Rheumatoid arthritis – sarilumab

The treatment of rheumatoid arthritis was greatly improved with the advent of the tumour necrosis factor alpha inhibitor drugs such as adalimumab (AbbVie’s Humira, currently the world’s biggest selling drug) and infliximab (Remicade from Janssen). However, not all patients respond well to or tolerate these drugs, and an alternative strategy might be to treat with a drug against the interleukin-6 receptor alpha instead. One such drug, tocilizumab (Genentech’s Actemra), is already on the market, and another, the fully human monoclonal antibody sarilumab, is being developed by Sanofi and Regeneron.

Several trials have been carried out. In one dose ranging placebo controlled Phase II study, 306 patients with active rheumatoid arthritis despite treatment with methotrexate were given placebo or sarilumab in subcutaneous doses according to one of five regimens: 100mg, 150mg or 200mg every two weeks, or either 100mg or 150mg weekly for 12 weeks.¹ Methotrexate was also administered. Those given the higher weekly dose achieved a significantly higher American College of Rheumatology 20% score, the primary endpoint, than placebo, at 72% compared with 46%. Higher ACR20 scores than placebo were also seen with the two highest two-weekly doses. The most common adverse events observed were infections, and none of these was serious. Alterations in neutropenia, transaminases and lipids were consistent with those seen with other IL-6Ra inhibitors.

In a Phase III study, subjects with moderate to severe rheumatoid arthritis and an inadequate response to methotrexate were randomised to receive 150 or 200mg of sarilumab or placebo every two weeks, plus weekly doses of methotrexate, for 52 weeks.² Both treatment arms showed a statistically significant improvement compared with placebo in ACR20 plus two other primary endpoints. Again, the most common adverse event to appear was infection, and elevations in alanine aminotransferase levels led to discontinuation of treatment in a handful of patients. Both doses gave a sustained clinical efficacy, and it was generally well tolerated.

Results of a pivotal double blind Phase III trial were reported recently.³ A total of 546 patients with rheumatoid arthritis who were inadequate responders to or intolerant of TNF-alpha inhibitors were given subcutaneous doses of 150mg or 200mg sarilumab every other week, or placebo, in addition to non-biologic disease modifying drugs, for 24 weeks. Those who had not responded adequately to treatment at week 12 were given 200mg sarilumab doses as a rescue therapy. A significantly higher proportion of those given either dose level of sarilumab achieved ACR20 responses and several other endpoints at week 24, with the ACR20 rate for the higher dose 61%, 56% at the lower dose, and 34% with placebo. It has now been submitted to the FDA for approval in rheumatoid arthritis.

Less success was seen in another autoimmune condition, ankylosing spondylitis. In a randomised, double blind, placebo controlled Phase II study, 301 patients with active ankylosing spondylitis despite conventional therapy were given 100, 150 or 200mg sarilumab every two weeks, 100 or 150mg every week, or placebo, for 12 weeks.4 However, at week 12 there was no statistically significant difference in the response rate between placebo and any of the dose regimens, and therefore it is no longer being pursued in this indication.

References

1. T.W. Huizinga et al. Ann. Rheum. Dis. 2014, 73, 1626

2. M.C. Genovese et al. Arth. Rheumatol. 2015, 67, 1424

3. R. Fleischmann et al. Arth. Rheumatol. 2015, 67 (suppl. 10), Abst 970

4. J. Sieper et al. Ann. Rheum. Dis. 2015, 74, 1051