Evaluating the Interleukin Antibodies and Their Future in Psoriasis Therapy
Interleukins 12 and 23 are uniquely similar in several key ways. For example, they are both cytokines that are produced by dendritic cells. They also share a common p40 subunit, are involved in adaptive immunity, and both contribute to the development of type 1 T-helper cell (TH1). However, where IL-12 primarily stimulates differentiation of Th1 cells and subsequent secretion of interferon-gamma and TNF-alpha and induces CLA (cutaneous lymphocyte antigen), IL-23 stimulates naive T-cells into Th17 cells that secrete IL-17 and also induces IL-22, resulting in cutaneous clinical changes of psoriasis.
While most biological agents actively inhibit TNF-a or block T-cells, the forthcoming ustekinumab (Stelara, Centocor) and the investigational drug, briakinumab (Abbott, previously referred to as ABT-874) represent a new class of biologic agents that target both IL-12 and IL-23. These two antibodies have structures indistinguishable from normal IgG1 antibodies and differ from other human antibodies only in the IL-12 p40 specific antigen-binding region. In this region, every natural human antibody is different from each other to allow for binding to a variety of specific antigens. Although they are similar, ustekinumab is a fully human IgG1 antibody generated in human immunoglobulin transgenic mice, and briakinumab is a fully human IgG1 antibody isolated from a human antibody phage display library.
The US approval for ustekinumab is still pending and more trials likely await briakinumab, but preliminary trial data for both drugs appear promising. This article will delve more deeply into the available data and aim to make sense of IL-12/23 antibodies in relation to more commonly used TNF inhibitors.
USTEKINUMAB
Ustekinumab is already approved in Europe for the treatment of moderate to severe plaque psoriasis, where the recommended dosing schedule is an initial injection of 45mg administered subcutaneously at weeks zero and four, and then every 12 weeks following initial treatment. For patients weighing more than 220lbs., the recommended dose is 90mg. Median half-life is approximately three weeks.
Approximately 2,000 subjects have been evaluated thus far, and clinical trial data offer a number of considerations regarding efficacy and safety. In the Phoenix I trial,1 patients received 45mg, 90mg, or placebo at week 0 and 4 and were evaluated at week 12, at which time regimen changes were permitted. From week 12 to week 40, the placebo group crossed-over to 45mg or 90mg at weeks 12, 16, and 28. At week 40, there was a randomized withdrawal phase in which non-responders were discontinued, while partial responders went to dosing every eight weeks, and those with greater than PASI 75 response were randomized to every 12 weeks or stopped treatment through week 76.
Sixty-seven percent of patients who initially received 45mg and 76 percent who received 90mg achieved PASI 75 at week 12. Notably, improvement was observed by within the first two weeks of treatment. Sustained results were maintained through week 76 in those patients receiving treatment every 12 weeks. Patients who stopped treatment at week 40 lost PASI 75 in about 15 weeks. Upon re-initiating treatment, they regained PASI 75 in about 12 weeks. It's worth noting that adverse events were similar between 45mg, 90mg and placebo groups.
In the Phoenix 2 trial, patients were again randomly assigned to received either placebo, 45mg, or 90 mg at weeks 0 and 4 and then every 12 weeks. At week 28, subjects who had achieved a PASI 50-75 were considered partial responders and were reassigned to either continue the 12-week dosage cycle or to increase the frequency of dosing to every eight weeks. Results indicated that 67 percent of patients in the 45mg ustekinumab group and 76 percent who received the 90mg dose achieved PASI 75 at week 12. Importantly, of the partial responders at week 28 who were reassigned to receive ustekinumab 90mg every eight weeks, 69 percent achieved PASI 75—more than two times the 33 percent of those who maintained the same dose every 12 weeks.
Common adverse events in the Phoenix 1 and 2 trials included injection site reactions, upper respitory infections, arthralgia, headache, and infections. Importantly, less then one percent of all reported adverse events, including cutaneous and non-cutaneous malignancies, were considered serious.
In the ACCEPT study, patients were randomized to receive either ustekinumab or etanercept.3 Patients receiving ustekinumab received either 45mg or 90mg at weeks 0 and 4, while patients receiving etanercept were given 50mg two times per week for 12 weeks. After 12 weeks, 68 percent of patients in the 45mg group achieved PASI 75 and 74 percent of those in the 90mg group achieved PASI 75. Meanwhile, 57 percent of such patients in the etanercept group achieved PASI 75 in 12 weeks. In patients who had one previous treatment of systemic, biologic, or phototherapy, 68 percent in the ustekinumab 45mg group and 74 percent of patients in the ustekinumab 90mg group achieved PASI 75, compared to 57 percent of the etanercept group. In patients with two previous treatments, 67 percent of the 45mg group and 74 percent of the 90mg group achieved PASI 75, whereas 51 percent of such patients in the etanercept group achieved PASI 75. For those who had received three previous treatments, 55 percent of the 45mg group and 72 percent of the 90mg group reached PASI 75, compared to 39 percent in the etanercept group. Adverse events were experienced in less than two percent of patients receiving ustekinumab, and included upper respiratory infection, arthralgia, headache, infection (less then one percent of infections were deemed serious). However, it's worth noting that there were four malignancies in ustekinumab group, as compared to zero in the etanercept group.
Another study showed the efficacy of ustekinumab in patients previously treated with phototherapy or biologic agents was similar to that in groups that had never been treated with phototherapy or biologic agents.4 In addition, adverse events in both groups were comparable.
BRIAKINUMAB
As noted, briakinumab has a structure indistinguishable from normal IgG1 antibodies and differs from other human antibodies only in the IL-12 p40 specific antigen binding region. In this region, every natural human antibody is different from each other to allow for binding to a variety of specific antigens. Data for the agent has been limited by small sample sizes, length of follow-up, and a lack of direct comparisons with other psoriasis treatments, but initial data on both safety and efficacy appear promising.5
One Phase 2 study6 randomized 180 patients into groups of 30 to receive one of six treatments of briakinumab: one 200mg dose at week 0; 100mg every other week for 12 weeks; 200mg weekly for four weeks; 200mg every other week for 12 weeks; 200mg weekly for 12 weeks; or placebo. By week 12, all groups except placebo had a PASI score greater than 90 percent. These results indicate high efficacy that will be monitored in further trials.
Patients receiving 100mg every other week had a PGA improvement of 84 percent at week 12. Moreover, by week 20, 60 percent had maintained improvement, while 50 percent maintained improvement at week 24; 30 percent maintained at week 36. Importantly, the 200mg weekly group saw 93 percent PGA improvement at week 12, with maintenance of 80 percent at week 20, 55 percent at week 24, and 30 percent at week 36.
Upon retreatment, the majority of patients regained PASI 75. It's worth noting that the time it took to achieve these responses is similar to the time to achieve response after initial treatment. After 12 weeks of treatment in the 200mg group, it took 184 days to lose PASI 75 in 83 percent of patients and 56 days of retreatment to re-capture it.
Interestingly, more patients discontinued therapy in the placebo group, compared to those treated with briakinumab. The most common adverse events were injection-site reactions. There were no opportunistic or serious infections reported. Infection occurred in 32 percent of briakinumab-treated patients and in 23 percent of controls. The most common infectious adverse events were nasopharyngitis and upper respiratory tract infection.
Importantly, less than one percent of all reported adverse events, including cutaneous and non-cutaneous malignancies, we considered serious.
LOOKING AHEAD
Ongoing Phase III trials will likely provide additional information necessary for briakinumab, but high and rapid PASI 75 response is noteworthy in phase II trials. Ustekinumab's high PASI 75 response after two doses coupled with the durability of response are impressive. Flexible dosing (either 45mg or 90mg) based on weight may be a benefit, as well.
The efficacy and safety data for ustekinumab and briakinumab compiled thus far look highly favorable, although more long-term studies will be valuable.
Dr. Bagel is on the speakers bureau for Abbott Labs, Genentech, Astellas, Amgen, Stiefel, and Warner-Chilcott.
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