Roy Fleischmann, MD, explores the successful results of the novel IL-6 inhibitor, olokizumab, from 2 randomized clinical trials of the phase 3 global research program CREDO.
Rheumatology Network interviewed Roy Fleischmann, MD, to discuss the successful results of the novel interleukin-6 (IL-6) inhibitor, olokizumab, in 2 randomized clinical trials of the phase 3 global research program CREDO (Clinical RhEumatoid Arthritis Development of Olokizumab). Fleischmann is Clinical Professor of Medicine at the University of Texas Southwestern Medical Center at Dallas and co-Medical Director of the Metroplex Clinical Research Center in Dallas.
Rheumatology Network: Can you tell me a little bit more about the initial draw to develop olokizumab for rheumatoid arthritis treatment?
Roy Fleischmann: Initially, olokizumab was developed a while ago. I'm guessing we worked with it approximately 10 years ago during a phase 1 study with olokizumab. And the reason was that olokizumab as an IL-6 inhibitor directly affects IL-6, which is different than the 2 approved molecules now which affect the IL-6 receptor. So, it was thought that perhaps by affecting IL-6 directly, one would get better efficacy and maybe improved safety. Also, because you affect the molecule itself around the receptor, you can use lower doses of the drug to obtain the effect.
RN: What sets olokizumab apart from other rheumatoid arthritis drugs and how does it work to treat this patient population?
RF: It is different from the conventional synthetics which are all oral drugs, not really targeted for rheumatoid arthritis, but they work fairly well in rheumatoid arthritis. Drugs in that class are drugs, like methotrexate and sulfasalazine, work in a minority of patients. About 30% of patients actually do quite well. There a number of other drugs there are available for treatment of rheumatoid arthritis that are biologic therapies, and there are different mechanisms for the biologics. Some effect tumor necrosis factor (TNF), some effect the T-cell, some effect the B-cell directly, and then there are 2 that are approved that affect IL-6. But by affecting the IL-6 receptor olokizumab was the only one that affects the IL-6 itself.
RN: What were the study designs and the primary endpoints of CREDO 2 and CREDO 3?
RF: CREDO 2 was designed to test the efficacy and safety of olokizumab in a phase 3 trial of patients with active rheumatoid arthritis or inadequate control by methotrexate. It was a placebo and active controlled trial because also in the trial was adalimumab. So there were 4 groups of patients, all on methotrexate. One group was on olokizumab 64 milligrams every 2 weeks, one was olokizumab 64 milligrams subcutaneously every 4 weeks, one was on adalimumab 40 milligrams subcutaneously every 2 weeks, and the fourth group was on placebo plus methotrexate.
RN: In respect to the CREDO 3, what was the study design in the primary endpoints?
RF: So we look at the efficacy and safety of olokizumab in a phase 3 trial of patients with active rheumatoid arthritis, who were inadequately controlled by TNF alpha inhibitor therapy. These patients have long standing disease and had already failed a TNF. And the study design was 2 doses of olokizumab both 64 milligrams subcutaneously but 1 every 2 weeks plus methotrexate and the other olokizumab every four weeks plus methotrexate, compared to placebo plus methotrexate. The placebo patients could be rescued by week 16 if they didn't have any strict response, so they weren't treated too long. And the placebo patients were then randomized to the olokizumab either every 2 weeks or every 4 weeks.
RN: And what were the results of this study?
RF: So the primary endpoint of the study was ACR20 response with a secondary endpoint being whether or not olokizumab is not inferior to adalimumab. And the efficacy results show that with respect to the ACR20 responses, or the ACR50 response, which is a secondary endpoint of each, or the ACR70 response, which is an exploratory endpoint. Both doses of olokizumab are actually fairly equally effective and very comparable to adalimumab. And both were superior to placebo plus methotrexate. We also looked at other endpoints, which were secondary like the disease activity score 28 (DAS28) C-reactive protein (CRP) less than 3.2, or exploratory was the DAS28 CRP less than 2.6, and a change in Health Assessment Questionnaire Disability Index (HAQ-DI), all of which showed the results similarly to adalimumab and superiority to palcebo. One of the problems in looking at an IL-6 study is the fact that IL-6 itself is involved with CRP. So, you can find patients who have an excellent CRP risk response and just because the IL-6 inhibitor we don't have a clinical response. The way to test this is actually do a clinical disease activity index (CDAI), and that was done in this study as well. And it was found that when you look for a CDAI low disease activity or CDAI remission, again, the same results. We're seeing both doses of olokizumab were similar to that of adalimumab and superior to placebo.
CREDO 3 showed that both regimens of olokizumab achieved the primary endpoint of the ACR20 response versus methotrexate plus placebo by week 12. And also showed the patients who are on placebo when switched over to olokizumab had a response to olokizumab that was similar to the patients were originally treated with olokizumab. And this was seen with the ACR20, as well as the DAS28 CRP list 3.2 as well as improved HAQ-DI. It showed that olokizumab could be effective in a fair number of patients that failed previous biologic therapy with a TNF.
RN: What is the clinical significance of these results?
RF: Well, this is actually very significant, because the 2 IL-6 inhibitors that are approved, the ones that affect the receptor, did studies against adalimumab, but they did them as monotherapy. So, they used the drug as monotherapy versus adalimumab monotherapy. And adalimumab monotherapy is probably 50% effective as adalimumab plus methotrexate. And IL-6 inhibitors themselves do a little bit better with methotrexate, but they're actually fairly good as monotherapy as well. So those 2 trials showed superiority to adalimumab. But it really wasn't the dose of adalimumab that's used in the majority of patients, it was the combination. This is the only study done with an IL-6 inhibitor plus methotrexate compared with adalimumab plus methotrexate, which showed that olokizumab is non-inferior to adalimumab.
RN: What is the clinical significance of the CREDO 3 study?
RF: The patient population that is underserved, to some extent, are the patients who fail on TNF. We know that about a third of patients, if they're treated with methotrexate or other conventional synthetic disease modifying antirheumatic drugs (DMARDs) can achieve remission. That's really good for that third, but what about the other two thirds? In the other two thirds, many will respond to any biologic or JAK inhibitor that you give, but there are still about 20% of patients who are treated with a TNF and don't respond. Now, what do you do with those patients? What this study shows is that this is a reasonable choice to use in those patients, as there are patients who have failed conventional synthetics as well as a TNF, who can achieve adequate disease control as well as improvement in functional status.
RN: Does your team plan on doing any further research on olokizumab for rheumatoid arthritis treatment?
RF: Well, we haven't really discussed that, but there are other studies that should be done. They should be a radiographic study, there should be a study that looks at patients with early RA. But the probability is that with its clinical response being so similar to adalimumab, it will show radiograph inhibition as the other IL-6 inhibitors have. And the fact that it was effective in patients with long standing RA, it should be even more effective in patients who are methotrexate naïve or in early RA. Another study would be the monotherapy study and how monotherapy olokizumab compares to combination.
RN: Is there anything else you would like our audience to know?
RF: One difference with olokizumab versus the other IL-6 inhibitors is that because this affects IL-6 directly, much less protein has to be administered and that may be advantageous with respect to injection site reactions. The other is that both doses, which is olokizumab 64 milligrams every 2 weeks and 4 weeks, were effective. I would expect the majority of patients would actually respond to be every 4 weeks. Some may require 2 weeks, but probably most every 4 weeks. And the other IL-6 agents are every week or 2. So, there is an advantage in terms of dosing frequency as well.