Natalizumab In Multiple Sclerosis Research Articles

Safety, anxiety and natalizumab continuation in JC virus-seropositive MS patients

The use of natalizumab in multiple sclerosis has been restricted by the risk of progressive multifocal leukoencephalopathy (PML). JC virus carriership, duration of natalizumab treatment and past immunosuppression are known risk factors. This has allowed for calculated risk assessment for individual patients to be implemented. Not much data are available about the effect of JCV carriership on patient willingness to continue natalizumab. Here, we evaluated the impact of JCV seropositivity on safety feelings, anxiety and treatment continuation for patients treated with natalizumab, using a visual analog scale, the Hospital Anxiety and Depression Scale and a decisional conflict scale. Seropositivity led to an elevated anxiety level for PML (p = 0.004). However, so far only 3% of patients have discontinued natalizumab because of JCV positivity in our cohort.

Registries for neurological drugs landscape

In Italy we can mention two experiences related to the use of registries for neurological drugs. The first one involved the use of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) in the treatment of probable Alzheimer's dementia of mild-moderate level; the second, currently in progress, concerned the use of natalizumab for the treatment of multiple sclerosis. The registry of the use of cholinesterase inhibitors in Alzheimer's dementia produced an observational study, whereas the registry on the use of natalizumab in multiple sclerosis, a rare experience in the international, can be regarded as an opportunity not fully appreciated in terms of public health. Natalizumab is prescribed in current clinical practice in patients other than those included in registration studies. In this paper the two Italian experiences will be presented with the understanding that registries cannot make up for the lack of proper registration studies, but can provide, especially when they are conducted and planned as observational studies, new scientific evidence on the risk/benefit profile of the drugs in the real world.

Cost–effectiveness of natalizumab in multiple sclerosis: an updated systematic review

As natalizumab (Tysabri®; Elan Pharmaceuticals, Inc., Dublin, Ireland) and other disease-modifying drugs are entering the market for multiple sclerosis, the treatment repertoire is expanding beyond the established first-line treatments. This is creating new opportunities but also increasing the uncertainty in the appropriate management of this condition with its considerable societal burden. As a result, economic evaluations are increasingly influential in healthcare decision making. Seven evaluations that included natalizumab have been published to date. They largely report favorable results for this treatment compared with other drugs. However, the models used to reach these conclusions have been subjected to significant debate, owing to limited data availability as well as the methodological complexities and uncertainties in the pharmacoeconomics of multiple sclerosis. This review critically discusses the available evidence based on the cost–effectiveness of natalizumab and uses the data to explain more general issues in the evaluation of similar drugs. The review also suggests how shortcomings in current studies may potentially be addressed in the future.

Clinical predictors of an optimal response to natalizumab in multiple sclerosis

Despite the high level of effectiveness of natalizumab (NTZ) in the treatment of patients with multiple sclerosis (MS), concerns about its high direct cost and its safety have restricted its use. Our aim was to identify and quantify the clinical factors that predict an optimal response to NTZ. Patients with MS undergoing treatment with NTZ for at least 12months were classified as optimal responders if, during treatment, they sustained a reduction in their Kurtzke Expanded Disability Status Scale (EDSS) score of 1 point or more or experienced a reduction in annualised relapse rate (ARR) of more than 1. The remaining patients were classified as suboptimal responders and non-responders. Our subject pool included 48 patients. The variables associated with optimal response included: ARR in the previous year of at least 2, an age at first administration of 37.5years or less, a baseline EDSS score of 4.5 points or less, a disease duration of 9.5years or less and, in patients with secondary-progressive MS, a progressive-phase duration of 4.5years or less. The characteristics of the disease at its onset did not affect responsiveness, indicating that patients with highly active disease and low disability are the ideal candidates for NTZ treatment, regardless of previous clinical characteristics.

Best practice in the use of natalizumab in multiple sclerosis

Natalizumab is approved for the treatment of patients with relapsing-remitting multiple sclerosis who have failed first-line treatment with traditional disease-modifying therapies or who have highly active disease. The drug has proved highly effective, both in a clinical trial setting and in clinical practice, with marked reductions in the rate of clinical relapses and slowed disease progression. These clinical outcomes are mirrored by a marked reduction in disease activity as evidenced by magnetic resonance imaging of the brain. However, natalizumab treatment has been associated with a risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal condition caused by JC virus (JCV) activation. When this condition was detected in a clinical trial shortly after approval, the drug was immediately and voluntarily withdrawn from the market. As a condition of its reinstatement, stringent pharmacovigilance measures and a risk management plan were enforced. The recent availability of a two-step enzyme-linked immunosorbent assay (ELISA) test for the presence of anti-JCV antibodies (free testing is available in a central laboratory for registered centers), along with an ever-improving understanding of other risk factors such as prior immunosuppressant use and duration of treatment, allow an increasingly refined stratification of the risk of PML. This improved stratification of risk can help guide decisions about treatment. This review will also deal with other topics of relevance to clinical practice such as the development of antinatalizumab antibodies and their negative implications in terms of hypersensitivity reactions and loss of efficacy, withdrawal of treatment, and compassionate pediatric use.

JC virus detection and JC virus-specific immunity in natalizumab-treated Multiple Sclerosis patients

BackgroundThe use of natalizumab in multiple sclerosis (MS) may favour JC virus reactivation; this phenomenon is usually asymptomatic but can, albeit rarely, evolve into frank progressive multifocal leucoencephalopathy (PML).MethodsJCV-specific CD8+ T lymphocytes were evaluated by flow cytometry over a 24-month period in 24 natalizumab-treated MS patients in whom JCV DNA was or was not detected in blood using quantitative real-time polymerase chain reaction; all these cases were asymptomatic.ResultsPerforin- and grazymes-containing VP-1-specific CD8+ T lymphocytes were reduced whereas CD107a-expressing cells were increased in JCV positive patients, suggesting an active degranulation of these cells; naïve CD8+ T lymphocytes were also decreased whereas memory cells were increased in patients in whom JCV reactivation was observed.ConclusionThe presence of a CD8+ T lymphocyte-mediated effector immune response offers a greater insight into reactivation of JCV and its clinical sequelae, and may help the monitoring of patients on natalizumab therapy.

Therapeutic Plasma Exchange for Progressive Multifocal Leukoencephalopathy Related to Multiple Sclerosis Therapy with Natalizumab

Abstract 4386 Background:Progressive multifocal leukoencephalopathy (PML) associated with natalizumab in multiple sclerosis (MS) treatment is a complication for which therapeutic plasma exchange (TPE) has been used. We describe such a case treated with TPE. Case Report:A 54 year old woman with a past medical history of relapsing-remitting MS presented with recent onset ataxia and bilateral upper and lower extremity weakness and right hand dysmetria. Two weeks prior to presentation, she completed 57 treatments with natalizumab, a monoclonal antibody against cellular adhesion molecule α4-integrin that blocks lymphocytes from crossing the blood-brain barrier. Brain MRI showed new non-enhancing lesions in the right cerebellum and anterior left temporal lobe. Natalizumab was discontinued and investigation revealed high serum and CSF titers of JC virus DNA indicative of PML. The patient underwent a total of 3 TPE’s (1 every other day) with 3L of 5% albumin solution (1.4 plasma volume [PV]) used as replacement each TPE. After TPE, the patient initially showed improvement of neurological function and was transferred to inpatient acute rehabilitation. However, 4 days later she suffered a seizure and developed slurred speech. MRI showed that the cerebellar lesion had extended into the pons. The patient also developed dysphagia requiring nasogastric tube feeding and poorly-localized pain requiring pain management. She was treated with steroids for possible Immune Reconstitution Inflammatory Syndrome (IRIS) and discharged to hospice care for rehabilitation and pain management. The patient’s condition continued to deteriorate and she died shortly after being arriving at hospice. Conclusion:Natalizumab selectively immune suppresses the CNS putting patients at risk for PML and TPE with or without immunadsorption, can rapidly reverse the immune suppression by clearing natalizumab. Although we did not measure natalizumab concentrations in our patient, 1 report showed that a series of 3 TPE’s (1.5 PV) significantly decreased natalizumab levels while another showed that 3–5 TPE’s (1–1.5 PV) was effective. The effect of reducing natalizumab is to exchange the problem of a typically fatal opportunistic infection for the problem of an aggressive potentially injurious immune response to that virus. IRIS itself requires intense management to prevent brain injury or death and while there is no set standard of care, steroids are typically used. According to the manufacturer’s global monitoring system, the majority of natalizumab induced PML cases are treated with TPE which typically induces IRIS within days to weeks. The most recent mortality rate for all PML cases related to this drug is 22%, significantly lower than that seen with AIDS or in the oncology setting. Although our patient initially improved after TPE, the proximity of the PML to her brainstem, with or without IRIS, made her particularly vulnerable. Whether TPE may lead to more severe IRIS, as suggested by one report, requires further study. Nevertheless, given the severe consequences of PML itself, we would recommend TPE for natalizumab -induced PML. Disclosures:No relevant conflicts of interest to declare.

PND74 How Have Manufacturers Overturned Negative Reimbursement Decisions? A Case Study Using Natalizumab for Multiple Sclerosis

To identify and explore how reimbursement decisions for natalizumab, a treatment for multiple sclerosis (MS), were overturned from an initial rejection to a recommendation. This analysis was conducted in conjuntion with a wider review of the global reimbursement landscape for MS therapies. We reviewed reimbursement decisions or recommendations from global payer decision-making agencies, including any decisions where an initial rejection was overturned. We reviewed the agency rationale for both the original and subsequent decisions, and how the manufacturer influenced the decision reversal. Since 2006, 17 payer decisions for natalizumab were identified (six recommendations, eight restricted recommendations and three rejections). The three rejected decisions were later overturned by the manufacturer submitting further evidence. To PBAC this involved re-defining the indirect comparison to consider the heterogeneity in the trials included. To SMC and CADTH post-hoc analysis was submitted for the specific subgroup of rapidly evolving severe relapsing remitting MS. For CADTH a 15% price discount was agreed in addition. Across all agencies clinical need was an important factor. By emphasising unmet needs, submitting further evidence in defined subgroups and ensuring indirect comparisons are methodologically sound, it has been possible to overturn initial negative decisions by payer agencies to restricted recommendations in define subgroup. Identification of the optimum treatable population has proved pivotal in the reversal of fortune.

Urinary JCV-DNA Testing during Natalizumab Treatment May Increase Accuracy of PML Risk Stratification

The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.

Downregulation of Intrathecal IgM Synthesis Associates with Optimal Response to Natalizumab in Multiple Sclerosis (P06.175)

Downregulation of Intrathecal IgM Synthesis Associates with Optimal Response to Natalizumab in Multiple Sclerosis (P06.175)

Cessation of Natalizumab in Multiple Sclerosis and Risk for Relapse Activity within the First 6 Months (P06.173)

Cessation of Natalizumab in Multiple Sclerosis and Risk for Relapse Activity within the First 6 Months (P06.173)

Assessment and Concordance of Serum Anti JC Virus Antibodies and JCV DNA Presence in Multiple Sclerosis Natalizumab Treated Patients (P07.054)

Assessment and Concordance of Serum Anti JC Virus Antibodies and JCV DNA Presence in Multiple Sclerosis Natalizumab Treated Patients (P07.054)

Immunological Markers of Optimal Response to Natalizumab in Multiple Sclerosis

To explore cell subsets and molecules that changed specifically in patients with multiple sclerosis (MS) who had an optimal response to natalizumab. Natalizumab is a monoclonal antibody that inhibits the migration of activated immune cells to the central nervous system. It shows high efficacy in modifying the natural history of MS and induces freedom of disease activity in about 40% of treated patients with MS. Prospective study of intrathecal immunoglobulin synthesis and cerebrospinal fluid lymphocyte subsets in patients with MS before and 1 year after beginning treatment with natalizumab. We monitored clinical and magnetic resonance imaging activity during a median time of 2 years. Two tertiary hospitals from the Spanish National Health Service. A total of 23 patients with MS. The differences between patients free of disease activity and patients with active disease during treatment. Of the 23 patients, 10 (43.5%) remained free of disease activity during follow-up. The remaining 13 patients (56.5%) had relapses or new lesions despite natalizumab therapy. We did not find differences in demographic variables or clinical data between both groups prior to natalizumab therapy. All patients showed a decrease in cerebrospinal fluid CD4(+) cells regardless of their response to treatment. Conversely, only patients free of disease activity showed a decrease in local IgM and, to a lesser extent, in IgG synthesis. They also showed lower percentages of B cells, particularly of CD5(+) and plasmablast subsets that virtually disappeared after treatment with natalizumab. These data indicate that inhibition of intrathecal antibody synthesis is associated with a complete therapeutic response to natalizumab in patients with aggressive MS.

Risk stratification and patient counseling for natalizumab in multiple sclerosis

Natalizumab has demonstrated efficacy in multiple sclerosis (MS), but is associated with increased risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection caused by the JC virus. At the time of natalizumab's reapproval in 2006, the estimated risk of PML was 1:1,000 (95% confidence interval 0.2–2.80) over 17.9 months of treatment.1 Since then, 3 risk factors for natalizumab-related PML have emerged2: 1) cumulative exposure to natalizumab, with risk increasing up to 3 years, after which risk appears to plateau; 2) previous treatment with cytotoxic or immunosuppressive (IS) drugs3; and 3) prior history of JCV infection, as indicated by the presence of JCV antibodies. Using a 2-step ELISA assay for anti-JCV antibodies, Gorelik et al.4 reported a 53.6% incidence of anti-JCV antibodies in patients with MS; the false-negative rate was 2.5%. To date, 28 natalizumab-related PML cases had blood specimens available 1 year or more prior to the development of PML. Using this assay, all 28 patients were seropositive, which is highly statistically significant ( p = 3.21 × 10−8).5 This assay is now clinically available in the United States …

Herpes encephalitis during natalizumab treatment in multiple sclerosis

In this case report we describe the first non-fatal herpes simplex virus encephalitis (HSE) case with natalizumab for multiple sclerosis (MS). A 36-year-old woman, previously treated with immunomodulatory and immunosuppressive drugs for MS, developed acute encephalitis after 6 monthly natalizumab perfusions. Brain imaging demonstrated suggestive bi-temporal lesions. Herpes simplex virus type-1 DNA was detected in cerebrospinal fluid. The patient improved gradually after a 21-day course of intravenous acyclovir, but neuropsychiatric changes remained 5 months later. Our non-fatal case of HSE and other reported cases of herpes infections provide evidence of an increased risk with natalizumab and point to the need for clinicians to maintain awareness.

The Toronto Observational Study of Natalizumab in Multiple Sclerosis

Natalizumab is indicated for the treatment of relapsing multiple sclerosis (MS) with insufficient response to first-line disease-modifying therapy (DMT). We studied the efficacy of natalizumab for treatment of MS in a single centre observational design. A retrospective observational study of 146 patients [66% female; mean age 37.4; 72% relapsing remitting MS (RRMS), 28% secondary progressive MS (SPMS)] referred for natalizumab treatment at St. Michael's Hospital MS Clinic between 2007 and August 2009. Data included demographic, clinical (Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR)) and patient self-report measures. The mean duration of treatment was 20 months in those treated with natalizumab and 97% had received prior DMTs. Eighty-three patients (57%) received at least 12 months of natalizumab treatment. In those who received at least 12 months of treatment, baseline ARR and EDSS were 1.6 and 2.7 in RRMS patients versus 1.0 and 5.4 in SPMS with relapses. The ARR decreased with natalizumab treatment to 0.38 (76% reduction, p<0.001) in RRMS versus 0.32 in SPMS patients (68% reduction, p=0.01). There was a treatment associated 11% reduction in EDSS to 2.4 (p=0.04) in RRMS, but no significant change in SPMS. Eighty-five percent of patients reported improved overall quality of life (QOL) and 62% indicated improved energy. There was a major reduction in relapse rate, stabilization in EDSS and improvement in QOL and energy in some patients on natalizumab, all similar to treatment effects in the pivotal trial.

De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate

Natalizumab (NAT) is an effective therapy for relapsing-remitting multiple sclerosis (MS), but is associated with an increased risk of progressive multifocal leucoencephalopathy after 2 years therapy. Thus, NAT treated patients often decide to stop NAT therapy after 2 years. Reports on recurrence of disease activity after NAT discontinuation are controversial. We studied disease activity in 13 MS patients who stopped NAT therapy and either remained without disease modifying therapy (no DMT, n = 6), or switched to glatiramer acetate (GLAT, n = 7). Annual relapse rate (ARR), expanded disability status scale (EDSS), and number of patients with contrast-enhancing-lesions (Gd+) on MRI before, during and within 1 year after NAT were determined. We observed recurrence of disease activity in both groups (5/7 GLAT treated patients and 6/6 patients without DMT) within 12 months after cessation of NAT (mean time to first relapse was 5.5 months for all patients). One of the GLAT treated patients and three patients without DMT had severe relapses with sustained EDSS worsening. No differences in ARR, EDSS and MRI parameters were seen between both groups. Patients with relapses after NAT therapy, however, tended to show higher disease activity (EDSS, ARR) before initiation of NAT therapy compared to patients without relapses. Duration of NAT treatment was not associated with higher disease activity after NAT discontinuation. In this observation the majority of patients showed reappearance of disease activity after discontinuation of NAT regardless of whether they switched to GLAT or remained without DMT. Further treatment strategies are warranted for patients who discontinue NAT therapy.

Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group—Italian Neurological Society

Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events.

PO10-TU-51 Natalizumab in multiple sclerosis: Dubai experience

PO10-TU-51 Natalizumab in multiple sclerosis: Dubai experience

Melanoma complicating treatment with Natalizumab (Tysabri) for multiple sclerosis

Sirs, Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is a humanized monoclonal antibody which targets the a4 subunits of the cellular adhesion molecules a4b1 and a4b7 integrins, blocking their interaction with their co-receptors VCAM-1, CS-1 and MadCAM-1 [3, 15]. This action reduces leukocyte trafficking into the brain and gut and mediates the beneficial effect of natalizumab in multiple sclerosis (MS) and Crohn’s disease [3]. The efficacy of natalizumab in patients with relapsing remitting MS was demonstrated in two phase III studies, AFFIRM and SENTINAL [10, 12]. These studies showed that when natalizumab was used as mono therapy or in combination with interferon beta-1a (Avonex) it significantly reduced relapse rate and slowed the progression of disability. Natalizumab was well tolerated with the most common adverse effects being headache, infusion reactions and a modest increase in urinary and respiratory tract infections [10, 12]. Neither trial identified any apparent increase in cancer incidence. We report on a patient with MS who developed malignant melanoma following treatment with natalizumab. This was a 48-year-old female who was randomised into the active arm of the AFFIRM Study [10]. She received 30 infusions of natalizumab (300 mg every 4 weeks) and was subsequently enrolled in the open label phase of the trial and received an additional five infusions. The treatment was stopped thereafter when the trial was put on hold following the reporting of the three cases of progressive multifocal leukoencephalopathy (PML) [1]. Five months later, she noticed an increase in the size of a mole which was present on the lateral aspect of her right shin for many years. The patient had no previous history of melanoma or atypical naevi. She did not receive prior immunosuppressant therapy and had no history of melanoma. On examination, the lesion appeared flat, with a darker centre and regular borders. It was not ulcerated and there were no satellite lesions. She underwent local excision and histopathological examination revealed an in situ malignant melanoma with a potential invasive component. There was no evidence of metastasis. Margin re-excision of the biopsy site was undertaken. No recurrence has since been detected. Natalizumab was approved by the US Food and Drug Administration in 2004. Since then, three cases of melanoma associated with its use have been reported. Polman et al. [10] reported a patient in the AFFIRM study who died of malignant melanoma. This was a 38-year-old male with MS who had a past history of malignant melanoma excised from the left shoulder. Following the first dose of natalizumab, a new skin lesion was noticed. He received four additional doses before the diagnosis of malignant melanoma was confirmed. Mullen et al. [7] reported two further cases. The first was a 46-year-old woman with MS who had a mole on her shoulder. Shortly after the first infusion of natalizumab, she noticed a rapid change in its appearance. Further assessment confirmed this to be malignant melanoma with metastatic spread to her regional lymph nodes. The second patient was a 45-year-old woman with MS and a family history of melanoma who had a choroidal nevus in her right eye which had been stable for several years. After A. Ismail J. Kemp B. Sharrack (&) Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK e-mail: b.sharrack@sth.nhs.uk