Potential patient benefit of a subcutaneous formulation of tocilizumab for the treatment of rheumatoid arthritis: a critical review

Figures & data

Table 1 Characteristics of studies of subcutaneous tocilizumab in rheumatoid arthritis patients

	Phase	Type of study	Number of patients	Treatment arms	DMARD	Primary endpoint	Study duration	Extension
MATSURI (Japan)^Citation12	I/II dose escalation	Open trial	8, 12, 12	81 mg q2w SC 162 mg q2w SC 162 mg qw SC	None	Serum TCZ concentration	24 w	None
BREVACTA (worldwide)^Citation13,Citation14	III db	RCT	437 vs 219	TCZ 162 mg q2w SC vs placebo	With	ACR20	24 w	Open label during 72 w
SUMMACTA (worldwide)^Citation15	III db, dd	Non-inferiority RCT	558 vs 537	TCZ 162 mg qw SC vs TCZ 8 mg/kg q4w IV	With	ACR20	24 w	Open label during 72 w
MUSASHI (Japan)^Citation16	III db, dd	Non-inferiority RCT	159 vs 156	TCZ 162 mg q2w SC vs TCZ 8 mg/kg q4w IV	None	ACR20	24 w	NA

Abbreviations: ACR, American College of Rheumatology response rate 20; db, double-blind; dd, double dummy; DMARD, disease-modifying antirheumatic drugs; IV, intravenous; NA, not available; qw, every week; q2w, every two weeks; q4w, every 4 weeks; RCT, randomized controlled study; SC, subcutaneous; TCZ, tocilizumab; vs, versus; w, weeks.

Table 2 Pharmacokinetics of different subcutaneous tocilizumab dosages compared to intravenous tocilizumab in rheumatoid arthritis patients

	TCZ dose	C max μg/mL 1 dose	C max μg/mL during the study	Mean AUC μg h/mL	Steady state weeks	C trough μg/mL
MATSURI^Citation12	81 mg q2w SC 162 mg q2w SC 162 mg qw SC	3.4 11 11	NA NA NA	NA NA NA	NA 15 15	NA 6–9 25–30 at 15 w
BREVACTA^Citation13	162 mg q2w SC + DMARD	10	17 at week 12	4,088 during weeks 12 to 14	20	7.4 at 24 w
SUMMACTA^Citation15	162 mg qw SC vs 8 mg/kg q4w IV + DMARD	NA	53 vs 233 at week 20	30,168 vs 41,304 during weeks 20 to 24	12	42 vs 18 at 24 w
MUSASHI^Citation16	162 mg q2w SC vs 8 mg/kg q4w IV monotherapy	NA	NA	NA	12	11 vs 12 at 24 w

Abbreviations: AUC, area under the curve; C max, maximal serum concentration of tocilizumab; C trough, pre-dose tocilizumab serum concentration; DMARD, disease-modifying antirheumatic drugs; IV, intravenous; NA, not available; qw, every week; q2w, every two weeks; q4w, every 4 weeks; SC, subcutaneous; TCZ, tocilizumab; vs, versus; w, weeks.

Table 3 Efficacy of subcutaneous tocilizumab in rheumatoid arthritis patients with inadequate response to DMARD

	TCZ dose	Week	ACR20%	ACR50–70%*	DAS28<2.6%	CDAI≤2.8%	Boolean %	HAQ-DI≥0.3%	Insufficient response %
MATSURI^Citation12	81 mg q2w SC	24	38	38–38	50	NA	NA	NA	NA
	162 mg q2w SC	24	83	83–50	83	NA	NA	NA	NA
	162 mg qw SC	24	92	92–67	100	NA	NA	NA	NA
BREVACTA^Citation13,Citation14	162 mg q2w SC	24	61	40–20	32	NA	NA	58	0.9
	+ DMARD	48	62	45–26	45	NA	NA	62
SUMMACTA^Citation15	162 mg qw SC	24	68	46–24	37	14	11	65	1.7
	+ DMARD
MUSASHI^Citation16	162 mg q2w SC monotherapy	24	79	64–37	50	16	16	57	1.7
SUMMACTA and MUSASHI studies^Citation15,Citation16	8 mg/kg IV q4w	24	70	47–27	38	15	11	67	1.3
	8 mg/kg IV q4w	24	89	67–41	62	23	16	68	0.6

Note:

* The numbers listed first in this column refer to the percentage of the patients achieving the ACR50 response, and the numbers listed second in this column refer to the percentage of patients achieving the ACR70 response. By definition, all the patients achieving ACR70 achieve ACR50.

Abbreviations: ACR, American College of Rheumatology response rate; CDAI, clinical disease activity index; DAS, disease activity score; DMARD, disease-modifying antirheumatic drugs; HAQ-DI, health assessment questionnaire disability index; IV, intravenous; NA, not available; qw, every week; q2w, every two weeks; q4w, every four weeks; SC, subcutaneous; TCZ, tocilizumab.

Table 4 Adverse events of subcutaneous tocilizumab in rheumatoid arthritis patients

	Patients with ≥1 AE (%, rate)	Patients with ≥1 SAE (%, rate)	Infection (%)	SI (%, rate)	ISR (%, rate)	SIR (%, rate)**	Neutropenia Grade 2% Grade 3% Grade 4%	ALT increase Grade 1–2%, Grade 3–4%	T Chol increase (%)#	Patients with anti-TCZ (%)	Withdrawal due to AE (%)
BREVACTA at 48 w^Citation14	NA, 374	NA, 13	30*	3.4, 3.8	22, 24	0.7, 0.8	NA NA NA	NA NA	NA	3.0	6.3
SUMMACTA at 24 w^Citation15	76, 603	4.8, 12	36	1.4, 3.1	10, 58	0.4, 0.7	13 3.0 0.2	54 1.0	15	0.8	4.8
MUSASHI at 24 w^Citation16	89, NA	7.5, NA	42	1.2, NA	12, NA	3.5, NA	11 3.0 0.0	24 0.6	24	3.5	1.7
8 mg/kg q4w in SUMMACTA and MUSASHI studies^Citation15,Citation16	77–91, 588	5.2–5.8, 15	39–45	1.4–2.9, 3.5	2.4–5.2, 33	0.2–6.9, 0.3	9.7–13 3.2–2.9 0–0	48–24 1.1–1.2	8.3–27	0.8–0.0	6.7–5.2

Notes: Rate determined per 100 patient-years

* at 24 weeks

# from total cholesterol <200 mg/dL (5.2 mmol/L) at baseline to ≥240 mg/dL (6.2 mmol/L)

** SIR from SAE in the SUMMACTA and BREVACTA studies, compared with SIR from AE in the MUSASHI study

*** from total cholesterol <200 mg/dL (5.2 mmol/L) at baseline to ≥240 mg/dL (6.2 mmol/L).

Abbreviations: AE, adverse events; ALT, alanine aminotransferase; anti-TCZ, anti-tocilizumab; I, infection; ISR, injection site reaction; q4w, every 4 weeks; NA, not available; SAE, severe adverse events; SI, severe infection; SIR, systemic immune reaction (AE within 24 hours of injection, not localized at the site of injection); T Chol, total cholesterol; w, weeks.

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