Ozoralizumab (OZR) is a novel tumor necrosis factor (TNF) inhibitor that was launched in Japan for treating patients with rheumatoid arthritis (RA) who have had an inadequate response to existing therapies. This post-hoc analysis aimed to compare the efficacy of OZR administered without methotrexate (MTX) with placebo or OZR administration in combination with MTX.
Methods
We analyzed the OZR group (30 mg) in the NATSUZORA trial (non-MTX, open trial) (OZR group; n = 94) and the placebo group (MTX group; n = 75) and the 30-mg OZR group (OZR + MTX group; n = 152) in the OHZORA trial (combined MTX, double-blind trial), and the covariates were adjusted by propensity score matching. Subsequently, the American College of Rheumatology (ACR) 20/50/70 response rates from baseline to 24 or 52 weeks were compared. Furthermore, to compare longitudinal data on disease activity indicators, a mixed-effects model for repeated-measures analyses was used.
Results
Comparing the OZR and MTX groups, 52 patients were matched in each group. The OZR group showed improvements in the ACR20 (OZR group, 67.3% vs. MTX group, 34.6%, p = 0.001), ACR50 (51.9% vs. 17.3%, p < 0.001), and ACR70 (26.9% vs. 11.5%, p = 0.047) response rates compared to those in the MTX group. Comparing the OZR and OZR + MTX groups, 77 patients were matched in each group. No significant difference was observed in the ACR20 response rate (OZR group, 58.4% vs. OZR + MTX group, 70.1%, p = 0.130). However, the OZR + MTX group showed higher ACR50 (44.2% vs. 62.3%, p = 0.024) and ACR70 (29.9% vs. 45.5%, p = 0.046) response rates.
Conclusion
OZR administration without MTX was associated with an improvement in the signs and symptoms of RA compared to placebo administration (continuation of MTX monotherapy). OZR and MTX administration showed better efficacy than OZR administration alone.
Prior Presentation: This work was previously presented at the 38th Annual Meeting of the Japanese Society for Clinical Rheumatology and Related Research on November 18, 2023.
Key Summary Points
Why carry out this study?
Ozoralizumab (OZR) is a tumor necrosis factor (TNF) inhibitor approved in Japan for the treatment of patients with rheumatoid arthritis (RA) who have had an inadequate response (IR) to existing therapy.
As the phase 3 clinical trial without concomitant methotrexate (MTX) was an open study, there was no comparison with a placebo, nor was there a direct comparison with or without concomitant MTX.
Using data from the NATSUZORA (without MTX) and OHZORA trials (with MTX), propensity score matching was performed to indirectly compare the OZR treatment group and placebo (continued MTX treatment) group and to indirectly compare the effects of OZR treatment with or without MTX.
What was learned from the study?
The OZR group treated without concomitant MTX exhibited better treatment efficacy than the placebo (MTX continuous treatment group) in cs-DMARD-IR patients, and the OZR treatment group with MTX showed improved efficacy compared to the group without MTX.
Similar to other TNF inhibitors, the treatment of RA with OZR in combination with MTX is preferable, whereas OZR can be used as a treatment option for patients who cannot receive MTX.
There are limitations to this posterior analysis; therefore, further OZR data should be accumulated in actual clinical practice.
Introduction
Rheumatoid arthritis (RA) is a typical autoimmune disease whose primary symptom is polyarthritis. Because joint damage progresses early after onset, appropriate diagnosis and treatment at an early stage are necessary. The treatment of RA aims at rapid clinical remission based on the concept of treat-to-target. It is recommended that remission should be maintained and that consideration should be given to reducing the drug dose [1, 2]. The standard initial treatment uses conventional synthetic (cs)-disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), but if insufficient improvement is observed, the treatment is switched to biological (b)-DMARDs or Janus kinase (JAK) inhibitors [3, 4]. In particular, although MTX is designated as the first line of treatment in each country’s guidelines, there are some patients who are unable to take MTX because of tolerability and other issues, and there are some who do not receive sufficient effects from treatment with other cs-DMARDs [3‐5]. Therefore, when used as treatment options for these patients, b-DMARDs and JAK inhibitors are required to be effective even when not used in combination with MTX.
Tumor necrosis factor (TNF) is an inflammatory mediator that causes a systemic inflammatory response and is involved in many diseases [6]. In RA, autoimmune reactions trigger persistent inflammation, and the overproduction of TNF is critical in disease progression. TNF inhibitors have shown remarkable therapeutic efficacy in patients with RA and remain important bDMARDs in the treatment of RA [7‐9]. Ozoralizumab (OZR), a novel TNF inhibitor, is a variable heavy-chain domain of heavy-chain antibody (VHH) fusion protein that binds to soluble and membrane-bound TNF-alpha and inhibits TNF-mediated signaling [10‐13]. OZR is a 38-kDa trivalent NANOBODY® compound comprising two humanized anti-human TNF-alpha VHHs and one humanized anti-human serum albumin VHH. OZR was approved in Japan in 2022 as a TNF inhibitor for patients with RA that is inadequately managed by currently available treatments. Its dosage and administration methods include the subcutaneous administration of 30 mg of OZR every 4 weeks.
The OHZORA trial was a double-blind study comparing OZR and placebo when used with concomitant MTX therapy in patients with an inadequate response to MTX (MTX-IR) [14, 15]. The efficacy of OZR without MTX was examined in the NATSUZORA trial; however, because NATSUZORA was an open trial, no comparative study on the efficacy of OZR with placebo without MTX has been conducted [16]. In addition, no research has been conducted to directly compare the effects of the presence or absence of MTX when using OZR. In this post-hoc analysis, propensity score matching (PSM) and a mixed-effects model for repeated measures (MMRM) were used to indirectly compare the efficacy of OZR therapy without MTX versus placebo (continuation of MTX treatment) or OZR used in combination with MTX.
Methods
Data Sources
This post-hoc analysis was conducted using data from a randomized, multicenter, double-blind, parallel-group, placebo-controlled phase II/III trial of OZR with MTX in Japanese patients with RA (jRCT2080223971, OHZORA trial) and a randomized, multicenter, open-label, phase III trial without MTX (jRCT2080223973, NATSUZORA trial). Details of the study designs, patient populations, and results of these trials have been published previously [14‐16]. In the OHZORA trial, 381 patients were assigned to receive placebo or 30 mg or 80 mg of OZR in a 1:2:2 ratio. The treatments were subcutaneously administered with MTX every 4 weeks for 24 weeks (period A) [14]. After 24 weeks in this study, all patients received either 30 mg or 80 mg of OZR (period B) [14, 15]. In the NATSUZORA trial, OZR (30 mg:80 mg in a 2:1 ratio) was administered subcutaneously every 4 weeks for 52 weeks without MTX [16].
In the full analysis set of the two studies, patients who met the following criteria were included in the current post-hoc analyses:
1.
Placebo group in the OHZORA trial (continued MTX monotherapy; “MTX group”)
2.
OZR (30 mg) group in the OHZORA trial (with MTX; “OZR + MTX group”)
3.
OZR (30 mg) group in the NATSUZORA trial (without MTX; “OZR group”).
Two PSM, defined below as PSM-A and PSM-B, were performed and analyzed. The target patient groups for each analysis are indicated.
PSM-A:
75 patients in the MTX group of the OHZORA trial (with MTX) and 94 patients in the OZR group of the NATSUZORA trial (without MTX)
PSM-B:
152 patients in the OZR+MTX group of the OHZORA trial (with MTX) and 94 patients in the OZR group of the NATSUZORA trial (without MTX).
Design of each clinical trial of OZR and matching analysis. Two types of matching analyses were performed using three groups from two clinical trials: PSM-A is an indirect comparison between the OZR and MTX groups; PSM-B is an indirect comparison between the OZR and OZR + MTX groups. csDMARDs conventional synthetic disease-modifying antirheumatic drugs, EE early escape, IR inadequate response, NA not applicable, MTX methotrexate, OZR ozoralizumab, PBO placebo, PSM propensity score matching, RA rheumatoid arthritis. *OZR was administered subcutaneously once every 4 weeks. **Patients who continued MTX treatment for at least 12 weeks
×
Efficacy Outcomes
Measurements and changes from baseline were calculated for each evaluation period (time point) for the following endpoints: American College of Rheumatology (ACR) 20/50/70 improvement rate (by nonresponder imputation, NRI), patient’s global assessment using a visual analog scale (VAS), physician’s global assessment using a VAS, patient’s pain assessment using a VAS (pain VAS), tender joint count (TJC), swollen joint count (SJC), high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), clinical disease activity index (CDAI), simplified disease activity index (SDAI), and health assessment questionnaire disability index (HAQ-DI).
In PSM-A, the MTX group in the OHZORA trial (with MTX) and the OZR group in the NATSUZORA trial were included up to 24 weeks because the blinding period was 24 weeks. In PSM-B, the data were tabulated from the start of treatment to 52 weeks. In the OHZORA trial, early escape (EE) criteria were established to rescue patients with an inadequate response, and those patients were placed in period B after 20 weeks of efficacy evaluation. Therefore, data after 24 weeks were excluded from the analysis for cases with EE, and data up to 20 weeks were used in the analysis.
The longitudinal data analysis of changes from baseline compared between treatment groups was conducted using an MMRM based on the assumption of missing at random.
Statistical Analysis
Data were analyzed using SAS version 9.4 (SAS Institute, Tokyo, Japan). The PSMATCH procedure in SAS was used to determine eligible cases. The covariate selection process included age, sex, and RA duration as essential variables, while other covariates were selected based on their clinical importance, including in real-world clinical practice. Considering that body weight was selected as a covariate in the population pharmacokinetic analysis of OZR [17], weight was used in this study instead of body mass index. Finally, the baseline values of the following variables were used as covariates: age, sex, duration of disease, TJC (28 joints), SJC (28 joints), physician’s global assessment using a VAS, patient’s global assessment using a VAS, hs-CRP, weight, usage of glucocorticoids, and CDAI. The method of the match statement in SAS was set to Greedy (K = 1), and Caliper was set to 0.20.
For patient background values (items that were covariates in PSM), the standardized mean difference (SMD) was used to assess the balance of patient characteristics between groups, with differences < 0.1 considered as balanced.
For continuous variables, the mean and associated standard deviation (SD) or median and associated interquartile range (IQR) were calculated. Student’s t test was used to test the efficacy endpoints, and the Kruskal–Wallis test was used to examine the equality of distribution across groups. For the categorical variables, frequency tabulations were performed, and the chi-square test was used to examine the equality of distribution across groups. The significance level was set at 15% (two-tailed) for tests of equality of the distribution of participant background items and at 5% (two-tailed) for other tests, unless otherwise specified.
The change from baseline at weeks 1–52 was tested using an MMRM with treatment group, period, and their interactions as the fixed effects and baseline as the covariate. The MMRM variance–covariance matrix was set to “unstructured.” However, because the hs-CRP values in PSM-B did not converge, “compound symmetry” was used. The Kenward–Roger method was used to calculate the degrees of freedom.
Compliance with Ethics Guidelines
This study is based on previously conducted studies and does not contain new studies with human participants performed by the authors. All studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Each study was approved by ethics committees, as described in the original papers [14‐16]. Written informed consent was obtained from all patients.
Results
PSM-A: Comparison Between the OZR Group and the MTX Group
Table 1 shows the baseline characteristics before and after matching the study population in PSM-A. From the 75 patients in the MTX group of the OHZORA trial and the 94 patients in the OZR group of the NATSUZORA trial, 52 patients were matched in each group after 1:1 PSM. Parameters that showed significant differences before matching were age, disease activity score (DAS) 28-CRP, physician’s global assessment, hs-CRP, and ESR. There were no significant differences between the groups extracted after matching, and many SMD values of the covariates converged to values of less than 0.1, which is considered well balanced [18, 19]. The MTX dose in the MTX group was 10.2 ± 3.0 mg/week and 10.2 ± 2.9 mg/week before and after matching, respectively.
Table 1
PSM-A: baseline characteristics of the study population
In PSM-A, the rate of improvement in ACR20/50/70 at 24 weeks was examined. The OZR group showed a significantly better improvement rate than the MTX group (Fig. 2) in ACR20 (OZR group, 67.3% vs. MTX group, 34.6%, p = 0.001), ACR50 (51.9% vs. 17.3%, p < 0.001), and ACR70 (26.9% vs. 11.5%, p = 0.047). In addition, longitudinal data analysis of the change from baseline (MMRM) was performed for the disease activity and patient-reported outcome indexes. Intergroup comparisons of SDAI, pain VAS, and HAQ-DI are shown in Fig. 3. The change in the OZR group was greater than that in the MTX group, and significant differences were observed between the groups from 1 week after the start of treatment. Data for other evaluation items (DAS28-CRP, DAS28-ESR, patient’s global assessment, physician’s global assessment, TJC, SJC, hs-CRP, ESR, and CDAI) are shown in Supplementary Fig. S1.
Fig. 2
Indirect comparison of the ACR improvement rates at 24 weeks. In PSM-A, the MTX group in the OHZORA trial and the OZR group in the NATSUZORA trial were included up to 24 weeks because the blinding period was 24 weeks. OZR (30 mg) was administered subcutaneously once every 4 weeks. NRI, χ2 test, *p < 0.05, **p < 0.01, ***p < 0.001. ACR American College of Rheumatology, NRI nonresponder imputation, MTX methotrexate, OZR ozoralizumab, PSM propensity score matching
Fig. 3
Between-group comparison of the changes from baseline PSM-A. MMRM model, *p < 0.05, **p < 0.01, ***p < 0.001. The error bars represent the unadjusted mean ± standard deviation. HAQ-DI health assessment questionnaire disability index, MMRM mixed-effects model for repeated measures, MTX methotrexate, OZR ozoralizumab, PSM propensity score matching, Pain VAS patient’s pain assessment, SDAI simplified disease activity index
×
×
PSM-B: Comparison Between the OZR Group and the OZR + MTX Group with MTX
Table 2 shows the baseline characteristics of the study population in PSM-B before and after matching. From 94 patients in the OZR group of the NATSUZORA trial and 152 patients in the OZR + MTX group of the OHZORA trial, 77 patients were matched in each group after 1:1 PSM. For the parameters that showed between-group differences (age, SJC28 score, hs-CRP, and use of glucocorticoid), there were no significant differences after matching. The MTX dose in the OZR + MTX group was 10.2 ± 2.9 mg/week and 9.7 ± 2.9 mg/week before and after matching, respectively.
Table 2
PSM-B: baseline characteristics of the study population
In PSM-B, the ACR improvement rate at 52 weeks was examined, and there was no significant difference between the two groups in ACR20 (58.4% vs. 70.1%, p = 0.130). Conversely, the OZR + MTX group showed significantly higher improvement rates in ACR50 (44.2% vs. 62.3%, p = 0.024) and ACR70 (29.9% vs. 45.5%, p = 0.046) than the OZR group (Fig. 4).
Fig. 4
ACR improvement rate at 52 weeks. In PSM-B, an indirect comparison was performed between the OZR + MTX group in the OHZORA trial and the OZR group in the NATSUZORA trial. OZR (30 mg) was administered once every 4 weeks. NRI, χ2 test, *p < 0.05. ACR American College of Rheumatology, NRI nonresponder imputation, MTX methotrexate, OZR ozoralizumab, PSM propensity score matching
×
A comparison of the SDAI, pain VAS, and HAQ-DI scores between groups based on longitudinal data analysis by the MMRM are shown in Fig. 5. The change in the OZR + MTX group tended to be greater than that in the OZR group, and significant differences were observed intermittently. Data for other evaluation items are shown in Supplementary Fig. S2.
Fig. 5
Between-group comparison of changes from baseline PSM-B. MMRM model, *p < 0.05, **p < 0.01, ***p < 0.001. The error bars represent the unadjusted mean ± standard deviation. HAQ-DI health assessment questionnaire disability index, MMRM mixed-effects model for repeated measures, MTX methotrexate, OZR ozoralizumab, PSM propensity score matching, Pain VAS patient’s pain assessment, SDAI simplified disease activity index
×
Safety
The safety profile of OZR has been previously reported [14‐16].
Discussion
The NATSUZORA trial was an open-label, uncontrolled study of OZR without MTX in patients with RA and an inadequate response (IR) or intolerance to csDMARD therapy. The results showed a marked improvement in the ACR20 response rate and other efficacy variables, including ACR50, ACR70, and DAS 28-CRP. In addition, the onset of drug efficacy was rapid, with most efficacy endpoints showing improvement after a week of treatment, which was maintained for up to 52 weeks [16]. The ACR20 response was comparable to the results of a trial that examined efficacy in combination with MTX [14], although clear comparisons were difficult because the NATSUZORA trial was an open trial without placebo control. In addition, the efficacy of the 24-week treatment was comparable to the efficacy of existing anti-TNF antibodies in Japanese patients treated without MTX [20‐22]. The results of the indirect comparison using these two PSMs suggested that the OZR group treated without concomitant MTX had better treatment efficacy than the placebo (MTX continuous treatment group) and that the OZR treatment group with MTX showed improved efficacy compared to the group without MTX.
First, in PSM-A, the OZR group showed a significantly better ACR improvement rate than the MTX group (Fig. 3). In particular, a threefold difference in ACR50 improvement rate and a more than twofold difference in ACR70 improvement rate were observed. In the longitudinal analysis, the change in each indicator obtained in the first week after administration was also significantly larger in the OZR group than in the MTX group (Fig. 4). The NATSUZORA trial enrolled patients with cs-DMARD (including MTX)-IR, while the OHZORA trial enrolled patients with MTX-IR. These results suggest that OZR treatment without MTX is more effective than MTX alone, although differences in target patients need be considered. Additionally, while the NATSUZORA trial did not obtain data for day 3, the results were considered consistent with the immediate response shown in the OHZORA trial [14].
Second, in PSM-B, the OZR + MTX group showed a higher improvement rate at 52 weeks than the OZR group. Although the difference in ACR20 was not significant, significant differences were observed in ACR50 and ACR70 (Fig. 4). In the longitudinal analysis using an MMRM, the between-group differences were small for some indexes (patient’s global assessment, physician’s global assessment, and TJC), but the changes tended to be greater in the OZR + MTX group for many indicators (Fig. 5, Supplementary Fig. S2). In the treatment of RA, a systematic review reported that although some bDMARDs have efficacy data as monotherapy, all classes of bDMARDs are more effective in combination with MTX [23]. For TNF inhibitors, the MTX combination group was superior in efficacy rate, remission rate, HAQ-DI, and inhibition of joint destruction in both studies targeting patients with early RA and those with MTX-IR [24‐26]. Similar to these reports, OZR also showed an additive effect of MTX concomitant use.
MTX has been reported to reduce the immunogenic risk of TNF inhibitors in combination therapy because of its immunosuppressive properties [27, 28]. In the NATSUZORA trial, some patients with positive neutralizing antibodies (NAb) have shown reduced efficacy [16]. Therefore, the incidence of antidrug antibodies (ADA) or NAb was compared in this analysis. A comparison of ADA and NAb expression rates in the extracted population (77 cases each) after matching showed no difference in ADA positivity rates. In contrast, the incidence of NAb positive patients was higher in the OZR group than in the OZR + MTX group (OZR group; 22.1% [17/77] vs. OZR + MTX group; 2.6% [2/77], p < 0.001) at 24 weeks and (OZR group; 29.9% [23/77] vs. OZR + MTX group; 11.7% [9/77], p = 0.009) at 52 weeks. The presence or absence of concomitant MTX may have affected the NAb positivity rate; however, as the efficacy difference was already observed at 4 weeks post-administration and sustained thereafter (Fig. 5, Supplementary Fig. S2), the contribution of NAb to the efficacy difference may be limited. Another mechanism for the combined effect of MTX and anti-TNF agents could be the suppression of TNF-producing cell proliferation by MTX. It has been shown that the simultaneous addition of MTX and anti-TNF agents to transmembrane TNF-expressing cells synergistically or additively promotes apoptosis [29], and a similar effect is expected for OZR.
There are several limitations of this post-hoc analysis. As explained in the “Methods” section, the data analyzed in this study were obtained from different clinical trial populations. In this study, a PSM with multiple covariates was performed to adjust for differences in the patient population. However, background adjustment may not be sufficient because of differences in patient inclusion criteria and measurement items. Specifically, the selection criteria for TJC, SJC, and CRP differed in the NATSUZORA trial and may have included patients with slightly milder diseases. In the NATSUZORA trial, there were no data on the usage of b-DMARDs, and poor prognostic factors such as rheumatoid factors, anti-citrullinated protein autoantibodies, and structural damage were not evaluated; therefore, these could not be incorporated as covariates. In addition, the OHZORA trial was conducted under conditions where no cs-DMARDs other than MTX were used concomitantly; therefore, the use of cs-DMARDs was not adjusted for. It is necessary to consider the possibility of bias due to the difference between blinded and unblinded outcomes. The sample size of the study was small, and sufficient statistical power may not have been obtained. Particularly in PSM-B, the loss of approximately half of the OZR + MTX group due to PSM was considered to be a major limitation.
Although the real-world clinical data on OZR should be further accumulated in the future, these data indicate that OZR has high efficacy in combination with MTX and may also be useful for patients who should avoid the use of MTX.
Conclusions
This post-hoc analysis, based on data from two clinical trials, showed that OZR without MTX showed more favorable therapeutic effects than placebo (continuation of MTX monotherapy) in patients with RA and cs-DMRAD-IR and could be an additional treatment option for patients who cannot receive MTX. In addition, OZR administration with MTX was more effective than non-MTX administration.
Acknowledgements
NANOBODY® is a registered trademark of Ablynx NV, an affiliate of Sanofi. Ablynx NV originally discovered and performed the initial development of the NANOBODY® compound ozoralizumab.
Medical Writing/Editorial Assistance
The authors thank the employees of Taisho Pharmaceutical Co., Ltd., for their support: Yuri Sato for study conception and design, Shunsuke Okamoto for assistance with statistical analysis, Masanao Kyuuma for reviewing the manuscript, and Isao Matsushita and Hironori Yamasaki for reviewing the statistical analysis described in the manuscript. The authors would like to thank Enago (www.enago.jp) for the English language review. This assistance was funded by Taisho Pharmaceutical Co., Ltd.
Author Contribution
All authors contributed to the study conception and design. Material preparation and data collection and analysis were performed by Yoshiya Tanaka, Cosmo Sasajima, Nobuko Horiuchi, Rumiko Matsumoto, and Masafumi Kawanishi. The study design and manuscript review were performed by Saeko Uchida, Tsutomu Takeuchi, and Yoshiya Tanaka. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The original clinical study of the data used for this analysis was conducted by Taisho Pharmaceutical Co., Ltd. In addition, the journal’s Rapid Service Fee was funded by Taisho Pharmaceutical Co., Ltd.
Data Availability
The data generated and/or analyzed during the current study that were used to support the findings of the study were supplied by Taisho Pharmaceutical Co., Ltd. Requests for access to these data should be made to the corresponding author.
Declarations
Conflict of Interest
Yoshiya Tanaka has received speaking fees and honoraria from AbbVie, Eisai, Chugai, Eli Lilly, Boehringer Ingelheim, GlaxoSmithKline, Taisho, AstraZeneca, Daiichi Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, and Astellas and has received research grants from Boehringer Ingelheim, Taisho, and Chugai. Yoshiya Tanaka is an editorial board member of Rheumatology and Therapy. Yoshiya Tanaka was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Tsutomu Takeuchi has received speaking fees from AbbVie, Chugai, Eisai, Eli Lilly Japan, Gilead Sciences, Pfizer Japan, and Taisho and consulting fees from AbbVie, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe, and Taisho. Nobuko Horiuchi, Cosmo Sasajima, Rumiko Matsumoto, Masafumi Kawanishi, and Saeko Uchida are employees of Taisho.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. All studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Each study was approved by the ethics committee at each research site, as described in the original papers [14‐16]. Written informed consent was obtained from all patients.
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