Data from the phase 3 CREDO-1 study was presented at the EULAR 2020 e-congress. In the study, 428 patients from Russia, Belarus, and Bulgari, with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy were enrolled into a 24-week, randomized, double-blind, placebo-controlled, multicenter study to examine the long-term safety, efficacy and tolerability of olokizumab.1
Patients were randomized to receive 64mg of olokizumab subcutaneous injections every 2 weeks (n=143; q2w group), every 4 weeks (n=142; q4w group), or placebo injection every 2 weeks (n=143). Baseline characteristics were comparable across all treatment groups. Non-responders were rescued starting at week 14, and subjects were eligible for open-label study extension after week 24.
The primary endpoint in the CREDO-1 study was the American College of Rheumatology 20% response (ACR20) at week 12 in the intent-to-treat population (ITT), and the secondary endpoints include the percentage of subjects with low disease activity, improvement of physical ability and safety outcomes.
From the findings, Dr. Rumen Stoilov, Professor at University Hospital St. Ivan Rilski, Sofia, Bulgaria, commented, “Both regimens of olokizumab were significantly better than placebo in all primary and secondary endpoints. Improvements in efficacy outcomes became evident after 4 to 8 weeks since the initiation of olokizumab and were maintained throughout 24 weeks.” He also highlighted that 90.9% of the q2w group (n=130), 94.4 of the q4w group (m=134) and 92.3% of placebo group completed the trial (Table 1).1
In addition, the ACR20 response rate in the ITT population was superior for olokizumab over placebo at weeks 12 and 24. In brief, 63.6% (n=91) and 70.4% (n=100) patients treated with olokizumab q2w or q4w, respectively, achieved ACR20 at week 12 compared to 25.9% (n=37) in the placebo group. Furthermore, the ACR50 response rate at week 24 was also significantly higher in both olokizumab groups , 42.7% (n=61) and 48.6% (n=69) for the q2w and q4w groups respectively, when compared to 7.7% (n=11) for the placebo group.
Likewise, for the secondary endpoint results, a higher proportion of patients receiving olokizumab reported a Disease Activity Score-28 (DAS28) below 3.2 at week 12, 33.6% (n=48) and 38.7% (n=55) for the q2w and q4w groups respectively, when compared to 3.5% (n=5) for the placebo group. A higher proportion of patients receiving olokizumab also reported a Clinical Disease Activity Index (CDAI) below or equal to 2.8 at week 24, 8.4% (n=12) and 7.7% (n=11) for the q2w and q4w groups respectively, when compared to 0% for the placebo group.1
Safety results illustrated that the overall treatment emergent adverse event (TEAE) was at 58.0%, 57.0% and 43.7% with a discontinuation rate of 4.9%, 3.5% and 0.7% in the q2w, q4w and placebo groups respectively. At least, one treatment emergent severe adverse event (TESAE) was reported in 5.6% (n=8) of the olokizumab groups, which was not statistically higher than 2.8% (n=4) in the placebo group. One death was observed in the q2w group due to septic shock. Staphylococcal and toxic shock syndrome were the leading causes of TESAEs cases. However, there were no reported cases of severe thromboembolism and gastro-intestinal proliferation. Although there were reported cases of elevated liver enzymes, none of the elevations met the Hy’s law criteria. The incidence of bilirubin level increase at week 24 was the same across all groups.1
During the discussion, Dr. Stoilov highlighted that the total cholesterol levels were elevated more significantly in the groups treated with olokizumab than in the placebo group. Interestingly, the serum lipid levels plateaued and remained stable at week 24 for the olokizumab group, and the serum lipid levels in the q2w group were comparable to the placebo group.1
Moreover, HDL and LDL levels remained higher for patients treated with olokizumab when compared to placebo. However, there was a decrease in LDL levels after week 12 for the q4w group. Also, a decrease in blood neutrophils was observed in all olokizumab treatment groups.1
In conclusion, the phase 3 CREDO-1 study revealed that treatment with olokizumab over 24 weeks was associated with significant improvements in the signs, symptoms and physical function of RA, with a safety profile consistent with phase 2 data. Furthermore, olokizumab demonstrated comparable efficacy data with other monoclonal antibodies targeting interleukin 6 or biological agents of the same mechanism. Importantly, there were no discernible differences between the two olokizumab regimes for efficacy or safety outcomes.