update: pml in ms - neurology · pml and anti‐jc virus antibody biogen tysabri safety update,...
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Update: PML in MSKenneth Tyler, MD
Reuler‐Lewin Family Professor & Chair
Department of Neurology
University of Colorado School of Medicine
There are no FDA Approved Drugs for Treatment of PML: All MedicationsDiscussed are “Off‐Label”
Dr. Tyler has done expert consulting related to PML and JC Virus for:PML Consortium, Genentech, Pfizer, Roche, Jansen, Biogen
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JC virus: structure
Non‐enveloped, icosahedral, ~50nm virions, 72 capsomeresCircular double‐stranded DNA, 5kbp: Encodes: NCCR, Agnoprotein, VP1, VP2, VP3, T antigen, t antigen
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JCV Structure
TEM of JCV in Oligodendrocyte nucleusX100,000 (E. Major)
SV40 at 3.4 A Resolution (S. Harrison)40-50nm, non-enveloped, icosahedral
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Taguchi F et al., Mol Immunol 26:1057, ‘82
HI Assay
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Kean J et al. , PLoS Pathogens 5:e1000363,‘09
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Brew et al. Nat Rev Neurol 6:667, 2010
sialic acid5‐HT2a receptor
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PML – Initial Description• “In the course of regular
post-mortem examinations of the brains of patients coming to autopsy at the MGH, my attention has been called in recent years to an unusual disorder of the cerebral white matter with distinctive features unfamiliar to me and my colleagues from our own experience or that of others.”(EPR NEJM 265:815, 1961)
>
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Primary – no cause
Immune deficiency disorders
Carcinoma
Myeloproliferative diseases
Lymphoproliferative diseases
Illnesses associated with PML1984
62%
7%2%
16%
7%6%
Granulomatous/Inflammatory disorders
230 cases published and unpublished cases (1958-1984)69 pathologically confirmed and 40 virologically and pathologically confirmed
Brooks & Walker, Neurol. Clin. ‘84
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AIDS associated PML 1983 v 2003
87.9%
Non-HIV
2.1%
80-85%
15-20%
Brooks and Walker 1958-1984
Berger 2000-2003
HIV
HIV
Non-HIV
0.15 per million incidence 0.6 per million incidence
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Khanna N et al. CID 48:1459, ‘09
82% HIV+
18% non-HIV
8% Heme. CA3% Solid Organ CA0.5% Rheum. Dis.
Molloy ES Arth Rheum 60:3761, ‘09
HAART
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Demyelination: Usually MultifocalLFB Myelin Stain
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Demyelination in PMLTypically multifocalSize variable 1mm‐to several cm’sNo mass, classically no inflammation
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Bizarre Enlarged Astrocytes in PML
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ISH+ signal for JCV DNA intranuclear inclusion bearing oligos
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Gross Pathology
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Symptoms and Signs of PML[109 confirmed cases, Brooks & Walker, 1984]
Motor weakness
20% 75% 95%
Visual deficits 45% 13% 58%Mental deficits 38% 20% 58%Incoordination 10% 19% 29%Speech 15% 10% 25%Sensory deficits 5% 5% 10%Sz 3% 7% 10%HA 5% 0% 5%Vertigo 4% 0% 4%
At Onset + At Diagnosis TOTAL
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Source: Biogen Idec, First 35 Tysabri-PML Cases
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Yousry et al. Ann Neurol 72:779, 2012
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A: T2C: T1
B: FLAIRD:DWIYousry et al Ann N 72:779, 2012
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CSF• Mild or no pleocytosis : mean 8 cells/ul, median 2 cells, rare>20)
• Sltly Elevated protein (55%): mean 67 mg/dl, rarely>200 mg/dl
• Normal glucose (>85%)
• PCR is ~95‐100% specific but sensitivity variable depending on viral
load (~70‐90%? to >95%) and assay sensitivity
– NINDS (E. Major) 10 DNA copies/ul vs. Commercial ~200 copies/ul
• Brain biopsy is ‘gold standard’‐
– specificity 100%
– sensitivity 90‐95%
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Berger J et al. Neurology 80:1430, 2013
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Berger et al. Neurology 80:1430, 2013
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Rx in PML
Brew et al. Nat Rev Neurol 6:667, 2010
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Clifford D et al. J Neurovirol 19:351, 2013
No Effect of Mefloquine in PML
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Neurology 85:104, 2015
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Landi et al.
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NEJM Vol. 353:362, 369, 375July 28, 2005
Risk:1 case per 1000 pts(95% CI 0.2-2.8)3116 ptsMean 17.9 dosesYousry TA et al. NEJM 354:924,‘06
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Treatment With Immunomodulatory Drugs Results in Altered T‐Cell Populations
• Decreased CD4+/CD8+ T‐cell
ratios in CSF following MS Rx
– Natalizumab1,2
– Fingolimod2
• Decreased numbers of CD3+
T‐cells in the blood and CSF
– Rituxan3,4
1. Stuve O et al, Arch Neurol. 2006;63:1383. 2. Kowarik M et al. Neurology. 2011;76:1214. 3. Cross A et al. J Neuroimmunol. 2006;180:63-70. 4. Piccio L et al, Arch Neurol. 2010;67:707-14.
Kowarik M et al. Neurology. 2011;76:1214.
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FDA AERS: ? PML Risk of new biologics and targeted CA therapeutics PRR (95% CI), 49 new drugs:
• Brentuximab vedotin (Adcetris){CD30} 24.5 (14.8‐40.6)
• Ofatumumab (Arzerra){CD20} 16.3 (9.6‐27.4)
• Alemtuzumab (Campath, Lemtrada) {CD52} 9.9 (6‐16.4)
• Obinutuzumab (Gazyva){CD20} 7.4 (2.4‐22.8)
• Ibrutinib (Imbruvica){BrutonTK inhib.} 5.6 (3‐10.5)
• Belimumab (Benlysta){Blys stim.} 4.5 (2.3‐9)
• Idelalisib (Zydelig){PI3K inhib.} 4.1 (1.3‐12.6)
Raisch et al. ExpOp. Drug Safety 15:1003, 2016
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Nieuwkamp DJ et al. NEJM 372:1474, 2015.
5Tecfidera MS PML CasesLymphopenia (<500/mm3)Duration of Rx (yrs)Age >50~230,000 pts Rx’d (1/2017)~1:46,000
~200x < natalizumab
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• #
9Cases8/9 >2.5 yrs on Rx1/9 ~1.5 yrsAge >49 in 8/9 (1=32)1:18,000 to 1:850035‐80x <natalizumab
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Drug Risk Categories• Class I (High)
– Natalizumab (0.1%‐1%)
– Efalizumab (3/166: 1.8%)
• Class II (Low/Infrequent)
– Rituximab (1/30,000 in RA)
– Mycophenylate Mofetil
– Brentuximab
– Belimumab (2/18,000)
• Class III (Unknown)
Alemtuzumab (no Cases in PML some in CLL Rx)
Fumaric Acid (4+ with fumarate, 1+ with dimethylfumarate in MS)
Fingolimod (3 Cases)
TNF alpha blockers (etanercept, infliximab)
Cyclophosphomide
Azathioprine
Methotrexate
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Natalizumab: PostmarketingUse*
Biogen Idec, data on file. * Excludes ~5100 patients exposed in clinical trials. Exposures are estimates.
Biogen. Dec. 2016
698 PML Cases1:231 pts exposed
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Biogen: Tysabri Postmarketing Safety Update. TY‐US‐0113(11). Dec. 2016
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Biogen. M‐TY‐US‐00196. Jun 2016
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Biogen: Tysabri Postmarketing Safety Update. TY‐US‐0113(11) & 0102(11). Dec. 2016
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Biogen. TY‐US‐0113(11) & 0102(11). Dec. 2016
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Biogen. TY‐US‐0113(11) & 0102(11). Dec. 2016
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PML and Anti‐JC Virus Antibody
Biogen Tysabri Safety Update, 2016
276/278 natalizumab‐PML MS patients (99%) Anti‐JCV Ab+ > 6 months prior
to PML diagnosis. Two negative at ‐8m and ‐9m.
.
Bloomgren G et al. N Engl J Med.2012;366:1870-1880.
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Neurology 86:484, 2016
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Plavina T et al. Ann N 76:802, 2014
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PlavinaT et al. Ann N 76:802, 2014
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Plavina T et al., [Biogen Idec] Abstract DX51. ACTRIMS. May 29-June 1, 2013, Orlando FL
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PML Risk Estimates by Index Threshold in Anti‐JCV Antibody Positive Patients With No Prior Immunosuppressant Use
Ticho B et al. [Biogen Idec] Abstr. #O228. European Neurol. June 9, 2013. Society Barcelona, Spain
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Prior Use of Immunosuppressants in Natalizumab Rx’d MS Patients
Bloomgren G et al. N Engl J Med. 2012;366:1870-1880.
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Surface Expression of CD62L on CD4+ T-cells in Blood and
Its Correlation to PML Development in MS Patients
Receiving NatalizumabTherapy
1. Schwab N et al. Neurology 2013;81:865-871. 2. ECTRIMS 2013: Schneider T et al., #232, Dynamic biomarkers for clinical efficacy and individual PML prevention under natalizumab therapy.
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Villar LM et al. Ann Neurol 77:447, 2015
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Biogen. TY‐US‐0113(11) & 0102(11). Dec. 2016
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Anti-JC Virus (JCV) Ab Levels in Sera From Natalizumab-Treated Patients Who Subsequently Developed PML (Pre-PML) Compared With Those in Anti-JCV
Antibody-Positive Patients Who Did Not Develop PML (Non-PML)
Trampe A et al. Neurology. 2012:78:1736.