Bates_EU Neurology 10/03/2010 10:07 Page 61
Natalizumab (Tysabri
®
) – Re-defining Efficacy in Multiple Sclerosis
natalizumab-treated patients who were disease-free at two years
Figure 3: Proportions of Disease-free Patients Receiving
represented a 16-fold improvement relative to placebo (see Natalizumab or Placebo in the Overall and Highly ActiveFigure 3).
The effect of natalizumab treatment was greatest in the second year,
Disease Populations
indicating that efficacy may increase over time.
34
50
A long-term study followed up a subgroup of 23 MS patients who had
previously been enrolled in two phase III trials evaluating
40
36.7
natalizumab.
35
At 14 months after natalizumab treatment cessation,
no clinical, radiographic or immunological rebound phenomena were
30
27.4
observed. In addition, decreased lymphocyte numbers and altered
cell ratios returned to normal during this period and no infectious
20
complications were observed. These findings from a limited patient
population suggest that disease recurrence and other complications
10
7.2
may not be problematic, at least during the period of observation,
1.7
Proportion of disease-free patients (%)
after treatment with natalizumab.
0
n=304 n=600 n=59 n=146
Overall population 5x Highly active* 16x
The effects of stopping natalizumab were investigated by analysing
Placebo Natalizumab
data from a large-scale safety extension
36
that included patients who
had participated in the AFFIRM study,
25
the SENTINEL study
23
and the
*Patients with ≥2 relapses in prior year and ≥1 Gd+ lesion at baseline.
p<0.0001, natalizumab versus placebo for both overall and highly active patients.
GLatiramer Acetate and Natalizumab Combination Evaluation (GLANCE)
5x: Expressing results as a composite of clinical and radiological measures, the
safety study (a phase II study of natalizumab with glatiramer acetate
improvement in the treatment group was five-fold over placebo.
16x: In the highly active disease subgroup, the proportion of natalizumab-treated patients
versus placebo with glatiramer acetate in 110 patients with RRMS over
who were disease-free at two years showed a 16-fold improvement over placebo.
24 weeks).
37
The safety extension study was terminated early when
34
Source: Havrdova, 2009.
dosing of natalizumab was voluntarily suspended following the report
of two cases of PML in MS patients; the suspension of natalizumab disease activity, which was comparable to observations in clinical
dosing provided an opportunity to evaluate the effects of stopping trials. The proportion of patients discontinuing was similar across all
therapy. The analysis included data from 946 original natalizumab four studies (8.2–15%), and the safety profile of natalizumab is similar
patients who returned for safety evaluations after the voluntary to that seen in the AFFIRM study.
25
A health economic study on
suspension; these patients had received a mean 34.13±4.08 doses natalizumab in the UK concluded that the therapy is cost-effective
(range 6–41) before natalizumab was stopped. The data confirmed that, compared with current DMTs in all patients with highly active RRMS.
39
as would be expected based on natalizumab’s mechanism of action
and pharmacodynamics, disease activity had returned to on-study Long-term Safety
placebo levels by four months following cessation of treatment. This Natalizumab was voluntarily withdrawn from the market one year after
return of disease activity, in terms of annual relapse rate, was similar in its FDA approval in 2004 following three confirmed cases of progressive
all clinical subgroups. Patients who had highly active disease before multifocal leukoencephalopathy (PML), an opportunistic viral infection
they were enrolled in the original studies showed a greater absolute of the brain: in two patients from the SENTINEL study and in one patient
increase in disease activity compared with those with less active MS. with Crohn’s disease.
40,41
The FDA and European Medicines Agency
This was believed to be a result of the greater severity of the underlying (EMEA) re-approved the drug in 2006 with revised labelling, and it is
disease process during the original studies. Disease activity following now recommended only as monotherapy.
42
Natalizumab is prescribed
cessation of natalizumab did not rebound in excess of pre-existing in the US through a risk minimisation programme that has mandatory
disease activity levels. In addition, the use of other DMTs after stopping enrolment. Patients and physicians are required to participate in the
natalizumab did not appear to delay the return of disease activity, but Tysabri Outreach: Unified Commitment to Health (TOUCH) programme,
this finding requires further confirmation in a larger patient population.
36
in which patients are screened for PML symptoms before each
natalizumab infusion.
43
As of 30 November 2009, there have been 28
Post-marketing Experience confirmed cases of PML in more than 60,000 Tysabri-treated patients in
As of June 2009, natalizumab was approved in over 40 countries for the post-marketing setting.
38
It should be noted that the absolute
the treatment of RRMS in patients who have an inadequate response number of PML cases should be evaluated in the larger context of
to or are unable to tolerate another MS medication. It is also approved the number of patients actually exposed to natalizumab; it is therefore
by the US Food and Drug Administration (FDA) in adult patients with a less important measure than the incidence. In patients treated for up
moderately to severely active Crohn’s disease. By the end of to three years, the risk of PML appears to increase with increasing
September 2009, around 60,700 patients had been treated with treatment duration. In patients treated for two to three years, the rate
natalizumab in the post-marketing setting.
38
An overview of post- of PML is consistent with that seen in pre-approval clinical trials. There
marketing data from natalizumab patient registries and treated is limited experience in patients who have received more than three
cohorts around the world, including effects on relapse rates and years of Tysabri treatment.
disability progression, is given in Table 2. These ‘real-world’ data
show that, generally, patients being treated in the clinic are slightly The duration of natalizumab dosing prior to PML diagnosis ranged
older and have longer disease duration, higher EDSS and higher from approximately one year to more than 3.5 years (12–44 infusions),
baseline ARR than patients recruited into clinical trials. Despite and the incidence of PML generally increases with duration of
these baseline differences, patients treated with natalizumab in exposure, as shown in Figure 4. To date, clinical signs and symptoms
clinical practice showed stabilisation of disability and attenuation of that prompted evaluation for PML in natalizumab-treated patients
EUROPEAN NEUROLOGICAL REVIEW
61
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122 |
Page 123 |
Page 124 |
Page 125 |
Page 126 |
Page 127 |
Page 128 |
Page 129 |
Page 130 |
Page 131 |
Page 132