Natalizumab: A new treatment for relapsing remitting multiple sclerosis

Figures & data

Table 1 Pharmacokinetic parameters after repeated doses of natalizumab 300 mg in patients with multiple sclerosis (Tysabri PI 2006)

Parameter	Mean ± SD
Cmax, μg/mL	110 ± 52
Css, μg/mL	23 to 29
CL, mL/h	16 ± 5
Vd, L	5.7 ± 1.9
t1/2, d	11 ± 4

Abbreviations:CL, clearance; C_max, maximum plasma concentration; C_ss, mean steady-state concentration; SD, standard deviation; t_1/2, elimination half-life;V_d, volume of distribution.

Table 2 Phase 2 studies of natalizumab

	Objectives	Inclusion criteria	N	Treatment	Results for primary endpoint
Tubridy et al 1999	Effect of natalizumab on MRI lesions in patients with RRMS or SPMS	18–55 years, EDSS of 2.0–7.0, ≥2 relapses within past 18 months, relapse-free in past 4 weeks	72	Natalizumab 3 mg/kg or placebo (1:1), at 0 and 4 weeks for a total of 2 infusions	Mean number of new active lesionsa through week 12: 1.8 natalizumab vs 3.6 placebo (p = 0.042) Mean number of new Gd+ lesions through week 12:1.6 natalizumab vs 3.3 placebo (p = 0.017)
Miller et al 2003	Safety and efficacy of natalizumab in patients with RRMS or SPMS	18–65 years, EDSS 2.0–6.5, ≥2 relapses in past 2 years, ≥3 T2 lesions	213	Natalizumab (3 or 6 mg/kg) or placebo (1:1:1) every 4 weeks for 6 months	Mean number of new Gd+ lesions through month 6: 0.7 natalizumab 3 mg/kg, 1.1 natalizumab 6 mg/kg, 9.6 placebo (p < 0.001 for comparison of each active group vs placebo)
O'Connor et al 2004	Effect of a single dose of natalizumab in patients with RRMS or SPMS during an acute relapse	18–65 years, EDSS ≥5.5, stable FSS scores for ≥30 days prior to qualifying acute relapseb	180	Natalizumab (1 mg/kg or 3 mg/kg) or placebo (1:1:1), single dose	Mean change in EDSS between treatment groups at 1 week after treatment: no treatment differences were observed
Goodman et al 2005	Safety and efficacy of natalizumab when added to the standard regimen of GA in patients with RRMS	18–55 years, MRI lesions, EDSS 0.0–5.0, GA treatment for past 12 months, ≥1 relapse in past 12 months	110	Natalizumab 300 mg or placebo (1:1), every 4 weeks by IV, in addition to GA SC daily	Rate of new active lesion development on MRI: study complete, but results not available

Notes: All studies were randomized, double-blind, parallel-group, and placebo-controlled;

a New active lesions were defined as the sum of new Gd+ lesions on T1-weighted images and new or newly enlarging lesions observed on T2-weighted images;

b To qualify as an acute relapse, relapse symptoms must have been present within 24 hours but appeared no longer than 96 hours prior to receiving study medication, and the patient's EDSS score had to be >3.0 at the time of the acute relapse.

Abbreviations:EDSS, Expanded Disability Status Scale; FSS, functional system subscale; GA, glatiramer acetate; Gd+, gadolinium enhancing; IFNβ-1a, interferon beta; IM, intramuscular; IV, intravenous; MRI, magnetic resonance imaging; RRMS, relapsing-remitting multiple sclerosis; SC, subcutaneous; SPMS, secondary progressive multiple sclerosis.

Table 3 Phase 3 studies of natalizumab: 2-year results

	Natalizumab (n = 627)	Placebo (n = 315)	P-Value
AFFIRM (Polman et al 2006)
Clinical endpoints
Annualized relapse rate, mean (95% CI)	0.23 (0.19, 0.28)	0.73 (0.62, 0.87)	<0.001
Sustained disability progressiona, % of patients	17	29	<0.001
MRI endpoints (lesions per patient)
No. of new or enlarging T2 lesions, mean ± SD	1.9 ± 9.2	11.0 ± 15.7	<0.001
No. of Gd^+ lesions, mean ± SD	0.1 ± 1.4	1.2 ± 3.9	<0.001

	Natalizumab + IFNβ−1a(n = 589)	Placebo + IFNβ−1a(n = 582)	P-Value
SENTINEL (Rudick, Stuart, et al 2006)
Clinical endpoints
Annualized relapse rate, mean (95% CI)	0.34 (0.29, 0.39)	0.75 (0.67, 0.84)	<0.001
Sustained disability progression, % of patients	23	29	0.02
MRI endpoints (lesions per patient)
No. of new or enlarging T2 lesions, mean ± SD	0.9 ± 2.1	5.4 ± 8.7	<0.001
No. of Gd^+ lesions, mean ± SD	0.1 ± 0.6	0.9 ± 3.2	<0.001

a Note: Defined as either a ≥1.0-point increase in EDSS from a baseline of ≥1.0, or a ≥1.5-point increase in EDSS from a baseline of 0.The change was required to be sustained for at least 12 weeks and could not be confirmed during a relapse.

Abbreviations: CI, confidence interval; Gd⁺, gadolinium enhancing; IFN, interferon; MRI, magnetic resonance imaging; SD, standard deviation.

[Tysabri PI] Biogen Idec, Inc.Tysabri® (natalizumab) package insert2006Cambridge, MABiogen Idec, Inc.

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