MAUI, HAWAII (FRONTLINE MEDICAL NEWS) – Rheumatologists, regulatory agencies, and the pharmaceutical industry all have gone off the deep end in their fretting over what appears to be a low rate of venous thromboembolic events in the major randomized trials of the oral Janus kinase inhibitors for RA, Mark C. Genovese, MD, asserted at the 2018 Rheumatology Winter Clinical Symposium.

“The reality is all of our drugs pose potential risks. Unfortunately, I think that at least for the moment, the field has turned all attention in one direction: VTE [venous thromboembolic] events. I suspect there’s some truth [to the possible associated risk]. Certainly we are seeing these events. The question is, how overdone is this?” according to Dr. Genovese, professor of medicine and cochief of the division of immunology and rheumatology at Stanford (Calif.) University.

He left no doubt he thinks this is a matter of lost perspective.

“I think the upadacitinib data has been entirely overshadowed by concerns about VTEs,” he said. “In the last year, we saw three significant phase 3 studies on upadacitinib arrive in the rheumatology community, and I think the only thing we talked about was VTEs.”

All parties interested in developing Janus kinase (JAK) inhibitors for the treatment of RA began to freak out about a possible increase in VTEs when in April 2017 the Food and Drug Administration turned down Eli Lilly and Incyte’s initial application for marketing approval of the JAK inhibitor baricitinib. Among the problems the agency cited was evidence of potential thrombotic risk.

The VTE rate in baricitinib clinical trials up to 48 weeks in duration was 0.53 events/100 patient-years, with no significant difference in risk between the2-mg and 4-mg doses. This appears to be a class effect for the oral JAK inhibitors, as low rates of VTE, albeit numerically higher than in placebo-treated controls, have also been recorded in the RA development programs for tofacitinib (Xeljanz) as well as the investigational agents filgotinib and upadacitinib, the rheumatologist noted.

This begs the question of whether these VTE rates are significantly higher than background rates in patients with RA or other rheumatologic diseases, which are known to be elevated relative to the general population. Indeed, a retrospective study of insurance claims data by investigators at Brigham and Women’s Hospital, Boston, concluded that the VTE rate in RA patients was 0.61 events/100 patient-years, 120% greater than in a matched patient population without RA. After fully adjusting for comorbid conditions and demographics, the relative risk increase associated with RA dropped to 40%, still significantly higher than in controls ( Arthritis Care Res [Hoboken]. 2013 Oct;65[10]:1600-7 ).

Similarly, Canadian investigators conducted a meta-analysis of 25 studies with VTE data in patients with RA, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, or inflammatory myositis. This meta-analysis included 10 studies of more than 5.2 million RA patients and nearly 900,000 controls. The conclusion: each of these rheumatic diseases was associated with a VTE rate more than three times higher than in the general population ( Arthritis Res Ther. 2014 Sep 25;16[5]:435 ).

“Patients with RA are at higher risk for VTE than those without RA. It’s unfortunate, and it’s certainly something I don’t think many of us have thought much about before. It’s something we don’t often get to see and something we don’t like to think about,” the rheumatologist observed.

Dr. Genovese admitted to a degree of personal frustration with the current tunnel vision focus on VTEs in JAK inhibitor trials. At the 2017 annual meeting of the American College of Rheumatology he presented the results of the phase 3 SELECT-BEYOND study in which 499 RA patients who had previously failed to respond or were intolerant to biologic therapy were randomized to once daily upadacitinib at 15 or 30 mg or placebo on top of background methotrexate. At week 12, the ACR 20 response rate was 65% for upadacitinib at 15 mg, 56% at 30 mg, and 28% in placebo-treated controls.

“That’s almost a 40% placebo-adjusted response rate. In fact, it’s the highest response I’ve ever seen in a biologic inadequate-responder population. This really looked pretty good, but I don’t think anyone ever took notice. Why not? Because we were all worried about VTE,” he said.

There were in fact a handful of VTEs in upadacitinib-treated patients, Dr. Genovese was quick to note. But he was more impressed by the week 12 ACR 20 responses in patients who had previously failed on three or more biologics: 71% with upadacitinib at 15 mg and 50% at 30 mg, compared with 23% in controls. Moreover, among patients with a baseline history of failure to respond to anti–interleukin-6 therapy, the week 12 ACR 20 rate was 56% with upadacitinib at 15 mg and 58% at 30 mg, versus 20% in controls.

“This looks like a pretty effective drug for patients who’ve failed everything else in our practice,” he commented.

Dr. Genovese reminded his audience that the rheumatology community has a history of overreacting to safety signals in the early days after introduction of new therapies. Examples: tuberculosis with tumor necrosis factor inhibitors, lymphoma with abatacept (Orencia), lymphoma with anti–tumor necrosis factor agents, and cardiovascular events with anti–interleukin-6 inhibition.

“PML [progressive multifocal leukoencephalopathy] is a breathtaking side effect with rituximab [Rituxan], but we’ve gotten over that. We recognize that it’s a potential problem, but we still prescribe rituximab,” the rheumatologist noted. “We’re probably going to need to address the issue of which of our patients are potentially at higher risk for VTE, and maybe we avoid this class in those patients. Like we now do as we look at patients we think are at increased risk for infection, or multiple sclerosis, or TB, we may also need to think of VTE risk.”

But the scale of VTE risk that available data link with JAK inhibition shouldn’t be allowed to torpedo this highly promising class of medications, he argued. There is a pressing unmet need for new therapies for RA with novel mechanisms of action. Only about one-half of patients on contemporary biologic therapies are still on that agent 5 years after initiating therapy.

“Virtually all our patients are partial responders. Everybody gets some benefit. But true remission is achieved by only a minority,” Dr. Genovese said. “The gap between where we are and where we want to be is actually much greater than we often perceive.”

He reported having financial relationships with AbbVie, which is developing upadacitinib, and more than a dozen other medical companies.


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