SEOUL, SOUTH KOREA – Results from a 4-year ustekinumab follow-up study paint a reassuring safety picture, with no evidence of cumulative toxicity, according to Dr. Kristian Reich.
Particularly welcome was the finding that a possible increased risk of major adverse cardiovascular events (MACE) noted during the initial placebo-controlled phase of the clinical trials was not been borne out at the 4-year follow-up mark.
The observed combined rate of MI, stroke, and cardiovascular death in psoriasis patients on the interleukin-12/23 antagonist for at least 4 years – 0.38 events per 100 patient-years – was significantly lower than expected based upon their Framingham Risk Score or U.K. General Practice Research Database (GPRD) profile, Dr. Reich said at the World Congress of Dermatology.
This finding is consistent with the notion that reducing systemic inflammation in patients with moderate to severe psoriasis via highly effective biologic therapy may reduce their disease-related cardiovascular risk to a level similar to, and perhaps even lower than, that of the general population, observed Dr. Reich, professor of dermatology at Georg-August University in Göttingen, Germany.
He noted the ustekinumab (Stelara) safety data from the ongoing open-label extensions of major randomized clinical trials includes 1,129 psoriasis patients on the biologic agent for at least 3 years and 619 treated for 4 years or more. Total follow-up exceeds 6,700 patient-years.
"This is one of the largest long-term databases for any biologic therapy for psoriasis so far," he pointed out.
Key findings from the 4-year analysis were reported in the following areas:
• MACE. Participants in the ustekinumab clinical trials program had a substantial burden of cardiovascular risk factors: a 48% baseline prevalence of obesity, along with hypertension in 27% of patients, dyslipidemia in 20%, a past or current history of smoking in 63%, and a family history of early coronary disease in 12%. Nearly 70% were men.
The 24 MACE events observed through 4 years of ustekinumab therapy compares with an expected 47 events based upon Framingham Risk Score and 70 expected events among similar psoriasis patients not on biologic therapy in the GPRD. This translates to an adjusted 49% risk reduction in ustekinumab-treated patients compared with Framingham expectation, and a 66% relative risk reduction compared with expectation for psoriasis patients in the GPRD.
The 4-year MACE rate with ustekinumab compares favorably with rates observed with other biologic agents in psoriasis patients. For example, the combined rate of MI or stroke in 506 Canadian psoriasis patients treated with etanercept (Enbrel) for up to 4 years was 0.84 events per 100 patient-years. And in a comprehensive 4-year adalimumab (Humira) safety report Dr. Reich presented at the world congress, the MACE rate was similar to the 0.38 per 100-patient-years seen with ustekinumab.
• Serious infections. The serious infection rate in the ustekinumab analysis was 1.1 events per 100 patient-years of exposure, compared with 1.3 events per 100 patient-years in the latest adalimumab analysis, and 1.6 per 100 patient-years of exposure to etanercept in an open-label extension phase of two phase-III trials totaling 912 patients.
"There's no indication that the serious infection rate with ustekinumab is increased beyond that expected with anti–tumor necrosis factor agents. And the per-year ustekinumab analysis shows no evidence of cumulative immunosuppression that would show up in a rising serious infection rate over time; it's absolutely stable over time," he said.
• Nonmelanoma skin cancer. The cumulative rate was 0.6 cases per 100 patient-years of exposure to ustekinumab, compared with 0.7 per 100 patient-years in the adalimumab analysis. As with serious infections, there was no sign of an increased rate of nonmelanoma skin cancers year by year with ustekinumab.
• Other malignancies. The rate of 0.6 per 100 patient-years of exposure to ustekinumab translated to an observed 41 events through 4 years of follow-up, closely similar to the 39 cases to be expected in a healthy population based on extrapolation from the National Cancer Institute's Surveillance, Epidemiology, and End Results database.
Follow-up of participants in the open-label extension of the ustekinumab clinical trials in psoriasis will continue through 5 years of exposure, with additional safety data accruing from clinical trials in psoriatic arthritis, according to Dr. Reich.
Dr. Reich is a consultant to Janssen, which markets ustekinumab outside the United States.