Update on Efficacy and Safety Evidence with Natalizumab in MS

The goal of treatment with natalizumab is “no evidence of disease activity,” which is defined as no relapses, no new T2 or gadolinium-enhancing (Gd+) lesions on magnetic resonance imaging (MRI), and no disease progression as measured by the Expanded Disability Status Scale (EDSS). The short-term goal of therapy with natalizumab is to control disease activity—relapses, disability progression, and MRI metrics of MS. The long-term goal of therapy is to potentially prevent the development of progressive disease with its attendant disability, while preserving patient safety.

The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Patients With Progressive Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy (AFFIRM) phase III clinical trial of natalizumab monotherapy showed reductions in clinical and MRI parameters in patients with relapsing-remitting MS, with a statistically significant reduction in annualized relapse rate (ARR; 68% at 1 year), which led to decreases in sustained progression of EDSS (42-54% at 2 years), and the number of new or enlarging T2 lesions (83%; all p<0.001 compared with placebo) and Gd+ lesions (92%; p<0.001).Reference Polman, O’Connor and Havrdova ³

In addition to AFFIRM and other clinical trials, which have the recognized limitations of short duration (i.e. 2 years relative to the life-long disease),Reference Marrie ^{4 ,} Reference Koch-Henriksen ⁵ longer-term extension studies, and accumulated clinical experience support natalizumab’s efficacy and tolerability profile.

The most recently published long-term data for natalizumab was from the Tysabri Observational Program, a prospective, observational, 10-year study (not a randomized controlled trial).Reference Butzkueven, Kappos and Pellegrini ⁶ In the 5-year interim analysis of 4821 patients (mean follow-up 26 months), 91% of whom received ≥1 disease-modifying therapy (DMT) before initiating natalizumab therapy, mean ARR decreased from 1.99 in the 12 months before baseline to 0.31 on natalizumab therapy (84% reduction with p<0.0001), and remained low. Additionally, mean EDSS scores remained unchanged up to 5 years in the analysis.

Other recent nonrandomized controlled trial evidence has shown that switching to natalizumab after failure of an injectable DMT (i.e. interferon beta [IFN-β], glatiramer acetate [GA]) is associated with significantly better disease control (fewer relapses, less disease progression as measured by EDSS, and fewer new MRI lesions) compared with switching to another injectable DMT.Reference Prosperini, Giannì and Leonardi ^{7 ,} Reference Trojano, Spelman and Kalincik ⁸ Furthermore, a propensity-matched analysis of the MSBase registry showed that patients who switched to natalizumab after failure of IFN-β or GA had lower relapse rates than those who switched to fingolimod (ARR decreased from 1.5 to 0.2 with natalizumab, from 1.3 to 0.4 with fingolimod; 50% relative postswitch difference in relapse hazard [p=0.002]).Reference Kalincik, Horakova and Spelman ⁹ In a recently published analysis, treatment with natalizumab has also been shown to be associated with significantly faster recovery from a relapse compared with placebo (55% and 67% increased probability of 12-week confirmed recovery in patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, respectively).Reference Lublin, Cutter, Giovannoni, Pace, Campbell and Belachew ¹⁰

Balanced with the body of evidence to support natalizumab’s efficacy, the safety profile of this compound is well-understood and is based on clinical experience with more than 132,600 patients who have been exposed to natalizumab to date (as of September 30, 2014). The most significant adverse event for these patients is the risk of PML.Reference Polman, O’Connor and Havrdova ^{3 ,} Reference Langer-Gould, Atlas, Green, Bollen and Pelletier ^{11 –} Reference Van Assche, Van Ranst and Sciot ¹³ In this light, it is paramount that clinicians continuously perform a benefit-risk analysis in patients being considered for natalizumab therapy, taking into consideration the risk of disease activity along with the risk of a serious adverse event.

Patient Selection

The standard use of natalizumab is in patients with relapsing-remitting MS with failure or insufficient response to an adequate course (i.e. at least 6 months) of one or more conventional DMTs, such as beta-interferons, GA, or oral agents. Failure or suboptimal response was defined by this expert panel as continued relapses or increased relapse rate from pretreatment levels and/or sustained worsening of neurological disability, with or without new lesions on MRI. With respect to the MRI criteria, the reference scan should be performed at least 6 months after treatment initiation, and the presence of Gd+ lesions or three or more new T2 lesions observed on this or any subsequent scan should prompt a reevaluation of therapy.Reference Sormani, Rio and Tintoré ¹⁴ The degree to which relapse rate and disability progression are unacceptable is a judgment call to be made on a case-by-case basis by the treating neurologist.Reference Freedman, Selchen and Arnold ¹⁵

Importantly, use of natalizumab should occur when there is evidence of disease activity despite the use of a first-line agent. In general, patients with a lower EDSS score at the beginning of therapy are more likely to benefit from natalizumab.

Other patient groups that could be considered for natalizumab treatment include:

• ∙ Those with intolerability to first-line DMTs and evidence of inflammatory disease activity;

• ∙ Patients with rapidly evolving severe MS (two or more relapses with incomplete recovery within 1 year or two or more moderate to severe relapses with complete recovery within 1 year and an active MRI scan [≥1 Gd+ enhancing lesion or three or more new T2 lesions]), regardless of prior exposure to treatment;

• ∙ Patients younger than 18 years of age who meet these criteria for treatment with natalizumab.

For older patients (>64 years), there are insufficient data for the use of natalizumab; treatment should be considered with added caution because PML risk increases after age in the sixth decade.Reference Brew, Davies, Cinque, Clifford and Nath ¹⁶

There is currently no evidence to suggest that natalizumab would be effective in patients with worsening disease progression resulting from the presence of primary or secondary progressive MS (SPMS) disease alone; however, an ongoing trial of natalizumab in SPMS—A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMSReference Mikol, Freedman and Goldman ¹⁷ —will provide important information in this regard.

Pretreatment Tests And Procedures

The following recommendations outline what constitutes an appropriate workup before initiating treatment with natalizumab.

Immune competence should be assessed at baseline by the following tests; if any results are positive or abnormal, natalizumab should not be initiated until the cause of the immunocompromised status is known and has resolved:

• ∙ Clinical history, focusing on unusual or severe prior infections, any current infections, and prior exposure to chemotherapy (natalizumab is generally not recommended for patients with prior exposure to immunosuppressive therapy; however, they should be assessed on a case-by-case basis);

• ∙ Complete blood count and differential, focusing on lymphocyte count;

• ∙ HIV screening should be considered—natalizumab is not recommended by this panel for use in HIV-positive individuals.

Other recommended baseline tests to be conducted before initiation of natalizumab:

• ∙ Detailed medical history with full neurological examination and EDSS performed by a trained neurologist;

• ∙ General physical examination;

• ∙ Brain MRI at baseline, unless one is available from the previous 6 months (using a standardized MRI protocol; e.g. the Consortium of MS Centers protocol ¹⁸ —a new protocol in development at the time of writing);

• ∙ Liver function tests;

• ∙ Pregnancy test;

• ∙ JCV antibody status—see the subsequent section for more detailed information on the JCV index and its ramifications.

Recommendations for PML Risk Stratification Incorporating the JCV Index

Extensive research has been conducted to profile the risk of PML in patients treated with natalizumab. As a result, three risk factors have been identified: the presence of JCV antibodies, prior immunosuppression, and duration of therapy. Risk stratification for PML has been greatly refined since the introduction of the anti-JCV antibody index, an optical density measurement of antibody level. The overall JCV-positivity rates with this assay have ranged from approximately 50% to 60%.Reference Gorelik, Lerner and Bixler ^{20 -} Reference Bhan, Lapierre and Freedman ²³

Since this index was introduced, we no longer simply consider a patient’s JCV serostatus, but also take into account the magnitude of positivity. Subjects with higher anti-JCV antibody indices are at higher risk of PML than JCV-positive patients with lower indices. The results of a quantitative analysis of risk by anti-JCV antibody index are shown in Table 1.Reference Plavina, Subramanyam and Bloomgren ²⁴ Note that there is a false-negative rate of approximately 2.0% to 2.5% per year, and seroconversion occurs in approximately 2% to 8% of natalizumab-treated patients per year.Reference Gorelik, Lerner and Bixler ^{20 ,} Reference Bozic, Richman and Plavina ²¹ It is also important to note that there can be fluctuation in the JCV index at lower levels.

Table 1 PML risk estimates by index threshold in anti-JCV antibody-positive patients with no prior immunosuppressant use

PML risk estimates across anti-JCV antibody index thresholds were calculated based on the PML risk stratification algorithm (from September 2012) and predicted probabilities shown in Table 1 for the anti-JCV antibody-positive population at or below respective index thresholds from 0.9 to 1.5. For index thresholds at or below 0.7, PML patient numbers were insufficient to allow for calculation of risk estimates.

* Based on existing PML risk stratification algorithm using September 2012 data for the anti-JCV antibody-positive group with no prior immunosuppressant use.

CI: confidence interval; IS: immunosuppressant.

Reproduced from Plavina T, et al. Ann Neurol. 2014;76:802-12. Epub 2014 Oct 24. DOI: 10.1002/ana.24286. John Wiley & Sons, Inc. Copyright © 2014 Biogen Idec.

Table 2 shows the panel’s recommendations for natalizumab therapy depending on these three risk factors. It should be stressed that the JCV index has no prognostic value among patients who have received prior immunosuppressant or chemotherapy.

Table 2 Summary of recommendations for natalizumab use by presence of absence of the three major risk factors

* Anti-JCV antibody index has no prognostic utility in patients with prior immunosuppressant use.

CI: confidence interval.

Adapted from O’Connor PW. Can J Neurol Sci. 2012;39:670-5.

Measurement of L-selectin levels may, in the future, be useful in terms of stratifying PML risk. Recent studies assessed lymphocyte surface expression of CD62L, also known as L-selectin, as a possible biomarker of PML risk in relapsing-remitting MS patients treated with natalizumab. Schwab and colleagues acknowledged the difficulty of quantifying L-selectin/CD62L expression and the need for additional validation of their hypothesis.Reference Schwab, Schneider-Hohendorf, Posevitz, Breuer, Göbel and Windhagen ²⁵ As such, the clinical utility of this proposed biomarker in natalizumab-treated patients remains to be established, and further investigation is warranted.

Recommendations on Washout Periods When Switching to Natalizumab

With little evidence available on desirable washout periods, the decision on the appropriate duration when switching to natalizumab should be individualized.

A treatment-free period may not be desirable in all patients, particularly those with rapidly worsening disease and/or high disease activity. For the DMTs IFN-β or GA, no washout is necessary. Similarly, for the oral DMTs dimethyl fumarate, fingolimod, and teriflunomide, no washout is typically necessary, unless there is significant lymphopenia (absolute lymphocyte count <0.5×1000/mmReference Polman, O’Connor and Havrdova ³ ). Treatment should not begin until the absolute lymphocyte count is 0.5×1000/mm³ or higher.

The safety of treating patients previously exposed to chemotherapeutic agents remains a highly controversial topic. The use of natalizumab following chemotherapy should only be considered with extreme caution and only in expert hands because of the increased risk of PML.

Recommendations for Monitoring During Natalizumab Treatment

Patients should be evaluated at a minimum of every 6 months, and more frequently if there are any concerns such as hypersensitivity reactions, infusion reactions, new neurological symptoms, or disease worsening.

The following evaluations should form part of routine follow-up visits:

• ∙ History of any new neurological symptoms and complete neurological examination.

• ∙ Updated medical history with a physical examination looking particularly for signs of opportunistic infection, malignancy (skin or otherwise), and liver disease.

• ∙ Liver function tests in patients at risk for hepatotoxicity. Some cases of hepatotoxicity have been reported in patients with preexisting liver disease or in the presence of other drugs that have been associated with hepatic injury. In some patients, liver injury recurred upon rechallenge.

• ∙ Neutralizing antibodies (NAbs) testing at 6 months after initiation of natalizumab therapy, or earlier in a patient who has experienced an unusual drug reaction, such as hives. The drug manufacturer arranges for reimbursed, third-party NAbs testing.

• ∙ Anti-JCV index, at least every 6 months, and potentially more frequently (e.g. 3 months) for those with higher risk of PML.

• ∙ Active evaluation of patients (clinically and radiologically) for any indicators of PML (see the following section) or disease worsening. The recommended MRI sequences include two- or three-dimensional axial fluid attenuation inversion recovery (FLAIR) and axial diffusion-weighted imagingReference Wattjes and Barkhof ²⁶ ; a contrast agent is not required.Reference Richert, Bloomgren, Cadavid, Dong-Si, Richman and Ticho ²⁷

When patients are initiated on natalizumab, enrolment in long-term safety/observational registries is recommended, if available, to help provide further information on long-term efficacy and safety.

Recommendations for Identification And Management of Possible PML Cases

Patient and, where applicable, caregiver education is a critical component of vigilance for PML. Before initiating therapy with natalizumab, patients should be informed of the risks of PML and be provided with information about the drug, its potential side effects, how to recognize signs and symptoms of PML, and what to do if new neurological symptoms develop.

Identification of Possible PML Cases

All patients should be instructed to promptly report any new neurological symptoms to their clinician, and reminders should be given to patients at each clinical visit. Tables 3 and 4 outline clinical and MRI features that help to distinguish PML from MS relapses.Reference Kappos, Bates and Hartung ^{28 ,} Reference Yousry, Pelletier and Cadavid ²⁹

Table 3 Clinical signs and symptoms of typical MS relapses and PML

Adapted from Kappos L, et al. Lancet Neurol. 2007;6:431-41.

Table 4 Recommendations for the diagnosis of early PML in natalizumab-treated multiple sclerosis patients

* Features especially helpful in the identification of small PML lesions. T1W, T1-weighted; T2W, T2-weighted.

Reproduced from Yousry TA, et al. Ann Neurol. 2012;72(5):779-87. DOI: 10.1002/ana.23676. John Wiley & Sons, Inc. Copyright © 2012 American Neurological Association.

An algorithm for evaluating possible PML cases has been proposed by the International Multiple Sclerosis Expert Forum and adapted by this panel (Figure 1). ³⁰ If there is suspicion of PML, dosing should be suspended, an MRI with Gd enhancement and diffusion-weighted imaging should be obtained as soon as possible, and the drug manufacturer should be contacted. If the MRI shows features suggestive of PML, a cerebrospinal fluid sample should be obtained and tested using polymerase chain reaction for the presence of JCV DNA, the causative agent of PML. Natalizumab redosing should only be initiated if the diagnosis of PML is excluded and the continuation of treatment is deemed by the clinician to be appropriate in an individual patient.

Figure 1 Suggested algorithm for natalizumab-treated MS patients with atypical MRI lesion or neurological symptoms Full MRI=FLAIR, T2 proton density, DWI, T1+Gd. Detection of JCV DNA should be based on ultrasensitive quantitative PCR procedure. In case of multiple negative JCV PCR results, NAbs testing and alternative diagnosis should be considered. Disease activity recurrence may interfere with the algorithm beyond 6 to 8 weeks after treatment interruption. Atypical neurological symptom or lesion as defined by any of the following aspects: peripheral cortical, juxta- or cortical location; basal ganglia location; cluster of punctate nodules; enlarging lesion(s) on repeat scans. CSF, cerebrospinal fluid; PCR, polymerase chain reaction; PML, progressive multifocal leukoencephalopathy. Adapted from The International Multiple Sclerosis Expert Forum (IMSEF) Group. Manuscript In preparation.

Other Opportunistic Infections And Malignancies

There have been no statistically significant differences in incidence rates of opportunistic infections and malignancies in patients treated with natalizumab compared with placebo in randomized trials.Reference Polman, O’Connor and Havrdova ^{3 ,} Reference Rudick, Stuart and Calabresi ³⁶ The incidence of infections and malignancies in the postmarketing setting is being actively monitored in long-term registry trials of natalizumab therapy. To date, there have been no unexpected serious adverse events, and the incidence of serious adverse events (including infections and hypersensitivity reactions) has been similar to that observed in clinical trials.Reference Panzara, Baldinetti and Belcher ³⁷

Malignancy has been a theoretical concern with monoclonal antibody therapies. Although there were no observed differences in incidence rates or the nature of malignancies between natalizumab- and placebo-treated patients in clinical trials,Reference Polman, O’Connor and Havrdova ^{3 ,} Reference Antoniol, Jilek and Schluep ³⁴ clinicians should be vigilant in monitoring patients for signs and symptoms of malignancy.

Recommendations for Managing Potential Adverse Events

In general, natalizumab has been associated with a favourable tolerability profile, with few treatment-emergent adverse events.Reference Polman, O’Connor and Havrdova ³ See Table 5 for a summary of selected adverse events and recommended management.

Table 5 Management of adverse events during natalizumab therapy

Serious adverse events should be reported to Health Canada’s Vigilance Program at the National Adverse Event Reporting Centre (toll-free at 866-234-2345 or by e-mail to [email protected]). The reporting of PML is mandatory.

Possible Considerations For Withholding Natalizumab Therapy

Vaccinations While On Treatment

There are no data available on the effects of vaccination in patients receiving natalizumab, nor are there data to suggest that infections can be transmitted via live or live-attenuated vaccines administered to patients receiving natalizumab. However, this group does not recommend the use of live or live-attenuated vaccines for patients receiving natalizumab; these vaccines should be administered before initiation of natalizumab therapy, wherever possible.

Evidence is conflicting regarding the effectiveness of killed vaccines in patients receiving natalizumab.

Recommended Duration of Natalizumab Therapy

The optimal duration of natalizumab therapy has yet to be elucidated and remains a controversial issue. See Table 2 for recommendations for duration of therapy based on presence or absence of major risk factors for PML.

Recent reports on long-term natalizumab therapy from prospective, observational studies suggest that the incidence and type of adverse events seen with long-term treatment are consistent with those seen with short-term treatment.Reference Butzkueven, Kappos and Pellegrini ^{6 ,} Reference O’Connor, Goodman and Kappos ⁴⁰ In the Natalizumab (Tysabri) Re-Initiation of Dosing (STRATA) redosing trial, 1094 patients who previously received natalizumab in a clinical trial (AFFIRM³ or Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis; SENTINELReference Rudick, Stuart and Calabresi ³⁶ ) received an infusion of 300 mg once every 4 weeks for up to 240 weeks. With the exception of PML risk, which increased with treatment duration (14 cases; 1.3% risk over the 240-week period), serious adverse events in STRATA were consistent with natalizumab’s known safety profile; evolution of EDSS scores and relapse rates were consistent with the known efficacy profile.Reference Haghikia, Langer-Gould and Rellensmann ³⁹

At this time, this panel of experts does not endorse routine “drug holidays” (e.g. utilization of natalizumab as an intermittent therapy) in patients who are demonstrating beneficial effects of therapy.

Possible Considerations For Discontinuation Of Therapy

Management of Patients After Natalizumab Discontinuation

Treatment after natalizumab should be individualized and can either be an oral or traditional injectable DMT. Patients should start their next DMT as soon as possible to help prevent return of disease activity.Reference Iaffaldano, Lepore and Lucisano ⁴⁴ This panel recommends that the maximum washout period be no more than 4 weeks before starting most other DMTs. In the case of alemtuzumab, the optimal washout period after stopping natalizumab is unclear and somewhat controversial. In the absence of evidence, the panel recommends that this decision be individualized for each patient, taking into account the reason for the switch in therapy, the specific patient’s risk of relapse, and his or her risk of developing PML. The use of chemotherapy immediately after natalizumab should only be considered with extreme caution and only in expert hands.

After natalizumab cessation, an MRI should be performed within 4 to 6 months to assess for return of disease activity, and to monitor for PML for up to 6 months after discontinuing natalizumab.

Disclosures

PWO’C has received honoraria from and served as a consultant to Biogen Idec. MK has served as a researcher and consultant and received research grants and consulting fees from Biogen, Genzyme, and Novartis; served as a researcher for and received research grants from Bayer, Sanofi, Teva, and Canadian Institutes of Health Research; and received operational grants from the MS Society of Canada.