Effectiveness of olokizumab for the treatment of rheumatoid arthritis

Rheumatology Network interviewed Roy Fleischmann, MD, to discuss the positive results of the new interleukin-6 (IL-6) inhibitor, olokizumab, in 2 randomized clinical trials of the global phase 3 research program CREDO ( Clinical Rheumatoid Arthritis Development of Olokizumab). Fleischmann is Clinical Professor of Medicine at the Southwestern Medical Center at the University of Texas at Dallas and Co-Medical Director of the Metroplex Clinical Research Center in Dallas.

Rheumatology Network: Can you tell me a bit more about the initial draw to develop olokizumab for the treatment of rheumatoid arthritis?

Roy Fleischmann: Initially, olokizumab was developed some time ago. I guess we worked with about 10 years ago in a phase 1 study with olokizumab. And the reason was that olokizumab as an IL-6 inhibitor directly affects IL-6, which is different from the 2 molecules now approved that affect the IL-6 receptor. Thus, it was believed that by directly affecting IL-6, one would achieve better efficacy and possibly improved safety. Also, because you are affecting the molecule itself around the receptor, you can use lower doses of the drug to get the effect.

IA: What distinguishes olokizumab from other rheumatoid arthritis medicines and how does it work to treat this patient population?

FR : It’s different from conventional synthetics which are all oral medications, not really targeted for rheumatoid arthritis, but they work quite well in rheumatoid arthritis. Drugs in this class are drugs, such as methotrexate and sulfasalazine, which work in a minority of patients. About 30% of patients do quite well. There are a number of other drugs available for the treatment of rheumatoid arthritis that are biologics, and there are different mechanisms for biologics. Some affect tumor necrosis factor (TNF), some affect T cell, some directly affect B cell, 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 IL-6 itself.

IA: What were the study designs and the main evaluation criteria for CREDO 2 and CREDO 3?

FR : CREDO 2 was designed to test the efficacy and safety of olokizumab in a phase 3 trial in patients with active rheumatoid arthritis or insufficient control with methotrexate. This was a placebo-controlled, active trial because there was also adalimumab in the trial. There were therefore 4 groups of patients, all on methotrexate. One group was on olokizumab 64 milligrams every 2 weeks, one was on 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.

IA: With regard to CREDO 3, what was the design of the study on the main evaluation criteria?

FR : We are therefore reviewing the efficacy and safety of olokizumab in a phase 3 trial in patients with active rheumatoid arthritis, who were insufficiently controlled by treatment with a TNF alpha inhibitor. These patients have long standing illness and had previously failed 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. . Patients on placebo could be saved at week 16 if they did not have a strict response, so they weren’t treated for too long. And the placebo patients were then randomized to receive olokizumab every 2 weeks or every 4 weeks.

IA: And what were the results of this study?

FR : Thus, the primary endpoint of the study was the ACR20 response with a secondary endpoint being whether olokizumab is not inferior or not to adalimumab. And the efficacy results show it 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. The two doses of olokizumab are actually quite effective and very comparable to adalimumab. And both were superior to placebo and methotrexate. We also looked at other endpoints, which were secondary like Disease Activity Score 28 (DAS28), C-reactive Protein (CRP) less than 3.2, or exploratory was DAS28 CRP lower to 2.6, and a change in the Health Assessment Questionnaire Disability Index (HAQ-DI), all of which showed similar results to adalimumab and superiority to palcebo. One of the problems with reviewing an IL-6 study is the fact that IL-6 itself is involved in CRP. So, you can find patients who have an excellent response to the risk of CRP and simply because the IL-6 inhibitor has no clinical response. The way to test this is actually to do a Clinical Disease Activity Index (CDAI), and this was also done in this study. And it was found that when looking for low CDAI disease activity or CDAI remission, again same results. We find that the two doses of olokizumab were similar to adalimumab and superior to placebo.

CREDO 3 showed that both olokizumab regimens met the primary endpoint of ACR20 response compared to methotrexate plus placebo at week 12. And also showed that patients who were on placebo when switching to olokizumab had a response to olokizumab that was similar to that of patients initially treated with olokizumab. And this has been seen with the ACR20, as well as the DAS28 CRP 3.2 listing as well as the HAQ-DI enhancement. It has shown that olokizumab may be effective in a number of patients who have failed previous biologic therapy with TNF.

IA: What is the clinical significance of these results?

FR : Well, that’s actually very important, because the 2 IL-6 inhibitors that are approved, the receptor-affecting ones, have been studied against adalimumab, but they’ve done them as monotherapy. Thus, they used the drug as monotherapy versus adalimumab as monotherapy. And adalimumab monotherapy is probably 50% effective in combination with adalimumab and methotrexate. And the IL-6 inhibitors themselves do a little better with methotrexate, but they’re also quite good as monotherapy. These 2 trials therefore showed superiority over adalimumab. But it really wasn’t the dose of adalimumab that is used in the majority of patients, it was the combination. This is the only study performed with an IL-6 inhibitor plus methotrexate versus adalimumab plus methotrexate, which showed that olokizumab is not inferior to adalimumab.

IA: What is the clinical significance of the CREDO 3 study?

FR : The patient population that is underserved to some extent are patients who fail TNF. We know that about a third of patients, if treated with methotrexate or other conventional synthetic anti-rheumatic drugs (DMARDs) can go into 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 biological inhibitors or JAKs you administer, but there are still about 20% of patients who are treated with TNF and do not respond. Now what are you doing with these patients? What this study shows is that this is a reasonable choice to use in these patients, as there are patients who have failed conventional syntheses as well as TNF, who can achieve adequate control. disease as well as improved functional status.

IA: Is your team planning to conduct further research on olokizumab for the treatment of rheumatoid arthritis?

FR : Well, we haven’t really discussed it, but there are other studies that should be done. They should be a radiographic study, there should be a study that examines patients with early RA. But the likelihood is that with its clinical response so similar to that of adalimumab, it will show radiographic inhibition as did other IL-6 inhibitors. And the fact that it has been effective in patients with long-standing RA should be even more effective in methotrexate-naïve or early RA patients. Another study would be the monotherapy study and how olokizumab monotherapy compares to the combination.

IA: Is there anything else you would like our audience to know?

FR : A difference with olokizumab from other IL-6 inhibitors is that, as it directly affects IL-6, much less protein has to be administered and this may be of benefit with regard to site reactions. injection. The other is that both doses of 64 milligrams of olokizumab every 2 weeks and 4 weeks were effective. I would expect the majority of patients to actually respond every 4 weeks. Some may take 2 weeks, but probably most every 4 weeks. And the other IL-6 agents are weekly or 2. So there is also an advantage in terms of dosing frequency.

About Antoine L. Cassell

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