Expert provides deeper insight into tocilizumab for giant cell arteritis
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
SNOWMASS, COLO. – The sustained remission rate in patients with giant cell arteritis was three times better with subcutaneous tocilizumab than with long-term prednisone in the landmark GiACTA trial, John H. Stone, MD, reported at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Moreover, the serious adverse event rate was significantly lower with the interleukin-6 receptor inhibitor tocilizumab (Actemra). This finding serves to underscore the pronounced, yet sometimes stealthy, toxicity of long-term, high-dose prednisone. Many rheumatologists have underplayed these side effects for lack of a better treatment option, because until the randomized, double-blind GiACTA trial, corticosteroids were the standard of care and only known effective therapy for giant cell arteritis (GCA), observed Dr. Stone, professor of medicine at Harvard Medical School, Boston.
“There’s finally something new in giant cell arteritis,” the rheumatologist declared. “The era of unending steroid therapy with no viable alternative is over.”
Dr. Stone was global principal investigator in GiACTA, a 14-country study including 251 GCA patients, roughly evenly divided between newly diagnosed patients and those with previously treated relapsing disease. GiACTA, he noted, was a study of several firsts: the first-ever clinical trial in any disease to utilize a blinded variable-dose steroid regimen, the first to feature a double-blind steroid-tapering regimen, and the first prospective study of 1 full year of tapered-dose prednisone.
The primary outcome was sustained remission as defined by absence of flare during study weeks 12-52 coupled with normalization of the C-reactive protein level to less than 1 mg/dL. This sustained remission endpoint was achieved in 14% of patients on 26 weeks of prednisone plus placebo and 17.6% of those on 52 weeks of prednisone and placebo.
“The results in the two steroid arms are lousy,” the rheumatologist pointed out. “This is I think one of the most astounding things about the trial.”
In sharp contrast, the sustained remission rate was 56% with 162 mg of subcutaneous tocilizumab once weekly plus 26 weeks of prednisone, and 53.1% with 162 mg of the humanized monoclonal antibody every 2 weeks plus 26 weeks of prednisone.
Tocilizumab’s steroid-sparing capability was impressive. The mean cumulative prednisone dose was 4,199 mg in patients on a 52-week prednisone taper plus placebo – a steroid regimen that most closely mimics what most rheumatologists have until now considered standard practice – versus only 2,098 mg in patients on once-weekly tocilizumab plus a 26-week prednisone taper.
Serious adverse events occurred in 24% of patients on prednisone-only, compared with less than 15% of those on tocilizumab. Quality of life scores as measured on the physical component score of the Short Form–36 were significantly better in the tocilizumab recipients.
“I think this speaks again to corticosteroid toxicity,” Dr. Stone said.
Another corticosteroid toxicity underscored in GiACTA was weight gain. At enrollment, patients with newly diagnosed GCA weighed significantly less than did those with previously diagnosed, relapsing disease for which they’d already been on long-term steroids. This body weight disparity was particularly pronounced in men. Men with relapsing GCA weighed a mean of 18.6 pounds more at baseline – nearly three additional body mass index points – than did newly diagnosed men who hadn’t been on aggressive steroid therapy.
“This is a steroid toxicity that I think sneaks up on us,” Dr. Stone observed.
The ongoing GiACTA study is continuing for an additional 2 years of open-label tocilizumab restricted to participants who flared during the initial double-blind phase or thereafter.
Joel M. Kremer, MD, rose from the audience to pronounce GiACTA “a home run.”
“I thought this was the most important study presented at the 2016 ACR annual meeting,” added Dr. Kremer, professor of medicine at the University of Albany (N.Y.) and president and founder of CORRONA, the Consortium of Rheumatology Researchers of North America.
The Snowmass symposium afforded Dr. Stone the opportunity to delve into aspects of GiACTA that time didn’t permit him to address at the 2016 ACR annual meeting:
• What’s the best dose of tocilizumab?
Weekly therapy appears to be preferable, although that’s a decision for the regulatory agencies. Time to first relapse post steroid taper was significantly longer with weekly than with biweekly tocilizumab, a result driven primarily by a markedly better result in the baseline relapser group. The pharmacokinetic data also support weekly dosing: Although patients randomized to weekly tocilizumab got twice as much of the biologic over the course of 52 weeks, their serum trough levels were actually six times higher than in those on biweekly therapy.
