Dr. Brown:
Welcome back to the Right Fit Report, with rheumatology insights brought to you by UCB. I’m Dr. Adam Brown of the Cleveland Clinic, and joining me today is my colleague, Dr. Monica Schwartzman of Schwarzman Rheumatology in New York.

Dr. Schwartzman:
Hello again, everyone.

Dr. Brown:
Before we jump in, a quick word about CIMZIA. CIMZIA is indicated for moderate to severe rheumatoid arthritis. Important Safety Information will be read at the end of this podcast. For more safety information, please visit CIMZIAhcp.com.

In this episode, we’re taking a look at the RAPID pivotal trial, the EXXELERATE trial, and its post hoc analysis. We’ll unpack the original study and the potential importance of the post hoc results, and discuss how rheumatoid factor, or RF levels, may impact patients’ response to therapy. But first, Dr. Schwartzman, give us a quick refresher on RF.

Dr. Schwartzman:
RF is an autoantibody and one of the biomarkers we use to diagnose rheumatoid arthritis. It has a role in identifying patients with the disease as well as the underlying pathophysiology of rheumatoid arthritis. Patients with higher RF levels are more likely to experience joint destruction, radiographic progression, erosive disease, and disability, and are less likely to experience therapeutic response. Additionally, it has been shown that patients with higher RF levels can have a decreased response to certain TNF inhibitors, which we will discuss later in the episode.  

Dr. Brown:
And higher RF can be linked with systemic issues, too.

Dr. Schwartzman:
Yes. In patients with RA, higher RF levels are also associated with higher disease activity and higher cardiovascular risk.

Dr. Brown:
My perspective on RF has evolved over the course of my practice. Early on, I thought of it primarily as a diagnostic tool.

Dr. Schwartzman:
And now it’s become clear that RF can also play into prognosis and therapeutic decisions. 

Dr. Brown:
We'll get back to RF, but before we dive into the EXXELERATE study and the post hoc analysis, I want to mention RAPID 1, a pivotal Phase 3, randomized, double blind, placebo-controlled study that evaluated CIMZIA plus methotrexate compared to placebo and methotrexate alone in TNFi-naïve adults with moderately to severely active RA. In the RAPID 1 study, CIMZIA demonstrated statistically significant improvement in the primary outcome, the ACR20 response at Week 24. 59% of patients treated with 200 mg CIMZIA plus methotrexate every 2 weeks achieved ACR20 at Week 24 compared with 14% on placebo, and that benefit was maintained through Week 52, with 53% of patients versus 13% achieving ACR20, respectively. The CIMZIA group also had significantly less radiographic progression compared to placebo at Week 52.

Dr. Schwartzman:
With that foundation, let’s discuss EXXELERATE, which was a Phase 4, head-to-head superiority trial in biologic-naïve patients with moderately to severely active RA and inadequate response to methotrexate. It compared CIMZIA plus methotrexate to adalimumab plus methotrexate to determine whether one TNFi demonstrated superior efficacy over the other.

Dr. Brown:
EXXELERATE enrolled 915 biologic-naïve patients with active RA who were not responding to methotrexate alone. They were randomized 1:1 to either CIMZIA plus methotrexate, starting with the standard loading doses, then transitioning to 200 mg every other week...or to adalimumab dosed at 40 mg every other week with methotrexate. Patients taking adalimumab were also administered placebo during the first 12 weeks to maintain blinding during the administration of the loading dose of CIMZIA.

At Week 12, patients were classified as responders if they reached low disease activity, defined as DAS28(ESR) ≤3.2, or had a DAS28(ESR) change from baseline reduction of at least 1.2 points. Responders remained on their original treatment, while non-responders switched to the other TNFi.

By Week 24, only patients who continued to meet low disease activity criteria stayed on treatment, and the responders were then followed for 2 years. The non-responders at Week 24 were withdrawn from the study.

Dr. Schwartzman:
The primary endpoints included the percentage of patients who achieved an ACR20 response at Week 12, and the percentage who reached low disease activity by DAS28(ESR) ≤3.2 at Week 104. Sixty-nine percent of patients taking CIMZIA achieved ACR20 at Week 12 and 35% achieved DAS28(ESR) ≤3.2 at Week 104, versus 71% and 33% of patients taking adalimumab, respectively.

It’s important to note that the primary endpoints of superiority were not met in the EXXELERATE trial.

Dr. Brown:
So, the key takeaway is that in the EXXELERATE trial, CIMZIA did not show superiority over adalimumab. The results were numerically similar regardless of which TNF inhibitor was used in combination with methotrexate in patients with moderately to severely active rheumatoid arthritis.

Dr. Schwartzman:
This is where RF comes into play. In a subsequent post hoc analysis of the EXXELERATE trial, researchers analyzed specific patient subgroups, focusing on rheumatoid factor levels to assess both drug concentration and clinical efficacy. Patients were stratified by baseline RF levels into quartiles—the lower rheumatoid factor patients were in quartiles 1 through 3, and had RF levels at or below 204 IU/mL, and patients in the fourth, “high” rheumatoid factor quartile, had RF levels greater than 204 IU/mL.

A key point to mention is that this is a post hoc analysis. Therefore, the results were not powered to show statistical significance, and clinical significance has not been established. For this reason, we cannot state the evidence as conclusive and should interpret it with caution.

Dr. Brown:
Interestingly, RF levels appeared to have a negative impact on response to adalimumab, but not to CIMZIA. First, when evaluating drug concentrations, adalimumab levels were lower in patients with high RF than in other adalimumab-treated patients, whereas CIMZIA concentrations were similar regardless of RF levels. Similarly, CIMZIA drug concentrations remained consistent in all patients for up to 2 years, also regardless of RF levels.

Dr. Schwartzman:
Looking at disease activity as measured by the DAS28-CRP, it was similar for patients in the lower rheumatoid factor quartiles regardless of whether they were treated with CIMZIA or adalimumab through Week 104. In the lower RF group, 64.8% of CIMZIA patients achieved low disease activity, and 65.1% of adalimumab patients achieved low disease activity.

Within the high RF subgroups, 48.3% of patients treated with adalimumab achieved low disease activity at Week 104. At the same time point, 65.7% of patients treated with CIMZIA in the high RF levels subgroup achieved low disease activity. In fact, CIMZIA-treated patients achieved remission or low disease activity regardless of RF levels.

Dr. Brown:
I think these findings are interesting and suggest that rheumatoid factor and drug structure may play an important role in guiding treatment decisions. In a disease like rheumatoid arthritis, where we have so many medications in our therapeutic armamentarium, understanding differences among both patients and therapeutic molecules, even within class, is critical in helping us monitor our patients.

Dr. Schwartzman:
I agree. If a patient has high RF, I may be more inclined to consider CIMZIA, given that patients achieved remission or low disease activity regardless of RF level, which was not seen with adalimumab, another TNF inhibitor. Regardless of which TNFi I choose, I monitor treatment response closely.

Dr. Brown:
CIMZIA has been an effective option for patients with moderately to severely active RA for many years, and these findings highlight why it may be the right fit specifically for patients with higher RF levels who are at risk of more aggressive disease.

Dr. Schwartzman:
Looking ahead to future research in RA, I think we’re moving toward more personalized medicine. Using markers like RF to stratify patients might help us match the right drug to the right patient earlier, eliminating guesswork and trial and error. The EXXELERATE post hoc analysis is an example of how subgroup data can give us important clues about tailoring therapy.

Dr. Brown:
To recap: In the post hoc analysis of the EXXELERATE study, patients treated with CIMZIA maintained drug concentrations regardless of their RF level at 2 years. Also, CIMZIA patients achieved low disease activity regardless of RF level.

Dr. Schwartzman:
It's an important reminder that not all patients with RA are the same. Poor prognostic factors, including high RF, can be influential in physicians' and patients' decision-making when developing treatment recommendations.

Dr. Brown:
Thanks for the discussion today. And thank you to our listeners! For more information on the EXXELERATE study and post hoc analysis, check out the references linked on the episode page.

And now, please stay tuned for the full Important Safety Information.