Tocilizumab (Actemra)

Figures & data

Figure 1. Overview of the process required to produce a biologic medicinal product. The production process is broken down into 2 main parts. The upstream processes are responsible for genetic manipulation of a host cell and the subsequent large scale production of the drug substance. The downstream processes are responsible for the purification of the drug substance and its formulation into a drug product.

Figure 2. The development and isolation of tocilizumab producing seed cells. This figure adapted from the production section of the IV tocilizumab EPAR, details the insertion of the gene coding for tocilizumab production into a host CHO cell and the subsequent processes to isolate and culture the tocilizumab producing CHO cell into a viable master and working cell bank.

Table 1. Overview and summary of the contents of the tocilizumab European Public Assessment Report (EPAR).

Section	Content
Quality Aspects	• Description of the active substance, physicochemical structure, molecular weight and a description of where the product is manufactured formulated and packaged.
	• Description of the process followed to produce a master cell bank and a working cell bank, fermentation process used to expand the cell mass and the process undertaken to purify the expanded cells to ensure homogeneity.
	• Description of the manufacturing process including both small and large scale process evaluation studies to ensure that each step of the manufacturing process is appropriately designed to produce tocilizumab.
	• Description of the process verification studies to ensure that the manufacturing process is able to effectively and reproducibly produce both intermediate compounds and the final product in multiple consecutive batches.
	• A description on how the final product is characterized to elicit the physicochemical and biologic characteristics and also to determine the presence of any impurities or any adventitious agents.
	• A description of the stability profile of both the monoclonal antibody alone and the final formulated injection.
Non-clinical aspects	• Description of the in vitro and in vivo animal based non-clinical studies performed to determine the safety and toxicology, pharmacodynamic and pharmacokinetic profiles of tocilizumab.
Clinical aspects	• Description of human studies and analyses conducted to elicit the pharmacodynamic and pharmacokinetic profile of tocilizumab.
	• Description of the pivotal human studies conducted to establish the efficacy and side effect profile of tocilizumab in patients with RA, sJIA and pJIA.
Pharmacovigilance	• Description of all measures to be taken to maintain appropriate future pharmacovigilance to monitor each adverse event identified in clinical studies.
Overall conclusions	• Analysis of overall risks and benefits associated with tocilizumab use
	• Summary of findings from previous sections and overall recommendation regarding the granting of a marketing authorisation

Table 2. Overview of all the marketing authorisations granted for tocilizumab.

Date	Details of marketing authorisation granted
November 2008	Treatment of rheumatoid arthritis either as a first line biologic or after the failure of a TNF inhibitor with or without methotrexate
April 2010	RA marketing authorization terms modified to state that tocilizumab improves physical function and slows the X-ray progression of joint damage when taken with methotrexate.
May 2011	Treatment of the active systemic form of Juvenile idiopathic arthritis (sJIA) in patients 2 y or older who have not responded to previous therapy with NSAIDs or steroids
April 2013	Treatment of polyarticular juvenile idiopathic arthritis (pJIA)
December 2013	New subcutaneous formulation of RoActemra for use in the same indications already approved for intravenous use
February 2014	Following syringe mechanical problems, marketing authorisation for use of the subcutaneous formulation of RoActemra was reinstated in the same indications already approved for intravenous use
July 2014	Treatment of patients with severe, active and progressive RA not previously treated with methotrexate.

Table 3. Description and results from the pivotal clinical trials involving tocilizumab use in patients with RA.

Study	Sample Size (n)	Design	Endpoint	Posology	Results
AMBITION	673	Randomized double blinded placebo controlled	ACR20 response at week 24	Group 1	Group 1
				IV TCZ (8mg/kg) every 4 weeks	• 70% ACR20 response
		Inclusion criteria: moderate or severe RA			• DAS28 reduced by 3.31
					• Patients 5 times more likely than Group 2 to achieve remission
		Exclusion criteria: previously failed MTX or biologics
				Group 2	Group 2
				MTX 7.5–20 mg every week	• 52% ACR20 response
					• DAS28 reduced by 2.05
LITHE	1196	Randomized double blinded placebo controlled	Genant-modified Sharp score,	Group 1	Group 1
		Inclusion criteria: RA <5 years, inadequate response to MTX and no previous biologics		IV TCZ (4mg/kg) every 4 weeks & MTX	• 56% ACR20 response
			HAQI		• 74% structural damage reduction
					• >0.3 UI HAQI improvement
			ACR20 response at week 52	Group 2	Group 2
				IV TCZ (8mg/kg)	• 51% ACR20 response
				every 4 weeks & MTX	• 70% structural damage reduction
				Group 3	Group 3
				Placebo & MTX	• Twenty-seven% ACR20 response
OPTION	623	Randomized double blinded parallel group	ACR20 response at week 24	Group 1	Group 1
		Inclusion criteria: moderate or severe RA, inadequate response to MTX		IV TCZ (4mg/kg) every 4 weeks & MTX	• 59% ACR20 response
					• Twenty-seven% DAS28 remission
				Group 2	Group 2
				IV TCZ (8mg/kg) every 4 weeks & MTX	• 48% ACR20 response
					• Thirteen% DAS28 remission
				Group 3	Group 3
				Placebo & MTX	• Twenty-six% ACR20 response
					• 0.8% DAS28 remission
TOWARD	1220	Randomized (in a 2:1 manner) double blinded placebo controlled	ACR20, ACR50, ACR70 response at week 24	Group 1	Group 1
		Conducted in multiple centers / countries		IV TCZ (4mg/kg) every 4 weeks and conventional DMARDs	• 61% ACR20 response
		Inclusion criteria: moderate or severe RA, multiple DMARDs			• Thirty% DAS28 remission
				Group 2	Group 2
				Placebo and conventional DMARDs	• Twenty-five% ACR20 response
					• Three% DAS28 remission
RADIATE	499	Double blinded placebo controlled	ACR20 response at week 24	Group 1	Group 1
		Inclusion criteria: RA refractory to anti-TNF therapy		IV TCZ (4mg/kg) every 4 weeks & MTX	• Thirty.4% ACR20 response
					• Seven.6% DAS28 remission
				Group 2	Group 2
				IV TCZ (8mg/kg) every 4 weeks & MTX	• 50% ACR20 response
					• Thirty.1% DAS28 remission
				Group 3	Group 3
				Placebo & MTX	• Ten.1% ACR20 response
					• One.6% DAS28 remission
ADACTA	325	Randomized double blinded parallel group phase 4	DAS28, ACR20, ACR50 and ACR70 response at week 24	Group 1	Group 1
		Inclusion criteria: intolerant or inappropriate to be on MTX		IV TCZ (8mg/kg) every 4 weeks and placebo	• 39.9% DAS28 remission
					• DAS28 reduced by 3.3
				Group 2	Group 2
				Adalimumab 40 mg every 2 weeks and placebo	• Ten.5% DAS28 remission
					• DAS28 reduced by 1.8
FUNCTION	1162	Double blinded placebo controlled	DAS28 remission at week 24	Group 1	Group 1
		Inclusion criteria: early progressive RA, MTX naive		IV TCZ 4mg/kg every 4 weeks & MTX	• 40% DAS28 remission
			Evaluation of radiographic and physical function outcomes at week 52	Group 2	Group 2
				IV TCZ 8 mg/kg every 4 weeks & MTX	• 45% DAS28 remission
					• 0.08 Van de Heijde-modified total Sharp score
					• 0.81 UI reduction in HAQI
				Group 3	Group 3
				IV TCZ 8 mg/kg every 4 weeks and placebo	• 39% DAS28 remission
				Group 4	Group 4
				Placebo & MTX	• Fifteen% DAS28 remission
					• One.14 Van de Heijde-modified total Sharp score
					• 0.64 UI reduction in HAQI
SUMMACTA	1262	Randomized, double-blind, active controlled, parallel group, multicentre study	ACR20 response at week 24	Group 1	Group 1
				TCZ-SC 162 mg weekly + placebo-IV every 4 weeks	69% ACR20 response
		Patients with moderate to severely active RA on concomitant MTX treatment
				Group 2	Group 2
				TCZ-IV 8mg/kg every 4 weeks + placebo SC weekly	73% ACR 20 response
					Similar safety profile observed between the 2 groups, apart from more injection site reactions with TCZ-SC.
BREVACTA	656	Randomized, double-blind, placebo controlled, parallel group study	ACR20 response at week 24	Group 1	Group 1
				TCZ-SC 162 mg fortnightly + DMARDs	61% ACR20 response
				Group 2	Group 2
				Placebo-SC fortnightly + DMARDs	32% ACR 20 response
				(escape therapy with TCZ-SC 162 mg offered from week 12 if inadequate responders)	Significantly less structural joint damage progression demonstrated in the TCZ-SC fortnightly plus DMARDs group as compared with the placebo plus DMARDs group.

Table 4. Description and results from the pivotal clinical trials involving tocilizumab use in patients with sJIA and pJIA.

Study	Sample Size (n)	Design	Endpoint	Posology	Results
CHERISH	188	Randomized double blinded placebo controlled withdrawal 3-part study with 16 weeks open lead-in phase and 64 weeks open label follow up	% ACR30 flare in Part II of the study	Part I
				IV TCZ 8 or 10 mg/kg every 4 weeks for 16 weeks (n = 188)
		Inclusive criteria: active pJIA with inadequate response or intolerant to MTX		Part II	25.6% in TCZ group, 48.1 % in placebo group
				IV TCZ 8 or 10 mg/kg every 4 weeks for 16 weeks (n = 82)
				OR
				Placebo every 4 weeks for 16 weeks (n = 84)
				Part III
				SC TCZ 162 mg every 4 weeks for up to 64 weeks (n = 160)
TENDER	112	Part I	Part I	Part I	Part I
		Randomized double blinded placebo controlled parallel group 2-arm study for 12 weeks	% of participants with ≥ 30% improvement in JIA ACR and absence of fever	IV TCZ (8mg/kg) every 2 weeks (n = 37)	85.3 and 24% for IV TCZ and placebo groups, respectively
		Inclusive criteria: active pJIA		OR
				IV TCZ (12mg/kg) every 2 weeks (n = 38)
				OR
				IV Placebo every 2 weeks (n = 37)
		Part II	Part II	Part II	Part II
		Single arm open-label extension study for 92weeks	% of participants with decrease dose of oral corticosteroids at week 104	IV TCZ (8mg/kg) every 2 weeks (n = 52)	• 76% with ≥ 20% decrease
				OR	• 73% with ≥ 50% decrease
				IV TCZ (12mg/kg) every 2 weeks (n = 40)	• 62% with ≥ 75% decrease
				OR	• 47% with ≥ 90% decrease
				TCZ switchers (n = 20)
		Part III	Part III	Part III	Part III
		Open label continuation study for 3 y	Long term safety from week 104 to week 260	IV TCZ 8 mg/kg every 2 weeks for up to 240 weeks (n = 53)	ACR responses at week 104
				OR	• ACR30: 100%
			Long term efficacy (JIA ACR30,50,70 and 90)	IV TCZ 12 mg/kg every 2 weeks for up to 240 weeks (n = 59)	• ACR50: 100%
				OR	• ACR70: 94.4%
				IV TCZ 8 or 12 mg/kg every 2 weeks for up to 156 weeks (n = 112)	• ACR90: 76.4%.
					ACR responses at week 260
					• ACR30 96.7%
					• ACR50 93.3%
					• ACR70 90%
					• ACR90 63.3%

Table 5. Description of the most common side effects associated with tocilizumab use and how to manage them.

Side effects	Action
Skin/soft tissue infections	• Antibiotic therapy
	• Omit infusion for 4 weeks and the restart when infection resolved
Liver function tests	• Monitor Monthly for first 6 months
	• No action if < 3 times Upper limit of normal range (ULN) – Consider modifying MTX dose
	• Omit for 4 weeks if 3–5 times the ULN
	• Cease if > 5 times the ULN
Hypercholesterolemia	• Baseline fasting lipid profile and monitor 2 to 3 times in first 6 months, then annually.
	• Treatment with statins if elevated according to local guidelines
Neutropenia	• Monitor monthly for first 6 months
	• No action required if greater > 1 × 10^9/l
	• Omit for 4 weeks if 0.5–1 × 10^9/l
	• Cease if < 0.5 × 10^9/l
Anaphylaxis	• Monitor carefully in first 6 infusions
	• Do not re-challenge if patient could not complete prior infusion