Ozoralizumab: first Nanobody® therapeutic for rheumatoid arthritis

ABSTRACT

Introduction

Ozoralizumab (Nanozora), a novel TNF inhibitor, was first approved in Japan in September 2022 as a next-generation antibody for the treatment of rheumatoid arthritis (RA). Ozoralizumab potently inhibits TNF action through two human TNFα-binding domains, and a human serum albumin-binding domain that prolongs its plasma half-life enabling 4-week administration intervals. Its molecular weight is 38 kDa, which is one-fourth that of the conventional immunoglobulin G.

Areas covered

Structural characteristics of ozoralizumab, preclinical findings, clinical data, and its recommended positioning in current RA treatments have been summarized.

Expert opinion

Studies using mouse models have shown the rapid distribution of ozoralizumab in inflamed joint tissues, presumably because of its small molecular size and albumin-binding action. In clinical studies, remarkable improvements in clinical symptoms and patient-reported outcomes were observed 2 days after subcutaneous administration of 30 mg ozoralizumab with concurrent methotrexate therapy. Moreover, the efficacy and tolerability of the drug for up to 52 weeks, with or without methotrexate, were confirmed. Ozoralizumab is expected to be a highly practical option for patients with RA as a new type of TNF inhibitor with early symptom improvement despite subcutaneous administration.

KEYWORDS:

• Antirheumatic agent
• ozoralizumab
• rheumatoid arthritis
• tumor necrosis factor
• VHH

1. Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent joint inflammation, synovial hyperplasia, and progressive destruction of the bone and cartilage [1]. Tumor necrosis factor (TNF) α is a pleiotropic cytokine that activates signaling pathways involved in cell survival, apoptosis, inflammatory response, and cell differentiation and is involved in various inflammatory diseases, including RA [2,3]. In the treatment of RA, anti-TNFα antibodies have made it possible to induce remission in many patients and, by maintaining remission, almost completely prevent the progression of joint damage and physical dysfunction, revolutionizing the treatment of RA [4,5]. Since 1998, five TNF inhibitors, including infliximab, have been approved and are currently available [4,5]. Ozoralizumab (Nanozora) is a novel, next-generation TNF inhibitor with variable heavy-chain domains of heavy-chain-only antibody (VHHs), also called Nanobody® molecules. Members of the family Camelidae, including the llama, produce heavy-chain-only antibodies that lack light chains, and VHHs are small antibodies that function as antibodies even as single molecules. Ozoralizumab was discovered and initially developed by Ablynx NV, an affiliate of Sanofi. Nanobody® is a registered trademark of Ablynx NV. Ozoralizumab has been approved in Japan for the treatment of RA in patients with inadequate responses to conventional treatment; the recommended dose is 30 mg administered subcutaneously every 4 weeks [6,7].

2. Overview of the market

A treatment-to-target strategy aimed at achieving rapid clinical remission after diagnosis has been proposed to treat RA [8]. The European League Against Rheumatism (EULAR) recommendations and American College of Rheumatology guidelines strongly recommend remission induction as a realistic treatment goal for patients [9,10]. In drug therapy for RA, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate (MTX), are the first choice of treatment. Biologic DMARDs (bDMARDs), such as TNF inhibitors, interleukin 6 (IL-6) inhibitors, and Janus kinase (JAK) inhibitors, which are targeted synthetic DMARDs (tsDMARDs), have been recommended for patients with an inadequate response to csDMARDs.

Despite the availability of multiple bDMARDs and JAK inhibitors, clinical remission is achieved in only 20–40% of patients [1,11]. Patients with inadequate response to prior treatments include those with primary failure, secondary failure, inadequate response, and intolerance. There is a need for drugs that are highly efficacious, less prone to secondary failures, and well-tolerated by such patients. TNF inhibitors are the most commonly used bDMARDs for RA because of their well-balanced efficacy and safety based on long-term use. For this reason, TNF inhibitors are often preferred over JAK inhibitors. The EULAR also recommends switching to a second TNF inhibitor in patients who do not respond to a first one [9]. Therefore, novel TNF inhibitors with different structures are still needed.

3. Introduction to the compound

3.1. Structural characteristics

Camelids, including llamas, produce heavy-chain-only antibodies without light chains [12,13]. The variable domains of heavy-chain of the heavy-chain-only antibody (VHHs) functions as an antibody even as a single molecule [13]. Because VHHs are relatively small molecules (12–15 kDa, approximately 1/10 that of immunoglobulin G [IgG]), they can bind to targets that conventional IgGs cannot approach, such as the active regions of enzymes and clefts in cell membranes. In addition, small molecules can simultaneously bind to multiple epitopes of the same target molecule or conjugate to different or the same VHHs. Besides, VHHs can be produced in systems such as Escherichia coli, reducing their production cost [14,15]. In addition to injections, pulmonary and nasal dosing have been considered as new routes of administration. Recently, orally administered VHH antibodies have been reported to reach the mucus of the large intestine and suppress inflammation [16,17]. The first VHH drug, caplacizumab, an anti-von Willebrand factor VHH antibody, was approved for the treatment of acquired thrombotic thrombocytopenic purpura in Europe (August 2018), United States (February 2019), and Japan (September 2022) [18,19].

Ozoralizumab, the first drug to be approved as a bispecific VHH antibody, consists of two human TNFα-binding domains and one human serum albumin (HSA)-binding domain linked by glycine-serine linkers composed of nine amino acids. Ozoralizumab consists only of variable domains and has no Fc regions (Figure 1). Many existing therapeutic antibodies, including anti-TNF antibodies, have an IgG structure and recognize antigens or drug targets with six complementarity determining regions (CDRs) (heavy and light chains). However, ozoralizumab differs from IgG antibodies in that it can recognize and bind to drug targets using three CDRs from one Nanobody® molecule [7].

Figure 1. Schematic representation of a conventional IgG antibody, heavy-chain-only antibody, and ozoralizumab.

Note: CH, constant domain of heavy chain; HSA, human serum albumin; IgG, immunoglobulin G; TNF, tumor necrosis factor; VH, variable domain of heavy chain; VHH, variable domain of heavy-chain of heavy-chain antibody; VL, constant domain of light chain.

An immunoglobulin single-variable domain phage library derived from llama H-chains was used to create ozoralizumab. Highly functional VHH chains were selected and humanized to create anti-TNFα-VHH and anti-HSA-VHH. A gene expression construct was generated by connecting two anti-TNFα VHHs and one anti-HSA-VHH via nine glycine-serine sequences. Ozoralizumab is produced using Chinese hamster ovary (CHO) cells [6] (Box 1).

3.2. Pharmacology

Ozoralizumab binds to human and rhesus TNFα with high affinity and K_d values of 20.2 and 16.1 pmol/L, respectively. However, the affinity of ozoralizumab for TNFα in rodents, such as mice, rats, and rabbits, was too low to determine the K_d values, as is the case with many antibody drugs. In addition, ozoralizumab binds to membrane-bound TNFα. With respect to the inhibition of anti-TNFα action in vitro, ozoralizumab inhibited human and rhesus TNFα-induced L929 cell death in a concentration-dependent manner, with IC₅₀ values of 22.5 and 9.6 pmol/L, respectively, and the inhibitory effect was more potent than that of etanercept, adalimumab, and infliximab. For inhibition of anti-TNFα action in vivo, ozoralizumab was shown to significantly inhibit the increase in the total number of infiltrated cells and neutrophils when administered at doses of 0.125 mg/kg or higher in a mouse air pouch model of inflammation. In human TNF-transgenic mice, ozoralizumab significantly suppressed macroscopic and histopathological arthritis scores at doses of 0.3 mg/kg or higher. Regarding antibody effector functions, ozoralizumab did not induce antibody-dependent cell-mediated cytotoxicity (ADCC) in membrane-bound TNFα-expressing NS0 mouse bone marrow-derived cells. In addition, ozoralizumab did not induce complement-dependent cytotoxicity (CDC) in membrane-bound TNFα-expressing CHO cells. Because ozoralizumab lacks an Fc region, it does not induce ADCC or CDC activities [20]. Furthermore, ozoralizumab markedly inhibited the progression of arthritis in a secondary failure animal model created by repeated administration of anti-TNFα IgG (adalimumab) to human TNF-transgenic mice. Given that ozoralizumab has a different structure from IgG-type antibodies, its potential as an effective treatment in cases of secondary failure of anti-TNFα therapy was suggested [7].

3.3. Binding to albumin

Ozoralizumab, with its HSA-binding domain, has two main advantages in RA treatment. The first is the potential reduction in renal excretion and possible prolongation of the plasma half-life. The second is the possible enhancement of drug distribution at the inflammatory sites by utilizing the accumulation of albumin in inflammatory tissues. Albumin binding effectively extends the half-life of small antibodies [21,22]. Ozoralizumab has a high binding affinity for human and rhesus serum albumin, with K_d values of 4.28 and 4.46 nmol/L, respectively [20]. The affinity of ozoralizumab for mouse and rat serum albumin is lower than that for humans. The plasma half-life of ozoralizumab in mice, cynomolgus monkeys, and humans is approximately 2, 7–10, and 18 days, respectively, reaching the same level as that of serum albumin in each species [20,23]. The distribution of the mouse surrogate antibody of ozoralizumab to inflammatory sites in arthritis model mice is reported to be improved through albumin binding, thus enhancing efficacy [24]. Furthermore, in fluorescence imaging studies of inflamed joints in a mouse model of collagen-induced arthritis, subcutaneous administration of fluorescently labeled ozoralizumab resulted in a higher fluorescence intensity in the extremities and a higher level of distribution at the inflammatory site than for adalimumab treatment (Figure 2) [25].

Figure 2. Distribution of ozoralizumab or adalimumab after a single subcutaneous injection in collagen-induced arthritis mice. Fluorescently labeled drug with Alexa 680 was administered at a dose of 2 mg/kg, respectively, and whole-body biofluorescent images were acquired. Fluorescence intensities are represented on a false scale, with blue indicating low intensity and red indicating high intensity. Reproduced from [25], © 2022 Oyama et al., licensed under CC by 4.0.

3.4. Pharmacokinetics

After a single subcutaneous administration of ozoralizumab at a clinical dose of 30 mg in combination with MTX in Japanese patients with RA, the plasma drug concentration reached its maximum level (C_max) after 6 days (t_max) [23]. The authors reported that the concentration then gradually decreased, with a half-life of 18.2 days; the C_max was 4.6 ± 1.2 μg/mL, and the AUC_0-∞ was 3,280 ± 1,280 h·μg/mL. The clearance (CL/F) was 10.4 mL/h, and the volume of distribution (V/F) was 5.9 L. In the same study, after repeated subcutaneous administration of 30 mg every 4 weeks, a steady state was reached by week 16, and the trough concentration was approximately 2 μg/mL, which was stably maintained through week 52. Among the TNF inhibitors, ozoralizumab has the lowest clearance [26–30] and the longest elimination half-life [26–29,31], which is comparable to that of human serum albumin (approximately 20 days), suggesting high plasma retention (Table 1). Thus, the HSA-binding domain of ozoralizumab appeared to contribute to its reduced clearance.

Table 1. Structure and pharmacokinetic parameters of TNF inhibitors in the treatment of rheumatoid arthritis.

TNF inhibitors	Ozoralizumab	Infliximab	Adalimumab	Golimumab	Etanercept	Certolizumab pegol
Structure	Humanized VHH antibody	Chimeric antibody	Fully human antibody	Fully human antibody	Receptor-Fc fusion protein	PEGylated humanized Fab′ fragment
Molecular size (kDa)	38	149	148	150	150	90
Dose^a (mg)	30	300^b	40	50	10	400
Injection route	Subcutaneous	Intravenous	Subcutaneous	Subcutaneous	Subcutaneous	Subcutaneous
t1/2 (day)	18.2	11.6	12.4	11.9	3.3	10.7
CL/F (mL/h)	10.4	11.0^c	22.1	38.0^b	144	28.5^d
Reference	[23]	[26]	[27]	[28]	[29]	[30,31]

Note: Pharmacokinetic parameters in Japanese subjects were presented for comparison with ozoralizumab.

^apharmacokinetic study dose, ^bconverted with the body weight 60 kg, ^cclearance, ^dpopulation pharmacokinetic result in a predominantly Caucasian population,^estudy conducted in the U.S.A.

CL/F, apparent clearance; Fab′, fragment antigen-binding; Fc, fragment crystallizable; PEG, polyethylene glycol; t_1/2, plasma elimination half-life; TNF, tumor necrosis factor; VHH, variable domain of heavy-chain of heavy-chain antibody.

4. Clinical efficacy

4.1. Phase II/III (OHZORA trial)

In the OHZORA trial [32,33], the efficacy of subcutaneous administration of ozoralizumab every 4 weeks for 52 weeks under concomitant use of MTX was investigated in patients with active RA who had an inadequate response to MTX. This trial was a multicenter, randomized, parallel-group study consisting of a double-blind period and an open-label period. A total of 381 patients were enrolled in the clinical trial and assigned to treatment groups (ozoralizumab 30 mg, 80 mg, or placebo) in a 2:2:1 ratio during the double-blind period. During the open-label period, patients in the placebo and ozoralizumab 30 mg groups who showed an inadequate response were reassigned to the 30 mg and 80 mg groups, respectively.

The American College of Rheumatology 20% (ACR20) response rate at week 16, one of the primary endpoints, was 79.6% and 75.3% in the ozoralizumab 30 mg and 80 mg groups, respectively, indicating a significant improvement compared with 37.3% in the placebo group. The ACR50/70 response rates also showed significant improvement compared with that in the placebo group. These improvements were observed immediately after administration and were significant compared with those of the placebo group from week 1, the first evaluation time point after administration at 30 mg. The efficacy of ozoralizumab was maintained until week 52 (Figure 3).

Figure 3. The American College of Rheumatology (ACR) 20/50/70 response rates up to week 52 in the OHZORA trial. (a) Response rates for ACR20, ACR50, and ACR70 at week 52 (last observation carried forward). (b) Changes in ACR20, (c) ACR50, and (d) ACR70 over time (observed data without imputation). Adapted with permission of Oxford University Press on behalf of the Japan College of Rheumatology from [33], © 2022 Japan College of Rheumatology, licensed under CC-BY-NC.

The changes from baseline in the modified total sharp score (ΔmTSS) at week 24, the other co-primary endpoint, showed no significant difference between the ozoralizumab 30 mg or 80 mg groups and the placebo group. In contrast, the proportion of patients with no progression of structural damage (ΔmTSS ≤0) at week 24 was significantly smaller in the ozoralizumab 30 mg and 80 mg groups than that in the placebo group (Figure 4).

Figure 4. Progression of structural damage (EXTRAP) in the OHZORA trial. Cumulative probability of change in mTSS at week 24 compared with baseline values. Percentages indicate rates of non-progression (ΔmTSS ≤0) in each treatment group. P values were calculated by the chi-square test without continuity correction or multiplicity adjustment. mTSS, modified total sharp score; MTX, methotrexate. Reproduced with permission from [32], © 2022 Takeuchi et al., licensed under CC BY-NC 4.0.

For secondary endpoints, including disease activity scores such as the simplified disease activity index　(SDAI) or clinical disease activity index (CDAI), patient-reported outcomes (PROs) such as patient pain visual analogue scale (VAS), and inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP), significant improvements were observed in the ozoralizumab 30 mg and 80 mg groups 2 days after the administration compared with those in the placebo group, with rapid improvement and efficacy maintained up to week 52.

4.2. Phase III: NATSUZORA trial

In the NATSUZORA trial [34], the efficacy of subcutaneous administration every 4 weeks for 52 weeks without MTX was investigated in patients with active RA who discontinued csDMARDs because of poor response or tolerability. This trial was designed as a multicenter, randomized, open-label study. A total of 140 patients were assigned to the ozoralizumab 30 mg or 80 mg group in a 2:1 ratio.

In both groups, the ACR response rate rapidly increased at week 1, the first evaluation time point after administration, and the response was maintained until week 52 (Figure 5). Similar trends were observed for other efficacies and inflammatory markers. Although improvement in PROs and some measures tended to be higher in the ozoralizumab 80 mg group than in the 30 mg group, there were no dose-related differences in the number of tender or swollen joints, physician’s global VAS, or hs-CRP, indicating that the two different doses were equally effective. Moreover, a subgroup analysis was conducted to assess the ACR20 response rates in patients receiving ozoralizumab monotherapy or in combination with csDMARDs. At week 52 in the ozoralizumab 30 mg and 80 mg groups, the ACR20 response rates in monotherapy patients were 79.1% and 80.0%, respectively, and those in patients with csDMARDs were 68.0% and 80.0%, respectively. The effect in the monotherapy group was equal to or greater than that in the csDMARD combination group [20].

Figure 5. Rates of the American College of Rheumatology (ACR) improvement up to week 52 in the NATSUZORA trial. Changes in ACR20 (a), ACR50 (b), and ACR70 (c) over time (actual observations). Adapted with permission of Oxford University Press on behalf of the Japan College of Rheumatology from [34], © 2022 Japan College of Rheumatology, licensed under CC BY-NC 4.0.

5. Safety and tolerability

In the OHZORA trial [32,33], the most common adverse events reported by week 52 was infection. The only fatal adverse event was disseminated tuberculosis in the ozoralizumab 80 mg group. The non-fatal serious adverse events were 8.4%, 5.8% and 11.1% in the ozoralizumab 30 mg, 80 mg groups and the group shifted from 30 mg to 80 mg during the trial, respectively, with most adverse events being mild-to-moderate in severity. In the NATSUZORA trial [34], the most common adverse event was infection. No adverse events led to death, and the incidence of serious adverse events was 13.8% in the 30 mg group and 15.2% in the 80 mg group. Most adverse events were mild-to-moderate in severity. Compared with other anti-TNFα agents, ozoralizumab was associated with no new adverse events of concern up to week 52 in either the OHZORA or NATSUZORA trials.

During the OHZORA trial with MTX, anti-ozoralizumab antibodies increased in 27.3% and 31.1% of patients in the 30 mg and 80 mg groups, respectively, and neutralizing antibodies were detected in 7.5% and 6.8% of patients in the 30 mg and 80 mg groups, respectively. During the NATSUZORA trial without MTX, anti-ozoralizumab antibodies increased in 46.8% and 39.1% of the patients in the 30 mg and 80 mg groups, respectively, and neutralizing antibodies were detected in 27.7% of the patients in the 30 mg group. In the 80 mg group, one patient (2.2%) was positive for neutralizing antibodies. Although the presence of anti-ozoralizumab antibodies was not associated with consistent efficacy or safety, a trend toward reduced efficacy was observed in some neutralizing antibody-positive patients in the 30 mg group in the NATSUZORA trial.

6. Regulatory affairs

In September 2022, ozoralizumab was approved in Japan for treating RA in patients with an inadequate response to conventional treatment at a subcutaneous dose of 30 mg every 4 weeks [6].

7. Conclusion

Ozoralizumab, a bispecific Nanobody® drug, demonstrated high affinity for TNFα and favorable pharmacokinetics in humans, allowing its administration at 4-week intervals in patients with RA. In Japanese clinical studies, the administration of 30 mg ozoralizumab, with or without MTX, resulted in the rapid improvement of clinical symptoms and its effect was maintained for up to 52 weeks.

8. Expert opinion

8.1. What, if any, advantage does the drug present over other therapies?

Given that ozoralizumab is a VHH antibody with an HSA binding domain, it is expected to be rapidly absorbed into the blood and transferred to inflamed tissues following subcutaneous administration. For example, in the OHZORA trial, improvements in inflammatory markers, clinical symptoms, and physical functions were observed 2 days after the subcutaneous administration of 30 mg ozoralizumab in patients with RA with insufficient MTX effects [32,33]. Ozoralizumab has a relatively long half-life of 18 days. In contrast to other biologics used in the treatment of RA, which are administered at 1- to 2-week intervals or require a loading dose, ozoralizumab is effective at an administration interval of 4 weeks [32–34]. Because ozoralizumab lacks an Fc region, it is expected to be less immunogenic than IgG-type antibodies, and the injection site reaction was confirmed to be as low as 1.4% in the two studies [20]. Because the subcutaneous injection volume of ozoralizumab is 0.375 mL, which is less than that of other TNF inhibitors, it is expected to cause less pain upon injection. In addition, the ozoralizumab dose is constant regardless of the presence or absence of MTX, making it an extremely convenient subcutaneous injection for the treatment of RA.

8.2. What, if any, impact is this drug likely to have on current treatment strategies?

Ozoralizumab showed rapid improvement in measures of disease activity, namely SDAI or CDAI, PROs (in particular, VAS), and inflammatory markers such as hs-CRP [32,34]. As patients with RA expect early improvement [35], I believe that ozoralizumab can be the first choice of TNF inhibitors or bDMARDs. In addition, ozoralizumab would also be the second drug of choice for secondary failure of TNF inhibitors and would eliminate the need to switch to drugs with another mode of action, given the rapid effect of ozoralizumab and the fact that it has different structural characteristics from other TNF inhibitors. Furthermore, because ozoralizumab can be administered at the same dose with or without concomitant MTX, dose reduction or discontinuation of MTX can be considered in patients who cannot tolerate MTX because of advanced age.

8.3. What data is still needed?

In non-clinical studies, ozoralizumab, a VHH antibody with an HSA-binding domain, was confirmed to be distributed more quickly to inflamed joints than IgG-type antibodies [25]. Thus, clinical data show a rapid transition of the drug to the synovial fluid in the inflamed joints are desired. Because serum albumin has a short lifespan in rodents, it is of interest whether the inflammatory site concentration persists in humans. In addition, the efficacy of ozoralizumab was confirmed in secondary failure model animals to which IgG-type TNFα inhibitors were repeatedly administered [7]. It would also be useful to confirm the efficacy of ozoralizumab in patients with secondary failures of other bDMARDs and in patients with inadequate responses to JAK inhibitors. Based on these characteristics, it would be beneficial to analyze the physiological traits of patients who are suitable for ozoralizumab and those who show a rapid response. The lack of a significant difference in the change from baseline in mTSS between the placebo and ozoralizumab groups at week 24 in the OHZORA trial may be partly explained by a decrease in the progression of joint destruction in the patient population of the trial owing to recent improvements in RA treatment [36–38]. As it has been suggested that ozoralizumab may inhibit the progression of structural joint damage [32], the long-term suppressive effect of the drug should be confirmed through additional clinical trials with extended evaluation periods and an enhanced study design, such as a larger study population. Although there is sufficient experience in treating RA with TNF inhibitors, ozoralizumab is a drug with a novel structure. Therefore, it is necessary to collect long-term efficacy and safety data after its launch in real-world clinical settings. A long-term extension study (NCT04077567; JapicCTI-194932) is currently being conducted in patients with favorable clinical courses.

8.4. Where is ozoralizumab likely to be in 5 years?

Ozoralizumab will probably be used in bDMARDs for patients with RA who require an immediate response, and in patients with secondary failure of conventional TNF inhibitors. In the future, the indications for ozoralizumab may be expanded to match those of other TNF inhibitors by exploiting the characteristics of the VHH antibody. In addition, if this drug is successful, it is possible that VHH antibodies will become the mainstream antibody therapy in the future, particularly considering the relative ease and low cost of these drugs.

Box 1. Drug summary box

Drug name Ozoralizumab

Phase Approved (in Japan)

Indication Rheumatoid arthritis

Pharmacology description/mechanism of action Inhibition of theinteraction between TNFα and TNF receptor

Chemical structure 363 amino acids, 38 kDa, trivalent variable domains of heavy-chain of heavy-chain-only antibody consisting of two anti-TNFα fragments and one anti-HSA fragment

Pivotal trials OHZORA [32, 33]

List of abbreviations

Abbreviation	=	Definition
ACR	=	American College of Rheumatology
ACR20/50/70	=	ACR 20%/50%/70% response rate
ADCC	=	antibody-dependent cell-mediated cytotoxicity
AUC0-∞	=	area under the curve
bDMARD	=	biologic disease-modifying antirheumatic drug
CDAI	=	clinical disease activity index
CDC	=	complement-dependent cytotoxicity
CDR	=	complementarity determining region
CHO	=	Chinese hamster ovary
Cmax	=	maximum concentration
CL/F	=	apparent clearance
csDMARD	=	conventional synthetic disease-modifying antirheumatic drug
EULAR	=	European League Against Rheumatism
HSA	=	human serum albumin
hs-CRP	=	high-sensitivity C-reactive protein
IC50	=	50% inhibition concentration
IgG	=	immunoglobulin G
IL-6	=	interleukin 6
JAK	=	Janus kinase
L929	=	mouse fibroblast cell line
mTSS	=	modified total sharp scor
MTX	=	methotrexate
NATSUZORA	=	A Phase III study of ozoralizumab in patients with active rheumatoid arthritis wihtout methotrexate therapy
NS0	=	mouse myeloma cell line
OHZORA	=	A phase II/III study of ozoralizumab in patients with active rheumatoid arthritis who have had an inadequate response to methotrexate therapy
PRO	=	patient reported outcome
RA	=	rheumatoid arthritis
SDAI	=	simplified disease activity index
tmax	=	time to Cmax
TNF	=	tumor necrosis factor
tsDMARD	=	targeted synthetic disease-modifying antirheumatic drug
VAS	=	visual analogue scale
V/F	=	apparent volume of distribution
VHH	=	variable domain of heavy-chain of heavy-chain antibody

Article highlights

• Ozoralizumab is the first Nanobody® drug for rheumatoid arthritis.

• It has a long plasma half-life of 18 days because of its ability to bind albumin.

• Owing its small molecular size and ability to bind to albumin, it has a high distribution rate to inflammation sites, so its effect appears quickly.

• The improvement rate was equal to or greater than that of other TNF inhibitors and was maintained up to 52 weeks.

• Low immunogenicity caused by the lack of Fc region.

Declaration of Interest

Y Tanaka has received speaking fees and/or honoraria from Abbvie, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Pfizer, Taiho and Tisho and has received research grants from Chugai, Eisai, Taisho and Tanabe-Mitsubishi. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Taisho Pharmaceutical Co., Ltd.