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New biologics in psoriasis – progress and problems

For more than a decade now, ‘psoriasisologists’ have been exposed to the message that biologics are good and represent progress. This may in part be due to the fact that big pharma has discovered psoriasis as an emerging market and invested heavily, now asking for a return of this investment. But evidence seems to be in their favour ever since in the year 2008 the CHAMPION trial proved superior efficacy of a biologic over methotrexate, which was (and still is) the cornerstone of systemic therapy for patients with psoriasis in many countries. And the paper by Belinch on et al. in this issue of the JEADV adds the safety part of the argument by showing a lower rate of discontinuationrelated adverse events amongst patients under biologic therapies when compared to conventional systemic therapies. Finally, biologics seem to make perfect sense as they can be regarded as research tools turned into drugs, exhibiting a clearly defined mode of action that claims to have been identified based on progress in the understanding of the pathophysiology of psoriasis. Although there is still room for improvement, I tend to agree to much of this line of reasoning, as there is now ample evidence from controlled clinical trials that biologics do have the edge over conventional systemic therapies when it comes to efficacy or safety, much of it being reproducible in registries that look at ‘real-life’ patients; hence the decision of the European Medicinal Agency (EMA) to award a first-line label to some of the biologics. But even company-paid rocket scientists are not always right, and development of biologics is not at all free of serendipity, as sometimes suggested. For example, the TNF-a blocker infliximab was originally developed in a quest to find a cure for sepsis, while we now consider severe infections a contraindication, and ustekinumab was originally selected for its ability to block IL-12 and only later turned out to be a good inhibitor of IL-23, which now is considered a major cytokine in psoriasis. So, if biologics are good, are newer biologics better? Asking this question and trying to address it directly represents a major progress in evidence-based medicine. Because, if you ask it seriously, there is only one way to find out: you have to try it. Thus, direct head-to-head comparator studies became the state of the art in this field of clinical research (and hopefully the times are over when people presented slides looking at the efficacy of different drugs, acknowledging that the data come from different trials, but showing them anyway). The choice of comparator for such a study tells much about the mindset of companies: Do they understand where the field will be once their drug is approved and chose an appropriate comparator? Do they believe they have something that will rock the field and go for a comparison advisors may call ambitious? To this end, it is great to see that so many head-to-head studies have been and are being performed, and two of them are published in this issue of the JEADV, as this is a particularly convincing approach, helping to advance our evidence-based knowledge and reducing the influence of opinion (leaders). And yes, some (but not all!) companies already have had the guts to do trials against what was considered the mightiest competitor on the market at the time of the study (I will refrain from giving references here, as this might result in a too lop-sided view.). If we want to add some granularity to the discussion, we need to define ‘old’ and ‘new’ biologics. As I see it, there are three ‘generations’ of biologics in the field of psoriasis: the first generation comprises the T-cell-directed alefacept and efalizumab, the second generation being the TNF-a inhibitors (adalimumab, etanercept, infliximab), and the third generation targeting the IL-23/IL-17 axis (brodalumab, ixekizumab, secukinumab and ustekinumab already on the market, with several specific IL-23 inhibitors following soon), but only the second and third generation still being used on a broad basis. The virtual (alefacept) or complete (efalizumab) abolishment of the first generation tells much about the evolutionary pressure in the field: While alefacept does not provide enough (and quick enough) efficacy for money, efalizumab was withdrawn from the market by the manufacturing company for safety reasons. Newer biologics are confronted with impressively effective drugs already on the market, thus pushing the bar higher and higher. This goes along with an ever more complete safety data base for those biologics that have been used for a while (To date, it can basically be excluded that there will be any new safety signal for TNF-a inhibitors in the light of millions of patient-years of exposure.). Thus, any ‘newcomer’ will have to provide a very ‘clean’ profile towards the end of its clinical development programme to be considered a valid option for us, the potential prescribers. This is good, as only the best candidates will finally see the light of approval. But it is also bad, as potentially quite useful molecules might be ‘killed’, although they could be valuable options in our therapeutic arsenal. I personally think it is advantageous to have numerous options for my patients, even if they are only ‘me-too’ drugs, using the same mode of action. This might help to avoid running out of options in patients who lose efficacy due to antidrug antibodies, as these could simply be offered a switch to another molecule with the same mode of action.