Inhibition of the IL-17A receptor with brodalumab for the treatment of psoriasis

Inhibition of the IL-17A receptor with brodalumab for the treatment of psoriasis


Hi, my name is Bruce Strober. I’m Professor and Chair at the University of Connecticut Health Center, Department of Dermatology, and I’m here to discuss the paper describing a comparison between brodalumab, an IL-17 receptor blocker, and ustekinumab,
a well-established IL-12/-23 inhibitor that’s been on the market for 7 years. This was a study published in the New England
Journal of Medicine in 2015, in October, and it’s really a compilation of two different studies done independently yet having the same study design. In essence, brodalumab examined at two different
doses (210 mg and 140 mg), given every 2 weeks as a subcutaneous injection, was compared
to ustekinumab given as a standard dose as per its label—in other words, 90 mg for
patients greater than 100 kg and 45 mg for all other patients less than that amount of body weight. So standard dosing, double-blind, assessor-blind,
very fair, reasonable data that you can believe in a clinical trial setting. Every patient had to have moderate to severe psoriasis. There actually was a placebo group in this study, which kept the patients and the assessors
honest, so to speak. And essentially it showed that at the 210
mg dose of brodalumab that you saw superiority of efficacy of that drug compared to ustekinumab,
and of course compared to placebo, at 12 weeks. In other words, patients achieved better response
rates; there were a higher number of patients who achieved a PASI 75 who got the higher-dose
brodalumab (210 mg) than patients getting ustekinumab who achieved a PASI 75. The number comparison was about 87% versus
69%, brodalumab versus ustekinumab, comparatively. Importantly, this study actually examined
PASI 100 achievement rates (full clearance of skin) and that really is, in my opinion,
the more important point: that brodalumab and other IL-17 inhibitors achieve PASI 100
clearance much more likely than older biologic therapies and certainly older conventional therapies. Basically, 40% of patients getting brodalumab
versus 20% getting ustekinumab achieve PASI 100, so in that regard patients are twice
as likely, in all reasonable estimations, to achieve full clearance on brodalumab 210
mg, which is likely to be the approved dose. So this follows on other studies of IL-17 inhibitors. There are two other IL-17 inhibitors: ixekizumab
and secukinumab, which both also show higher efficacy than ustekinumab and other biologic
therapies, either in head-to-head studies or in their independent analyses done in Phase 3. So IL-17 inhibition is the superior approach
to clearing patients with psoriasis, there’s no doubt about it, at the doses we can use
of those drugs. It should be noted, though, that secukinumab
and ixekizumab are both approved drugs for the treatment of moderate to severe psoriasis
and they work slightly differently than brodalumab—they block IL-17 directly, whereas brodalumab blocks
the receptor for IL-17. So slightly different MOA, yet we’re seeing
no matter how you do it, you get high levels of clearance. Now the issue of course comes down to safety. Ustekinumab, the drug we’re using, like
I said, for many years, is clearly a very safe medication and it’s very well tolerated
and has an advantage of being infrequently dosed— as you likely know it’s dosed at
Week 0 and then 1 month later, and then every 3 months thereafter, very infrequent dosing. And the IL-17 drugs will be self-injected
and dosed more frequently, to a variety of dosing regimens, but in general it’s going
to be every 2 weeks or every month, depending on drug and where you are during the course of therapy. So more frequent injections for the IL-17 blockers. Of the other key differences (or perhaps tolerability
and side effects), ustekinumab, like I said, very clean drug: maybe slightly increased
risk for upper respiratory tract infections but mostly patients don’t have infections,
don’t have malignancies, don’t have nuisance side effects and tolerability issues, or painful
injections for that matter. Whereas the IL-17 blockers have one very common
side effect, which is oral candidiasis, mucosal candidiasis, mostly mild in nature: most patients can be treated right through it with appropriate therapies. That said, it is an issue you need to look
out for probably in about 5% of patients, roughly speaking, for any of the IL-17 blockers
and brodalumab was not unique in that regard. The other issue that is hanging over the head
“quote-unquote” of brodalumab, not ixekizumab and secukinumab, is a really ill-defined risk
for suicidal ideation and suicidal attempts. There were noted six suicides in the entire
program for brodalumab, with the denominator being 6000+ patients, so one in a thousand
risk, in all of the brodalumab studies, of suicide. The FDA weighed in on this and clearly
they and nobody else really has a firm grasp of the true relatedness of suicidality, suicidal
behavior to this drug and, in the end, we’re gonna have to wait for post-marketing
surveillance studies to either refute or establish the risk as real. So it’s left to be seen how the regulatory
authorities both in the US and overseas weigh in on suicidality and brodalumab. It is clear to me they’re not going to create
the issue for ixekizumab and secukinumab, which don’t appear to have this signal in
their clinical trials program. Now the other issue I should mention is a
rare risk of inflammatory bowel disease, onset or exacerbation, in people getting IL-17 blockers. Again, it’s a very infrequent finding—probably
less than one in a thousand in patients in the studies for all three IL-17 inhibitors—though
it is clear if a person has a pre-existing history of inflammatory bowel disease (Crohn’s
disease or ulcerative colitis) that we need to be careful and probably lower those drugs
and IL-17 inhibition drugs down the treatment hierarchy, probably use TNF inhibitors and
ustekinumab for those drugs. It should be noted that IL-12/-23 inhibition
probably treats inflammatory bowel disease and there’s probably a forthcoming approval
for ustekinumab in the treatment of Crohn’s disease within the next 6 to 12 months; so
completely opposite story for IL-12/-23 inhibition. And finally, we don’t know how IL-17 inhibitors
will treat psoriatic arthritis or systemic inflammation more broadly. There are good data, though, showing that
secukinumab and ixekizumab treat psoriatic arthritis signs and symptoms and
inhibit joint destruction. So a high level of confidence is building
that IL-17 inhibition would be a good approach to psoriatic arthritis; in fact, secukinumab
already has FDA approval for that disease state and I’m guessing down the line the
other IL-17 blockers will too. So we are seeing advantages with the IL-17
inhibitors with regard to efficacy, no doubt about it; they are more efficacious than
the previous biologics, be they IL-12/-23 inhibitors or TNF blockers. We are not going to say now that they’re safer—they
have unique safety issues, which seemed for the most part rare and manageable and I’m
comfortably using IL-17 inhibitors in my clinic. I think they have the makeup of first-line drugs. And finally, the issue of cost and access
will remain as a prevalent concept in all treatment scenarios, so whether or not you
choose IL-17 inhibition as first, second, or third line for your patients, I would say
you’re always on firm footing. I have high confidence these drugs are here
to stay and will be more and more integrated into how we treat moderate-to-severe psoriasis.

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