Tysabri review launched in Europe(11/05/15)
In light of growing evidence, the European Medicines Agency (EMA) has been asked to launch a review of the multiple sclerosis drug Tysabri to assess whether advice on managing known risks for progressive multifocal leukoencephalopathy (PML) should be revised.
PML is a rare brain infection caused by the JC virus (JCV), which has symptoms that may resemble those of an MS attack and may be fatal or result in severe disability. In addition to the presence of anti-JCV antibodies, other risk factors for PML are treatment duration, especially beyond two years, and immunosuppressant use before receiving Tysabri. Patients with all of the above risk factors have a significantly higher risk for PML.
Tysabri was approved in the European Union in June 2006 as a single disease-modifying therapy in highly active relapsing remitting MS (RRMS). It's indicated for patients with high disease activity despite treatment with a β-interferon or glatiramer acetate and in those with rapidly evolving severe RRMS. Tysabri was first approved by the US Food and Drug Administration (FDA) in November 2004.
The review will involve evaluating the data on the risk for PML, with the aim of better defining the risk and identifying further measures to minimize it and will be carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), which will make a set of recommendations. The PRAC recommendations will then be forwarded to the Committee for Medicinal Products for Human Use.
The final stage of the review procedure is the adoption by the European Commission of a legally binding decision applicable to all EU member states.
The EMA has recently been made aware of new information in three key related issues, a statement from the agency notes:
Risk estimates: Tysabri treatment decisions are based on an algorithm in which the estimated PML incidences are calculated in a static way by pooling data from all sources (clinical studies, registries, spontaneous reports). However, interim data from the STRATIFY 2 study for patients with positive anti-JCV antibody status with and without a history of immunosuppressive treatment suggested a higher risk for PML than currently described in the algorithm.
Diagnosis of PML before the development of clinical symptoms: New data seem to suggest that asymptomatic PML cases have a higher survival rate (95.6 per cent) than do symptomatic cases (77.1 per cent). Current recommendations are to perform MRI within 3 months before initiating treatment and then annually. Recent literature suggests that more frequent MRI testing may detect a greater proportion of asymptomatic cases.
Anti-JCV antibodies: It was thought that a negative serologic anti-JCV antibody test suggested a very low probability of PML (about 0.01 per cent), but evidence from the AFFIRM and STRATIFY 1 studies showed nearly 13 per cent of negative patients could become positive during follow-up.
Currently, it's recommended that these patients be retested every six months for antibodies, but a more sensitive second-generation enzyme-linked immunosorbent assay was recently developed. Whether this affects current recommendations for antibody testing needs to be assessed.
Tysabri is a monoclonal antibody, administered through intravenous injection, that is designed to recognize and attach to a protein on the surface of leucocytes. By blocking this protein, the drug prevents leukocytes from going from the blood to the brain, thereby reducing inflammation and nerve damage caused by MS.
Source: Medscape Multispeciality Copyright © 1994-2015 by WebMD LLC (11/05/15)
Freedom from relapse was maintained in multiple sclerosis patients on Tysabri who received the infusion drug less frequently than the recommended 4-week interval, with lower risk of progressive multifocal leukoencephalopathy (PML), preliminary results from an ongoing analysis have indicated.
Among 886 patients treated with "extended" dosing at 10 American MS centers, the mean annualized relapse rate was the same at 0.1 per year as in 1,078 patients receiving Tysabri at the standard 4-week interval, according to Lana Zhovtis-Ryerson, MD, of NYU Langone Medical Center in New York City. MRI lesions counts were also similar.
Although patients testing positive for the JC virus - the pathogen whose reactivation triggers PML, a sometimes fatal brain inflammation - comprised 59 per cent of the extended dosing group, none have so far developed PML, she reported to the American Academy of Neurology's annual meeting.
With a total of 1,023 patient-years of exposure to Tysabri in this JC-positive subgroup, published risk algorithms show an expected incidence of 2.5 cases, Zhovtis-Ryerson and colleagues calculated.
At this point the finding of zero cases with extended dosing is not statistically significant, the researchers cautioned - but if the exposure reaches 1,248 patient-years with still no cases, it will be significant.
Meanwhile, two PML cases have developed in the standard-dosing group, among whom 41 per cent are JC-positive and who have received a mean of 30 Tysabri doses (SD 22).
Brian Weinshenker, MD, of the Mayo Clinic, who was not involved with the study, told MedPage Today the approach deserves more study but urged caution in adopting it clinically.
He noted if just one patient in the extended dosing group developed PML, "it would have completely negated any trend to reduced risk."
PML has been the primary concern with Tysabri almost since it was introduced in 2004. When several cases turned up shortly after its approval, the drug was withdrawn for some months, then relaunched with a restricted distribution program that included clinician and patient education on the risk.
The question of how to reduce PML risk with Tysabri, which exceeds one per cent in patients positive for JC virus and who have two other risk factors (treatment duration and history of immunosuppressant therapy), has occupied MS neurologists since the relaunch. Most studies have shown patients who discontinue the drug or take long "holidays" experience a spike in relapse risk. Switching to another drug has not prevented such spikes because a months-long washout period after Tysabri discontinuation is needed before starting a different agent.
Some clinicians have been experimenting instead with longer dosing intervals, in the belief that the four-week schedule keeps the drug's target - alpha4beta1 integrin, an adhesion molecule involved in immune cell trafficking - so saturated that JC virus immune surveillance is eliminated. Extending the interval may relax the immune suppression just enough to keep latent JC virus under control while still maintaining the anti-relapse effect.
In the current study, Zhovtis-Ryerson and colleagues sought to capture this empirical experience by canvassing centers that have adopted the strategy with some patients.
They defined extended dosing as any interval from 31 days up to 61 days. They further subdivided the extended dosing patients into those with early extended dosing and late extended dosing. Another 309 patients had dosing that varied and could not be classified into either of those groups.
Patients in the extended dosing groups were at somewhat higher risk for PML than those treated at the recommended interval, with a higher proportion testing positive for JC virus, more patients with a history of immunosuppressant therapy (18 per cent versus 11 per cent), and more total Tysabri doses (mean 39 versus 30). Patient age, disease duration, and gender balance did not differ markedly between standard and extended dosing groups, however.
Among extended dosing patients, the mean duration of that schedule was 23 months overall. These varied only modestly between the early, late, and variable dosing regimens.
Treatment efficacy (Tysabri 's forte) was excellent irrespective of dosing interval. Some 65 per cent of standard and 65 per cent of extended dosing groups showed no evidence of disease activity (NEDA). That is, no active MRI lesions and no clinical activity. The variable extended dosing group suffered a little bit in this respect, with 55 per cent meeting the NEDA standard compared with about 70 per cent for both early and late dosing.
Weinshenker commented that selection of patients for extended dosing, which was not random, might have involved "biases against committing more aggressive MS patients on the extended interval program, which might reduce the ability of the investigators to detect reduction in efficacy."
Nevertheless, he said, extended dosing "is a promising and sensible approach that might turn out to be effective."
Zhovtis-Ryerson and colleagues have established a registry called EXTEND to which other clinicians may contribute, at www.msbase.org. They are also planning a prospective study to examine effects of the different regimens on disability progression over time.
The study had no external funding and authors declared they had no financial interests relevant to the work.
Source: Medpage Today © Medpage Today 2015 (23/04/15)
In a study of 1,964 patients with multiple sclerosis, researchers at the NYU Langone Multiple Sclerosis Comprehensive Care Center found that extending the dose of natalizumab from four weeks up to eight weeks was shown to be well-tolerated and effective in patients, and resulted in no cases of the potentially fatal side effect progressive multifocal leukoencephalopathy (PML).
The drug showed similar efficacy in treating disease activity among patients, according to the study led by Lana Zhovtis-Ryerson, MD, an assistant professor of neurology at the NYU Langone Multiple Sclerosis Comprehensive Care Center.
Natalizumab is an infusion drug known as a monoclonal antibody that is used to prevent MS symptoms and flare-ups and slow worsening disability.
However, taking the medication for longer than two years may increase risk for a rare but potentially fatal side effect called PML, an untreatable brain infection that occurs in up to 1.3 percent of patients taking natalizumab.
The medication is typically prescribed in 300-milligram infusions every four weeks.
"There remains much unknown about whether the drug will lose effectiveness if dosing is extended," explains Dr. Zhovtis-Ryerson. "Our study showed treatment with natalizumab was safe for patients with similar efficacy reported as the standard dosing, potentially enabling patients to stay on effective MS medication at a reduced frequency of infusions and with lower risk of PML. "
Zhotvis-Ryerson and colleagues at 10 American MS. Centers sought to compare the safety and efficacy of an extended dose of natalizumab to the standard dose. They retrospectively compared 1,078 patients taking a standard 4-week dose to 886 taking an extended dose between 4 weeks, 3 days and 8 weeks, 5 days.
The researchers found extending the dosing schedule of natalizumab to between 5 and 8 weeks does not affect the drug's efficacy profile with 65 per cent of participants in each group not showing clinical MS activity, and comparable rates of new lesions reported on imaging. Zero cases of PML were reported in the extended dosing group, while two cases were reported in the standard dose group, though the researchers said statistical significance has not been reached yet. No other major adverse events were reported.
"While the findings are encouraging, more research is needed to determine whether extending natalizumab dosing may reduce disability progression," says Dr. Zhovtis-Ryerson.
Natalizumab is manufactured by Biogen and Elan, and sold under the name Tysabri.
Source: MedicalXpress © Medical Xpress 2011-2015, Science X network (21/04/15)
Hematopoietic mobilization: Potential biomarker of response to natalizumab in multiple sclerosis.
Mattoscio et al.
OBJECTIVE: To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 integrin antibody natalizumab in MSers.
METHODS: We evaluated CD45lowCD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated MSers (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated MSers with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10).
RESULTS: Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and non-mobilizer subgroups. Non-mobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer MSers, who also showed a specific naive/memory B-cell profile.
CONCLUSIONS: The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab.
Source: Neurology. 2015 Mar 11. © 2015 American Academy of Neurology.(18/03/15)
Prematurely severe cognitive impairment in multiple sclerosis patients could be an effect of autoantibodies against the N-methyl-D-aspartate (NMDA) receptor complex, with natalizumab (Tysabri) withdrawal a potential contributor, a case report from Germany suggested.
In an MS patient who had to be confined to a nursing home at age 39 because of cognitive deficits amounting to dementia, immunoglobulin G-type antibodies to the NMDA receptor's NR1 subunit were found in cerebrospinal fluid samples, according to Klemens Ruprecht, MD, of Charité-Universitätsmedizin Berlin, and colleagues.
These autoantibodies are "the characteristic laboratory finding of anti-NMDA receptor encephalitis," they wrote online in JAMA Neurology.
When severe cognitive deficits appear at young ages, Ruprecht and colleagues concluded, they could "be related to a superimposed antibody-mediated autoimmune encephalitis."
Cognitive deficits are common in MS patients but the mechanisms underlying them are not well understood, the researchers noted. Normally these come on gradually and at later ages. However, as in the current case, occasionally such deficits appear early and progress rapidly. In such cases, clinicians should consider causes outside the MS disease process, Ruprecht and colleagues suggested.
"The diagnosis of those patients will require a high degree of clinical suspicion as cognitive symptoms are rather frequent in MS and may mask or be confounded with features of antibody-mediated encephalitides," they wrote. "Nevertheless, testing for antineuronal antibodies appears warranted in patients with MS with unusual neuropsychiatric symptoms."
Also, in the patient who was the subject of the case report, the anti-NMDA antibody pathology may have had some relation to treatment with natalizumab.
The woman was first diagnosed with MS at age 33. Her disease course was unremarkable until age 37 when she gave birth, and then rapidly developed cognitive deficits marked primarily by memory loss. She was treated aggressively with MS therapies including natalizumab, cyclophosphamide, and mitoxantrone, with no impact on the progression of cognitive decline.
At age 43, during her fourth year of nursing home residency, she underwent a complete re-evaluation that included analysis of current and stored serum and CSF samples. At that point, anti-NMDA antibodies were discovered in the CSF samples, including those taken shortly after the cognitive symptoms appeared.
The natalizumab was withdrawn 2 years after the patient started on it, out of concern for the risk of progressive multifocal leukoencephalopathy since she had also been on immunosuppressive therapy.
Five months later, she developed a "fulminant" MS relapse, the researchers indicated, which was accompanied by a spike in anti-NMDA antibody titers -- a sign that the latter may have had some connection to the natalizumab withdrawal.
Ruprecht and colleagues noted that the drug suppresses CD138-positive plasma cells. "Therefore, it seems plausible that natalizumab withdrawal facilitated entry of NMDA receptor antibody-producing plasma cells to the central nervous system," they wrote.
The patient died of urosepsis last December, almost 8 years after the onset of cognitive symptoms.
She represented only the second known case of anti-NMDA encephalitis in an MS patient, the researchers indicated, and the first in whom the antibodies targeted the receptor complex's NR1 subunit (NR2B was the target in the previous case).
But they suggested the comorbid conditions may occur more frequently than these case reports might suggest, because cognitive impairments are common in MS and clinicians may not think to look for other causes.
The study was funded by the German government. Authors reported relationships with Bayer Healthcare, Merck Serono, Biogen Idec, Novartis, Ovamed, Teva, Diamed, Genzyme, and Sanofi.
Primary source: JAMA Neurology
Source reference: Fleischmann R, et al "Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis" JAMA Neurology 2014; DOI: 10.1001/jamaneurol.2014.1817.
Source: Medpage Today © 2014 MedPage Today, LLC (11/11/14)
Smoking appears to increase the likelihood of developing neutralizing antibodies to natalizumab (Tysabri, Biogen Idec), which cause the drug to have little, if any, therapeutic effect in multiple sclerosis (MS), a new study suggests.
The study was presented by Tomas Olsson, MD, Karolinska Hospital, Stockholm, Sweden, at the recent MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.
"The lung seems to be an important immunoreactive organ where irritation such as smoking may increase risk not only for inflammatory diseases, but also neutralizing antibodies to biologicals like interferon β and monoclonal antibodies such as natalizumab," he concluded.
"While smoking should not prohibit use of natalizumab, the percentage of patients developing antibodies, neutralizing the effect of the treatment, is not negligible," Dr Olsson commented to Medscape Medical News. "Therefore patients should be advised about our findings. This comes on top of an increased risk for MS with smoking, and probably a worse disease course."
In his presentation, Dr Olsson explained that smoking is thought to contribute to the induction of neutralizing antibodies to interferon β-1a, so he and his colleagues aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of MS.
The study was based on 1338 natalizumab-treated patients with MS included in either of two Swedish case-control studies in which information on smoking habits was collected. Treatment-related information was obtained from the Swedish national MS registry and antibody status from the Swedish Nab lab. Enzyme-linked immunosorbent assay was applied before therapy start and after 6, 12 and 24 months. Through use of logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies.
Results showed that compared with nonsmokers, the odds ratio (OR) of developing anti-natalizumab antibodies was 2.4 (95% confidence interval [CI], 1.2 - 4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking.
The increased risk remained when smoking within 2 years prior to screening was considered (OR, 2.7; 95% CI, 1.5 - 5.1).
Still Try Natalizumab in Smokers
Commenting on the study for Medscape Medical News, Heinz Wiendl, MD, University of Münster, Germany, called this an "interesting observation," but he said the findings would not discourage him from using natalizumab in smokers.
"The prevalence of neutralizing antibodies to natalizumab is quite low — maybe affecting around 5% to 9% of patients. We can easily identify the patients who develop these antibodies because they don't respond to the drug."
He continued: "If a patient has neutralizing antibodies the drug effect will be zero. Natalizumab is a strong drug and there should be an obvious reduction of relapses and MRI lesions when a patient starts on it. If this does not happen, I think we can assume there are neutralizing antibodies present and then we would switch to a differemt treatment."
Dr Olsson has received nonrestricted MS research grants and/or compensations for lectures and advisory boards from Biogen Idec, Genzyme, Novartis, TEVA, and Merck. Dr Wiendl reports honoraria and consultation fees from Bayer HealthCare, Biogen Idec, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme BioVentures, and Teva Pharmaceutical Industries.
MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract PS5.4. Presented September 11, 2014.
Source: Medscape Multispeciality © 1994-2014 by WebMD LLC (06/10/14)
A new test seems to be able to stratify patients at risk for progressive multifocal leukoencephalopathy (PML) while receiving the multiple sclerosis (MS) drug natalizumab more effectively than anything available at present.
The test is based on observations that patients who develop PML appear to have very low levels of L-selectin (CD62L) on CD4+ T cells in the months or years before they develop the condition.
"We believe that very low levels of L-selectin is a predictive test for the future risk of PML on natalizumab," stated Dr. Heinz Wiendl, University of Münster, Germany.
He presented the data at the recent MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.
Dr. Wiendl explained that he and his colleagues noticed that some patients receiving long-term natalizumab had reductions in levels of L-selectin. "In particular patients who developed PML tended to have very low levels of L-selectin, so we thought it might be a good biomarker," he said.
They therefore went back and analyzed blood samples from a larger group of natalizumab recipients. "We now have data on 1000 patients treated with the drug, of whom 15 have developed PML," he reported.
"Of these 15 patients, 14 showed very low levels of L-selectin (less than 21.6) in samples of peripheral blood taken months or years before PML developed."
Asked for comment on these findings, Robert J. Fox, MD, Mellen Center for Multiple Sclerosis at Cleveland Clinic in Ohio, said he thought this was one of the "most exciting developments" presented during the meeting.
Dr. Wiendl told Medscape Medical News that he is now testing all patients after 18 months of natalizumab and then every 6 months thereafter. "If one value is low then the patient is at significant risk of PML and we stop the drug."
Dr. Wiendl believes that L-selectin is far more selective than JC virus V (JCV) antibodies for identifying patients at risk for PML.
"About half of patients test positive for JCV antibodies, but only about 10% of patients have low levels of L-selectin," he noted. "JCV positivity puts patients at a risk of about 1 in 100 of developing PML, but with low L-selectin levels the risk is more like 1 in 10," he estimated.
The L-selectin test is also more reliable in patients who have had previous immunosuppression, he added.
Synergistic With JCV Antibody Status
Dr. Wiendl is not advocating that L-selectin replace the JCV antibody test but rather that they be used together. "I see it as a combined effort, as the 2 markers appear to be synergistic," he said.
The problem, however, is that the L-selectin test is not easy to perform. It involves purifying and isolating mononuclear cells and then performing multicolor flow cytometry. "At the moment our L-selectin test is just at the transition from academic to clinical," he noted. It is now undergoing validation in different cohorts in France and Spain.
Dr. Wiendl's team is offering the test to centers in Germany, Austria, Switzerland, and Benelux (Belgium, the Netherlands, and Luxembourg) at present and is open to the idea of expanding the service to other countries. However, there is a logistical issue in that the blood has to be processed within 24 to 36 hours so the mononuclear cells are still viable, which limits long travel distances to the laboratory. Dr. Wiendl is looking at ways to commercialize the test to enable more widespread use.
Dr. Fox emphasized the importance of risk stratification for complications such as PML. "With these complications what we try to do is risk-stratify and risk-mitigate," he told Medscape Medical News. "We want to stratify patients to understand their risk, and then mitigate that risk as best we can. This test promises to help us do just that."
He said the sensitivity and specificity of the L-selectin test were reported to be about 90%, "which is very encouraging."
"I would be eager to have the test available for general clinical use so that we can use that to help guide patients regarding their risk, and not just predicting the risk but also perhaps identifying those that are in the early stages of having developed PML," he added.
Dr. Wiendl reports honoraria and consultation fees from Bayer HealthCare, Biogen Idec, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Genzyme BioVentures, and Teva Pharmaceutical Industries; grants and contracts with Bayer HealthCare, Biogen Idec, the German Ministry for Education and Research, Deutsche Forschungsgesellschaft, the Else Kröner Fresenius Foundation, the Fresenius Foundation, the Hertie Foundation, Merck Serono, Novartis, the NRW Ministry of Education and Research, the Interdisciplinary Center for Clinical Studies in Münster, Germany, the RE Children's Foundation, sanofi-aventis/Genzyme, and Teva Pharmaceutical Industries. Dr. Fox reports he has received personal consulting fees from Novartis, Biogen Idec, GlaxoSmithKline, MedDay, Questcor, Teva, and XenoPort; has served on advisory committees for Biogen Idec and Novartis; and received research grant funding from Novartis.
MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract PS6.5. Presented September 11, 2014.
Source: Medscape Multispeciality © 1994-2014 by WebMD LLC (30/09/14)
The risk of developing progressive multifocal leukoencephalopathy (PML), as a consequence of infection/reactivation with JC virus (JCV), is consistent in natalizumab-treated multiple sclerosis (MS) patients, with 430 cases of PML reported so far.
The risk of PML is higher in JCV seropositive patients, and it is recommended that only MS patients without JCV antibodies should be enrolled in the treatment postulating that they do not have JCV infection.
We have studied forty-two natalizumab-treated MS patients, and urine and blood were collected monthly for up to 60 months. JCV and BK virus (BKV) DNA presence was verified using quantitative real-time PCR assays, and serum anti-JCV antibodies were measured with the Stratify and/or Stratify DxSelect tests.
JCV and BKV DNA were not found in the blood samples, whereas they were found at least once in the urine of 21 of 42 (50 %) and of 25/42 (59.5 %) patients, respectively. JCV DNA urinary shedding increased up to month 24 of natalizumab treatment (45.2 %), and the effect of time was significant for JCV (p = 0.04), but not for BKV (p = 0.39). JCV viruria and seropositivity did not completely correlate, since three patients shedding JCV DNA in the urine were seronegative according to the serological tests.
The results indicated that natalizumab therapy may increase the rate of JCV urinary shedding. Additionally, we confirmed that the identification of JCV carriers cannot solely rely on serological tests, but sensitive methods for viral DNA detection should be adopted to more precisely identify the truly JCV uninfected cases.
Source: Science Index Copyright © 2014 ScienceIndex.com (23/07/14)
Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab -
Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)
Marinella Clerico, MD; Irene Schiavetti, BS; Stefania F. De Mercanti, MD; Federico Piazza, MD; Dario Gned, MD; Vincenzo Brescia Morra, MD; Roberta Lanzillo, MD; Angelo Ghezzi, MD; Anna Bianchi, BS; Giuseppe Salemi, MD; Sabrina Realmuto, MD; Patrizia Sola, MD; Francesca Vitetta, MD; Paola Cavalla, MD; Damiano Paolicelli, MD; Maria Trojano, MD; Maria Pia Sormani, BS; Luca Durelli, MD
Importance: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS).
Objective: To evaluate the effect of therapeutic choices on the mean annualised relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS.
Design, Setting, and Participants: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centres (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab.
Interventions: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod.
Main Outcomes and Measures: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year.
Results: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery.
Conclusions and Relevance This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug.
Trial Registration Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.
Source: JAMA Neurology © 2014 American Medical Association (02/07/14)
Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: A longitudinal study.
Mancuso R, Franciotta D, Rovaris M, Caputo D, Sala A, Hernis A, Agostini S, Calvo M, Clerici M.
Retrospective studies show that natalizumab modifies oligoclonal immunoglobulin (IgG) bands (OCBs) in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients.
In this study, we prospectively analyzed both serum and CSF samples from 24 MS patients, before and after 2 years of natalizumab-based therapy. Our results showed complete (55%) or partial (27%) disappearance of the OCBs in CSF samples that were taken after 2 years of therapy.
Intrathecal IgG production, represented by the IgG index and IgGLoc, was also quantitatively reduced. Our data showed that natalizumab substantially modulates both intrathecal polyclonal and oligoclonal IgG production: This effect was much more potent than was previously reported.
Source: Mult Scler. 2014 Jun 16. pii: 1352458514538111. [Epub ahead of print] & Pubmed PMID: 24948690 (26/06/14)
A recent study suggests that treatment with natalizumab (Tysabri) beyond 2 years compared with switching to other drugs can control relapsing-remitting multiple sclerosis (RRMS) with adequate safety.
The longer a patient with RRMS is treated with natalizumab, the greater the risk of developing progressive multifocal leukoencephalopathy (PML), especially in patients who are infected with JC virus after 2 years of monthly treatments.
"Our study provides evidence to support the choice of continuing treatment with natalizumab after the 24th administration," Luca Durelli, MD, from the Department of Clinical and Biological Sciences at the University of Torino and the San Luigi Gonzaga University Hospital in Obassano, Italy, reported here at the 24th Meeting of the European Neurological Society (ENS).
Between 2005 and May 2014, among 125,800 patients with MS treated in the postmarketing setting, 462 cases of PML have been reported, of which 23% were fatal, for an incidence of 3.6 cases/1000 treated. The highest prevalence has been in patients receiving natalizumab for 2 to 3 years.
In this present prospective, multicenter, observational Tysabri discontinuation study after the 24th natalizumab administration (TY-STOP), 130 adult patients with clinically and radiologically stable RRMS were stratified according to their choices of treatment after the 24th dose of natalizumab, 300 mg every 28 days, and observed every 3 months for 1 year.
Treatment options presented to the patients after the 24th natalizumab dose were to continue receiving natalizumab ("continuers"), to start treatment with a different therapy ("switchers"), or to stop any disease-modifying therapy ("quitters").
First-line therapy options were interferon β-1a, interferon β-1b, or glatiramer acetate. Second-line options were fingolimod (since December 2011), natalizumab, or mitoxantrone (only 2 patients).
Of the 130 patients, Professor Durelli reported on 124 (95.4%) who had completed the entire 1-year follow-up, which consisted of 43 (35%) who continued natalizumab and 81 (65%) who interrupted it.
The following baseline characteristics did not significantly differ between the patients who continued natalizumab and those who did not: age, body mass index, age at disease onset, sex, disease duration at baseline, disability scores, annual relapse rates, MRI activity, and disease-modifying therapies before natalizumab initiation.
The as-treated population consisted of 73 (59%) quitters, 16 (13%) switchers, and 35 (28%) continuers.
For the intention-to-treat population, after 1 year of observation following the decision to stay on natalizumab or not, there was no significant difference in the mean Expanded Disability Status Scale scores, but the annualized relapse rate had tripled (0.24 ± 0.48 for those remaining on natalizumab vs 0.73 ± 0.85 for those not; P = .004) and the presence of MRI activity in the previous year had doubled (26.8% vs 51.3%, respectively; P = .018).
Results were similar for the as-treated population, with no significant differences in disability scores but a higher annualized relapse rate among quitters and switchers compared with continuers. MRI activity during the follow-up year was higher among quitters but not among switchers compared with continuers.
Professor Durelli said that in the as-treated population, the overall frequency of adverse effects was similar among the patients treated with the different therapies, and "during the period of observation no new safety issues emerged."
Among the continuers, there was 1 case of pyelonephritis and 1 acute myocardial infarction. Among switchers, 1 case of PML occurred in a patient who had been receiving natalizumab for 28 months. The patient made a full recovery after being treated with plasma exchange and mirtazapine.
In no patient who stopped natalizumab did disease activity return worse than it had been before natalizumab therapy.
Professor Durelli concluded that in patients with relapsing-remitting MS, "interruption of treatment with natalizumab after the first 24 courses exposes [patients] to an increased risk of clinical and/or MRI MS disease activity." He added the study results can support a choice of continuing natalizumab beyond 24 months.
Relapse Activity Increase
Session chairman Kjell-Morten Myhr, MD, PhD, professor of neurology at the University of Bergen, Norway, told Medscape Medical News that the study "very well showed the efficacy of Tysabri. When stopping Tysabri and starting them on a less potent treatment, the relapse activity will increase."
Infection with JC virus is a major risk factor for PML in patients treated with natalizumab, and 60% to 80% of adults in the United States and Europe are positive for antibodies to it, indicating exposure. "Of course, it would be best for the treatment of the disease itself continuing with the Tysabri, but it's a difficult issue with the risk of PML," he said.
He commented that he had the impression that the study patients had not been screened for JC virus before natalizumab initiation, probably because screening was not yet available.
"For those that are JC virus negative, there is no reason to stop after 24 months. They should continue," he said. "These patients that could be considered for stopping or switching are JC virus positive after 24 months." In keeping with usual practice, he recommended that JC virus–negative patients be tested every 6 months because they can become infected at any time.
Dr. Myhr said in his experience, when the risks of PML are explained to patients and they elect to continue natalizumab, sometimes they come back in a few months and have decided to switch to another drug because they say that they are continuously thinking about the risk.
"It's difficult for patients to make decisions, and I think they need time to make their decisions. So we really need good biomarkers to differentiate the risk for this serious complication," he said, noting that the JC virus index will be 1 biomarker "to identify those with a low risk but still a risk but lower than those with a high index."
Professor Durelli had no disclosures. Dr. Myhr has received honoraria for lecturing; participation in advisory boards or pharmaceutical company–sponsored clinical trials; and travel support from Allergan, Almiral, Bayer Schering, Biogen Idec, Novartis, Merck-Serono, Roche, and Sanofi-Aventis.
24th Meeting of the European Neurological Society (ENS). Abstract OS1115. Presented May 31, 2014.
Source: Medscape Medical News © 2014 WebMD, LLC (13/06/14)
MS rebound after stopping Tysabri(09/06/14)
Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis.
Gueguen A, Roux P, Deschamps R, Moulignier A, Bensa C, Savatovsky J, Heran F, Gout O.
OBJECTIVE: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.
METHODS: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared.
RESULTS: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9?months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients.
CONCLUSIONS: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.
Source: J Neurol Neurosurg Psychiatry. 2014 May 29. pii: jnnp-2014-307591. doi: 10.1136/jnnp-2014-307591 & Pubmed PMID: 24876183 (09/06/14)
Age-dependent effects on the treatment response of natalizumab in MS patients.
Matell H, Lycke J, Svenningsson A, Holmén C, Khademi M, Hillert J, Olsson T, Piehl F.
BACKGROUND: Natalizumab is approved for treatment of active forms of relapsing-remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18-50 years. The effect of natalizumab has not been specifically studied in older patients.
OBJECTIVE: We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program.
METHODS: In three MS centers registry data for patients aged >50 years were validated.
RESULTS: At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count were negatively correlated with age in a smaller subgroup of patients.
CONCLUSION: These results were in agreement with previous findings suggesting that inflammation is more pronounced in younger patients and therefore the beneficial effects of potent anti-inflammatory treatments are subsiding with older ages.
Source: Mult Scler. 2014 May 27. pii: 1352458514536085. & Pubmed PMID: 24866201 (06/06/14)
Disability progression in patients who switch from Natalizumab to Fingolimod or injectable therapies (31/05/14)
Transitioning from natalizumab to fingolimod was linked to a self-reported worsening of disability in patients with multiple sclerosis, according to data from a North American Research Committee on Multiple Sclerosis (NARCOMS) analysis presented by Stacey Cofield, PhD, at the 2014 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Sixth Cooperative Meeting with Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Cofield is Deputy Director of the CombiRx Statistical and Data Management Center and the NARCOMS Coordinating Center at the University of Alabama-Birmingham (UAB) School of Public Health.
In her presentation, titled “Disability Progression after Switching from Natalizumab to Fingolimod or Injectable Therapies: A NARCOMS Analysis,” Cofield, who is also an associate professor in the Department of Biostatistics at UAB, noted that natalizumab is a highly effective treatment for multiple sclerosis.
“However, the clinical outcomes of natalizumab-treated patients who have switched to other treatments are not well understood,” she noted.
The study was done to compare changes in patient-determined disease steps (PDDS) -- a patient-reported outcome of disability in patients with multiple sclerosis -- between natalizumab-treated patients who remained on natalizumab and patients who switched treatment after a minimum of two years. For the study, researchers collected information on 547 NARCOMS participants who were on at least 2 years of continuous natalizumab treatment.
“Scores from the first survey were compared between participants whose only disease-modifying treatment during follow up was natalizumab and patients who switched to treatment with fingolimod or injectable therapies,” said Cofield.
Injectable therapies included interferon beta or glatiramer acetate.
Adjusted mean PDDS was not different between groups after two years of natalizumab therapy, but at the end of follow up, the mean PDDS increase was 0.31 points for the natalizumab-only group, 0.58 for patients who switched to fingolimod, 0.71 for patients who switched to injectables.
The difference between natalizumab and the injectable therapies groups was significant (P = 0.007).
In addition, there was a difference between groups in the proportion of patients with a greater than one point increase in PDDS (30.8% of the natalizumab-only group, 46.0% of the fingolimod group, and 42.3% of the injectable therapies group; P = 0.03).
On average, patients who switched to treatment with injectable therapies reported larger disability increases than patients who remained on natalizumab.
Age, gender, and starting PDDS were similar in all groups, but median months of total follow up were significantly different (48 months for the natalizumab-only group, 54 months for the fingolimod group, and 60 months for the group that switched to treatment with injectable therapies).
“The study found that age, gender, and starting PDDS were associated with changes in PDDS (P < 0.03) and total follow up was not different between groups after 2 years,” said Cofield.
Switching from natalizumab to fingolimod or injectable therapy was associated with an increased likelihood of reported disability progression.
Since the study included self-reported data, “causality cannot be concluded,” Cofield said.
Source: Copyright HCPLive 2006-2013 Intellisphere, LLC. All Rights Reserved. (31/05/14)
RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. The objectives of RESTORE were to explore the course of MS disease activity and the effects on pharmacokinetic, pharmacodynamic, and immune parameters in patients undergoing an interruption of natalizumab therapy for up to 24 weeks as compared with those in patients remaining on natalizumab. It also assessed the effects of alternate therapies during natalizumab interruption and after restarting natalizumab. Patients with MS receiving natalizumab were randomized into three treatment arms in a 1:1:2 ratio: natalizumab:placebo:alternate immunomodulatory therapy (interferon b-1a, glatiramer acetate or methylprednisolone).
A total of 175 patients were enrolled. At the baseline visit, all patients received a standard 300-mg natalizumab infusion. Starting at week 4, patients randomized to natalizumab or placebo received infusions every four weeks through to week 24 in a double-blind fashion. Patients randomized to other therapies who chose interferon b-1-a (IM IFN-b-1a) or glatiramer acetate (GA) received their first injections on day 0. Patients randomized to other therapies who chose methylprednisolone (MP) received infusions every four weeks starting at week 12. Clinical, MRI, and laboratory evaluations were performed every four weeks during the randomized treatment period starting at week 0, at the time of suspected relapse, and at the final visit. At week 28, patients resumed open-label infusions of natalizumab and stopped placebo or other therapy. Participants were followed for an additional 24 weeks, concluding the study at week 52.
Disease recurred in a large proportion of RESTORE patients who discontinued natalizumab treatment. The safety evaluations were generally consistent with the labeled risk profile for each of the respective marketed products, notably for natalizumab. Natalizumab treatment interruption resulted in occurrence of MRI disease activity as early as 12 weeks, and of clinical disease activity as early as 4–8 weeks, after the last natalizumab dose. Relapses occurring during the first one to three months have also been observed. In RESTORE, GA starting after the last dose of natalizumab and monthly MP starting 12 weeks after the last natalizumab dose did not appear to be effective in disease suppression, as compared with continued natalizumab treatment.
Authors: Karceski S.
Source: MSIF & Neurology. 2014 Apr 29;82(17):e155-7. doi: 10.1212/WNL.0000000000000423 (14/05/14)
- New Tysabri® analysis shows improved walking speed in significant number of MS patients.
- Additional data show escalation to Tysabri following relapse improves clinical outcomes compared to remaining on or switching between first-line Interferon Beta and Glatiramer Acetate.
Biogen Idec announced that a post hoc analysis of data from the AFFIRM study shows Tysabri® (natalizumab) significantly increased the proportion of relapsing-remitting multiple sclerosis (RRMS) patients with confirmed improvement in walking speed (CIWS) relative to placebo at two years. Additional data from observational registry studies show that switching to Tysabri after experiencing a multiple sclerosis (MS) relapse while taking interferon beta (IFNβ) or glatiramer acetate (GA) reduced the risk of future relapses and treatment discontinuation. These data were presented at the 66th American Academy of Neurology (AAN) annual meeting in Philadelphia, Pa. (April 26-May 3, 2014).
“We know that MS has a significant impact on ambulation – a key concern for many people living with this disease – which is why we analyzed data from AFFIRM to evaluate the potential impact of Tysabri on walking speed,” said Alfred Sandrock, M.D., Ph.D., group senior vice president and chief medical officer at Biogen Idec. “Tysabri was associated with a 20 percent increase in walking speed, a clinically relevant improvement, in a significantly greater number of patients compared to placebo.”
Walking Speed Impacted with Tysabri
AFFIRM was a two-year, randomized, multi-center, placebo-controlled, double-blind study of 942 patients with RRMS that evaluated the effect of Tysabri on the progression of physical disability and the rate of clinical relapses. A post-hoc analysis of AFFIRM assessed the impact of Tysabri on the proportion of patients with CIWS compared to placebo. CIWS was defined as greater-than or equal to 20 percent increase in walking speed from baseline in the timed 25-foot walk (T25FW) confirmed 12 weeks later.
Results show that, over the course of two years, CIWS was significantly associated with improvement in patient-reported physical functioning. Treatment with Tysabri increased the proportion of patients with CIWS at year two by 79 percent compared to placebo (Tysabri, 12.3%; placebo 6.9%; p=0.0133). These effects were more significant and occurred earlier in patients with more advanced disability – with CIWS being increased by as much as five-fold compared to placebo at one year.
While many MS clinical trials measure disability progression, which includes a measure of ambulation by the Expanded Disability Status Scale (EDSS), these data from AFFIRM suggest that CIWS may be a more sensitive endpoint in capturing improved ambulation in RRMS patients.
These data were presented in a platform presentation on Tuesday, April 29 at 2:15 p.m. ET:
Natalizumab Treatment Improves Walking Speed in MS Patients: A Post Hoc Analysis of AFFIRM (S4.006)
Efficacy Effect Observed With Switch to Tysabri
Two additional studies used propensity-matched registry data to evaluate the effects of transitioning to Tysabri after an on-treatment relapse while taking INFβ or GA, compared to remaining on, or switching between, INFβ and GA. Results show that switching to Tysabri decreased the risk of future relapses, disability progression and treatment discontinuation for MS patients.
Because there are no randomized clinical trials comparing treatment options for patients with ongoing disease activity, comparisons of propensity-matched data from large observational cohorts are useful to estimate the relative risks associated with treatment decisions in a clinical setting. In these studies, researchers matched patients across three large observational clinical trials: Tysabri Observational Program (TOP), an ongoing observational, open - label, 10 - year prospective study of relapsing - remitting MS (RRMS) patients; MSBase, an ongoing, longitudinal database open to all practicing neurologists worldwide; and MSCOMET, a longitudinal MSBase registry substudy assessing the efficacy of IFNβ and GA in 1,000 patients in 14 countries.
In the first study, researchers matched 759 MS patients who participated in the MSCOMET study to the same number of patients in the TOP. They assessed time to first relapse, treatment discontinuation and disability progression over one year in those who relapsed on IFNβ or GA in the 12 months prior to study entry and either transitioned to Tysabri or stayed on their original first-line therapy. Data show that switching to Tysabri versus remaining on IFNβ or GA after an on-treatment relapse decreased the risk of relapse by 57 percent and reduced the risk of treatment discontinuation by 52 percent. Researchers also analyzed a smaller subset of patients (n=227 patient pairs) to assess disability progression. They found the incidence of three-month confirmed disability progression was lower in patients who transitioned to Tysabri than in those who persisted on IFNβ or GA; however, this difference was not statistically significant, likely due to the small sample size and small number of observed progression events.
In the second study, researchers compared annual relapse rate, treatment discontinuation and disability progression over one year within two subgroups of patients who participated in MSBase and the TOP: subgroup one, patients taking IFNβ who switched to GA compared to those who switched to Tysabri (n=578 for each cohort); and subgroup two, patients taking GA who switched to IFNβ compared to those who switched to Tysabri (n=165 for each cohort). Results show that transitioning to Tysabri treatment versus switching from IFNβ to GA reduced the risk of relapse by 63 percent and discontinuation risk by 62 percent. Transitioning to Tysabri treatment versus switching from GA to IFNβ also reduced the risk of relapse by 53 percent and discontinuation risk by 48 percent. Researchers then combined the subgroups to assess three-month confirmed disability progression; results showed that transitioning to Tysabri versus switching between IFNβ and GA reduced the risk of disability progression by 32 percent.
These data were presented as posters:
Comparative Efficacy of Switching to Tysabri Versus Switching to Interferon-Beta or Glatiramer Acetate after On-Treatment MS Relapse Using Propensity-Matched Registry Data (P3.175) was available for viewing on Tuesday, April 29 from 3:00-6:00 p.m. ET
Comparison of Switching to Tysabri Versus Remaining on Interferon-Beta or Glatiramer Acetate after On-Treatment MS Relapse Using Propensity-Matched Registry Data (P7.208)will be available for viewing on Thursday, May 1 from 3:00-6:00 p.m. ET
Source: MarketWatch Copyright © 2014 MarketWatch, Inc (01/05/14)
Researchers report drug mobilises a kind of cell easily infected by a virus that attacks the brain.
Researchers report that they think they have figured out why patients who take the multiple sclerosis drug Tysabri face a high risk of developing a rare, and sometimes fatal, brain infection.
A common virus that can cause the brain disease progressive multifocal leukoencephalopathy (PML) likes to infect and hide in certain blood cells that are triggered to mobilise by Tysabri, the study authors explained. Even more troubling, the researchers discovered that current tests may be missing some who harbour the virus.
"Right now, the risk of PML in patients treated with [Tysabri] for more than two years is about one in 75 patients. That's a very high risk," said study author Eugene Major, a senior investigator at the U.S. National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Md.
"We need to be able to understand why this therapy puts patients at risk. As we further define that, we'll be able to develop better tests and better treatment decisions can be made," Major said.
In PML, the normally harmless "JC virus" attacks the white matter of the brain, stripping nerve cells of their insulation. Without this insulation, nerve cells can't effectively carry brain signals. The disease causes progressive weakness, paralysis, changes in vision and speech, and problems with thinking and memory.
According to the NINDS, 30 percent to 50 percent of patients with PML die within a few months of diagnosis. Those who survive the infection may face permanent disability.
Though most people carry the JC virus, PML is rare. It tends to strike people with suppressed immune function, such as patients with AIDS or those taking powerful immune-suppressing drugs like Tysabri.
The drug has had a troubled history. First approved by the U.S. Food and Drug Administration in November 2004, it was pulled off the market three months later after cases of PML occurred in ongoing clinical trials.
Since Tysabri was allowed back on the U.S. market in 2006 with strict prescribing conditions, more than 440 cases of PML have been reported in patients taking the drug, according to the study background. In 2010, the FDA added a warning about the heightened risk of PML to the drug's labeling.
A combination of three factors seems to put patients at highest risk: treatment with Tysabri for more than two years; receiving other kinds of immune-suppressing medications; and testing positive for antibodies to the JC virus.
To find out why the drug carries such a high risk of PML, researchers collected blood samples from two groups of MS patients -- those just starting treatment with Tysabri, and those who had been on the drug for more than two years. They compared those samples to blood taken from healthy volunteers.
The investigators were looking for a particular type of cell in the blood -- a kind of stem cell that turns into white blood cells called B-cell lymphocytes.
"Turns out in these MS patients treated with [Tysabri], the number of these blood stem cells is three- to 10-fold higher than you'd see normally under normal physiologic conditions," Major said.
"JC virus is able to infect these blood stem cells as they become a B lymphocyte," he explained. His working theory has been that these infected B lymphocytes then carry the infection into the brain.
To test that theory, the researchers wanted to see if they could find traces of the JC virus in circulating blood stem cells.
And they did. Of 26 patients who were just starting treatment with Tysabri, 50 percent had traces of the JC virus in their circulating blood stem cells. Of 23 patients who had taken the drug for more than two years, 44 percent had JC virus DNA in more than one kind of blood stem cell type. In contrast, only 17 percent of the 18 healthy volunteers had signs of the JC virus in those cells.
"It was somewhat surprising to us that quite a high percentage of individuals had detectable viral DNA in these blood stem cells," Major said.
But what isn't exactly clear is how this could affect their risk of developing PML. Most patients who tested positive for JC virus had only a few copies of the virus, suggesting that they were still at low risk of infection. Patients who had taken the drug for more than two years had higher virus counts than those who were just starting treatment.
"We need to look at additional patients, and follow them for a long period of time," Major said.
Perhaps most concerning, 10 study participants had evidence of the JC virus in their blood but tested negative for antibodies to it. That suggests current tests for the virus may be missing some patients who could be at high risk for PML infection, the authors explained.
An expert who was not involved in the study, which was published online March 25 in the journal JAMA Neurology, said the findings left some questions unanswered.
"Clearly, Tysabri seems to engender the release of JC virus-containing cells from the bone marrow," said Dr. Gary Birnbaum, a neurologist and director of the Multiple Sclerosis Treatment and Research Center in Golden Valley, Minn. "This could explain why risks of PML are high in patients on this drug," he noted.
"What isn't clear is why the risk escalates dramatically after two years, since JC virus-bearing cells emerge early in the course of treatment," Birnbaum pointed out.
Additionally, Birnbaum said it was "disquieting" that researchers found evidence of the JC virus in patients who then tested negative for antibodies to it.
"Thus, testing individuals for exposure to JC virus by measuring antibodies to the virus may be insufficient to fully assess their risks for developing PML," he said.
Source: WebMD ©2005-2014 WebMD, LLC (26/03/14)
Australia’s Therapeutic Goods Administration (TGA) revealed today that it is monitoring reports of melanoma in patients being treated with natalizumab and encourages consumers and health professionals to report all such cases.
Natalizumab, Biogen Idec’s blockbuster drug Tysabri, which generated global in-market sales of $1.7 billion last year) is used to treat patients with relapsing-remitting multiple sclerosis to delay the progression of physical disability and reduce the frequency of relapse.
Melanoma is potentially life-threatening and Australia has one of the highest incidence rates of this condition in the world.Three cases of melanoma in patients being treated with natalizumab have been reported to the TGA.
An ongoing TGA review of this issue has found insufficient evidence to show a definite link between natalizumab and melanoma. However, given the high incidence of melanoma in Australia, this remains an issue of concern for the TGA.
Source: The Pharma Letter © The Pharma Letter Limited 2014 (19/03/14)