Biologic Therapy for Psoriasis

Overview

The original biologic therapies developed for psoriasis became available in the early part of the 21st century. Their development was initially driven by the concept that there was a tremendous unmet need for long-term, chronic therapy for patients with more severe psoriasis. The most effective oral systemic medications available, methotrexate and cyclosporine, had side effects associated with long-term continuous use, and those that seemed safer, including narrowband ultraviolet B (NB-UVB) phototherapy and acitretin, were not as predictably effective and could be intolerable or inconvenient for patients. It was thought that creation of monoclonal antibodies or fusion proteins that specifically bound to their target and did not have a great impact on the intracellular workings of multiple organs would result in fewer side effects and could have significant efficacy. Thus, due to the large number of patients who had insufficient control of their disease, in a very short time, there was a rapid expansion of the biologic medications available for extensive psoriasis.

Development of biologics for psoriasis came in two forms. The first was the invention of new medications created specifically for psoriasis, attacking targets thought to be central to the pathophysiology of disease. The alternative pathway was to test medications that had already proven effective for inflammatory bowel disease (IBD) or inflammatory arthritis that had given hints of benefit for cutaneous psoriasis. Ironically, those medications that were initially created more rationally for psoriasis turned out to be less effective and with potentially greater safety concerns than those borrowed from other indications.

Alefacept, the first biologic medication for psoriasis that blocked T cell costimulation by inhibiting CD2-LFA3 interactions had psoriasis area and severity index (PASI) 75 scores of only 28% for a single course of treatment. Efalizumab, an anti-LFA1 monoclonal antibody that blocked both T cell migration and costimulation, had somewhat similar efficacy with a PASI 75 of 29.5% and 31.4% but was taken off the market due to side effects, primarily an unacceptably high incidence of progressive multifocal leukoencephalopathy (PML) in patients chronically treated with this medication.

Thus, the concept of scientifically creating new biologic medications for psoriasis initially met with little success. Much more successful were those medications taken from other disease states, anti-tumor necrosis factor (anti-TNF) treatments and those directed against targets that were not even known to be part of the psoriasis disease pathway at the earlier stages, particularly IL-23. These agents will now be reviewed in much greater detail. The biologic therapy drugs are shown in Table 12-1.

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Anti-TNF Agents

At the time of their initial use in psoriasis, it was not clear why anti-TNF agents, developed initially for Crohn’s disease and rheumatoid arthritis (RA), would have any impact on psoriasis. It was noted very early when anti-TNF treatments became available, particularly infliximab, that patients who had concomitant psoriasis had great improvement in their skin. Additionally, clinical trials for psoriatic arthritis (PsA) with etanercept showed improvement in subjects’ skin, along with the improvement in joint disease. Despite not having a good explanation for why these medications would improve psoriatic skin disease, development for psoriasis went forward.

In retrospect, it was the lack of an appropriate model of the pathophysiology of psoriasis that hindered an understanding of why anti-TNF therapy would work for psoriasis. As pathways associated with IL-17 became evident as the primary driver of psoriatic plaques, a deeper understanding of anti-TNF therapy became clear. TNF is a primary activating cytokine for mononuclear cells that produce IL-23 and induce the production of IL-17, IL-20 and IL-22 in the skin. Evidence suggests that blockade of TNF can inhibit this system and shut down the cytokine cascade that is required for the local responses necessary for the production of clinical psoriasis. Interestingly, these concepts were only identified after anti-TNF agents were commonly used for psoriasis, demonstrating how observation will often trump theory in drug development.

Anti-TNF Efficacy

Four anti-TNF treatments are approved for moderate to severe plaque psoriasis: etanercept, infliximab, adalimumab and certolizumab pegol. While, as described in the section on anti-TNF therapies for PsA, these molecules are structurally distinct, they are thought to be mechanistically very similar. They all bind TNFa and inactivate and remove it from areas of inflammation. Etanercept accomplishes this through use of the naturally occurring human TNF receptor constructed into a fusion protein, while adalimumab and infliximab are monoclonal antibodies. Certolizumab pegol consist of a recombinant, humanized antigen-binding fragment with specificity for human TNFa conjugated to polyethylene glycol. It is likely that these differences in structure may account for the differences in outcome associated with these medications that are seen in psoriasis therapy to a greater extent than with PsA. To better understand the similarities and differences between these medications, all four will be considered together.

No treatments for psoriasis have the wealth of excellent information in the form of multiple, well-designed clinical trials than the four anti-TNF agents. Unlike oral systemic treatments, the four anti-TNF agents were tested in the era of greater clinical trials science and the sample sizes are much greater than, for example, trials with cyclosporine. Additionally, while it is never completely appropriate to compare drugs not tested in a head-to-head trial, with anti-TNF agents, clinical trials for psoriasis have become standardized to a much greater extent, making our interpretation of these trials much easier.

The standard end point for the pivotal, phase 3 clinical trials for psoriasis is the percentage of subjects who have achieved a 75% reduction in their PASI score from baseline (Figure 12-1) or a rating of clear or almost clear on a PGA (0 or 1). For the anti-TNF treatments, the primary end points were measured at 12 weeks for etanercept, 10 weeks for infliximab, 16 weeks for adalimumab and 12 or 16 weeks for certolizumab pegol. While these time points seem particularly short-term for a disease that is a chronic condition, the structure of these trials require that the primary end points cannot be longer. These studies are placebo-controlled monotherapy trials. In other words, unlike in arthritis trials where subjects can remain on methotrexate or NSAIDs, patients with extensive psoriasis in these studies are without significant therapy for up to 16 weeks. Thus, it would be unethical to permit longer periods with only placebo in these trials.

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Short-Term Efficacy

Etanercept

As mentioned, the primary end point of clinical trials for psoriasis with anti-TNF agents is a short-term response. The phase 3 trials for all four of these medications are remarkably consistent in their outcomes for their respective drugs. Etanercept was the first of the agents to be tested. Two large phase 2 trials were performed, one in North America and one in Europe and Canada. Slightly different dosing regimens were used for the two studies. In the North American trial, etanercept was dosed at either 25 mg weekly, 25 mg twice weekly, or 50 mg twice weekly for 12 weeks and compared with placebo. Subjects were studied at 24 weeks, as well, on their randomized dose, although there was no further placebo control at that time. The European study took a slightly different approach. Subjects were treated in the same dosing groups during the placebo-controlled period but the high-dose group was then decreased to the 25-mg twice-weekly dose for the second 12 weeks of the study.

The consistency of the results in these two studies is striking. In both studies, at the 12-week primary end point, 49% of the high-dose subjects achieved a PASI 75. The lower-dose group had a PASI 75 of about 34% in both studies. In both of these studies, there was an excellent placebo control with rates of response <5%. At 24 weeks, outside of the placebo-controlled period, the outcomes varied. When the subjects were allowed to continue the 50-mg twice-weekly dose, greater numbers responded in the second 12 weeks with a PASI 75 of 59%. After 24 weeks, 42% and 44% of the subjects obtained a PASI 75 in the low-dose groups of the global study and the US study, respectively. Figure 12-2 shows PASI 75 through week 24 of the etanercept global study.

Of note, of the subjects who were required to “step-down” to 25 mg twice weekly in the global study, some gained and some lost a PASI 75 in the second 12 weeks, resulting in a 50% PASI 75. This number is much closer to the result of the group treated continuously with the lower dose, making it unclear whether the higher-dosing schedule initially resulted in a greater number of patients having a PASI 75 with the “step-down” dosing schedule in comparison to the lower-dose schedule, or if it is just a result of the subjects getting to their response faster. Thus, while the indication for etanercept use includes this “step-down” schedule, it may be reasonable to use the lower dose initially in patients who do not have acutely severe disease.

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Infliximab

The second anti-TNF agent to be studied for psoriasis was infliximab. As mentioned in the PsA module, infliximab is given intravenously on a weight-based dosing schedule. In psoriasis, two randomized, placebo-controlled, phase 3 studies were performed in Europe and in North America that had very similar initial placebo-controlled periods. In both studies, the end point was at 10 weeks after doses at week 0, 2 and 6. Unlike in arthritis where the addition of methotrexate was encouraged, these trials were monotherapy without concomitant immune modulators. In the European study, a dose of 5 mg/kg was tested, while in the North American Study both 3 and 5 mg/kg were used.

Like the etanercept trials, the short-term efficacy of infliximab in these two trials was quite similar. The European trial had a PASI 75 of 80% at 10 weeks (Figure 12-3), while the American trials showed 76% in the 5-mg/kg group and 70% in the 3-mg/kg group. While the two doses seem quite similar in the short term, they differentiate with longer-term use. This differentiation can first be seen at the 26-week time point where the 5-mg/kg group maintains the 78% PASI 75 rate while the 3-mg/kg group has fallen to a PASI 75 of 65%. Thus, the recommended dose of infliximab is 5 mg/kg at the dosing intervals studied.

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Adalimumab

The third approved anti-TNF agent to be tested for psoriasis was adalimumab. Unlike the other two agents, there was only one trial only comparing adalimumab with placebo done in both North America and Europe. The other trial was a placebo-controlled comparator trial to methotrexate performed in Europe. In both cases, the primary end point of these trials was at 16 weeks of treatment. The dosing schedule for adalimumab was somewhat different than for inflammatory arthritis. As opposed to strict every-other-week dosing with 40 mg, the psoriasis trials used 80 mg at week 0, 40 mg at week 1 and then every other week. This schedule was meant to capture higher responses earlier in the course of treatment for more severely affected subjects.

Remarkably, as with etanercept and infliximab, these trials also have very similar results, although with a slight twist. In the placebo-controlled, non-methotrexate study, the PASI 75 was 71% with a good placebo-control rate of about 7% (Figure 12-4). In the methotrexate comparator study, the response at 16 weeks was 80% but with a placebo-control rate of 18.9%. Thus, the treatment effects of the trials, that is, the effect minus the placebo-control rate, were 64% and 61%, respectively. Again, these are remarkably consistent results. Unfortunately, 24-week data for adalimumab required extrapolation from the original trial and an open-label crossover trial. However, the best estimate is that the 40-mg every-other-week dose showed a PASI 75 of 70% at 24 weeks.

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Certolizumab Pegol

The most recent anti-TNF agent to be approved for psoriasis was certolizumab pegol, indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The recommended dose of certolizumab pegol is two 200-mg subcutaneous injections every other week. Three multicenter, randomized, double-blind studies assessed the safety and efficacy of certolizumab pegol: CIMPASI-1, CIMPASI-2 and CIMPACT.

CIMPASI-1/2 are ongoing 144-week replicate studies conducted at clinic sites across North America and Europe. Eligible patients were randomized to placebo, 200-mg certolizumab pegol Q2W (after a loading dose of 400 mg at weeks 0, 2 and 4), or 400 mg certolizumab pegol Q2W until week 16. The coprimary endpoints were the proportion of patients who achieved a PASI 75 and PGA of “clear” or “almost clear” with at least a 2-point improvement at week 16. At week 16, significantly higher PASI 75 responder rates were observed for 200-mg certolizumab pegol (CIMPASI-1/2: 66.5%/81.4%) and 400-mg certolizumab pegol (75.8%/82.6%) compared with placebo (6.5%/11.6%; P <0.0001 for all comparisons; Figure 12-5). Significantly higher PGA 0/1 response rates were also observed at week 16 for 200-mg certolizumab pegol (CIMPASI-1/2: 47.0%/66.8%) and 400-mg certolizumab pegol (57.9%/71.6%) compared to placebo (4.2%/2.0%; P <0.0001 for all comparisons).

CIMPACT is an ongoing 96-week study also conducted at clinic sites across North American in Europe. Eligible patients received placebo for 16 weeks, 200-mg certolizumab pegol Q2W (after a loading dose of 400 mg at weeks 0, 2 and 4) for 16 weeks, 400-mg certolizumab pegol Q2W for 16 weeks, or etanercept 50 mg twice weekly for 12 weeks followed by a 4-week washout period. The primary endpoint was the proportion of patients who achieved a PASI 75 at week 12, for the comparison of both certolizumab pegol doses vs placebo. At week 12, 61.3% and 66.7% of patients treated with 200-mg and 400-mg certolizumab pegol achieved a PASI 75 response, respectively, compared to 5% of placebo-treated patients (P <0.0001 for both comparisons).

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Long-Term Efficacy

The long-term efficacy for anti-TNF agents is less clear than the short-term data due to clinical trial design and the time the studies were performed. For example, in the best short-term etanercept trials, the phase 3 pivotal studies were only 24 weeks and the subjects were really not studied longitudinally for longer periods. In the infliximab studies, subjects were followed for 1 year continuously. With adalimumab and certolizumab pegol, there were longer longitudinal continuous study periods in the phase 3 trials but, due to trial design, subjects had strict criteria for continuing in the study and re-randomizations were performed, making the continuous-treatment group relatively small.

No long-term data are available for the pivotal phase 3 trials with etanercept. The best study investigating long-term data with monotherapy that can be compared with other anti-TNF agents was a longer-term trial with continued high-dose etanercept. This trial showed a PASI 75 of 63% at week 48, similar to the PASI 75 of 60% at week 24 in this trial. The week 24 data are very close to the phase 3 US trial suggesting continued consistency. At 96 weeks of therapy, however, the PASI 75 decreases to 51% in this trial. It is critical to remember that the dosing in this trial is higher after week 12 than the recommended dosing for etanercept. Therefore, any extrapolation to the approved 50-mg once-weekly dose is based on assuming that the drug will behave similarly at lower doses, an assumption that is not necessarily correct. With step-down dosing, a loss of a number of subjects clearly takes place with the lower dose but some patients may achieve a PASI 75 as well. One of the reasons some dermatologists choose to start with the 50-mg once-weekly dose rather than using the step-down dosing schedule is to keep patients from confronting the loss of response associated with the decrease in dose.

The 1-year data with infliximab is perhaps the easiest to understand. After the initial loading period, subjects were treated with every-8-weeks infliximab at their assigned dose. After 1 year of treatment, there is a notable loss of response in these study subjects. In the European study, 61% of subjects had a PASI 75, down from 80% at week 10. Likewise, in continuously treated subjects in the North American trial, 55% and 44% of the 5-mg/kg and 3-mg/kg groups had a PASI 75 at week 50. There are multiple potential reasons for this loss of response. The first is the magnitude of the dose reduction. Subjects go from three doses in 6 weeks to one dose every 8 weeks. Additionally, patients in these trials develop anti-infliximab antibodies at a relatively high rate since, unlike in arthritis, the drug is being used without other medications (such as methotrexate) that blunt the antibody response. Many dermatologists will use low-dose methotrexate (7.5 to 10 mg/week) in all patients on infliximab to try to blunt this loss of response.

As mentioned, the longer-term data on adalimumab may be some of the most difficult to understand. In the placebo-controlled trial, subjects were allowed to continue in the trial only if they had a PGA of 0 or 1 at two time points in the first year. Thus, only the high-responding patients continued in the trial and there was not chance for subjects to improve on continued therapy if they did not have response at the two time points. Additionally, at week 33 of the first year, the high-responding patients were re-randomized to a drug withdrawal arm to investigate retreatment. Finally, after 1 year, subjects were enrolled in a long-term extension trial and followed longitudinally. Given all the care that needs to go into interpreting this research, critical examination of the data has led to a number of conclusions. First, in general, subjects treated with adalimumab have some loss of effect during the first year of treatment. This loss of effect may continue after the first year but it clearly decreases in frequency after the first year. The absolute magnitude of this loss is difficult to ascertain and compare with the other two anti-TNF agents since the methodology is so distinct in this trial. Like the other medications, there may be a resistance to adalimumab due to antibody formation to adalimumab or other reasons.

Similar to adalimumab, the longer-term trial design for certolizumab pegol studies was complex. At week 16 of CIMPASI-1/2, certolizumab pegol-treated PASI 50 responders and placebo-treated PASI 75 responders continued receiving their respective treatments through week 48 of the maintenance period. Placebo-treated patients who were PASI 50 responders but not PASI 75 responders received certolizumab pegol 200 mg Q2W (after 400 mg loading doses). Certolizumab pegol-treated PASI 50 non-responders received open-label 400-mg certolizumab pegol Q2W. In pooled data through week 48, PASI 75 response rates for 400-mg certolizumab pegol Q2W were 66.7% and 75.0% in patients with and without prior anti-TNF use, respectively and 61.4% and 63.4%, respectively, for 200-mg certolizumab pegol Q2W. At week 48, PGA 0/1 response rates for 400-mg certolizumab pegol Q2W in patients with and without prior anti-TNF use were 53.8% and 59.6%, respectively and 50.0% and 53.5%, respectively, for 200-mg certolizumab pegol.

At week 16 of CIMPACT, patients achieving a PASI 75 were re-randomized from 400-mg certolizumab pegol Q2W to 400 mg Q2W, 200 mg Q2W, or placebo, and from certolizumab pegol 200 mg Q2W to 400 mg Q4W, 200 mg Q2W, or placebo for the 32-week maintenance period. Etanercept-treated PASI 75 responders were re-randomized to certolizumab pegol 200 mg Q2W (after 400 mg loading doses) or placebo. PASI 75 non-responders at week 16 received 400 mg certolizumab pegol Q2W. At week 48, PASI 75 responder rates were greater for patients re-randomized from certolizumab pegol to either the same or a different dose of certolizumab pegol than those re-randomized from certolizumab pegol to placebo (from 200 mg Q2W to: placebo, 45.5%; 200 mg Q2W, 79.5%; 400 mg Q4W, 88.6%; from 400 mg Q2W to: placebo, 36.0%; 200 mg Q2W, 80.0%; 400 mg Q2W, 98.0%). The greatest responses were observed for patients who continued 400-mg certolizumab pegol Q2W.

One final question associated with long-term efficacy of anti-TNF agents is continuous vs intermittent use. Data suggest that stopping treatment and then re-starting after disease has returned results in a lower rate of response. This rate has been determined differently for the different medications but about 60% to 75% of patients who have already responded to treatment will respond a second time if their disease is allowed to return. Thus, the recommendation for all anti-TNF medications is to use them continuously if possible. However, it is possible to tell patients that if they need to stop for any of a variety of reasons, most but not all, will respond to treatment again.

Pediatric Psoriasis

One area of specific interest for anti-TNF therapies is in pediatric psoriasis. While the prevalence of pediatric psoriasis is significantly less than in adults, this condition can have significant impact on both physical and social development in children. A major advance in the care of pediatric patients with psoriasis has been made with the approval of etanercept for both children and adolescents with psoriasis. In a study of children and adolescents from ages 4-17, etanercept therapy had a highly significant PASI 75 response vs placebo (57% to 11%). This improvement was well maintained for up to 5 years on etanercept therapy. Importantly, no new safety signals were discovered in trials with etanercept in the pediatric population.

Anti-TNF Safety in Psoriasis

To understand the safety of anti-TNF therapy for psoriasis, it is critical to understand the similarities and differences in risk between inflammatory arthritis where there is much better data and longer-term registry data in psoriasis. The critical point to examine is whether the magnitude of the risks of anti-TNF agents, particularly in the greatest area of concern, serious and opportunistic infections, is the same between the two disease states.

Reviews of the safety risk for TNF agents across clinical trials databases for different indications are very illustrative and consistent (Table 12-2). What is clear from these two analyses is that the risks for infection in the psoriasis studies are much lower than those in RA or PsA. This difference could be due to less impact of these drugs in psoriasis patients or, more likely, a subject population at much lesser risk. Subjects in the psoriasis trials were younger, overall healthier and were not exposed to multiple immunosuppressant medications compared with the arthritis trials. Therefore, a lower rate of infection in the psoriasis trial experience would be expected.

Interestingly, in the placebo-controlled periods of psoriasis trials, an increased risk of infection cannot be demonstrated. In a meta-analysis of infection risk of anti-TNF trials for psoriasis, there was no difference between placebo and the treatment groups when there was control for time of exposure. Moreover, in following the clinical trials in subjects with adalimumab over time, there seems to be no increase in the frequency of infectious events, at least for 3 years of continuous use of adalimumab. While all this seems quite encouraging, it needs to be remembered that clinical trials have entry criteria that exclude many potential subjects at higher risk for side effects, making it less likely to be able to see effects. Since there are no long-term registries of psoriasis patients available to date, it is prudent to refer to the long-term inflammatory arthritis registries and warn patients that these medications could potentially increase their risk of infection.

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Ustekinumab

Ustekinumab is a biologic agent approved for the treatment of moderate to severe plaque psoriasis. While the target of the medication, the p40 subunit shared by IL-12 and IL-23, it works by the same basic pathway. As previously mentioned, IL-23 is a critical cytokine in activating those cells that produce IL-17, IL-20 and IL-22, all central to the pathophysiology of psoriasis. Rather than impacting the mononuclear cells that produce IL-23, such as anti-TNF agents, ustekinumab binds and removes the IL-23 itself. This down-regulates many of the pathways necessary for psoriasis and has been shown to have clear efficacy in the disease. What is unclear is the role for the inactivation of IL-12 and whether this is necessary for the effectiveness of the drug.

Efficacy

Owing somewhat to ustekinumab being developed later than the anti-TNF agents, a strong argument can be made that the clinical trials of this medication have the greatest amount of information of any agent for psoriasis, particularly in deciphering long-term responses. In two phase 3 trials, ustekinumab was given at doses of either 45 mg or 90 mg at a schedule of week 0, week 4 and then every 12 weeks thereafter. The primary time point was at 12 weeks. The PASI 75 results of these trials, done both in North America and Europe, were between 66% and 67% for the 45-mg group in two trials and 66% and 75% in the 90-mg dosing group (Figure 12-6). At 28 weeks, there was a slight increase in benefit with the 45-mg dose group having a PASI 75 of 70% to 71% and the 90-mg group with a PASI 75 of 79% in both trials. The differences between the two dosing schedules were not statistically different. However, when the data were controlled for weight, in subjects >100 kg, the 90-mg dose was superior. Thus, the dose of ustekinumab is based on patient weight with patients weighing >100 kg getting the 90-mg dose. Additionally, in the first head-to-head trial of biologics, ustekinumab was shown to be superior to etanercept at 12 weeks.

The long-term follow-up of subjects in the ustekinumab trials was excellent. The two phase 3 studies followed subjects longitudinally for up to 5 years. Although there were some confounding factors, including potential dose escalation in both frequency and dose, as well as some patients undergoing randomized withdrawal in one of the trials, about 70% of subjects continued to be followed in these trials for an extended period of time. Three-year data on continued response are available and approximately 80% of subjects who had a PASI 75 at 40 weeks maintained it for 3 years. Moreover, retreatment data suggested that a somewhat higher rate of re-capturing response was present with ustekinumab, a rate of about 80%.

Like etanercept, ustekinumab has also been studied and approved by the FDA for use in a younger population. In the CADMUS trial, ustekinumab was tested in adolescents with moderate to severe psoriasis from ages 12-17. In this trial, ustekinumab was tried in two different doses, a standard dose (SD) of 0.75 mg/kg given at the normal adult dosing intervals or a half-standard dose (HSD). PASI 75 responses were significantly higher in the subjects treated with ustekinumab than placebo (78.4% HSD, 80.6% SD vs 11% placebo). While the two dosing groups seemed similar at PASI 75, at higher levels of response, particularly complete clearance, the SD schedule seemed to have greater efficacy. Like etanercept, ustekinumab had no new safety signals in the adolescent population.

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Safety

Unlike anti-TNF agents, the only significant safety data available for ustekinumab are from the psoriasis clinical trials. The obvious concerns for this medication that de-activates cytokines involved in immune responses are infection and cancer. A number of analyses of long-term data have been performed with the clinical trials population with ustekinumab. In these papers, the risks of ustekinumab seem to be equivalent to placebo in the clinical trials and do not increase with prolonged exposure to the medication. However, the caveat associated with anti-TNF clinical trials is even more significant with ustekinumab. Research studies may underestimate risks due to selection of a healthier population treated and we cannot rely on safety data from registries in other indications with ustekinumab as they do not exist. Another agent that blocked the same pathway, briakinumab, had some evident risk in both infection and skin cancer but was a more potent agent than ustekinumab making the applicability of these findings unclear. Thus, we must wait for larger and less selected groups of patients to be studied in postmarketing registries to fully understand the risks or potentially lack of risks associated with ustekinumab.

While no other risks associated with ustekinumab have been confirmed, one area deserves note. Early trials of ustekinumab and the briakinumab trials hinted at an increase in major adverse cardiac events (MACE). This finding did not seem to continue into the phase 3 trials of ustekinumab. Nonetheless, some authors express continued concern about this finding. Like infection and cancer, a better understanding of this potential risk will become more clear over time. At this time, it is relatively clear that if this relationship is in fact real, the clinical magnitude is likely relatively small.

Anti-Interleukin 17 Medications

Starting with secukinumab, there are now four medications approved for the treatment of moderate to severe psoriasis that inhibit the activity of IL-17. As mentioned in the section on pathophysiology, IL-17 is a central cytokine in the connection between the immune system and the keratinocyte response in psoriasis. IL-17 plays a key role in inducing keratinocytes to have altered proliferation and maturation along with the production of cytokines and chemokines that magnify the immune response. The medications that target this pathway are antibodies that bind to IL-17A (secukinumab and ixekizumab), IL-17A and IL-17F (bimekizumab), or block activation through the IL-17RA receptor (brodalumab). All four of these medications have been shown to be highly efficacious in treating psoriasis.

Secukinumab

Secukinumab was the first anti–IL-17 agent approved by the FDA in 2015. Secukinumab is a monoclonal antibody that directly inhibits IL-17, the critical cytokine in connecting the immune response to keratinocyte abnormalities in cutaneous psoriasis. By blocking IL-17, secukinumab should not only normalize the visible keratinocyte responses but also downregulate many of the feedback loops that cause psoriasis plaques to persist.

Efficacy

The efficacy of secukinumab has been evaluated in a large phase 3 program. Additionally, secukinumab has the most extensive series of controlled trials investing efficacy in subtypes of psoriasis of any approved agent for psoriasis to date. In the pivotal trials, not only was secukinumab compared with placebo, but multiple trials directly comparing secukinumab with other biologics, including etanercept and ustekinumab, were performed.

The two pivotal trials of secukinumab compared doses of 150 mg and 300 mg to placebo (ERASURE) with the second trial (FIXTURE) adding a comparison arm to etanercept. In both of these trials, there was an extremely rapid response seen with secukinumab and high levels of response seen at the primary endpoints of the studies at 12 weeks (Figure 12-7). The response at week 12 for the 300-mg dose were 77% to 82% in the trials when compared to 44% in etanercept and about 5% in the placebo groups. Moreover, extremely high-level responses, measured by a PASI 90 were from 54% to 59%. All of these responses were higher in the 300-mg group than the 150-mg group. Finally, 16-week results of a non–placebo-controlled, randomized trial of the 300-mg dose of secukinumab compared with ustekinumab demonstrated a superior response of secukinumab at PASI 90 and 100 levels.

The longer-term results of the secukinumab clinical trials have been very encouraging. Both the FIXTURE and ERASURE studies maintained dosing in their original groups for 52 weeks. In these studies, 80% to 84% of subjects who achieved a PASI 75 retained that response at the week 52 analysis. Additionally, the reported rate of anti-drug antibody development has been <1% in clinical trials of secukinumab, suggesting that maintenance of response may be a significant strength of this medication.

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Safety

The large phase 3 clinical trials of secukinumab discussed suggest not only excellent efficacy outcomes but a good safety profile as well. Blockade of IL-17 could inhibit responses to cutaneous pathogens. Thus, bacterial infections of the skin and candida infections would be the most predictable issues associated with this pathway. In the clinical trials, cutaneous bacterial or viral infections did not seem to increase with secukinumab therapy when compared with placebo or etanercept. However, there were dose-dependent increases in the number of candida infections seen. Importantly, these were almost all very mild and were generally easily treatable. Other infectious sequelae did not seem to be at issue with secukinumab treatment.

Despite secukinumab’s robust safety data base from clinical trials, long-term, in-office usage will help to determine the medications overall safety profile. One area of particular interest will be to see if secukinumab has any impact on the incidence or severity of inflammatory bowel disease (IBD), in both Crohn’s disease and ulcerative colitis, in patients with psoriasis. One study of secukinumab for Crohn’s disease suggested that some subjects may actually worsen when treated with secukinumab. Clinical trials have suggested that this is not a significant issue in psoriasis patients with IBD, it is important for clinicians to proceed with caution if they are to use secukinumab, or any agent that blocks IL-17, in patients who may have or are at high risk for IBD.

Ixekizumab

Ixekizumab was approved for treatment of moderate to severe plaque psoriasis in March 2016. It is a humanized monoclonal antibody that binds to IL-17A and, thus, inhibits both the immune response in psoriasis and the keratinocyte response to immune activation.

Efficacy

The phase 3 program for ixekizumab consisted of three clinical trials, two comparing ixekizumab with etanercept and placebo and one comparing ixekizumab with placebo with evaluation of long-term maintenance of effect. In these trials, ixekizumab was clearly more efficacious than etanercept and placebo and demonstrated a high frequency of effectiveness even when measured at the higher response levels of PASI 90 and 100.

Dosing of ixekizumab was evaluated at 160 mg at week 1 then either 80 mg every other week or 80 mg every 4 weeks. Only the higher frequency was approved as treatment by the FDA and will be reported. In the placebo-controlled trial (UNCOVER-1), the PASI 75 was 89% (Figure 12-8) with the PASI 90 and 100 at 71% and 35% (with the placebo rates being 4%, 1% and 0%). These extremely high response rates were mirrored in the etanercept comparison trials, UNCOVER 2 and UNCOVER 3. The PASI 75, 90 and 100 rates in these trials were 87% to 90% (Figure 12-8), 68% to 71% and 35% to 40% compared to etanercept rates that maximized at 41%, 18% and 4%. The PASI 75, 90 and 100 placebo rates were 2% to 7%, 1% to 3% and 0% to 1%.

Long-term evaluation of the efficacy of ixekizumab is on ongoing. The UNCOVER 1 trial was designed as a randomized withdrawal trial with only subjects who had high level responses allowed to continue to full evaluation. Of those subjects who reached a PASI 75 at 12 weeks, 75% were able to maintain that level of response after 60 weeks of treatment. Decreasing the dose led to greater loss of response. Full evaluation of longer-term data from all three phase 3 trials is expected to be published soon.

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Safety

As would be predicted by the similar mechanism of action, safety data from the clinical trials for ixekizumab look quite similar to that of secukinumab. Increases in the number of mild, easily treatable candida infections were noted. Serious infection rates were low. Additionally, small numbers of cases of inflammatory bowel disease were noted.

The full, longer-term evaluation of safety with ixekizumab remains to be published. Like other drugs that have not been used for any significant length of time in clinical practice, care needs to be taken in evaluating safety. Ideally, when ixekizumab has been prescribed for a general psoriasis population for a few years, a better understanding of its actual safety will be available.

Brodalumab

Brodalumab is a monoclonal antibody that inhibits IL-17 activity at the receptor level by blocking the IL-17A receptor (IL17AR). By using this mechanism, it not only blocks IL-17A like secukinumab and ixekizumab, it also removes the activity of IL-17F and IL-17C, both of which bind to this receptor. It is unclear as to the impact of this difference on both the safety and efficacy of this medication. Brodalumab was approved for the treatment of moderate to severe plaque psoriasis in February 2017 at a dose of 210 mg given every other week.

Efficacy

The phase 3 development program for brodalumab included 3 pivotal trials AMAGINE 1, 2 and 3. While AMAGINE 1 was similar to other placebo-controlled psoriasis trials, AMAGINE 2 and 3 were comparator trials to ustekinumab with complete clearance (PASI 100) as the primary endpoint of these studies. In all of these studies, brodalumab was used subcutaneously at doses of either 140 mg or 210 mg every other week. It showed significant benefit vs placebo at the PASI 75 and 100 level in the first 12 weeks in all studies (210 mg – 83%-86% and 37%-44% vs placebo at 2%-8% and 0%-1%, respectively). In AMAGINE 2 and 3, both levels of response were significantly higher than for treatment with ustekinumab (Figure 12-9).

Longer term treatment out to 52 weeks showed a high level of maintenance of response. AMAGINE 1 was a randomized withdrawal study that demonstrated a relatively rapid loss of response when treatment was terminated but an excellent maintenance of response when brodalumab was continued. In fact, AMAGINE 1, 2 and 3 all demonstrate a slight increase in the number of patients who attain complete clearance with continued therapy with maintenance of response at the PASI 75 level.

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Safety

Similar to secukinumab and ixekizumab, the safety data on brodalumab in the clinical trials were generally good. Infection and malignancy rates were similar to placebo and to ustekinumab in the comparator trials. Caution remains necessary when considering treating patients with IBD with brodalumab. Of course, long-term data on safety will only be developed with study in the clinical setting.

There is one important safety concern that is unique to brodalumab compared to secukinumab and ixekizumab. In the phase 3 clinical trials program, four completed suicides occurred under treatment with brodalumab as opposed to 0 in the placebo or ustekinumab groups. While the rate of completed suicides is low, the numerical imbalance with the comparator groups has led the Food and Drug Administration (FDA) to place a boxed warning for suicide risk on the approval. This warning strongly suggests evaluation of suicide risk for patients treated with brodalumab at regular intervals. Interestingly, the EMEA determined that there was no statistical risk that could be identified and no warning on brodalumab use was included in the approval. Long-term evaluation of suicide risk with brodalumab is critical for a full understanding of this issue.

Bimekizumab

Bimekizumab is an IgG1 monoclonal antibody that binds to human IL-17A, IL-17F and IL-17A/F cytokines, inhibiting their interaction with the IL-17 receptor complex. Its efficacy and safety in adults with plaque psoriasis has been established in three phase 3 trials – BE VIVID, BE READY and BE SURE. It has also been assessed against secukinumab in a head-to-head comparison trial. Bimekizumab received FDA approval in October 2023 and is currently indicated for the treatment of adults with moderate to severe plaque psoriasis.

Efficacy

BE VIVID randomized (4:2:1) 567 adult patients to receive one of three regimens: 1) bimekizumab 320 mg Q4W for 52 weeks; 2) ustekinumab 45 mg (for patients weighing ≤100kg) or 90 mg (for patients weighing >100kg) at weeks 0 and 4, then Q12W through week 52; or 3) placebo Q4W for 16 weeks, then bimekizumab 320 mg Q4W to week 56. The primary endpoints were the proportion of patients achieving a 90% reduction in the PASI score and the proportion of patients achieving an IGA score of 0 or 1 (with at least a 2-grade improvement from baseline) at week 16. An improvement in the PASI score was observed in 85% of bimekizumab-treated patients, compared to 50% of ustekinumab-treated (P<0.0001) and 5% of placebo-treated patients (P<0.0001) (Figure 12-10A). An IGA response of clear or almost clear was documented in 84%, 53% and 5% of patients in the bimekizumab, ustekinumab and placebo group, respectively (P<0.0001 for both comparisons against bimekizumab) (Figure 12-10B).

In BE READY, 435 adults were randomly assigned (4:1) to receive bimekizumab 320 mg Q4W or placebo Q4W for 16 weeks. The primary endpoints were identical to BE VIVID – the proportion of patients achieving a PASI 90 response and the proportion of patients achieving a clear or almost clear (score 0 or 1) IGA response with at least a 2-grade improvement from baseline at week 16. Among the patients in the bimekizumab group, 91% achieved a PASI 90 response and 93% achieved the IGA response, significantly more than patients in the placebo group (1% for both endpoints) (P<0.0001 for both endpoints) (Figure 12-11). All patients from the bimekizumab group who achieved PASI 90 at week 16 were reassigned (1:1:1) to either bimekizumab 320 mg Q4W, bimekizumab 320 mg Q8W, or placebo, for 40 additional weeks. Patients from the placebo group who achieved a PASI 90 response continued to receive placebo Q4W to week 56. Responses obtained throughout the first 16 weeks were maintained through to week 56.

BE SURE enrolled 478 patients, randomizing them (1:1:1) to bimekizumab 320 mg Q4W for 56 weeks; bimekizumab 320 mg Q4W for 16 weeks then Q8W for 40 weeks (56 weeks in total); or adalimumab 80 mg at baseline, then 40 mg after 1 week and Q2W for 24 weeks and finally bimekizumab 320 mg Q4W to week 56. The primary endpoints were the same as in BE VIVID and BE READY, ie, the proportion of patients achieving a PASI 90 response and an IGA response of 0 or 1 with at least a 2-grade improvement from baseline at week 16. The majority of bimekizumab-treated patients achieved a PASI 90 response (86.2% of patients for both dose groups combined), compared to less than half of the adalimumab-treated patients (47.2%)(P<0.001)(Figure 12-12A). An IGA score of 0 or 1 was attained by 85.3% of all bimekizumab-treated patients and 57.2% of adalimumab-treated patients (P<0.001)(Figure 12-12B).

Patients who completed BE VIVID, BE READY, or BE SURE with a PASI 90, PASI 100, PASI≤2 and/or BSA≤1% response were eligible to enroll in the BE BRIGHT open-label extension trial, where they received bimekizumab 320 mg Q4W or Q8W based on their previous treatment regimen and PASI response. The efficacy outcomes were defined as the maintenance of previously achieved endpoints (PASI 90, PASI 100, PASI≤2, BSA≤1%) throughout 3 years of bimekizumab treatment. A majority of patients who achieved PASI 90 (83-96%), PASI 100 (76-86%), PASI≤2 (84-97%) and BSA≤1% (82-94%) at week 16 maintained the response to year 3 of treatment.

The safety and efficacy of bimekizumab was compared to secukinumab in a phase 3b, randomized, double-blind trial. A total of 743 patients were randomized (1:1) to either bimekizumab SC 320 mg every 4 weeks or secukinumab SC 300 mg weekly until week 4, and every 4 weeks until week 48. The primary endpoint, PASI 100 at week 16, was achieved by 61.7% in the bimekizumab group and 48.9% of patients in the secukinumab group, demonstrating both non-inferiority and superiority of bimekizumab to secukinumab (P <0.001 for both non-inferiority and superiority). A significantly greater proportion of bimekizumab-treated patients (67.0%) had a PASI 100 response at week 48, compared to secukinumab-treated patients (46.2%; P <0.001).

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Safety

The rate of treatment-emergent adverse events (TEAEs) in BE VIVID was similar across all treatment groups, supporting the bimekizumab safety profile observed in previous studies. In BE READY, the rate of TEAEs was higher in patients receiving both bimekizumab Q4W and bimekizumab Q8W than in patients receiving placebo, throughout the entire study (week 0 to 56). However, the rate of serious TEAEs was similar in all groups. The most common reported AEs in both trials were nasopharyngitis, respiratory tract infection and oral candidiasis. In BE VIVID, oral candidiasis was present in 15% of patients receiving bimekizumab, with 1 case being severe and 3 cases leading to discontinuation of treatment. In BE READY, all oral candidiasis cases were mild or moderate and no cases led to discontinuation.

In BE SURE, a higher rate of AEs was observed in both bimekizumab groups compared to the adalimumab group, throughout weeks 0 to 24. However, the rate of serious AEs was higher in the adalimumab group. From week 24 to 56, the AE rate decreased in the bimekizumab groups and increased in the week 24 adalimumab to bimekizumab switch group. The most common AEs related to bimekizumab were upper respiratory tract infections, oral candidiasis, hypertension and diarrhea. Around 10% of patients treated with bimekizumab had a case of oral candidiasis, with the majority classified as mild or moderate and 2 classified as severe.

Safety data pooled over a 2-year period of bimekizumab treatment and in the BE BRIGHT extension trial showed that longer duration of bimekizumab exposure did not increase the incidence of AEs. In an analysis of 3 years of pooled safety data from BE VIVID, BE READY, BE SURE and BE BRIGHT, no new safety signals were identified. The 3-year and per-year incidence of Candida infections in these trials in shown in Table 12-3.

In the head-to-head comparison trial of bimekizumab and secukinumab, the frequency of overall AEs, serious AEs, and discontinuation due to AE were similar across the two groups; however, the incidence of oral candidiasis was higher with bimekizumab (19.3%) than with secukinumab (3.0%).

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Anti-Interleukin 23, P19 Medications

Development of medications that bind to the p19 subunit of IL-23 stems from the recognition that IL-23 is the key regulatory cytokine in the psoriasis, IL17/23 pathway and that inhibition of IL-12 may be unnecessary. As mentioned above, IL-23 is the key regulatory cytokine that induces differentiation and activation of Th17 cells in psoriasis. Additionally, IL-23 may be critical in the survival of these cells in active plaques. Thus, multiple new medications have been and are being developed that target this cytokine while not directly impacting IL-12. To date, three medications targeting IL-23 p19 have been approved by the FDA, guselkumab, tildrakizumab and risankizumab.

Guselkumab

Guselkumab was approved in July 2017 for moderate to severe psoriasis as the first medication to target the p19 subunit of IL-23. Guselkumab is a fully human monoclonal antibody that inhibits the pro-inflammatory IL17/23 pathway.

Efficacy

There have been three phase 3 pivotal trials for guselkumab in moderate to severe plaques psoriasis. Two of these trials, VOYAGE 1 and VOYAGE 2 compare the efficacy and safety of guselkumab, dosed at 100 mg sq weeks 0 and 4 and then every 8 weeks thereafter, to adalimumab. In these trials, the primary efficacy endpoint is a PASI 90 rather than a PASI 75 like most earlier studies in psoriasis. The short-term design of these two trials was identical with the primary endpoint at 16 weeks and continued blinded comparisons between guselkumab and adalimumab at week 24. In these studies, the PASI 90 was superior to both adalimumab and placebo at week 16 (VOYAGE 1: 73.3% vs 49.7% vs 2.9%, VOYAGE 2: 70.0% vs 46.8% vs 2.4%). The superiority to adalimumab increased between weeks 16 and 24 in both studies (Figure 12-13).

Longer term evaluation of efficacy, up to 48 weeks, was different between the two studies. In VOYAGE 1, the comparison between guselkumab and adalimumab was continued through the entirety of the 48 weeks. At the end of this time period, 76.3% of guselkumab patients were at a PASI 90 level of response compared to 47.9% of patients who were treated with adalimumab. In VOYAGE 2, the guselkumab subjects were re-randomized at week 24 to either continue guselkumab therapy every 8 weeks or placebo. In the subjects who continued on guselkumab, the overwhelming majority maintained their PASI 90 response. Interestingly, in the placebo-treated patients, the median time to loss of the PASI 90 response, a very high bar for this analysis, was 15.2 weeks. This finding demonstrates a high level of maintenance of response for an extended period, even after stopping the medication.

The NAVIGATE trial was a very different clinical trial design meant to determine if subjects with suboptimal responses to ustekinumab at an investigator’s global assessment (IGA) of >2 would have a greater response to switching to guselkumab than continuing on ustekinumab. The primary endpoint for this study was the proportion of patients who achieved an IGA of 0 or 1 with an overall 2 grade improvement in IGA from weeks 28 through 40 after re-randomization to either continue on ustekinumab or transition to guselkumab. The results suggested that transition to guselkumab had a superior outcome at this endpoint than those that stayed on ustekinumab (31.1% vs 14.3%). Like other medications, responses at greater than 48 weeks for treatment with guselkumab have not been reported.

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Safety

It is interesting to consider whether it is reasonable to extend our understanding of ustekinumab safety to guselkumab and the other anti–IL-23 medications. On a theoretical level, these medications leave the IL-12, Th1 system intact which would suggest a lesser impact on infection or cancer risk. Conversely, the higher levels of response could more closely correlate to the safety questions that arose with briakinumab. Thus, for an objective evaluation of the safety of anti–IL-23 drugs in general and guselkumab in particular, it is critical to consider each medication independently.

In all, the safety profile of guselkumab seems extremely favorable. The rates of serious infection and malignancy and major adverse cardiac events are similar to placebo and to adalimumab in the VOYAGE trials. In NAVIGATE, there are no signals for major adverse events. Importantly, as opposed to other biologic therapies for psoriasis, there do not seem to be any specific populations for whom guselkumab cannot be used. Similar to other medications discussed, long term safety with guselkumab is not yet available.

Tildrakizumab

Tildrakizumab is a humanized monoclonal antibody first approved for the treatment of moderate to severe psoriasis in March 2018. Unlike guselkumab, tildrakizumab uses the ustekinumab dosing schedule with doses at weeks 0,4 and then every 12 weeks. Tildrakizumab binds to the p19 subunit of IL-23 and thus inhibits the pro-inflammatory cytokine cascade in psoriasis.

Efficacy

Tildrakizumab was studied in two large placebo-controlled phase 3 trials reSURFACE 1 and reSURFACE 2. In reSURFACE 2, tildrakizumab was also compared to etanercept. Unlike the guselkumab trials, the primary endpoint of these studies was PASI 75 at 12 weeks of therapy with the comparison to etanercept continuing until week 28 in reSURFACE 2. While both 100-mg and 200-mg dosing were studied, only the 100-mg dose was approved by the FDA and will be discussed here. In these trials, the PASI 75 results for tildrakizumab was superior to placebo and to etanercept at week 12 (reSURFACE 1: 64% vs 6% and 61% vs 48% with etanercept vs 6%; Figure 12-14). Complete clearance, as measured by PASI 100 were additionally superior with tildrakizumab (reSURFACE 1: 14% vs 1%, reSURFACE 2: 12% vs 5% vs. 0%). The efficacy of tildrakizumab increased with continued use at weeks 28 and 52, suggesting that the 12-week endpoint is not sufficient for evaluation of tildrakizumab efficacy. Longer-term evaluation of efficacy is ongoing.

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Safety

Similar to other medications in this class, safety data demonstrate no evident signals of concern for tildrakizumab. Rates of serious infection, malignancy, and major adverse cardiac events were very low and similar to those for placebo. Like guselkumab, and encouraging for the anti-IL-23 medications in general, no concerns for specific populations was evident. Thus, there are no obvious contraindications from other medical conditions when using tildrakizumab.

Risankizumab

Risankizumab is humanized immunoglobulin G1 monoclonal antibody that selectively binds to the p19 subunit of IL-23, inhibiting the release of pro-inflammatory cytokines. It is the most recently approved anti-IL-23 agent, receiving FDA approval for the treatment of moderate to severe psoriasis in April 2019. The dosing schedule is similar to tildrakizumab, with 150 mg doses given at weeks 0 and 4 and every 12 weeks thereafter.

Efficacy

The efficacy of risankizumab was assessed in four phase 3, randomized, double-blind, multicenter studies: UltIMMa-1, UltIMMa-2, IMMvent and IMMhance. In UltIMMa-1 and UltIMMa-2, patients were randomized (3:1:1) to receive: 150 mg risankizumab at weeks 0, 4 and every 12 weeks thereafter; 45 mg or 90 mg ustekinumab (depending on weight) at weeks 0, 4 and every 12 weeks thereafter; or a matching placebo. The co-primary endpoints were the PASI 90 rate and a static PGA (sPGA) score of 0 or 1 at week 16. Risankizumab proved superior to both ustekinumab and placebo (Figure 12-15): in UltIMMA-1, 75.3% of patients in the risankizumab group achieved PASI 90 at week 16, compared to 42.0% in the ustekinumab (P <0.0001) and 4.9% in the placebo group (P <0.0001); in UltIMMA-2, PASI 90 was achieved by 74.8% of patients receiving risankizumab by week 16, in comparison to 47.5% of ustekinumab group patients (P <0.0001) and 2.0% of placebo group patients (P <0.0001). In both UltIMMA-1 and UltIMMA-2, a statistically higher proportion of patients receiving risankizumab also achieved an sPGA score of 0 or 1 at week 16 compared to both ustekinumab and placebo.

IMMvent was an active-comparator-controlled study in which patients were randomized (1:1) to receive 150 mg risankizumab at weeks 0, 4 and every 12 weeks thereafter, or 80 mg adalimumab at week 0 and then 40 mg adalimumab every other week. Like in the two UltIMMa studies, the co-primary endpoints were PASI 90 and an sPGA score of 0 or 1 at week 16. Risankizumab demonstrated greater efficacy than adalimumab, with 72% of risankizumab-receiving patients achieving PASI 90 at week 16, compared to 47% of patients receiving adalimumab (P <0.0001). Risankizumab was also statistically superior to adalimumab in the proportion of patients with sPGA scores of 0 or 1.

Finally, the objective of IMMhance was to assess the efficacy of risankizumab vs placebo as well as continuous risankizumab treatment versus treatment withdrawal. The study was divided into three parts: in Part A1, patients were initially randomized (4:1) to receive risankizumab 150 mg or placebo at weeks 0 and 4; in Part A2, all patients received risankizumab at week 16; and in Part B (beginning at 28 weeks), risankizumab group responders from Part A with an sPGA score of 0 or 1 were randomized (1:2) to receive risankizumab 150 mg (the continuation group) or placebo every 12 weeks (the withdrawal group). Risankizumab was superior to the placebo with respect to both primary endpoints in Part A1, the PASI 90 rate at week 16 (73.2% with risankizumab vs 2.0% with placebo; P <0.0001) and the sPGA 0/1 rate at week 16. The primary endpoint in Part B was the proportion of patients achieving an sPGA score of 0 or 1 at week 52. In the risankizumab group, 87.4% of patients achieved the primary endpoint of Part B, compared to 61.3% of patients in the placebo group (P <0.001), demonstrating the superior efficacy of continuous treatment compared to treatment withdrawal.

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Safety

The safety findings were consistent among the four phase 3 studies of risankizumab, demonstrating that this drug is well tolerated in both the short- and long-term. In the two UltIMMA trials and IMMvent, the overall safety profile of risankizumab was similar to those of ustekinumab, adalimumab and placebo, with a comparable adverse event incidence. In IMMhance, the incidence of adverse events remained stable and no new safety signals emerged over a period of two years. Collectively, these data indicate that, like other IL-23 p19 inhibitors, risankizumab possesses a favorable overall risk-benefit balance.

Biologic Medications in Development for Psoriasis

While there has been tremendous progress in the development of biologic immunotherapy in psoriasis in the past 15 years, there remain many patients who would benefit from a greater variety of options. Other biologic medications are in development for psoriasis that work along similar pathways as some of the medications noted above.

2019 Joint American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) Guidelines for the Treatment of Psoriasis with Biologics

The current guidelines on the use of biologic agents for the treatment of psoriasis were jointly released in 2019 by the AAD and the NPF. Separate recommendations are provided for each biologic agent, including:

• Etanercept: Recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis, including that affecting the scalp, nails and other subtypes (pustular or erythrodermic) of moderate-to-severe plaque psoriasis. Etanercept is also recommended for the treatment of psoriasis of any severity when associated with significant PsA. A combination of etanercept and topical agents or etanercept and methotrexate is recommended to augment the treatment efficacy in moderate-to-severe plaque psoriasis. The guidelines also state that etanercept may be combined with apremilast, acitretin, cyclosporine or narrowband UVB therapy to improve efficacy of psoriasis treatment.
• Infliximab: Recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis. Infliximab is also recommended for the treatment of psoriasis of any severity when associated with significant PsA. The guidelines also state that infliximab can be recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis affecting the palms and soles (plaque-type palmoplantar psoriasis), or that affecting the nails or the scalp. It may be recommended for the treatment of other subtypes (pustular or erythrodermic) of moderate-to-severe plaque psoriasis in adult patients. A combination of infliximab and topical agents can be recommended to augment efficacy for the treatment of moderate-to-severe plaque psoriasis and combinations with other agents (including acitretin, methotrexate and apremilast) may be recommended to improve efficacy as well.
• Adalimumab: Recommended as a monotherapy treatment option for adult patients with moderate-to-severe plaque psoriasis, including that affecting the nails and palmoplantar psoriasis. Adalimumab is also recommended for the treatment of psoriasis of any severity when associated with significant PsA. The guidelines further state that adalimumab can be recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis affecting the scalp and with other subtypes (pustular or erythrodermic) of moderate-to-severe psoriasis. A combination of adalimumab and topical agents can be recommended to augment efficacy for the treatment of moderate-to-severe plaque psoriasis. Combinations with nonbiologic systemic agents (including acitretin, methotrexate, cyclosporine and apremilast) or narrowband UVB therapy may also be recommended.
• Ustekinumab: Recommended as a monotherapy treatment option for use in adult patients with moderate-to-severe plaque psoriasis. Ustekinumab can be used as a monotherapy for adult patients with moderate-to-severe plaque psoriasis affecting the nails, the scalp and plaque type palmoplantar psoriasis. Ustekinumab is also recommended for the treatment of psoriasis of any severity when associated with significant PsA. To augment efficacy for the treatment of moderate-to-severe plaque psoriasis, ustekinumab may also be combined with topicals, nonbiologic systemic agents including apremilast, methotrexate, acitretin and cyclosporine and narrowband UVB therapy
• Secukinumab: Recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis, including that affecting the nails and palmoplantar plaque psoriasis. Secukinumab can be recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis affecting the head and neck, including the scalp, as well as in adult patients with moderate-to-severe palmoplantar pustulosis, and those with erythrodermic psoriasis. It may be used in patients with plaque psoriasis when associated with PsA.
• Ixekizumab: Recommended as a monotherapy treatment option for use in adult patients with moderate-to-severe plaque psoriasis and in adult patients with plaque psoriasis of any severity when associated with PsA. Ixekizumab can also be recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis affecting the scalp or the nails, as well as adult patients with erythrodermic psoriasis and those with generalized pustular psoriasis.
• Brodalumab: Recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis. Brodalumab can also be used as a monotherapy in adult patients with generalized pustular psoriasis.
• Guselkumab: Recommended as a monotherapy treatment option for use in adult patients with moderate-to-severe plaque psoriasis and in adult patients with scalp, nail and plaque-type palmoplantar psoriasis.
• Tildrakizumab: Recommended as a monotherapy treatment option in adult patients with moderate-to-severe plaque psoriasis.
• Risankizumab: The current AAD-NPF guidelines pre-date the approval of risankizumab, but state that it can be used as monotherapy in adult patients with moderate-to-severe plaque psoriasis.

More information and further recommendations can be found in the current AAD-NPF Guidelines. Note that, since the Guidelines were published before the approval of bimekizumab, they do not address the appropriate use of that IL-17 inhibitor.

Conclusion

The choices for biologic therapy for psoriasis have expanded greatly in the past 15 years. The four anti-TNF agents (etanercept, infliximab, adalimumab and certolizumab pegol) have been joined by four anti–IL-17 agents (secukinumab, ixekizumab, brodalumab, and bimekizumab) and by three agents that inhibit IL-23 (ustekinumab, guselkumab, tildrakizumab and risankizumab). These agents are providing patients suffering from psoriasis with the hope of long-term treatment efficacy with excellent safety. All of these medications are imperfect, but the benefit of this expansion of options is the promise of finding the right medication working by the right mechanism for almost every patient. While the pipeline for biologic medications for psoriasis is likely to slow, there are still new, promising, medications in development. Thus, biologic immunotherapy for psoriasis remains the most effective and safest option for patients with moderate to severe psoriasis and will likely remain as such for the foreseeable future.