Actemra

GLOBAL DATA

 

In all five Phase III studies, patients treated with ACTEMRA 8 mg/kg had statistically significant higher ACR20, 50 and 70 response rates at 6 months compared with control (Table 1). In AMBITION, superiority of ACTEMRA 8 mg/kg was demonstrated against the active comparator, methotrexate (MTX).
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, number of prior treatments or disease status. Time to onset was rapid (as early as Week 2) and the magnitude of response continued to improve with duration of treatment. Continued durable responses were seen for over 24 months in the ongoing open-label extension studies (OPTION, TOWARD, AMBITION and RADIATE). 
In patients treated with ACTEMRA 8 mg/kg, significant improvements were noted on all individual components of the ACR response including: tender and swollen joint counts; patient and physician global assessment; disability index scores; pain assessment and C-reactive protein (CRP), compared with patients receiving placebo plus MTX or other disease modifying anti-rheumatic drugs (DMARDs) in all studies.
Patients in all five studies had a mean Disease Activity Score (DAS28) of 6.5-6.8 at baseline. Significant reduction in DAS28 from baseline (mean improvement) of 3.1-3.4 was observed in ACTEMRA treated patients compared with control patients (1.3-2.1). The proportion of patients achieving a DAS28 clinical remission (DAS28 <2.6) was significantly higher in patients receiving ACTEMRA (28-34%) compared with 1-12% of control patients at 24 weeks. In LITHE, 47% of patients achieved a DAS28 <2.6 at 52 weeks compared with 33% of patients at Week 24.
In a pooled analysis of OPTION, TOWARD and LITHE, the proportion of patients achieving an ACR20, 50 and 70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the ACTEMRA 8 mg/kg plus DMARD vs. the ACTEMRA 4 mg/kg plus DMARD group (p<0.03). Similarly, the proportion of patients achieving a DAS28 remission (DAS28 <2.6) was significantly higher (31% vs. 16%, respectively) in patients receiving ACTEMRA 8 mg/kg plus DMARD than in patients receiving ACTEMRA 4 mg/kg plus DMARD (p<0.0001).

 

Table 1. ACR responses in placebo-/MTX-/DMARDs-controlled studies (% patients)

   

	Study I AMBITION		Study II LITHE		Study III OPTION		Study IV TOWARD			Study V RADIATE
Week	TCZ 8 mg/kg	MTX	TCZ 8 mg/kg + MTX	PBO + MTX	TCZ 8 mg/kg + MTX	PBO + MTX	TCZ 8 mg/kg + DMARD	PBO + DMARD		TCZ 8 mg/kg + MTX	PBO + MTX
	N = 286	N = 284	N = 398	N = 393	N = 205	N = 204	N = 803	N = 413		N = 170	N = 158
ACR 20
24	70%***	53%	56%***	27%	59%***	27%	61%***	25%		50%***	10%
52			56%***	25%
ACR 50
24	44%**	34%	32%***	10%	44%***	11%	38%***	9%	29%***		4%
52			36%***	10%
ACR 70
24	28%**	15%	13%***	2%	22%***	2%	21%***	3%		12%**	1%
52			20%***	4%

 

TCZ                  - Tocilizumab

MTX                 - Methotrexate

PBO                 - Placebo

DMARD            - Disease modifying anti-rheumatic drug

*                       - p< 0.05, TCZ vs. PBO + MTX/DMARD 

**                      - p< 0.01, TCZ vs. PBO + MTX/DMARD 

***                    - p< 0.0001, TCZ vs. PBO + MTX/DMARD

 

Radiographic response
In LITHE, in patients with an inadequate response to MTX, inhibition of structural joint damage was assessed radiographically and expressed as change in modified Sharp score and its components, the erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with significantly less radiographic progression in patients receiving ACTEMRA compared with control (Table 2).

 

Table 2. Radiographic mean changes over 52 weeks in Study LITHE

 

	PBO + MTX (+ TCZ from week 24) N = 393	TCZ 8 mg/kg + MTX N = 398
Total Sharp-Genant score	1.13	0.29*
Erosion score	0.71	0.17*
JSN score	0.42	0.12**

 

PBO                 - Placebo

MTX                 - Methotrexate

TCZ                  - Tocilizumab

JSN                  - Joint space narrowing

*                       - p≤ 0.0001, TCZ vs. PBO + MTX

**                      - p< 0.005, TCZ vs. PBO + MTX

 

Health-related and quality of life outcomes
ACTEMRA treated patients reported an improvement in all patient-reported outcomes (Health Assessment Questionnaire Disability Index [HAQ-DI]), Short Form-36 and Functional Assessment of Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were observed in patients treated with ACTEMRA compared with patients treated with DMARDs.

 

Haemoglobin levels
Statistically significant improvements in haemoglobin levels were observed with ACTEMRA compared with DMARDs (p<0.0001) at Week 24. Mean haemoglobin levels increased by Week 2 and remained within normal range through to Week 24.

 

JAPANESE DATA

 

Reduction of sign and symptoms
In the phase III SAMURAI and SATORI trials patients treated with 8 mg/ Kg Actemra has shown a significantly better ACR 20, 50 and 70 responses as compared to the comparator arm. 

In the Satori trial the ACR 20 , 50 and 70 responses were 80.3 %, 49.2%, 29.5% as compared to 25%, 10.9% and 29.5 % of the control group.

In the Samurai study the ACR 20, 50 and 70 responses at 52 weeks were 78%, 64% and 44% respectively as compared to 34%, 13% and 6 % in the DMARD group.

 

Improvement in activities of daily living (ADL)
Evaluation of improvement in activities of daily living (ADL) from before administration to the last observation by MHAQ score (indicator of degree of activity limitation and nursing care necessity, etc.) showed a significant reduction of mean MHAQ in the tocilizumab group compared with the control group in the phase III clinical trials.

 

Inhibition of progression of structural joint damage
In the Samurai trial Progression of joint destruction from before administration up to 52 weeks after administration was assessed by X-ray score (Modified Sharp Score) of the hands and feet, and the results showed that the total Sharp score was increased by 2.34 in the tocilizumab group compared with 6.12 in the control group, and progression of joint destruction was significantly retarded compared with the control group.

 

Polyarticular-course Juvenile Idiopathic Arthritis (pJIA)
Nineteen patients with pJIA were administered 8 mg/kg tocilizumab three times at 4-week intervals. Improvement of 30%, 50%, and 70% in the JIA criteria at the last observation was seen in respectively 94.7%, 94.7%, and 57.9% of patients, showing clear improvement of their underlying disease.

 

Systemic Juvenile Idiopathic Arthritis (sJIA)
Tocilizumab administered six times at 2-week intervals in a double-blind controlled study showed an improvement of 30% or higher according to the JIA criteria. The rate of maintained response was 80.0% in the tocilizumab group, which was significantly higher than that in the placebo group (17.4%). Similarly, the period in which response was maintained was also significantly longer in the tocilizumab group than in the placebo group.

 

Castleman’s disease
Tocilizumab was administered eight times at a dose of 8 mg/kg at 2-week intervals to 28 patients with Castleman’s disease. Inflammatory markers (CRP, fibrinogen, and ESR), generalised fatigue (evaluated by visual analog scale), anemia (Hb), and hypoalbuminemia, etc., significantly improved after the initial dose and throughout the treatment period.

 

Reference:

Ø       RoACTEMRA® (tocilizumab) Summary of Product Characteristics. Roche Registration Limited. January 2009.

Ø       ACTEMRA® (tocilizumab) Full Prescribing Information. Current at September 2008