and raise antidrug antibodies. Antidrug antibodies have a very simple effect
on biologic therapies: they lower the drug level. If you lower the drug level, treatment becomes
less and less adequate for that drug level and patients see a recrudescence of psoriasis. Now, a more recent molecule that was approved
for the treatment of moderate to severe psoriasis is secukinumab; and secukinumab recently was
described with regard to its immunogenicity in a publication. This publication, with the first author Kristian
Reich, examined secukinumab in six different clinical trials for psoriasis in Phase 3. The patients in these studies were evaluated
at five different time points, including at baseline, for the presence of antidrug antibodies
with regard to secukinumab. And what was found over thousands of patients
was that immunogenicity was quite rare. In fact, the percentage of patients demonstrating
an immunogenic response to secukinumab was 0.4 and, if you specifically looked at the
percentage of patients who showed antidrug antibodies that actually neutralized secukinumab
(blocked its ability to bind to IL-17 in other words), that number was more like 0.1 percent. So it’s safe to say somewhere between 1
in 250 and 1 in 1000 patients will be “quote-unquote” victimized by immunogenicity. Nevertheless, the authors of this paper showed
that even in patients showing immunogenicity loss of response wasn’t a consequence. So the upshot is: secukinumab is a low immunogenic
molecule and it is more likely to retain response because of this fact. Now, in the real world we use secukinumab
quite often, and I personally have used it in scores of patients and do see loss of response
over time. Specifically, patients can clear or almost
clear in the first 2–3 months of therapy, but at Month 6, 9, or 18 the psoriasis starts
to come back. The dosing interval is inadequate (which is
monthly with this drug). In other words, you might have to use an every
3- or 2-week interval to keep the patients responding, and even that fails over time,
speaking to something going on that lowers the effectiveness of the drug that wasn’t
present at the beginning of therapy. Now, what might that something going on be? It could be immunogenicity …but I just told
you the studies don’t show immunogenicity for this molecule, so what am I talking about? Well, for one: immunogenicity studies are
wholly dependent on the assay used. If the assay is only slightly sensitive for
the presence of relevant antibodies against drug then it isn’t depicting the whole picture,
it’s only describing some of the population that, in reality, is being victimized by antidrug
antibodies. But, let’s say for the sake of argument
the paper is right (there are very few patients that have immunogenic problems), what else
could account for loss of response for a drug that was primarily effective in the beginning
of its therapy? Well, that might be that the target of the
drug (in this instance IL-17A, but it could be any target: TNF, IL-12, IL-23), the target
of the drug in some way either becomes less relevant to the disease pathophysiology, or
compensatory mechanisms (biologic compensatory mechanisms) make it harder for the current
drug level used for dosing to “swamp out” the current level of the target. The target blood levels or tissue levels go
up and, therefore, the dosing, the pharmacokinetics of the drug, are now inadequate. So, in many regards, the discussion about
immunogenicity is not really in my mind fully relevant. The only thing I care about—and what anyone
should care about—is whether a drug keeps working and, if it doesn’t keep working,
it doesn’t really matter why it’s not continuing to work. We need perhaps to either up-dose or change
to another therapeutic or, as I often do, combine the drug with a molecule like methotrexate,
which is known in clinical studies to reduce immunogenicity. So there are many strategies we can use, we
can employ, to maximize long-term efficacy and maintain drug levels at the level they
need to be to clear psoriasis. In my mind, it will always be the holy grail
of psoriasis therapy to keep really strong responders as strong responders, for very
long periods of time.

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