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