Peficitinib for the treatment of rheumatoid arthritis: an overview from clinical trials

ABSTRACT

Introduction

The treatment of rheumatoid arthritis (RA), a chronic, systemic, autoimmune disease, has been greatly advanced by the introduction of biologic disease-modifying antirheumatic drugs (DMARDs); however, many patients still fail to achieve disease remission. Peficitinib, an orally bioavailable inhibitor of the Janus kinase (JAK) receptor family, was approved in Japan in 2019 and Korea in 2020 for the treatment of RA.

Areas covered

This review provides an overview of JAK inhibitors currently marketed or in development; the pharmacodynamics and pharmacokinetics of peficitinib; and the efficacy and safety data for peficitinib from Phase 2b and 3 trials.

Expert opinion

Peficitinib has proven clinical efficacy in Asian patients (Japan, Korea, and Taiwan) with RA who have an inadequate response to conventional DMARDs. In Phase 3 trials, clinical improvements and prevention of joint destruction were demonstrated for both 100 mg and 150 mg once-daily peficitinib versus placebo, and treatment for up to 52 weeks was well tolerated. Safety signals, in particular the increased incidence of herpes zoster-related disease, appeared in line with other JAK inhibitors. Post-launch monitoring will establish the long-term safety and effectiveness of this drug, and further studies are necessary to determine its potential use in non-Asian populations.

KEYWORDS:

• Clinical studies
• Janus kinase (JAK) inhibitor
• peficitinib
• pharmacokinetics
• rheumatoid arthritis

1. Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, joint destruction, and organ manifestation [1,2]. Methotrexate (MTX), a conventional synthetic disease-modifying antirheumatic drug (csDMARD), is the standard first-line therapy for RA [3] and is often considered an anchor drug both alone and in combination with other medications [4]. In patients with an inadequate response to MTX and/or other csDMARDs, biologic DMARDs (bDMARDs) such as tumor necrosis factor (TNF) inhibitors have proven effective in reducing RA symptoms and slowing disease progression [5,6]. Biologic DMARDs have also proven more effective at preventing structural joint damage compared with csDMARDs [7]. However, there remains a significant unmet need for new, clinically effective therapies [6], as one-third of patients treated with bDMARDs are intolerant to or have an inadequate response to therapy [8].

The Janus kinase (JAK) family of non-receptor protein tyrosine kinases, which includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), is involved in cytokine signal transduction by associating with the intracellular domains of cytokine or growth factor receptors involved in immune responses, inflammatory reactions, and hematopoiesis [9,10]. Increased expression of JAKs and their target substrates, signal transducers and activators of transcription (STATs), is seen in the synovium of patients with RA [11–13]. JAKs are therefore considered to be a promising target for RA treatment [10,14–17].

2. Overview of current JAK inhibitors

Currently approved JAK inhibitors include tofacitinib (licensed in more than 80 countries worldwide [18]), baricitinib (over 55 countries [19]), peficitinib (Japan and Korea [20–22]), and upadacitinib (30 countries [23–25]) [26,27]. Tofacitinib (Xeljanz®, Pfizer [28]) is a potent selective JAK inhibitor that preferentially inhibits JAK1 and JAK3 [26,29]. It is effective in both MTX-naïve patients [30] and those with an inadequate response to MTX and other DMARDs, including TNF inhibitors [31]. Baricitinib (Olumiant™, Eli Lilly [32]), the second drug launched as a JAK inhibitor for RA [33], is predominantly a JAK1/2 inhibitor [34] and Phase 3 trials showed rapid and significant clinical outcomes following baricitinib treatment [35]. Peficitinib (ASP015K, Smyraf®, Astellas Pharma), a pan-JAK inhibitor, has been approved for clinical use in Japan and Korea [20–22] and is in late-stage clinical development as an RA treatment in other Asian countries (Box 1) [40,41]. Upadacitinib (ABT-494, Rinvoq™, AbbVie [23]) is a selective JAK1 inhibitor [42,43]. It has demonstrated efficacy as both combination therapy and monotherapy in clinical trials [44–46] and has been approved in the US, Japan, and the European Union (including the UK) [23–25].

Other oral JAK inhibitors that have completed Phase 2 or Phase 3 trials include filgotinib and decernotinib. Filgotinib (GLPG0634, Gilead) is a selective JAK1 inhibitor that has shown clinical efficacy during Phase 3 trials in RA [47–49]. A Marketing Authorization Application for filgotinib for the treatment of adults with RA is now under evaluation by the European Medicines Agency [50], and a New Drug Application has been submitted to the Japanese Ministry of Health, Labor and Welfare [51]. Decernotinib (VX-509, Vertex Pharmaceuticals Incorporated) was a selective JAK3 inhibitor tested for treatment of RA in Phase 2 and 3 studies but has been discontinued due to safety concerns [52].

3. Introduction to peficitinib

3.1. Pharmacodynamics

In vitro kinase assays show that peficitinib is a pan-JAK inhibitor, inhibiting JAK activity with half maximal inhibitory concentrations (IC₅₀) of 3.9 nM (JAK1), 5.0 nM (JAK2), 0.7 nM (JAK3), and 4.8 nM (TYK2) [29]. Peficitinib prevented IL-2-induced human T-cell proliferation, which involves JAK1/3, with 14-fold greater potency than against erythropoietin-induced proliferation of the human erythroleukemia cell line TF-1, which involves JAK2 activity [53]. This lower inhibition of JAK2 compared with JAK1/3 may reduce the incidence of adverse hematopoietic effects associated with JAK2 inhibition [9,54].

Peficitinib inhibited IL-2-induced human T-cell proliferation (IC₅₀ 18 nM) and STAT5 phosphorylation (IC₅₀ 127 nM) in a concentration-dependent manner [29,53]. In a rat model of adjuvant arthritis, peficitinib administered prophylactically (at the same time as the adjuvant) dose-dependently suppressed both paw swelling and bone destruction, which were almost completely ameliorated at the highest dose (30 mg/kg). When used therapeutically in established disease, peficitinib suppressed paw swelling in a dose-dependent manner, improved body weight, and significantly reduced radiological bone destruction score [29].

Box 1. Drug summary.

Drug name	Peficitinib hydrobromide
Phase	Approved in Japan and Korea
Indication	Rheumatoid arthritis
Pharmacology description/MOA	JAK inhibitor
Route and frequency of administration	Oral, once daily
Chemical name	4-{[(1R,2s,3S,5s,7s)-5-Hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide monohydrobromide
Chemical structure
Pivotal trials
RAJ1 [36]	A 12-week, double-blind, Phase 2b trial in Japanese patients with active rheumatoid arthritis not receiving concomitant DMARD therapy. Treatment with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg once daily or placebo
RAJ3 [37]	A randomized, double-blind, Phase 3 trial in patients who had an inadequate response to prior DMARD treatment. Patients from Japan, Korea, and Taiwan were randomized to 52 weeks’ treatment with peficitinib 100 mg or 150 mg once daily (alone or in combination with csDMARDs), placebo, or open-label etanercept
RAJ4 [38]	A randomized, double-blind, Phase 3 trial in patients who had an inadequate response to methotrexate. Patients from Japan were randomized to 52 weeks’ treatment with peficitinib 100 mg or 150 mg once daily, or placebo, in combination with methotrexate
RAJ2 [39]	An open-label extension study of patients from RAJ1, RAJ3, and RAJ4 to assess safety and effectiveness of peficitinib

Peficitinib inhibited IL-2-induced human T-cell proliferation (IC₅₀ 18 nM) and STAT5 phosphorylation (IC₅₀ 127 nM) in a concentration-dependent manner [29,50]. In a rat model of adjuvant arthritis, peficitinib administered prophylactically (at the same time as the adjuvant) dose-dependently suppressed both paw swelling and bone destruction, which were almost completely ameliorated at the highest dose (30 mg/kg). When used therapeutically in established disease, peficitinib suppressed paw swelling in a dose-dependent manner, improved body weight, and significantly reduced radiological bone destruction score [29].

3.2. Pharmacokinetics and metabolism

3.2.1. Peficitinib exposure

At the time of writing, there were few published pharmacokinetic studies and most pharmacokinetic data are therefore derived from publicly available documents.

Peficitinib is absorbed rapidly: after a single dose under fasting conditions, median time to maximum plasma concentration (t_max) was 1.0–1.8 h [55]. The maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC) both showed dose proportionality [55]. Peficitinib can be taken at any time of day but is administered with a meal [20]. After a single oral dose of peficitinib 150 mg was administered in healthy Japanese adults (18 subjects), fed-state administration resulted in a 56.4% increase in C_max and a 36.8% increase in the area under the plasma concentration–time curve from time zero to time of last measurable concentration (AUC_last), compared with fasted-state administration [20]. Following multiple oral doses of peficitinib 150 mg once daily in healthy Japanese adults (24 subjects) after a meal, peficitinib plasma concentrations reached a steady state on day 3; steady-state C_max and area under the plasma concentration–time curve over 24 h (AUC_24 h) were 613.2 ng/mL and 2643 ng·h/mL, respectively; and the median (min, max) t_max was 3.0 h (1.5, 4.0) [56]. The accumulation ratio in the steady-state to post single-dose administration was 1.2 [20].

An in vitro study showed that the binding rate of peficitinib to plasma proteins, of which the main protein was albumin, was 72.8–75.2% [20]. Peficitinib metabolism is mediated mainly by sulfotransferase 2A1 and nicotinamide N-methyltransferase [57]. After a single oral administration of ¹⁴C-labeled peficitinib to healthy Caucasian subjects, the area under the plasma concentration–time curve from time 0 to infinity (AUC_inf) of metabolites accounted for 67% of total radioactivity in plasma, and approximately 50% of the dose was excreted as metabolites [57]. In urine, 14% of the peficitinib dose was excreted as the unchanged form [57]. While peficitinib is mostly cleared by metabolism, peficitinib is also cleared by other mechanisms (renal and possibly biliary excretion) [57].

3.2.2. Interaction studies

As patients with RA often require combination DMARD therapy, usually with MTX, drug interaction studies were key to establishing peficitinib as a viable therapeutic option for RA. Co-administration of peficitinib with MTX did not affect the pharmacokinetic profile of either drug in a patient setting [58].

Peficitinib is a substrate of P-glycoprotein and co-administration of peficitinib with the P-glycoprotein inhibitor verapamil was found to increase mean peficitinib C_max by 39% and mean AUC_inf by 27% [59]; however, peficitinib co-administration with verapamil was generally well tolerated [59], and the increase in exposure is considered not clinically significant. Peficitinib has also been found to inhibit the organic anion transporting polypeptide 1B1 (OATP1B1), a hepatic uptake membrane transporter, and peficitinib co-administration with the OATP1B1 substrate rosuvastatin led to a 15% increase in rosuvastatin C_max and 18% increase in AUC; however, these differences were not considered clinically meaningful [60]. Co-administration of peficitinib with the CYP3A substrate midazolam increased the C_max of midazolam by 13% and the AUC by 37% [20]; however, this change may also not be clinically relevant.

Phase 1 studies have been conducted to assess the impact of renal and hepatic impairment on peficitinib pharmacokinetics in Japanese subjects. Following a single dose of peficitinib 150 mg, the AUC_inf geometric mean ratios (GMR) in subjects with mild, moderate, and severe renal impairment versus subjects with normal renal function were 0.87 (90% confidence interval [CI] 0.61–1.25), 0.83 (90% CI 0.58–1.19), and 1.09 (90% CI 0.74–1.60), respectively [61]. Thus, peficitinib plasma concentration does not appear to be significantly affected by impaired renal function.

In a comparison of subjects with moderate hepatic impairment versus subjects with normal hepatic function, receiving a single dose of peficitinib 150 mg, the AUC_inf GMR was 1.92 (90% CI 1.39–2.66) [62]. A reduced peficitinib dose of 50 mg once daily is therefore recommended in patients with moderate hepatic impairment [20]. However, the AUC_inf was not markedly different between subjects with mild hepatic impairment and those with normal hepatic function (GMR: 1.19 [90% CI 0.86–1.64]) [62]. Mean terminal elimination half-life (t_½) (10.43–11.16) was comparable between subjects with normal hepatic function and those with mild or moderate hepatic impairment [62]. Peficitinib has not been studied in subjects with severe hepatic impairment.

3.3. Clinical efficacy

3.3.1. Phase 2 trials

Two global, randomized, placebo-controlled, Phase 2b trials, RA21 and RA22, were conducted to evaluate the safety and efficacy of peficitinib versus placebo [63,64]. In the RA21 study, 378 patients with an inadequate response to prior MTX across 43 sites in North America, Latin America, and Europe received peficitinib 25 mg, 50 mg, 100 mg, 150 mg, or placebo once daily, in combination with MTX, for 12 weeks (Table 1) [63]. However, differences versus placebo for the primary endpoint, American College of Rheumatology (ACR)20 response at Week 12, were not statistically significant with peficitinib 25 mg, 100 mg, or 150 mg, partly due to unexpectedly high placebo responses (75.0%) in patients from Latin America [63].

Table 1. Phase 2 and 3 studies evaluating the clinical efficacy of peficitinib in patients with RA.

Study details	Patients enrolled	Treatment groups (n)	Primary endpoints and other important endpoints
RA21; NCT01554696 [63]; Phase 2b; global	MTX–IR, N = 378	In combination with MTX: placebo (72); peficitinib mg once daily, 25 (66), 50 (78), 100 (84), 150 (78)	Primary: ACR20 at Week 12, %	Placebo, 44.4; peficitinib 25 mg, 43.9; 50 mg, 61.5*; 100 mg, 46.4; 150 mg, 57.7
			ACR50 at Week 12, %	Placebo, 26.4; peficitinib 25 mg, 18.2, 50 mg, 33.3; 100 mg, 33.3; 150 mg, 37.2
			ACR70 at Week 12, %	Placebo, 11.1; peficitinib 25 mg, 9.1; 50 mg, 15.4; 100 mg, 16.7; 150 mg, 19.2
RA22; NCT01565655 [64]; Phase 2b; global	DMARD-IR, N = 289	Alone or in combination with DMARDs: placebo (51); peficitinib mg once daily 25 (59), 50 (57), 100 (58), 150 (64)	Primary: ACR20 at Week 12, %	Placebo, 29.4; peficitinib 25 mg, 22.0; 50 mg, 36.8; 100 mg, 48.3*; 150 mg, 56.3**
			ACR50 at Week 12, %	Placebo, 9.8; peficitinib 25 mg, 15.3; 50 mg, 24.6*; 100 mg, 27.6*; 150 mg, 28.1**
			ACR70 at Week 12, %	Placebo, 7.8; peficitinib 25 mg, 6.8; 50 mg, 15.8; 100 mg, 19.0; 150 mg, 10.9
			HAQ-DI difference vs placebo at Week 12, LSM (95% CI)	Placebo, –; peficitinib 25 mg, −0.02 (−0.18, 0.21); 50 mg, −0.12 (−0.31, 0.07); 100 mg, −0.11 (−0.30, 0.09); 150 mg, −0.17 (−0.36, 0.02)
			DAS28-CRP <2.6 at Week 12, %	Placebo, 9.8; peficitinib 25 mg, 6.8; 50 mg, 12.5; 100 mg, 22.8; 150 mg, 20.3
			DAS28-ESR <2.6 at Week 12, %	Placebo, 3.9; peficitinib 25 mg, 6.8; 50 mg, 7.1; 100 mg, 17.5*; 150 mg, 17.2*
RAJ1; NCT01649999 [36]; Phase 2b; Japan	Active RA, N = 281	Placebo (56); peficitinib monotherapy mg once daily 25 (55), 50 (57), 100 (55), 150 (58)	Primary: ACR20 at Week 12/ET, %	Placebo, 10.7; peficitinib 25 mg, 23.6; 50 mg, 31.6*; 100 mg, 54.5***; 150 mg, 65.5***
			ACR50 at Week 12/ET, %	Placebo, 5.4; peficitinib 25 mg, 7.3; 50 mg, 8.8; 100 mg, 30.9***; 150 mg, 29.3**
			ACR70 at Week 12/ET, %	Placebo, 1.8; peficitinib 25 mg, 0.0; 50 mg, 1.8; 100 mg, 16.4**; 150 mg, 12.1
			HAQ-DI difference vs placebo at Week 12/ET, LSM (95% CI)^a	Placebo, – ; peficitinib 25 mg, −0.02 (−0.20, 0.15); 50 mg, −0.11 (−0.28, 0.07); 100 mg, −0.34 (−0.51, −0.16)***; 150 mg, −0.39 (−0.57, −0.22)***
			DAS28-CRP <2.6 at Week 12/ET, %	Placebo, 5.4; peficitinib 25 mg, 0; 50 mg, 7.0; 100 mg, 27.3**; 150 mg, 20.7*
			DAS28-ESR <2.6 at Week 12/ET, %	Placebo, 3.6; peficitinib 25 mg, 1.8; 50 mg, 3.5; 100 mg, 11.1; 150 mg, 13.8
RAJ3; NCT02308163 [37]; Phase 3; Japan, Korea, Taiwan	DMARD-IR, N = 507 (prior biological DMARD use 15.0%)	Alone or in combination with conventional DMARDs: placebo (101); peficitinib mg once daily 100 (104) and 150 (102), open-label etanercept 50 mg/week (200)	Primary: ACR20 at Week 12/ET, %	Placebo, 30.7; peficitinib 100 mg, 57.7***; 150 mg, 74.5***; etanercept, 83.5
			ACR50 at Week 12/ET, %	Placebo, 8.9; peficitinib 100 mg, 30.8***; 150 mg, 42.2***; etanercept, 52.5
			ACR70 at Week 12/ET, %	Placebo, 1.0; peficitinib 100 mg, 13.5^†; 150 mg, 27.5***; etanercept, 30.5
			HAQ-DI change from baseline at Week 12/ET, LSM (95% CI)	Placebo, 0.09 (−0.04, 0.23); peficitinib 100 mg, −0.25*** (−0.38, −0.11); 150 mg, −0.30*** (−0.43, −0.17); etanercept, −0.31 (−0.43, −0.20)
			DAS28-CRP <2.6 at Week 12/ET, %	Placebo, 5.0; peficitinib 100 mg, 24.5***; 150 mg, 34.7***; etanercept, 45.5
			DAS28-ESR <2.6 at Week 12/ET, %	Placebo, 1.0; peficitinib 100 mg, 11.7^†; 150 mg, 17.8**; etanercept, 31.7
RAJ4; NCT02305849 [38]; Phase 3; Japan	MTX–IR, N = 518 (prior biological DMARD use 18.9%)	In combination with MTX: placebo (170); peficitinib mg once daily 100 (174), 150 (174)	Primary: ACR20 at Week 12/ET, %	Placebo, 21.8; peficitinib 100 mg, 58.6***; 150 mg, 64.4***
			Co-primary: mTSS change from baseline at Week 28/ET, mean (SD)	Placebo, 3.37 (5.46); peficitinib 100 mg, 1.62 (4.23)***; 150 mg, 1.03 (2.86)***
			ACR50 at Week 12/ET, %	Placebo, 7.6; peficitinib 100 mg, 29.9***; 150 mg, 46.0***
			ACR70 at Week 12.ET, %	Placebo, 2.4; peficitinib 100 mg, 12.1***; 150 mg, 23.6***
			HAQ-DI change from baseline at Week 12/ET, LSM (95% CI)	Placebo, 0.02 (−0.04, 0.09); peficitinib 100 mg, −0.25*** (−0.31, −0.18); 150 mg, −0.37*** (−0.43, −0.30)
			DAS28-CRP <2.6 at Week 12/ET, %	Placebo, 7.7; peficitinib 100 mg, 31.4***; 150 mg, 35.1***
			DAS28-ESR <2.6 at Week 12/ET, %	Placebo, 2.4; peficitinib 100 mg, 12.8***; 150 mg, 19.3***
RA25; NCT01711814 [65]; Phase 2 long-term extension; global	LTE for RA21 and RA22, N = 611 (prior biological DMARD use 35.5%, prior anti-TNF use 31.1%)	Peficitinib 100 mg once daily	Primary: 2-year safety (AEs and clinical laboratory evaluations)	Total AEs, 75.8% SAEs, 13.1% Serious infections, 2.7/100 PY Herpes zoster (including herpes zoster ophthalmic), 1.6/100 PY) Malignancy, 0.6/100 PY
			ACR20 (relative to baseline of preceding trial) at Week 105, %	44.0
			DAS28-CRP <2.6 at Week 105, %	22.0
RAJ2; NCT01638013 [39]; Phase 3 long-term extension (completed 30 September 2019); Japan, Korea, Taiwan	LTE for RAJ1, RAJ3 and RAJ4, N = 843	Peficitinib mg once daily 50, 100, 150	Safety (AEs, vital signs, 12-lead ECGs, chest radiography, laboratory tests)	TEAEs, 89.8% SAEs, 16.4% Drug-related TEAEs, 69.5% Serious infections, 2.3/100 PY Herpes zoster-related disease, 6.8/100 PY Malignancy, 1.1/100 PY
			Efficacy variables	At the baseline of this extension study (week 0), ACR20, ACR50, and ACR70 response rates were 71.6%, 52.1%, and 34.7%, respectively. These rates were maintained during the extension study and at the end of treatment were 78.9%, 61.4%, and 42.7%, respectively.
CNA3; NCT03660059; Phase 3 (recruiting – estimated completion date Aug 2022); China, Korea, Taiwan	MTX–IR, N = TBC	In combination with DMARDs: placebo, peficitinib mg once daily 100, 150 (patient numbers per arm TBC)	Primary: ACR20 response rate at Week 24/ET

P values are given for differences versus placebo: *p < 0.05, **p < 0.01, ***p < 0.001, ^†p = not estimable

^aPreviously unpublished data

The RAJ3 etanercept arm was an open-label safety arm and was not included in statistical comparisons versus placebo

The imputation method for the primary endpoint of each study was as follows: (i) For RA21 and RA22, when all ACR component values were missing, non-responder imputation was used for the missing ACR responses at Week 12. If not all ACR component values were missing at Week 12, the last observation carried forward (LOCF) method was used to impute missing values and then the ACR response was calculated; (ii) For RAJ1, RAJ3, and RAJ4, in the case of early termination, ACR components were analyzed using the LOCF method first, and then ACR responses were calculated at Week 12/ET. For RAJ4, linear extrapolation was used at Week 28/ET for change from baseline in mTSS

ACR, American College of Rheumatology; AE, adverse event; CI, confidence interval; CRP, C-reactive protein; DAS, disease activity score; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; ET, early termination; HAQ-DI, Health Assessment Questionnaire Disability Index; IR, inadequate response; LSM, least squares mean; LTE, long-term extension; MTX, methotrexate; N/A, not available; SAE, serious adverse event; TEAEs, treatment-emergent adverse events; TBC, to be confirmed

The RA22 study, conducted at 41 sites in North America, Mexico, and Europe, included 289 patients with an inadequate response to prior DMARDs who received peficitinib 25 mg, 50 mg, 100 mg, 150 mg, or placebo once daily, alone or in combination with DMARDs, for 12 weeks (Table 1) [64]. Response rates for the primary endpoint, ACR20 at Week 12, were significantly different versus placebo in the peficitinib 100 mg and 150 mg groups [64].

A third Phase 2b trial conducted in Japan, RAJ1, randomized 281 patients not receiving current DMARDs to receive peficitinib monotherapy (25 mg, 50 mg, 100 mg, or 150 mg) or placebo once daily for 12 weeks [36] (Table 1). Response rates for the primary efficacy variable, ACR20 at Week 12/early termination (ET), were 10.7%, 23.6%, 31.6%, 54.5%, and 65.5% in the placebo and peficitinib 25 mg, 50 mg, 100 mg, and 150 mg groups, respectively, and were significantly different versus placebo with peficitinib 50 mg, 100 mg, and 150 mg.

3.3.2. Phase 3 studies

In the 52-week, randomized, double-blind RAJ3 trial (NCT02308163) conducted in Japan, Korea, and Taiwan, peficitinib (100 mg and 150 mg once daily), alone or in combination with DMARDs, was evaluated against placebo or open-label etanercept (50 mg once weekly for safety comparison) in patients with active RA (n = 507) who had an inadequate response to prior DMARDs (Table 1) [37]. The primary efficacy endpoint of ACR20 response rate at Week 12/ET was significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p < 0.001) (Table 1 and Figure 1). Subgroup analyses indicated that both peficitinib doses produced numerically higher ACR20 response rates than placebo regardless of concomitant DMARD use; however, these subgroup analyses were not powered for statistical comparisons [37]. In addition, it was difficult to compare peficitinib with etanercept, as etanercept was an open-label treatment and not included in statistical comparisons versus the other treatment arms [37].

Figure 1. ACR20, ACR50, and ACR70 scores at Week 12/ET in the RAJ3 trial.

The 52-week, randomized, double-blind, placebo-controlled RAJ4 trial (NCT02305849; n = 518) evaluated peficitinib (100 mg or 150 mg once daily) in combination with MTX in Japanese patients who had an inadequate response to MTX (Table 1) [38]. The primary endpoint of ACR20 response rate at Week 12/ET was significantly higher in the peficitinib 100 mg (58.6%) and 150 mg (64.4%) groups versus placebo (21.8%) (p < 0.001) [38]. The co-primary endpoint, change from baseline in van der Heijde-modified total Sharp score (mTSS) at Week 28/ET, was significantly lower in the peficitinib 100 mg (1.62) and peficitinib 150 mg (1.03) groups compared with placebo (3.37) (p < 0.001) (Figure 2) [38]. Peficitinib 100 mg and 150 mg prevented joint destruction more effectively than placebo (Figure 2) [38].

Figure 2. Change from baseline in mTSS, JSN, and erosion scores at Week 28/ET in the RAJ4 trial.

3.4. Safety and tolerability

In the Phase 2b RAJ1 trial, the total incidence of treatment-emergent adverse events (TEAEs) was similar in the placebo group (64.3%) and combined peficitinib groups (64.0%) (Table 2) [36]. Seven patients experienced serious TEAEs, two of which (spontaneous abortion in the peficitinib 25 mg group and cholecystitis in the peficitinib 100 mg group) were deemed to be related to the study drug [36]. Herpes zoster occurred in four patients (two each in the peficitinib 25 mg and 100 mg groups), while malignancy was not observed in any of the peficitinib groups [36].

Table 2. Summary of TEAEs in RAJ1, RAJ3, and RAJ4.

	RAJ1		RAJ3					RAJ4
	Weeks 0–12		Weeks 0–12			Weeks 0–52		Weeks 0–12		Weeks 0–52
	Placebo (N = 56)	Peficitinib 25 + 50 + 100 + 150 mg (N = 225)	Placebo (N = 101)	Peficitinib 100 mg + 150 mg (N = 206)	Etanercept (N = 200)	Peficitinib 100 mg + 150 mg (N = 206)^a	Etanercept (N = 200)	Placebo (N = 170)	Peficitinib 100 mg +150 mg (N = 348)	Peficitinib 100 mg +150 mg (N = 348)
TEAEs, n (%)
Any TEAE	36 (64.3)	144 (64.0)	54 (53.5)	114 (55.3)	119 (59.5)	181 (87.9)	178 (89.0)	84 (49.4)	193 (55.5)	307 (88.2)
≥Grade 3 TEAEs	3 (5.4)	15 (6.7)	8 (7.9)	9 (4.4)	6 (3.0)	33 (16.0)	29 (14.5)	8 (4.7)	25 (7.2)	61 (17.5)
Drug-related TEAEs^b	N/A	N/A	29 (28.7)	71 (34.5)	75 (37.5)	126 (61.2)	122 (61.0)	47 (27.6)	137 (39.4)	241 (69.3)
Serious TEAE	1 (1.8)	6 (2.7)	4 (4.0)	5 (2.4)	4 (2.0)	15 (7.3)	18 (9.0)	4 (2.4)	8 (2.3)	32 (9.2)
Drug-related serious adverse events^b	0	N/A	3 (3.0)	3 (1.5)	4 (2.0)	6 (2.9)	9 (4.5)	2 (1.2)	6 (1.7)	18 (5.2)
Deaths	0	1 (0.4)^c	0	0	0	0	0	0	0	1 (0.3)^d
TEAEs leading to discontinuation	10 (17.9)	22 (9.8)	4 (4.0)	9 (4.4)	5 (2.5)	19 (9.2)	13 (6.5)	7 (4.1)	10 (2.9)	25 (7.2)

^aPatients who switched from placebo to peficitinib were excluded

^bPossible or probable, as assessed by investigator or records where relationship is missing

^cOne death, due to cerebral hemorrhage, was reported in the peficitinib 50 mg group in a patient with hypertension and type 2 diabetes mellitus; this event was assessed by the investigator as not related to peficitinib

^dOne patient who switched from placebo to peficitinib 100 mg at Week 28 committed suicide; this event was assessed by the investigator as not related to peficitinib

Patients receiving placebo were switched to peficitinib 100 or 150 mg at Week 12 in the RAJ3 trial and at Week 12 or 28 in the RAJ4 trial

N/A, not available; TEAE, treatment-emergent adverse event

Reproduced from the following articles with permission from BMJ Publishing Group Ltd: Ann Rheum Dis, Takeuchi T, Tanaka Y, Iwasaki M, et al., 75:1057–1064, 2016 (RAJ1); Ann Rheum Dis, Tanaka Y, Takeuchi T, Tanaka S, et al., 78:1320–1332, 2019 (RAJ3); Ann Rheum Dis, Takeuchi T, Tanaka Y, Tanaka S, et al., 78:1305–1319, 2019 (RAJ4) [36–38]

In the Phase 3 trials, the percentage of patients who had TEAEs during the first 12 weeks of both studies was similar for both peficitinib doses compared with placebo or with open-label etanercept: 55.3% and 55.5% of peficitinib-treated patients in RAJ3 and RAJ4, respectively, versus 53.5% (RAJ3) and 49.4% (RAJ4) of those receiving placebo (Table 2) [37–38]. The incidence of serious infections and herpes zoster-related disease was higher in the peficitinib groups than in the placebo group in both studies; however, no dose-dependency was observed for serious infections, herpes zoster-related disease, or malignancies (Table 3). Although there are concerns of an increased risk of thromboembolic events with JAK inhibitors [66], no thromboembolic events were reported in these trials [37–38]. Reassuringly, peficitinib was also associated with an increase in hemoglobin levels in both the RAJ3 and RAJ4 trials [37–38], instead of a decrease in hemoglobin that has been attributed to JAK2 inhibition; this increase is likely to be due to its anti–inflammatory effect [67].

Table 3. Summary of adverse events of special interest in RAJ3 and RAJ4 from Week 0 to Week 52.

Study, adverse event	Placebo	Peficitinib 100 mg	Peficitinib 150 mg	Peficitinib 100 mg + 150 mg^a	Peficitinib 100 mg + 150 mg + placebo switcher^b	Etanercept 50 mg (open-label)
RAJ3
No. of patients evaluated	101	104	102	206	296	200
Serious infections
Patient-years	22.6	88.2	92.1	180.3	245.7	195.5
No. of patients with ≥1 incidence	0	1	2	3	5	4
Incidence rate/100 patient-years (95% CI)	0.0	1.1 (0.2, 8.1)	2.2 (0.5, 8.7)	1.7 (0.5, 5.2)	2.0 (0.8, 4.9)	2.0 (0.8, 5.5)
Herpes zoster-related disease
Patient-years	22.6	86.8	90.9	177.7	241.2	194.0
No. of patients with ≥1 incidence	0	5	4	9	14	5
Incidence rate/100 patient-years (95% CI)	0.0	5.8 (2.4, 13.8)	4.4 (1.7, 11.7)	5.1 (2.6, 9.7)	5.8 (3.4, 9.8)	2.6 (1.1, 6.2)
Malignancies
Patient-years	22.6	88.1	92.8	180.9	246.4	197.3
No. of patients with ≥1 incidence	0	2	0	2	3	1
Incidence rate/100 patient-years (95% CI)	0.0	2.3 (0.6, 9.1)	0.0	1.1 (0.3, 4.4)	1.2 (0.4, 3.8)	0.5 (0.1, 3.6)
RAJ4
No. of patients evaluated	170	174	174	348	496	-
Serious infections
Patient-years	62.9	159.5	160.8	320.3	407.8	-
No. of patients with ≥1 incidence	0	6	6	12	14	-
Incidence rate/100 patient-years (95% CI)	0.0	3.8 (1.7, 8.4)	3.7 (1.7, 8.3)	3.7 (2.1, 6.6)	3.4 (2.0, 5.8)	-
Herpes zoster-related disease
Patient-years	62.6	156.2	159.8	316.0	402.9	-
No. of patients with ≥1 incidence	2	13	6	19	23	-
Incidence rate/100 patient-years (95% CI)	3.2 (0.8, 12.8)	8.3 (4.8, 14.3)	3.8 (1.7, 8.4)	6.0 (3.8, 9.4)	5.7 (3.8, 8.6)	-
Malignancies
Patient-years	62.9	162.2	163.0	325.2	413.2	-
No. of patients with ≥1 incidence	1	1	0	1	1	-
Incidence rate/100 patient-years (95% CI)	1.6 (0.2, 11.3)	0.6 (0.1, 4.4)	0.0	0.3 (0.0, 2.2)	0.2 (0.0, 1.7)	-

Patient-years were calculated from initial dose up to first incidence of the event for patients who had ≥1 event, and from initial dose through follow-up for patients who had no events; incidence rate was calculated as (100 × number of patients who had ≥1 incidence/total patient-years)

^aPatients switching from placebo to peficitinib were excluded^bPatients switching from placebo to peficitinib at Week 12 (RAJ3) or Week 12 or 28 (RAJ4) were included

CI, confidence interval

Reproduced from the following articles with permission from BMJ Publishing Group Ltd: Ann Rheum Dis, Tanaka Y, Takeuchi T, Tanaka S, et al., 78:1320–1332, 2019 (RAJ3); Ann Rheum Dis, Takeuchi T, Tanaka Y, Tanaka S, et al., 78:1305–1319, 2019 (RAJ4) [37,38]

3.5. Regulatory affairs

Peficitinib was approved as an RA treatment in Japan in March 2019 [20,68] and in Korea in January 2020 [21,22]. The worldwide rights except for Japan were initially licensed to Janssen Biotech in October 2012 and were transferred to Astellas Pharma in December 2014 [68]. A further study of peficitinib for the treatment of patients with RA and an inadequate response or intolerance to MTX is ongoing in China, Taiwan, and Korea (CNA3, NCT03660059; Table 1).

4. Conclusion

Peficitinib is an oral pan-JAK inhibitor with proven clinical efficacy in Asian patients with RA who have had an inadequate response to MTX and/or other conventional DMARDs. In pivotal Phase 3 studies, ACR20 was achieved by up to 75% of patients treated with peficitinib, and prevention of joint destruction was demonstrated for both 100 mg and 150 mg once-daily doses versus placebo. Across the peficitinib safety database, there is no clear signal that the safety profile of peficitinib differs from those of other JAK inhibitors.

5. Expert opinion

Peficitinib may prove a valuable addition to the treatment options for Asian patients with RA who have not responded to conventional therapies. The guidance in Japan for dosing in adults recommends 150 mg orally once daily after a meal, which can be reduced to 100 mg once daily depending on the patient’s condition [20]. However, laboratory data, such as hepatic function parameters and neutrophil count, and patient characteristics, such as age, will determine the initial dose of peficitinib for individual patients. The safety profile of peficitinib appears similar to that of other JAK inhibitors; the incidence of herpes zoster-related disease, although approximately doubled with peficitinib compared with etanercept in the Phase 3 RAJ3 trial, remained almost within the range previously observed with tofacitinib (in Japanese/Korean populations [69]) and baricitinib (in Japanese/Korean/Taiwanese populations [70]). Of note, the Shingrix® vaccine was approved for use in Japan in 2018 [71], which may prove a useful measure to mitigate the risk of herpes zoster-related disease.

It is interesting to note that peficitinib performed better in clinical trials of patients in Asian countries [36–38] compared with global trials [63,64]. In the Kivitz et al. study, which recruited patients across North America, Latin America, and Europe with moderate-to-severe RA and an inadequate response to MTX, statistically significant treatment differences versus placebo were only observed for peficitinib 50 mg and there was a high placebo response, particularly among patients from Latin America [63]. Since peficitinib exposure is greater in Japanese versus Caucasian subjects [60] and Asian patients tend to have a lower body weight compared with their American and European counterparts [72], a peficitinib dose of 150 mg may be sufficient for patients from Asia but it remains to be seen if the same or higher dose is required for patients from other regions. Of note, body weight was not a covariate in the population pharmacokinetic analysis of peficitinib [56]; thus, the cause of the reduced efficacy of peficitinib 150 mg in Caucasian patients remains unclear. Further studies in non-Asian patients are required to establish the most effective dose in these populations.

To complement the clinical trial data available in Japan and East Asia, post-marketing surveillance of peficitinib has already been initiated (from July 2019 in Japan), and acquisition of real-world safety data following market launch is expected to enrich what is already known about this drug.

Article Highlights

• Peficitinib, an inhibitor of the Janus kinase (JAK) family of signal transducers, has been approved in Japan and Korea for the treatment of rheumatoid arthritis (RA).

• In two randomized, placebo-controlled, Phase 3 trials in Asia, significant clinical improvements and prevention of joint destruction were seen with peficitinib 100 mg and 150 mg once daily, compared with placebo.

• The incidence of treatment-emergent adverse events was similar between peficitinib, placebo, and etanercept.

• The incidence of serious infections and herpes zoster-related disease was higher with peficitinib than with placebo; however, no dose dependency was observed for serious infections, herpes zoster-related disease, or malignancies. Rates of herpes zoster-related disease were almost within the range seen with other JAK inhibitors in Asian populations.

• Further studies and post-launch data are expected to confirm the safety and effectiveness of peficitinib in long-term clinical use.

Declaration of interest

Y Tanaka has received speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Eli Lilly, Chugai, AbbVie, Pfizer, YL Biologics, Bristol-Myers Squibb, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, and Teijin, and research grants from Asahi Kasei, Mitsubishi Tanabe, Bristol-Myers Squibb, Eisai, Chugai, Takeda, Sanofi, UCB, Daiichi Sankyo, and Ono. Meanwhile, H Izutsu is an employee of Astellas Pharma Inc. The authors have 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.

Acknowledgments

T Patrick and I Easthope of Cello Health MedErgy (Europe) are acknowledged for their medical writing support.

Additional information

Funding

This manuscript has been funded by Astellas Pharma Inc.Astellas Pharma Inc. conducted reviews of drafts for the accuracy of scientific content. Medical writing support was utilized during the composition of this manuscript and was funded by Astellas Pharma Inc.