Rheumatology Drug Updates: Sirukumab Promising for RA, Plus Efficacy Duration of Ustekinumab for Plaque Psoriasis

Sirukumab Promising for RA

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Sirukumab, an investigational human monoclonal antibody that selectively binds to the interleukin (IL) 6 cytokine, has completed a randomized, double-blind, placebo-controlled, parallel-group, Phase 3 clinical trial (SIRROUND-T) in patients with rheumatoid arthritis (RA).¹

During the trial, which took place between July 25, 2012, and Jan. 12, 2016, researchers randomized adult patients (N=878) from 183 hospitals and private rheumatology clinics worldwide. Participants had active RA, four or more tender and swollen joints, and were intolerant or refractory to at least one prior anti-TNF drug. For up to 52 weeks, participants were randomly assigned (1:1:1) to receive either placebo subcutaneously every two weeks (n=294), 50 mg sirukumab subcutaneously every four weeks (n=292) or 100 mg sirukumab subcutaneously every two weeks (n=292). Patients were allowed to continue background disease-modifying anti-rheumatic drugs (DMARDs) and were stratified during randomization by methotrexate use. At baseline, 60% (n=523) of patients had previously used two or more biological DMARDs, whereas 19% (n=166) had not used a DMARD.

The primary outcome was the proportion of patients achieving at least a 20% ACR20 improvement at Week 16 in the intention-to-treat population. An additional primary outcome was a 20% or greater improvement from baseline in three of five assessments: pain via Visual Analogue Scale (VAS), Patient’s Global Assessment of Disease Activity via VAS, Physician’s Global Assessment of Disease Activity via VAS, physical function on the Health Assessment Questionnaire–Disability Index [HAQ-DI], and/or C-reactive protein concentrations. Secondary endpoints—ACR50, AC70 and ACR90 responses—were evaluated at Week 24. Also, the safety evaluation was performed on all patients who received at least one dose of study drug.

At Week 18, any placebo-treated patients who had a less than 20% improvement in swollen and tender joints were randomly assigned to either active-treatment group according to early escape criteria. At Week 24, all remaining placebo-treated patients were randomly assigned to an active-treatment group.

The ACR20 responses at Week 16 were: 24% (n=71) for placebo-treated patients, 40% (n=117) for patients treated with 50 mg sirukumab every four weeks, and 45% (n=132) for those treated with 100 mg sirukumab every two weeks. Additionally, more patients achieved ACR20, ACR50 and ACR70 responses at Week 24 with either dosage of sirukumab compared with those who received placebo. Also, more patients treated with 100 mg sirukumab every two weeks achieved an ACR90 response by Week 24 than those with placebo (P<0.0001).

Adverse events during the 24-week, placebo-controlled period were similar across groups. The most common adverse events at Week 24 and Week 52 were injection-site reactions with erythema. Among sirukumab-treated patients, five deaths were reported from a cerebrovascular accident, metastatic breast cancer, myocardial infarction, pneumonia and sudden death. Only the death from pneumonia is thought to be “possibly related” to treatment.

This study showed that in refractory and difficult-to-treat patients with RA, subcutaneous sirukumab achieved rapid and continuous improvements to disease activity, as well as improvements in physical function and health status. The treatment is an effective biologic with a different mechanism of action and a positive safety profile. In September 2016, a Biologics License Application was submitted to the U.S. Food and Drug Administration, seeking approval for sirukumab to treat adults with moderate to severe active RA.²

Sirukumab is also currently in Phase 3 clinical trials for giant cell arteritis.³

Ustekinumab Has Longer Efficacy Duration than TNFis for Plaque Psoriasis

A recent study showed that patients with severe plaque psoriasis who were treated with ustekinumab had better retention rates than those treated with other biologic drugs.⁴ The researchers investigated biologic treatment drug survival rates in psoriasis patients and sought to identify predictors for drug survival rates. Drug survival is a term used to quantify the loss of drug efficacy over time. Such factors as patient adherence, patient expenditures, prescriber preference, adverse events and local healthcare regulation may affect a drug survival rate.

The survival analysis study included patients drawn from the Clalit Health Services (CHS) HMO (health maintenance organization) database, which is the largest public HMO in Israel, including data on more than 4.3 million individuals. Following Israeli guidelines for the biologic treatment of psoriasis, all patients met the following criteria: 1) their involved body surface area had to be greater than 50% or their Psoriasis Area and Severity Index had to be greater than 50; 2) sensitive areas, defined as genitalia, palms and face, had to be involved; and 3) at least two prior standard systemic treatments had failed. According to the CHS internal guidelines, tumor necrosis factor inhibitors (TNFis) (e.g., adalimumab, etanercept and infliximab) were used as first-line and second-line biologic treatments, unless absolutely contraindicated. TNFis have been available to treat psoriasis in Israel since 2008. Ustekinumab is indicated after failure of two prior TNFis as a third-line therapy.

A multivariate analysis was performed with modifications. During the study, 970 patients received 1,575 biologic treatments, and 865 patients discontinued treatment. Predictors of drug survival were concomitant methotrexate use and biologic naivety. Negative treatment predictors included being female and the duration of prior systemic treatment.

Ustekinumab had a significantly higher drug survival rate compared with other biologics (40.8 months). The other drug survival times were 26.4 weeks for adalimumab, 26.35 months for etanercept and 26.4 months for infliximab.

Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Aletaha D, Bingham CO, Tanaka Y, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): A randomized, double-blind, placebo-controlled, parallel-group, multi-national, Phase 3 study. The Lancet. 2017 Feb 15. pii: S0140–6736(17)30401-4. doi: 10.1016/S0140-6736(17)30401-4. [Epub ahead of print]
2. Janssen Pharmaceutical Co. of Johnson & Johnson. News release: Janssen submits application seeking approval of sirukumab in United States for rheumatoid arthritis. 2016 Sep 23.
3. GlaxoSmithKline plc. GSK pipeline Phase III: Sirukumab. 2017.
4. Shalom G, Cohen AD, Ziv M et al. Biologic drug survival in Israeli psoriasis patients. J Am Acad Dermatol. 2016 Dec 28. pii:S0190–9622(16)31008-8. doi: 10.1016/j.jaad.2016.10.033. [Epub ahead of print]