Dermatology Q&A: First Head-to-Head Data Highlight Safety and Efficacy of Biologics

The withdrawal of efalizumab (Raptiva, Genentech) from the market in April 2009 heightened concern for biologic safety among regulators, manufacturers, and physicians. Yet, despite reporting on the unknown and unforeseen consequences of biologic therapy, a new horizon of gene-based interleukin agents has re-invigorated interest in biologics and their role in the treatment of psoriatic disease. Ustekinumab (Stelara, Centocor) was approved by the FDA in 2009 due to compelling efficacy data and a strong safety profile.

One of the touchstone studies in the approval of ustekinumab was the ACCEPT trial, a phase 3 study of ustekinumab in over 900 patients. Initial results were reported in 2008, but new head-to-head data from the trial1 provides greater perspective about the broader dimensions of biologics and may offer insights into how that curve is developing. Ahead, Alan Menter, MD, a lead investigator on the trial, reflects on the new data, as well as what the future holds for biologic therapy.

What do new findings tell us about the efficacy of ustekinumab, particularly when compared to data on etanercept and other biologics?
“The results represent the first major comparative study between two biologics, and given its size can give us a fresh perspective on both drugs,” says Dr. Menter. In terms of the dosage schedule, Dr. Menter notes that ustekinumab's efficacy was significant in early stages of treatment: 68 and 74 percent of ustekinumab- treated patients—receiving 45mg and 90mg, respectively provided at weeks zero and four— achieved PASI 75 at week 12, compared with 57 percent of patients who received 50mg etanercept (Enbrel, Amgen Wyeth) twice per week for 12 weeks. Dr. Menter says the therapy crossover was perhaps the most interesting aspect of the study, as patients who had an inadequate response to etanercept at week 12 received two injections of ustekinumab 90mg at weeks 16 and 20. “Nearly half of these patients (48.9 percent) achieved PASI 75 at weeks 28,” he says.

How do head-to-head studies increase physicians' knowledge of a particular drug or drugs?
“While it is possible to perform loose comparison of data on different biologics, it generally is not considered a good practice of science, since the design, endpoints, dosage, and considerations of clinical trials are all different,” explains Dr. Menter. “It's very hard to do without bias.” But when a study is designed specifically to accommodate two different agents, results can unveil new information about each drug and enable a different approach to each. Dr. Menter notes that the design of head-to-head studies can be more difficult to create, but is essential for achieving the best results. This is especially so for biologic agents with different dosing and delivery, he says. “In the case of this study, one possible criticism is the lack of a placebo in either arm,” notes Dr. Menter. A placebo may provide more concrete efficacy data about each agent, individually, as well as in comparison.

Nevertheless, Dr. Menter explains that this particular head-to-head study provides a strong perspective of how interleukin biologic agents and TNF biologic agents perform under the same conditions. “Interestingly, the data for etanercept in this trial was stronger than the majority of the phase III data on etanercept,” says Dr. Menter. He points out that headto- head studies also gives investigators the ability to look at remission rates more directly. The median remission time for the 45mg ustekinumab group was 14 weeks, as compared to 18 weeks for the 90mg group, and seven weeks for the etanercept group.

Dr. Menter suspects this will be the beginning of a number of head-to-head trials to come. “Another head-to-head trial is being planned right now which will examine briakinumab (Abbott) and etanercept,” he says.

How compelling is the safety data for ustekinumab, particularly in light of the boxed warnings and heightened concern regarding safety and the biologics?
“Safety is a major issue in the discussion of biologics, and while we have a fair amount of data for the TNF agents, we have about three years worth on the interleukin 12 and 23 agents,” notes Dr. Menter. “The 12- and 24-week safety data that has accumulated is positive and encouraging. We are going to need five and 10 year safety data in order to grasp the full breadth of the safety spectrum,” he continues. These issues will come into clearer focus in the next few years. “Right now, a registry called PSOLAR is registering 4,000 patients for the purposes of learning more about psoriasis comorbidities, risks, and adverse events over an eight to 10 year period,” says Dr. Menter. Similar registries have been created for infliximab and other biologics, as well. Once these registries have been compiled and evaluated for several years, clinicians will be privy to much more information about longterm safety of biologics, according to Dr. Menter.

Can you assess the future of IL biologics in psoriasis therapy? What does this data tell us about the future of biologic therapy in psoriatic disease?
“TNF agents still constitute the vast majority of biologic agents on the market, as we still have much to learn about the impact that the interleukin agents will have in the long-term,” Dr. Menter explains. Among the research foci of current and future trials on ustekinumab will be its potential to treat psoriatic joint disease. Trials are being initiated now.

“The most encouraging aspects of the IL 12/23 agents is that the genetic basis for polymorphisms in interleukins 12 and 23 that have been described,” explains Dr. Menter. Assessing psoriasis now encompasses genetic criteria in addition to immunologic criteria, which, according to Dr. Menter will broaden knowledge about psoriasis as a systemic disease.

Given the amount of unique trials, registries, and events involving biologic therapies, Dr. Menter enthuses about their continued development and importance in treating and learning about psoriatic disease. He points to the mainstream exposure of key psoriasis trials as evidence of this increased prominence. “It is nice to see the acceptance of psoriasis in mainstream medicine,” he notes. This, coupled with the new properties of biologic therapy and the disease that clinicians and investigators are learning makes this an exciting time for psoriasis therapy.

Looking ahead, Dr. Menter feels that more interest and data will be essential toward addressing the increased concerns, not just about biologics but about psoriatic disease. “As more interest is generated in psoriasis and biologic agents, the big question will be how are they going to impact the general health of our patients,” Dr. Menter says. The discourse about psoriasis comorbidities—such as myocardial infaraction and obesity—continues to be of primary importance, he indicates, and he remains hopeful that future trials will address these issues. “As we consider the growing properties of treatments and the disease, maintaining results will be of equal importance as achieving results, and we have to consider how psoriasis therapies may potentially motivate patients to live healthier,” Dr. Menter suggests. “There are long-term concerns we will have to deal with, but the more practical issues of health and of the inflammatory effects of the disease are essential considerations, as well.”

1. Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, Guzzo C, Xia Y, Zhou B, Li S, Dooley LT, Goldstein NH, Menter A; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010 Jan 14;362(2):118-28.