Microsoft word - tysabri position statement version 2 final
Position Statement for TYSABRI® (natalizumab) and STRATIFY JCVTM in Multiple
Rationale for this Position Statement
This Position Statement was developed by ten Australian neurologists who specialise in
the management of multiple sclerosis (MS). The Statement includes information on
TYSABRI and its key features in relation to the treatment of MS patients, in addition to
information on STRATIFY JCVTM, which is an assay for detecting JC Virus (JCV)
antibodies and its role in the risk stratification and management of PML.
The following MS experts were involved in the development of this Position Statement:
Dr Michael Barnett
Professor Bruce Brew
Professor Simon Broadley
Associate Professor Helmut Butzkueven
Professor William Carroll
Dr Suzanne Hodgkinson
Professor Allan Kermode
Associate Professor John King
Dr Christopher Kneebone
Professor Richard Macdonell
Working sessions of the above experts were organised with the support of Biogen Idec
Australia. This Position Statement was developed on the basis of the experts’
experience and knowledge of the use of natalizumab.
Medical writing and editorial support was provided by Ms Kate Trimble from Nitecs Pty
Limited and was funded by Biogen Idec Pty Limited.
The Product Information for TYSABRI should also be consulted for more detailed
information on the product. TYSABRI Clinical Profile
TYSABRI is a highly specific α4-integrin antagonist and was approved in Australia for the treatment of patients with MS with the relapsing-remitting form of the disease on the basis of its targeted mode of action and its positive effects on various clinical and magnetic resonance imaging (MRI) outcomes in the placebo-controlled clinical studies. The studies included AFFIRM1 (Natalizumab Safety and Efficacy in Relapsing-Remitting MS), SENTINEL2 (Safety and Efficacy of Natalizumab in Combination with Avonex IFNB-1a in Patients with Relapsing-Remitting MS) and GLANCE3 (Glatiramer Acetate and Natalizumab Combination Evaluation). Further evidence of “real world” efficacy of TYSABRI has been confirmed in the ongoing TYSABRI Observational Program (TOP).4 TYSABRI is indicated as monotherapy for the treatment of patients with relapsing remitting multiple sclerosis (MS) to delay the progression of physical disability and to reduce the frequency of relapse.
TYSABRI Safety Profile, PML Risk and the Role of STRATIFY JCVTM
TYSABRI Safety Profile
In placebo-controlled studies involving 1,617 MS patients treated for up to 2 years,
43.5% of patients treated with TYSABRI reported adverse effects compared to 39.6% of
placebo treated patients. Adverse effects reported more frequently with TYSABRI
included headache, fatigue, urinary tract infections and arthralgia. A range of infusion
reactions, each relatively infrequent, have been reported (23.1% of patients treated with
TYSABRI versus 18.7% with placebo). Hypersensitivity reactions were observed in 4%
of patients treated with TYSABRI and anaphylactic reactions were reported in less than
1% of patients. Treatment of the anaphylactic reactions included immediate
discontinuation of the TYSABRI infusion and administration of antihistamines and/or
of hypersensitivity reaction, treatment with TYSABRI must be
In some cases, infusion reactions may be managed by pre-treatment with
steroids and antihistamines. Development of antibodies against natalizumab was
observed in 10% of patients and persisting antibodies were identified in 6% of patients
which results in loss of efficacy of TYSABRI.
Opportunistic infections have been reported with the use of TYSABRI predominantly in
immunosuppressed patients or those with significant comorbidity.
TYSABRI should not
be administered to patients with increased risk for opportunistic infections, including
those immunocompromised due to current or recent immunosuppressive therapies (e.g.
azathioprine, mitoxantrone), or systemic medical conditions resulting in significantly
compromised immune system function (e.g. human immunodeficiency virus (HIV), organ
transplant, active malignancy). TYSABRI should not be administered in combination
with immunomodulatory agents (e.g. interferon beta or glatiramer acetate).
Overall, TYSABRI has shown a very good tolerability profile, however use of
natalizumab has been associated with an increased risk of developing a rare viral brain
infection, progressive multifocal leukoencephalopathy (PML) which may lead to severe
disability or even death. PML is an opportunistic infection of the CNS caused by the JC
virus, a type of human polyomavirus. The infection rate and therefore seroprevalence of
JCV in humans is estimated at around 50-60%, with primary infection usually occurring
in childhood, almost always having an asymptomatic course. The virus persists in the
kidneys, bone marrow or lymphatic tissue, and controversially in the brain. It is often
intermittently shed in the urine of healthy individuals.
The underlying pathology of PML involves active replication of the JC virus in glial cells
of the brain causing lytic death of oligodendrocytes. Previously the infection typically
arose in severely immunocompromised patients such as those with HIV infection or
organ transplantation. PML is extremely rare in immunocompetent individuals.
Patients with PML may present with cognitive or behavioural symptoms, which have
been most commonly observed either alone, or in association with motor, language, or
visual symptoms. Any new neurological symptoms or personality changes lasting more
than two days should be reviewed by the treating clinician. MRI findings show typical
subcortical lesions often with gadolinium enhancement, which is usually less intense and
more granular or punctate than that typically observed with MS lesions. It is still too
early to draw broad conclusions about outcomes in patients who have developed PML
whilst receiving TYSABRI as data are insufficient, however preliminary findings indicate
that early diagnosis of PML, heightened clinical vigilance, and cessation of TYSABRI on
suspicion of PML are associated with better outcomes for MS patients.5
Whilst TYSABRI use has been associated with an increased risk of PML, the absolute
risk for PML in patients treated with TYSABRI cannot be precisely estimated. As of 2nd
January 2013 on the basis of worldwide post-marketing reports, the estimated overall
risk of PML is 2.84 per 1000 patients (95% CI 2.54-3.16 per 1,000 patients)6; for the
most current PML incidence figures please refer to the Tysabri®
Program (TAPP) website (www.tapp.com.au).
In TYSABRI patients who develop PML, Immune Reconstitution Inflammatory Syndrome
(IRIS) occurs in almost all cases after withdrawal or removal of TYSABRI, e.g. by
plasma exchange (PLEX), and PLEX is recommended when PML is suspected. IRIS is
thought to result from the restoration of CNS immune function in patients with PML. IRIS
presents as a worsening in neurological status that may be rapid, which can lead to
serious neurological complications and may be fatal. Monitoring for development of IRIS,
which has occurred within days to several weeks after plasma exchange in TYSABRI
treated patients with PML, is essential and appropriate treatment of the associated
inflammation during recovery from PML should be undertaken, using high dose
intravenous glucocorticoids. The role of prophylactic glucocorticoids to prevent or
reduce the severity of IRIS is recommended by some experts, as IRIS is an almost
universal occurrence in TYSABRI related PML. Moreover, there is a reasonably large
body of anecdotal evidence that PML does not worsen when corticosteroids in high dose
are given over short periods. PML Risk Stratification and the Role of STRATIFY JCVTM
Given the widespread use of TYSABRI and the potentially life-threatening consequences
of PML, there is a need to identify patients who may be at a higher risk of developing
PML. There are three risk factors that have been identified for MS patients receiving
treatment with TYSABRI and the development of PML:
1. Treatment duration, especially beyond 2 years. There is limited experience in
patients who have received more than 4 years of TYSABRI treatment. Therefore, the risk of PML in these patients cannot currently be estimated.
2. Immunosuppressant use at any time prior to receiving TYSABRI. 3. The presence of anti-JCV antibodies.
A two-step JCV antibody assay known as STRATIFY JCVTM has been developed, which combines ELISA with an immunoadsorption step. Preliminary assessments detected JCV antibodies in 54% of MS patients who were tested.7 An annual seroconversion rate of 2-3% has been observed, whereby patients convert from JCV antibody negative to persistent positive status.7 With this assay, assessment of JCV antibodies in archived serum samples obtained from 75 TYSABRI-treated patients at 6-187 months prior to PML diagnosis showed that samples from all patients tested positive for JCV antibodies.8 Therefore, detection of JCV antibodies in combination with other known risk factors such as prior use of immunosuppressants and duration of TYSABRI treatment could stratify PML risk in patients with MS who are being treated, or are being considered for treatment, with TYSABRI.
Patients who have all three of the above risk factors have the highest risk of PML, being approximately 10 in 1,000 patients treated, as determined during studies using the STRATIFY JCV assay. Table 1 shows the estimated risk of PML development when the three risk factors are taken into consideration.
Table 1 PML risk stratification9
JCV Antibody positive no
JCV Antibody positive
prior IS use
with prior IS use
Adapted from Bloomgren et al 2012. PML incidence data based on 212 confirmed PML cases as of February 29, 2012;
analysis assumes 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test
positive for anti-JCV antibodies prior to the onset and diagnosis of PML; 34.5% had prior immunosuppressant (IS) use.
Calculation assumes one expected case of JCV antibody negative PML in patients exposed to at least 18 months of
The risks and benefits of continuing treatment with TYSABRI should be carefully
considered in patients who have all three of these risk factors for PML. Patients with no
prior exposure to JCV have a very low risk of PML irrespective of duration of treatment
and prior immunosuppressant use. TYSABRI should be administered with caution to
patients who have previously received immunosuppressants in the recent or distant past,
and only with knowledge of JCV antibody status, to assess the risk of developing PML.
Data beyond 4 years of treatment are limited.
Considerations for the use of TYSABRI and STRATIFY JCV
TM Antibody Assay
TYSABRI therapy is to be initiated and supervised by neurologists, in centres with timely access to MRI. Prescribing neurologists must discuss the benefits and risks of TYSABRI therapy with the patient, provide them with the Consumer Medicine Information and a Patient Alert Card and obtain individual, written, fully informed consent from the patient (or legal guardian where appropriate) for the use of TYSABRI. Neurologists should counsel patients on the importance of uninterrupted dosing, particularly in the early months of treatment. The Alert Card reminds patients that because of the risks of PML and opportunistic infections with TYSABRI, they must contact their doctor if they have unusual or prolonged new neurological symptoms or if they have severe or prolonged symptoms of infection. Patients should be instructed that they should inform all their healthcare providers that they are receiving treatment with TYSABRI. At a minimum the neurologist should re-evaluate the patient 3 months after the first infusion, 6 months after the first infusion and every 6 months thereafter. More frequent monitoring may be warranted for patients in higher risk groups for developing PML. Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic benefit beyond 6 months. Continued therapy beyond 2 years should be considered only following a reassessment of the potential for benefit and risk. Testing of MS patients for JCV antibodies with STRATIFY JCV is recommended as part of the benefit-risk evaluation for treatment decisions as follows:
For all patients treated with TYSABRI in whom JCV antibody status is unknown
For all patients where the neurologist is considering commencing TYSABRI
If the STRATIFY JCV assay indicates a positive result, other risk factors should be carefully considered together with other possible treatment alternatives before starting/continuing TYSABRI. In patients who have all three PML risk factors (i.e., JCV antibody positive, prior immunosuppressant use and >2 years exposure to TYSABRI) the risk-benefits of continuing therapy with TYSABRI should be carefully re-evaluated.
In the case of a negative result, TYSABRI is a suitable treatment earlier in the disease, even in situations where the disease activity is not high, or in the case of adverse events or continuing disease activity in response to other treatments. TYSABRI treated patients who are JCV antibody negative should be retested every 6 months, and the benefit-risk balance should be reassessed should their serostatus change to positive. In the case of a JCV antibody positive result, no repeat JCV antibody testing is required. JCV antibody assays should not be used alone to diagnose PML: seropositivity is necessary as an indicator of JCV infection but not sufficient for the diagnosis. JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum. Before initiation of treatment with TYSABRI, a recent (usually within 3 months) MRI should be available as a reference. In JCV negative patients this should be repeated on a yearly routine basis to update this reference. In JCV positive patients the MRI should be repeated after the first 12 months of therapy and subsequently MRIs are recommended to be performed at 6 monthly intervals. If there has been prior immunosuppressant use, increasing the MRI frequency to 3 monthly is recommended. MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML; FLAIR (fluid-attenuated inversion recovery) and DWI (diffusion-weighted imaging) sequences should be included in the MRI as this is a more sensitive method than T2 for distinguishing PML from MS lesions. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If new neurological symptoms suggestive of PML occur, further dosing is to be suspended until PML has been excluded. If any doubt exists, further evaluation, including MRI scan (compared with pre-treatment and previous post-treatment MRI), CSF testing for JCV DNA and repeat neurological assessments, should be performed. If initial investigations prove negative, but clinical suspicion for PML still remains, TYSABRI should not be restarted and repeat investigations should be undertaken. Once the clinician has excluded PML, dosing of TYSABRI may resume. PML has been reported following discontinuation of TYSABRI in patients who did not have findings suggestive of PML at the time of discontinuation. Patients and healthcare professionals should continue to be vigilant for any new signs or symptoms that may be suggestive of PML for approximately six months following discontinuation of TYSABRI.10 Physicians should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive or psychiatric symptoms). Patients should also be
advised to inform their partner or caregivers about their treatment, since they may notice
symptoms that the patient is not aware of.
If a patient develops PML, the dosing of TYSABRI must be permanently discontinued to
enable reconstitution of the immune system in the CNS. Treatment with corticosteroids
should be administered to reduce the severity of IRIS. References
1. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of
natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899-910.
2. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for
relapsing multiple sclerosis. N Engl J Med 2006; 354:911-923.
3. Goodman AD, Rossman H, Bar-Or A, et al. GLANCE: Results of a phase 2, randomized,
double-blind, placebo-controlled study. Neurology 2009; 72:806-812.
4. Kappos L, Belachew S, Butzkueven H, Pellegrini F, Trojano M, Wiendl H, Zhang A,
Hotermans C. Multiple Sclerosis Patients Treated with Natalizumab in the TYSABRI® Observational Program (TOP). P04.134 AAN, New Orleans, 2012
5. Kappos L, Bates D, Edan G, et al. Natalizumab treatment for multiple sclerosis: updated
recommendations for patient selection and monitoring. Lancet Neurol 2011; 10:745-58.
6. http://www.tapp.com.au/members/Tysabri_Safety_Update_180113.pdf accessed
7. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk
stratification. Ann Neurol 2010; 68: 295–303.
8. Goelz SE, Gorelik L, Subramanyam M. Assay design and sample collection can affect
anti-John Cunningham virus antibody detection. Ann Neurol 2011; 69: 429–31.
9. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S,
Plavina T, Scanlon JV, Sandrock A, and Bozic C. Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. NEJM 2012; 366 (20): 1870-80.
(natalizumab) Australian Product Information, date of most recent amendment
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