Three years of experience: the Italian registry and safety data update.

Abstract

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

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MS TREATMENT
The pharmacovigilance program on natalizumab in Italy: 2 years
of experience
G. Tedeschi Æ Æ M. P. Amato Æ Æ R. D’Alessandro Æ Æ F. Drago Æ Æ C. Milanese Æ Æ P. Popoli Æ Æ P. Rossi Æ Æ
G. Savettieri Æ Æ M. R. Tola Æ Æ N. Vanacore Æ Æ A. Covezzoli Æ Æ M. De Rosa Æ Æ G. Comi Æ Æ Carlo Pozzilli Æ Æ
Antonio Bertolotto Æ Æ Maria Giovanna Marrosu Æ Æ Luigi M. E. Grimaldi Æ Æ C. Piccinni Æ Æ N. Montanaro Æ Æ
Laura Periotto Æ Æ Rosamaria Iommelli Æ Æ Antonio Addis Æ Æ Nello Martini Æ Æ L. Provinciali Æ Æ G. L. Mancardi
? Springer-Verlag 2009
Abstract
program on natalizumab therapy in multiple sclerosis was
settled in Italy by a collaborative effort of the Italian Drug
Agency (AIFA) and a group of experts and neurologists
appointed by the National Society of Neurology (SIN).
After 2 years, 1,818 patients are registered in the database.
The majority of cases (88.6%) failed the therapy with beta
interferon or glatiramer acetate and had relapses or accu-
mulated disability during immunomodulating treatment,
while 11.4% of patients enrolled in the surveillance study
were not previously treated with immunomodulating ther-
apies and had a rapidly evolving clinical course. Almost
10% of the patients treated with natalizumab interrupted,
for various different reasons, the therapy. Treatment was
well tolerated and side effects were similar to those
At the end of 2006 a country-based surveillance
reported in the registrative studies. The majority of treated
cases are stable or ameliorated.
Keywords
Surveillance program ? Pharmacovigilance
Multiple sclerosis ? Natalizumab ?
Introduction
Natalizumab is a recombinant humanized monoclonal
antibody directed against alpha 4 integrin, an adhesion
molecule expressed on the surface of circulating lympho-
monocytes. Activated immune cells penetrate inside the
central nervous system throughout the interaction of
alpha 4 integrin with the adhesion molecule (VCAM-1)
G. Tedeschi (&)
Dipartimento di Scienze Neurologiche, Seconda Universita ` di
Napoli e Istituto Hermitage Capodimonte, Naples, Italy
e-mail: gioacchino.tedeschi@unina2.it
G. Tedeschi ? M. P. Amato ? R. D’Alessandro ? F. Drago ?
C. Milanese ? P. Popoli ? P. Rossi ? G. Savettieri ?
M. R. Tola ? N. Vanacore ? L. Periotto ? R. Iommelli ?
A. Addis ? N. Martini ? L. Provinciali ? G. L. Mancardi
Tavolo Neurologico AIFA, Rome, Italy
A. Covezzoli ? M. De Rosa
Cineca-Consorzio Interuniversitario, Bologna, Italy
C. Piccinni ? N. Montanaro
Centro Regionale di Valutazione e Informazione sui Farmaci
(CReVIF), Universita ` di Bologna, Bologna, Italy
G. Comi
Dipartimento di Neurologia, Istituto Scientifico San Raffaele,
Milan, Italy
C. Pozzilli
Ospedale S. Andrea, Universita ` La Sapienza, Rome, Italy
A. Bertolotto
Centro di Riferimento Regionale Sclerosi Multipla,
AOU S.Luigi Gonzaga, Orbassano, Turin, Italy
M. G. Marrosu
Centro Sclerosi Multipla, Universita ` di Cagliari, Cagliari, Italy
L. M. E. Grimaldi
UO di Neurologia, Fondazione Istituto San Raffaele, G.Giglio,
Cefalu `, Palermo, Italy
123
Neurol Sci (2009) 30 (Suppl 2):S163–S165
DOI 10.1007/s10072-009-0143-6

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expressed on the surface of endothelial cells. Natalizumab
prevents the interaction between these receptors decreasing
therefore the passage from the blood to the brain of
mononuclear leukocytes. The activity of natalizumab was
first demonstrated in EAE [1] and then in large, random-
ized, double-blind, placebo-controlled phase III studies
[2, 3]. After the appearance of two cases of progressive
multifocal leukoencephalopathy (PML) and the withdrawal
of the drug from the market, natalizumab was finally
approved by FDA and EMEA during 2006. In our country
the drug was available and reimbursed by the National
Health Service at the end of 2006 in treating RR MS that
does not respond to interferon beta and glatiramer acetate
(Group A) or also in patients with a rapidly evolving severe
MS even not treated previously with immunomodulating
drugs (Group B). A postmarketing surveillance program
was established by the Italian Drug Agency (AIFA),
together with Cineca and a group of experts and neurolo-
gists appointed by the Italian Neurological Society (SIN).
The program was designed to obtain mainly information on
the utilization and safety of natalizumab. In this paper, we
present the data of the Italian Pharmacovigilance program,
after 2 years of experience.
Materials and methods
A web-based IT infrastructure was developed by Cineca-
Interuniversity Consortium, to collect all the requested
information for the accreditation of Centers, the inclusion
of eligible patients, the follow-up and the reporting of
adverse events.
Results
On 2 March 2009, 1,818 patients were registered in the
database. The national mean is 0.4 patients treated with
natalizumab for every 10,000 inhabitants: Lombardia,
Piemonte, Lazio, Sardegna, Molise and Valle d’Aosta have
more patients enrolled than the national mean, while
Liguria and Abruzzo perfectly are online with the mean.
Sardegna is the country area with the highest number of
cases treated with natalizumab compared to the population
of the region, while Lombardia has the highest absolute
number of cases (n = 366). The accredited MS centers for
the Italian surveillance program are 184 and 150 are the
centers with at least one case enrolled. The number of cases
treated for more than 12 months is 893, and 391 are the
patients that received more than 18 infusions. The five
more active centers are, in order of number of treated cases,
the Sant’Andrea Hospital, Rome; San Raffaele Hospital,
Milano; Binaghi Hospital, Cagliari; San Luigi Gonzaga
Hospital, Torino Orbassano and San Raffaele-Giglio
Institute, Cefalu `. The majority of registered patients are of
Group A, n = 1,584, (88.6%), cases that did not respond to
a course of beta interferon or glatiramer acetate and had
relapses or accumulated disability during treatment; and
204 (11.4%) are of Group B, patients not previously treated
with immunomodulating therapies and with a rapidly
evolving clinical course. The mean age at registration was
36.2 years for Group A, and 32.9 years for Group B, while
the duration of the disease was 10.1 and 4.8 years,
respectively. Mean EDSS was 3.5 for patients of Group A
and 3.5 for patients of Group B. The cases enrolled in the
Italian pharmacovigilance study have therefore a longer
duration and a higher EDSS as compared to the registrative
study AFFIRM [2], where the duration of the disease
before therapy with natalizumab was 5 years and mean
EDSS was 2.3. Almost 75% of cases of Group A had in the
past year 2 or more relapses, which resulted in permanent
neurological deficit in 85% of cases. There was an increase
of the lesional load at MRI in 75% of cases as compared to
the MRI carried out in the last year and 61% had at
enrollment an active MRI with Gd-enhancing areas. As
expected, patients of Group B were more active, with 95%
of cases with 2 or more relapses in the last 12 months that
determined irreversible neurological sequelae in 98% of
cases. An increase in the year before accrual of T2-positive
areas detected at MRI was shown in 98% of cases and an
active MRI at inclusion with appearance of new enhancing
areas was present in 78% of the cases.
Adverse events
Serious adverse events were reported in 22 cases: 1 case of
bacterial meningitis, 1 patient who developed a cutaneous
melanoma, 3 cases of serious allergic reaction, 1 case of
adenocarcinoma of the tongue and others different events.
Side effects were reported in the follow-up reports: 330
patients out of 1,307 with at least one follow-up inserted
had at least one not serious side effect (25%). The most
reported side events were hypersensitivity reactions in 5%
of these cases, infections of the urinary tract or other
irrelevant infections of the upper respiratory system, nau-
sea or diarrhea, headache, fever or flu-like symptoms and
articular pain in the other cases.
Dropouts
In Group A, 185 out of 1,584 patients (11.7%) interrupted
the therapy for different reasons, as side effects, drug
inefficacy, termination of the therapeutic cycle, presence of
neutralizing antibodies, pregnancy and others. In Group B,
in 17 out of 204 (8.3%) cases the treatment was withdrawn
for similar reasons.
S164 Neurol Sci (2009) 30 (Suppl 2):S163–S165
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Clinical outcome
Considering the number of cases with at least one follow-
up inserted in the database (1,307 patients), and the EDSS
at enrollment, 51.3% were classified as improved, 44%
were stable and 5% worsened.
Conclusion
The country-based surveillance program of natalizumab is
one of the most important efforts organized by AIFA and
the medical community for a drug with a particular safety/
efficacy profile. All the MS cases that in Italy are treated
with natalizumab are registered and their adverse events
are detected. At the moment, the safety profile appears
similar to that reported in the registrative studies. The
dropout is around 10% and the efficacy, evaluated with the
follow-up forms, appears excellent. In order to obtain all
the possible information, the pharmacovigilance program
should be implemented with external independent moni-
tors, to control the quality of data available and to give
support to the centers in order to correctly fill the forms,
especially to those centers with a high number of patients.
Other new endpoints should be identified, for example, the
clinical characteristic of responders and nonresponders and
the evolution of cases that interrupted the therapy, com-
pared to patients who continued the treatment.
Conflict of interest statement
no conflict of interest related to the publication of this manuscript.
The authors declare that they have
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