Craig Leonardi, MD
The much anticipated introduction ustekinumab (Stelara®) for the treatment of moderate to severe psoriasis came about in 2010. This fully humanized monoclonal antibody directed against the p40 subunit of IL 12 and 23 has demonstrated in phase II and III studies that it is a “high performance” drug: fast acting, long duration of action and great efficacy. However, according to Craig Leonardi, MD, a principal investigator for ustekinumab, there appears to be a potential cardiovascular safety signal which came in the form of MACE events (Major Adverse Cardiovascular Events ie myocardial infarction, stroke and sudden death). These MACE events appear to be a “class effect” as it is also found in the other anti p40 antibody briakinumab, which is in phase III development. When both phase II and III data were analyzed for both anti-IL12/23 blockers there were 10 MACE events in the 3,100 drug treated patients and none in the 1,400 placebo treated control group. Because these studies are not powered to demonstrate statistical significance of this small but finite signal none was found. It should be noted that MACE events do not encompass other cardiovascular signals such as angina, coronary bypass surgery or TIAs. The incidence of these non-MACE events is unknown. This MACE safety signal has not found in the numerous trials involving thousands of moderate to severe psoriasis patients who received anti-TNF therapies who presumably have the same metabolic risk factors for MACE events. Comparator groups such as those found in the Framingham study population really do not apply. Drug study populations preselect for healthy patients. The placebo-controlled group is still the best comparator group and there were at least 1,400 patients in that group for both.
Dr Leonardi pointed out that MACE events occur early in the course of the drug therapy, usually within the first 8 months and level off. Speculation regarding a mechanism for the MACE events would likely involve some form of plaque disruption. There is some independent investigational data that demonstrate a significant rise (a 13-fold increase) in serum p40 levels at week 12 which decrease back to baseline by 8 months after injection of these anti- p40 molecules. This finding seems counter intuitive to what one would expect after introducing an antibody against p40 cytokines. The elevation likely comes from an intracellular reservoir that enters into the serum over a period of time. Interestingly, the course of p40 subunits in the serum roughly parallels the development of MACE events. It is known that p40 can dimerize and become pro-inflammatory which if we continue on our speculator path could lead to plaque disruption and a MACE event.
Briakinumab’s application to the FDA for approval has been pulled and in July of 2011 Abbott halted all clinical trials involving briakinumab pending further evaluation of MACE events. Additionally there are many questions to be answered including regarding briakinumab’s early SAE’s such as infections cutaneous and systemic squamous cell carcinomas reported in the first 28 weeks following the introduction of the drug in study patients.
Unlike the history behind TNF inhibitors which had long-term safety profile in the rheumatology and gastrointestinal field the IL 12/23 blockers are new and dermatology specific. In light of the current cardiovascular signal where does ustekinumab fit in our therapeutic tool box for psoriasis patients?
Dr. Leonardi’s Recommendations: It should be understood that this is a “class effect” of the IL 12/23 blockers not observed in analysis of TNF inhibitor safety data. Consider all options when selecting a biologic therapy. Patients with moderate to severe psoriasis typically have cardiac risk factors. Consider starting with a low dose regardless of the patient’s weight. Although there is not data to support its use consider starting a patient on 81 mg of ASA. Await further analysis of the safety data. Unlike the anti TNF therapies that came to us from rheumatology and gastroenterology, the IL 12/23 blockers have no point of reference. Scientific analysis of the p40, IL 12 and IL 23 serum levels during long term treatment.
To add to Dr. Leonardi’s recommendations, in my patients with early signs of psoriatic arthritis such as enthesitis (inflammation of the insertions of ligaments and tendons into bone) with possible early join involvement I still favor the use of anti-TNF therapy when considering a biologic agent because of their longstanding efficacy in psoriasis patients with early signs of psoriatic arthritis.
Post Maui Derm Footnotes:
Since Dr. Leonardi’s presentation a paper co-authored by Dr. Leonardi discussing this potential safety signal among antii-IL 12/23 antibodies was published in JAMA (JAMA Aug 24/31 Vol 306 No. 8 (864 -871). The article concluded: “Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF treatments. This study may have been underpowered to identify a significant difference.”
Centocor recently released Stelara’s 4-year safety data, which did not demonstrate any new safety signals. This comes as good news particularly when one considers that the appearance of Raptiva’s (efalizumab) safety signal (PML) occurred at year 4.