Date post: | 31-Jul-2015 |
Category: |
Health & Medicine |
Upload: | gavin-giovannoni |
View: | 1,645 times |
Download: | 2 times |
Rituximab or other MABs: why, where, when and how outside of MS. How to use these drugs, and when.
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry London, UK
Disclosures
Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Objectives
Objectives
• History of monoclonal antibodies • Monoclonal nomenclature • Off-label use • Targeted therapies • Examples from across the spectrum of neurology
• HSCT • CNS & systemic vasculitis • IgG4 disease • NMO • Neurosarcoidosis • Myasthenia gravis • CIDP • Multifocal motor neuropathy
History
Monoclonal antibodies
Nomenclature
Monoclonal nomenclature
Muromonab-CD3 (OKT3) Infliximab (anti-TNFa) Rituximab (anti-CD20)
Alemtuzumab (anti-CD52) Tocilizumab (anti-IL6R)
Eculizumab (anti-C5) Ocrelizumab (anti-CD20)
Adalimumab (anti-TNFa) Ofatumumab (anti-CD20) Belimumab (anti-BAFF) Otelixizumab (anti-CD3)
Off-label use
Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, unapproved dosage, or unapproved form of administration.
BMT/HSCT
Summary list
Off-label use of monoclonal antibodies in neurology
• Anti-CD20 (rituximab)
• NMO
• MG
• CNS vasculitis
• IgG4 disease
• Anti-IL6-R (tocilizumab )
• NMO
• Anti-TNFα (infliximab, adalimumab)
• Neurosarcoidosis
• Anti-CD52 (Campath-1h/alemtuzumab)
• CNS vasculitis
• Anti-C5 (eculizumab)
• MG
• MMN
Anti-CD20 (rituximab)
CNS Vasculitis
Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis
Stone et al. N Engl J Med 2010;363:221-32.
Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis
Stone et al. N Engl J Med 2010;363:221-32.
Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab
Walshe et al. Ann Rheum Dis 2008;67:1322–1327.
1. Before Alemtuzumab administration other immunosuppressive medications are discontinued except prednisolone, which is continued at 10 mg/day.
2. Alemtuzumab is administered IV on consecutive days at doses of 4, 10, 40, 40 and 40 mg (total 134 mg). 3. Hydrocortisone 100 mg IV and chlorpheniramine 10 mg are given for infusion prophylaxis 4. Acyclovir and nystatin swish and swallow medications are given for infection prophylaxis. 5. Further courses of Alemtuzumab are allowed for recurrent disease in those patients who do not tolerate
the initial treatment or have a relapse.
Immunoglobulin-G4-related hypertrophic pachymeningitis with antineutrophil cytoplasmatic antibodies effectively treated with rituximab
Popkirov et al. Journal of Clinical Neuroscience, Volume 22, Issue 6, 2015, 1038 – 1040.
Baseline 3 weeks 7 months
Neuromyelitis Optica
Wingerchuk et al. Lancet Neurol 2007; 6: 805–15.
Treatment of Neuromyelitis Optica: Review and Recommendations
104 patients
Kimbrough et al. Multiple Sclerosis and Related Disorders 1 (2012) 180–187
Treatment of Neuromyelitis Optica: Review and Recommendations
Kimbrough et al. Multiple Sclerosis and Related Disorders 1 (2012) 180–187
Treatment of neuromyelitis optica with rituximab:
retrospective analysis of 25 patients
Jacob et al. Arch Neurol. 2008 Nov;65(11):1443-8.
Outcomes 5 years after response to rituximab therapy in ITP
Patel et al. Blood 2012: 119: 5989
Source: www.clinicaltrials.gov
Anti-CD20
Early p
ro-B
Late
pro
-B
Larg
e pr
e-B
Sm
all p
re-B
Imm
atur
e B
Nai
ve B
cel
l
Mat
ure
B cel
l
Plasm
a ce
ll
Stem
cell
Pre-B Receptor
Cytoplasmic chain IgM IgM/IgD
IgG Class Switch
CD19
CD20
CD22
Bone Marrow Periphery
B cell ontogeny
Source: www.clinicaltrials.gov
Anti-CD19
Tocilizumab (anti-IL6R)
Disease amelioration with Tocilizumab (anti-IL6R) in a treatment-resistant patient With NMO
Kieseier et al. JAMA Neurol. 2013;70(3):390-393.
Source: www.clinicaltrials.gov
Hu-Anti-IL6R
Anti-C5 (eculizumab)
Innate memory (effector pathways) complement and lectin-binding pathways
Source: www.clinicaltrials.gov
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ECULIZUMAB IN PATIENTS WITH REFRACTORY GENERALIZED MYASTHENIA GRAVIS
Howard et al. Muscle Nerve. 2013 Jul;48(1):76-84.
REFRACTORY GENRALIZED MG 1. AChR-ab–positive gMG 2. Persistent, moderate-to-severe muscle
weakness despite treatment with at least 2 immunosuppressive agents, including prednisone for at least 1 year.
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ECULIZUMAB IN PATIENTS WITH REFRACTORY GENERALIZED MYASTHENIA GRAVIS
Howard et al. Muscle Nerve. 2013 Jul;48(1):76-84.
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ECULIZUMAB IN PATIENTS WITH REFRACTORY GENERALIZED MYASTHENIA GRAVIS
Howard et al. Muscle Nerve. 2013 Jul;48(1):76-84.
An open label clinical trial of complement inhibition in multifocal motor neuropathy
Fitzpatrick et al. J Peripher Nerv Syst. 2011 Jun;16(2):84-91.
Anti-TNFα (infliximab, adalimumab)
Medically refractory neurosarcoidosis treated with infliximab
Pereira et al. Intern Med J. 2011 Apr;41(4):354-7.
Induction: 3 mg/kg infliximab given as an IV at 0, 2, and 6 weeks Maintenance: 3 mg/kg every 8 weeks thereafter Refractory : up to 10 mg/kg or treating every 4 weeks Infliximab should always be given in combination with methotrexate or azathioprine.
Influence of immunogenicity on the long-term efficacy of infliximab in Chron’s disease
Baert et al., N Engl J Med 2003;348:601-8.
Adverse Events
“There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don't know. But there are also unknown unknowns – there are things we do not know we don't know.”
United States Secretary of Defense, Donald Rumsfeld
Rumsfeldometer
1. Known-knowns - there are things we know that we know
2. Unknown-knowns - these are the things we know will occur
3. Known-unknowns - there are things that we now know we don't know
4. Unknown-unknowns - there are things we do not know we don't know
Adverse events
1. Known-knowns a. Cell lysis syndromes - infusion reactions b. Anti-drug antibodies c. Serum sickness-type reaction and immune complex disorders d. Injection site reactions
2. Unknown-knowns a. Opportunistic infections b. Secondary malignancies c. Transplancental effects
3. Known-unknowns a. Premature immunosenescence
4. Unknown-unknowns a. Off target effects, for example delayed secondary autoimmunity b. ?
Conclusions
Conclusion
• Therapeutic monoclonal antibodies are a mature technology with a proud history
• Targeted therapies • Scientific rationale for off-label use
• Predictable adverse event profile • Infusion reactions
• Injection site reactions
• Anti-drug antibodies
• Increasing number of uses across the spectrum of neurology • HSCT
• CNS & systemic vasculitis
• IgG4 disease
• NMO & NMO-spectrum disorders
• Neurosarcoidosis
• Myasthenia gravis
• CIDP & multifocal motor neuropathy
• High costs
Questions