PLEX: For whom and how? Current and potential uses for MS and NMO

Transcription

1 PLEX: For whom and how? Current and potential uses for MS and NMO Brian G. Weinshenker MD, FRCP(C) Rochester MN Disclosures Royalties related to patent for discovery of NMO-IgG licensed to RSR, Ltd. Consulting contracts related to NMO clinical research: Asahi Kasei Kuraray Medical Co, Japan Elan Pharmaceuticals Novartis Pharmaceuticals GlaxoSmithKline Pharmaceuticals Chord Pharmaceuticals Chugai Pharmaceuticals Member DSMB Biogen Idec (Chair) Novartis Mitsubishi (Chair) Member Attack Adjudication Committee MedImmune (Chair) 1

2 Outline History of PLEX in CNS demyelinating disease Use in progressive forms of MS Treatment for acute attacks of MS and demyelinating disease Treatment for of acute attacks of NMO Maintenance treatment of NMO Use of PLEX for natalizumab-associated PML Severity Fulminant: Marburg s variant of MS; ADEM; Balo s concentric sclerosis Isolated: ON, transverse myelitis Prototypic MS RR SP Benign MS Restricted Distribution: Devic s syndrome Relapsing Myelitis Progressive: Chronic myelopathy; Progressive ataxia; Dementia Chronicity 2

3 PLEX for Progressive Forms of MS Vamvakas E, Pineda AA, Weinshenker BG. J Clin Apheresis 1995; 10:

4 Meta-analysis of RCT of PLEX for Progressive MS Follow up 6 months 12 months All Controlled All Controlled Change in DSS (-0.149) (-0.167) Relative odds of worsening ( 1 DSS) Relative odds of improvement ( 1 DSS) * 0.441* 1.981* 2.321* 2.129* 2.258* *p<0.05 Based on review of 6 studies, 4 of which were controlled Values shown reflect difference in change in mean DSS or relative odds of worsening/improvement by 1 DSS point in treatment versus control group after exclusion of 4 outliers Vamvakas E, Pineda AA, Weinshenker BG. J Clin Apheresis 1995; 10: Meta-analysis of RCT of PLEX for Progressive MS Conclusions: There is a need for further clinical research into the possibility of a beneficial effect of PLEX in patients with CPMS likely to experience neurologic decline over the ensuing 12 months. Targeting treatment to a particular subgroup of CPMS patients may be necessary for PLEX to prove effective. *p<0.05 Based on review of 6 studies, 4 of which were controlled Values shown reflect difference in change in mean DSS or relative odds of worsening/improvement by 1 DSS point in treatment versus control group after exclusion of 4 outliers Vamvakas E, Pineda AA, Weinshenker BG. J Clin Apheresis 1995; 10:

5 Plasma exchange for acute attacks of CNS demyelinating disease Background Idiopathic inflammatory demyelinating diseases of the CNS cause acute attacks of neurological disability Rarely, attacks fail to respond to steroids and lead to severe permanent disability or death Fulminant IIDDs (e.g., Marburg s variant, neuromyelitis optica) do so commonly 5

6 PLEX: Early experience in CNS Demyelinating Disease Uncontrolled studies (12 series; 29 patients): dramatic, rapid improvement after plasma exchange Weiner et al. (1989): controlled trial in 116 attacks of MS results largely negative possible adjunctive benefit when coadministered with ACTH/Cyclophosphamide benefit only in RRMS, not prog MS Weiner HL, Dau PC, Khatri BO, et al. Neurology 1989;39:

7 PLEX: Preliminary Mayo Clinic Experience 6 consecutive patients All para, hemi, or quadriplegic; 2 aphasic; 2 ventilator-dependent 6-9 exchanges No immunosuppressive treatment Improvement marked in 5/6; median EDSS = 4.5 (range ) Median time to improvement 4.0 days Rodriguez et al. Neurology 1993; 43: Mayo Clinic Controlled Study Randomized Sham controlled Double blind All IIDD s Informative patients Severe deficit >3 weeks Failed corticosteroids Robust outcome Moderate/marked improvement Specific targeted deficit No confounding treatments Crossover Weinshenker BG et al. Neurology 1999;46:

8 Randomized (n=22) Active TPE 7 treatments over 14 days (n=11) Sham exchange 7 treatments over 14 days (n=11) Success (n=5) Failure and alive (n=6) Success (n=1) Failure and dead (n=2) Failure and alive (n=8) Crossover to sham (n=6) Crossover to active (n=8) Success (n=0) Failure (n=6) Success (n=3) Failure (n=5) CP Follow-up Efficacy 9/22 satisfied primary outcome 8/9 received active treatment Success occurred 8/19 (42.1%) courses of active treatment 1/17 (5.9%) courses of sham treatment Weinshenker BG et al. Ann Neurol 1999; 46:

9 Comparison of Randomized Trials of TPE for Acute Attacks Weiner et al Mayo Clinic N Attack severity DSS>1 Severe Duration 5 days - 8 weeks 3 weeks - 3 months Prior steroids Not permitted Required Design Parallel, DM, sham Crossover, DM, sham Endpoint DSS 1 or 2 Mod/Mkd Impvmt in TND Concomitant Rx ACTH, cytoxan None Retrospective Analysis of Patients Treated with Plasma Exchange for Severe Attacks of CNS Demyelinating Disease B. Mark Keegan, MD Robyn McClelland, PhD Charles Darby, MSc Brian Weinshenker, MD 9

10 Patients Treated with Plasma Exchange : Diagnosis N= RR-MS ADEM ATM NMO Diagnosis Marburg Focal cerebral Other Final Initial Proportion with Moderate to Marked Improvement (n=59) 100.0% 90.0% 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% RR-MS ADEM ATM NMO Marburg Focal cerebral Other Total 10

11 Success According to Epoch of Treatment (n=59) N Epoch N Success (%) Success (%) Success According to Study Type (n=59) Controlled Study Type Uncontrolled Success (%) N 11

12 Multivariate Regression Model Predicting Successful Treatment Factor Success rate OR (95% CI) p Gender F M ( ) Days to TPE < ( ) > ( ) EDSS at TPE < ( ) Reflexes nl or increased absent ( ) PLEX: Predictors of Response 12

13 PLEX: Predictors of Response PLEX: Predictors of Response 13

14 PLEX: Predictors of Response Correlation with Imaging Of 15 patients receiving PLEX for an acute demyelinating syndrome 60% almost complete radiologic resolution 20% partial resolution 20% no resolution Several patients developed new lesions No correlation betweeen radiological resolution and clinical response 14

15 Further Support: Acute, Severe Attacks of CNS Demyelinating Disease Author N Exchanges Diagnosis Syndrome Response quadriplegia 2; MS 4; ATM1; 6 5 (3-5) paraplegia 3; 6 of 6 NMO 1 cerebellar 1 Bennetto (UK); J Neurol 2004 Meca-Lallana (Spain); Rev Neurol 2003 Ruprecht (Germany); Neurology 2004 Llufriu S (Spain); Neurology MS 9; ADEM 1; TM 1 paraplegia 8; ataxia 4; dysphagia 3 7 of 11 improved in first month 10 5 (3-5) RRMS 4; CIS 6 ON 10 7 of (5-15) RRMS 18; SPMS 3; CIS 2; ADEM 7; NMO 4; Marburg 2; TM 1; ON 4 ON 4; others varied 15 (37%) at 12 days [non ON]; 1 (25%) at 12 days [ON] Autoimmune Demyelination Pattern I Pattern II Macrophagemediated Antibodymediated C CP

16 Oligodendrocyte Dystrophy Pattern III Pattern IV Distal oligodendrogliopathy Apoptosis Primary oligodendrogliopathy Neurodegneration CP PLEX: Role of IgG? Patients (no.) Success Success Failure Failure p< Pattern I Pattern II Pattern III 6 Keegan BM et al. Lancet 2005; 366:

17 Confirmatory Sham-Controlled Study for Acute Attacks: PLASMASEP Study (France; Pr. Bruno Brochet, PI) Purpose: To compare plasma exchanges versus sham exchanges on residual disability in MS patients experiencing a disabling relapse not improved after steroid treatment. Research study design: Double blind (patient/ evaluating neurologists ) randomised, parallel study (ratio 1/1) Primary outcome: 5 graded-scale of improvement based on objective scales and functional assessment after 1 month. Secondary endpoints: safety; improvement at 3 and 6 months PLEX for Neuromyelitis Optica 17

18 Efficacy for Attacks of Neuromyelitis Optica Author N Exchanges Diagnosis Syndrome Response EDSS baselineedss improvemen 3/6 moderate Watanabe ON 3; (functionally S (Japan); NMO 6 (5-8) 1.5 (0-8) myelitis 3 important); 1 mild; 1 M SJ 2007 no change Wang KC (Taiwan); J Clin Neurosci 2011 Bonnam M (French WI); M SJ 2009 Lim YM (Korea); M SJ NMO 18 (29 attac ks) 6 (5-15) 31 7 (3-9) NMO and LETM NMO and LETM ON 1; myelitis 8; ON and myelitis 3 Myelitis Myelitis 20; ON9; cerebral 2 6 moderate; 3 mild; 8/9 improved to baseline at one month 8.7 (range ) EDSS reduction ±1.4 in PE points in patients group vs receiving PLEX plus 8.0±1.4 in steroids vs -1.2 in steroids only those receiving group steroids only 65% functional improvement (moderate to marked) 5.5 (3.5-10) EDSS1.5 (1-3.5) [non ON] EDSS 2.6±2.3 in PE add-on vs 1.2±1.6 in steroids only final EDSS: 4.0 (2-8.5) at 1 month 18

19 PLEX: Predictors of Response Maintenance PLEX for Neuromyelitis Optica 19

20 Maintenance PLEX for Neuromyelitis Optica Khatri B et al. Maintenance plasma exchange therapy for steroidrefractory neuromyelitis optica. J Clin Apheresis 2012; 27: Retrospective analysis of 7 patients with NMO, refractory to treatment, treated in one center Mean 76 Tx (range ) over mean 7.1 yrs (range 2-16) Results: Reduced attacks 5/7 EDSS improved by 1 point RNFL thickness stabilized Interruption in 5 associated with worsening Restarting (3) associated with improvement and not restarting (2) associated with death Maintenance PLEX for Neuromyelitis Optica Prospective observational study Protocol NCT (clinicaltrials.gov) Wingerchuk and Keegan, Mayo Clinic, Arizona and Rochester Evaluation of feasibility, adherence, safety, tolerability and preliminary efficacy Assess AQP4-IgG kinetics 20

21 PLEX for Natalizumab Removal Treatment of natalizumab-induced progressive multifocal leukoencephalopathy (PML) Natalizumab Binds α 4 integrin on lymphocytes Impairs lymphocyte trafficking into CNS Approved by FDA for relapsing forms of MS >100 cases of PML now reported Risk increased in those seropositive for JC virus and in those with previous immunosuppression 21

22 Treatment of natalizumab-induced progressive multifocal leukoencephalopathy (PML) Khatri BO et al (Neurology 2009; 72: 402-9): Natalizumab reduced by >90% by 3 treatments of PLEX Suggest 5 treatments to reduce levels <1 ug/ml to achieve <50% integrin saturation Successful treatment of PML reported with PLEX (Wenning W NEJM 361: ) PLEX: Guidelines 22

23 ASFA Guidelines: Apheresis for CNS Demyelinating Disease Neurology 2011;76:

24 Conclusions IIDD s are heterogeneous clinically, pathologically and immunologically Benefits of PLEX well established for acute attacks of demyelinating disease of a variety of underlying pathologies, including NMO Meaningful rapid improvement occurs in approximately 50% Benefit may associate with presence of Ig in lesions of MS, but difficult to determine who will be a responder with certainty Areflexia and flaccidity are associated with poor response 24