Sarilumab, an investigational fully human monoclonal antibody against interleukin-6 receptor alpha, proved to have good safety and efficacy for methotrexate-nonresponsive rheumatoid arthritis patients with doses given every 2 weeks in a multicenter, phase II dose-ranging study.

The dosing regimens that appeared to have the best balance between efficacy and safety – 150 mg every 2 weeks and 200 mg every 2 weeks – gave American College of Rheumatology 20 (ACR 20) response rates of 67% and 65%, and as with other biologic drugs, had nonserious infections as the most common adverse events, reported Dr. Tom Huizinga of Leiden (the Netherlands) University Medical Center and his associates.

Sarilumab at those doses also was associated with neutropenia and increases in liver function tests and serum lipids, which are similar to laboratory changes observed with tocilizumab (Actemra), a humanized monoclonal antibody directed against interleukin-6 (IL-6) receptor alpha. Tocilizumab has been approved in the United States for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs.

IL-6 activity is a target for the treatment of rheumatoid arthritis because of the cytokine’s role in driving inflammation and its elevation in the serum and synovial fluid of patients with RA.

Patients in the trial, dubbed SARIL-RA-MOBILITY Part A, had active RA for at least 3 months despite methotrexate treatment for a minimum of 12 weeks on a stable dose (10-25 mg/wk) for at least 6 weeks prior to the screening visit. Participants’ mean age was 52 years (range, 18-75 years), and 79% were women. They continued on methotrexate after being randomized to one of five subcutaneous sarilumab dosing arms or placebo for 12 weeks of treatment plus 6 weeks of posttreatment follow-up.

Of the five active treatment arms in the double-blind, placebo-controlled trial of 306 patients – 100 mg every 2 weeks, 150 mg every 2 weeks, 200 mg every 2 weeks, 100 mg every week, and 150 mg every week – only 100 mg every 2 weeks was ineffective, with an ACR 20 response seen in 49% of patients, compared with 46% of patients who received placebo. The ACR 20 responses in the other sarilumab regimens ranged from 62% at 100 mg every week to 72% at 150 mg every week (Ann. Rheum. Dis. 2013 Dec. 2 [doi: 10.1136/annrheumdis-2013-204405]).

Secondary endpoints in the trial also showed that the lowest dose of sarilumab was ineffective in comparison with placebo, according to ACR 50 and ACR 70 responses, changes from baseline in individual disease activity measures (swollen joint count, tender joint count, physician and patient global assessment of disease activity, patient’s pain score, C-reactive protein levels, and Health Assessment Questionnaire score), as well as Disease Activity Score in 28 joints (DAS28-CRP).

For most of those measures, the doses of 150 mg every 2 weeks and 200 mg every 2 weeks gave results similar to those of two higher doses in terms of statistically significant improvement compared with placebo. In some cases, the responses seen with sarilumab at 200 mg every 2 weeks were numerically similar to or greater than those observed with the highest dose.

"These data, taken together with the more convenient dosing interval, support [biweekly] dosing as optimal for sarilumab when dosed at 150 mg and 200 mg," the investigators wrote.

The investigators were unsure why the placebo arm had such a high ACR 20 response rate (46%), but they noted that investigators in the CHARISMA trial involving tocilizumab suggested that "extending the time period during which patients received stable methotrexate prior to trial entry may reduce the high placebo rate."

Of the 24 patient discontinuations that were due to treatment-emergent adverse events, 22 were a result of neutropenia (as mandated by protocol) and 2 were due to infection (1 Escherichia coli urinary tract infection and 1 herpes zoster infection). Infection rates with sarilumab did not appear to be associated with neutropenia.

All of the efficacious dosing arms increased alanine aminotransferase levels during the dosing period, rising to three to five times the upper limit of normal in seven patients and from 5 to 10 times the upper limit of normal in four patients, most of which resolved on treatment or at the end of the study. Similar rates of increase in aspartate transferase levels were seen with sarilumab treatment.

Increases in the mean total cholesterol level at week 12 ranged from 9% to 21% in the four efficacious treatment arms, compared with 5% in the placebo group.

The trial was funded by Sanofi and Regeneron Pharmaceuticals, which are developing sarilumab. Three investigators reported financial ties to Sanofi and/or Regeneron and other manufacturers of drugs for RA, and the rest are employees and/or shareholders of Sanofi or Regeneron or were during the conduct of the study.

jevans@frontlinemedcom.com

Investigational interleukin-6 receptor inhibitor for RA shows efficacy, safety