25th EADV Congress. Late-breaking insight: Ixekizumab vs. ustekinumab head-to-head data in psoriasis

25th EADV Congress. Late-breaking insight: Ixekizumab vs. ustekinumab head-to-head data in psoriasis


Moving to a second important late breaker,
a comparison between ixekizumab (IL-17A inhibitor), and ustekinumab (a p40 inhibitor). Why is this important? With the arrival of a new class—and I think
it’s fair to say that the IL-17A inhibitors are there, they are no longer at the horizon,
they are there—we already have secukinumab in our hands for several months, ixekizumab
in some countries can already be prescribed, my country, Germany, likely be prescribable
from next spring on. The companies all started doing comparison
trials to etanercept; now etanercept when it was developed many, many years back was
a fantastic drug, but nowadays, efficacy-wise, compared to the other drugs, many would think
it’s a weak comparator; and also regulatory authorities turn away from etanercept as a
useful comparison. So the real comparison today for the new class
is, in my eyes, either adalimumab or ustekinumab; so this is why this comparison here, between
ixekizumab and ustekinumab was really awaited. We published last year in The Lancet the comparison
to etanercept and there was a big gap between the PASI 75, 90, 100 response with ixekizumab
being superior to etanercept, but I think the comparison to ustekinumab that is what
is really waited for. So here it comes, and the study design has
two parts—there is an induction phase that goes until Week 12, and there’s a maintenance
phase that goes until Week 52—and what was presented here is the induction phase. Now, how was it done? Ixekizumab given at the high dose (the dose
that we have in the label), which means 160 mg at baseline and then 80 mg from the next
week on, every 2 weeks until Week 12, and from then on it will be 80 mg once per month—but
again, I will not talk about this today. Ustekinumab given according to label, so a
weight-based dosing of either 45 mg if you are 100 kg or below, or 90 mg if you are more
than 100 kg, shots at baseline, Week 4, and then every 12 weeks thereafter. The primary endpoint here was PASI 90, and
I think this is interesting and it makes us realize that really PASI 90 is what is our
new treatment goal is, what patients and we want to achieve right now with therapies. Another thing I should say is that the patients
enrolled in this trial were patients that would fulfill the label of ustekinumab (Stelara),
which is a clear second-line label; so these patients had to have failed conventional therapies
or had to develop side effects or had to have contraindications against conventional therapies,
and only then could they be enrolled in a clinical trial. I’m saying this because the other comparison trial between an IL-17A inhibitor and ustekinumab— secukinumab versus ustekinumab—was actually in patients that could be naïve to systemic therapy, and we know that this will have an impact
on the clinical response. Now what was the important outcome at Week 12? PASI 90: 74% with ixekizumab (the high dose)
compared to 42% with Stelara. Now that’s a 30% gap and I will come back
later to how I would interpret this. Similarly, big difference in PASI 100 responses:
we have 40% at Week 12 with ixekizumab compared to just over 14%, so 40 almost with ixekizumab
compared to 14 (1–4) with ustekinumab, again going into this 30% difference direction. DLQI, does this mean something for our patients? DLQI 0/1, again meaning no impact of psoriasis
on our daily life. What were the percentages at Week 12? They were 63% in the ixekizumab arm compared
to 45% in the ustekinumab arm, reflecting and showing to us that this difference in
the clinical outcome—the high level of the clinical outcome, PASI 90—does impact differences
in the DLQI outcome, in the quality of life of the patients. Now, as a scientist you should always be able
to give a limitation of your study, and I would mention as a limitation here that Week
12 is probably not an optimal time point to show what ustekinumab can really do. It was selected because in the pivotal trials
for ustekinumab, Week 12 was the time of the primary endpoint; it was the time of the primary
endpoint in the ixekizumab trials. So from a formal aspect that’s absolutely
OK, but from a clinical aspect we know that ustekinumab works best at Week 22, Week 24. So to really understand what these drugs are
doing head-to-head, I will wait for—and they will come from this study—I will wait
for the longer-term results. What we also learned—just as a little bit
of a whipped cream on top of what I just said—how you can push your statistical methods forward,
because what they actually did in this trial is they did not just compare outcomes side-by-side
at Week 12 with a Fisher’s exact test. They actually did a logistic regression analysis,
where they took into account factors that we know influence outcome: like duration of
therapy, like weight, like geographical region, like baseline disease activity. And not only that, but they also corrected
for multiple comparison because there’s a long list today of key secondary endpoints
in this clinical trial, and this is interesting and the P-values for PASI 75, for PASI 90
remained statistically significant in doing so, but it tells me that we are also developing
the culture forward, the methodological culture that we will use in looking at these clinical trials.

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