MG Research Update. Jeffrey T. Guptill MD, MA, MHS Assistant Professor of Neurology Duke University Medical Center

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1 MG Research Update Jeffrey T. Guptill MD, MA, MHS Assistant Professor of Neurology Duke University Medical Center

2 Overview Clinical trial update Highlights from 2015 Scientific Session A few other items Will not cover MGTX trial or MG Tx guidelines separate talks scheduled on that

3 Clinical Trial Update Methotrexate Objective: determine if oral methotrexate is an effective therapy for patients with MG who are prednisone dependent. Patients will be randomized to receive either methotrexate or placebo. Primary outcome measure: prednisone area under the dose-time curve (AUDTC, months 4-12) Results: no difference in prednisone dose CFZ533 Therapy that inhibits B cell activation without B cell depletion Initially studied in preventing organ transplant rejection Objective: to evaluate safety, tolerability, pharmacokinetics/pharmacodynamics and efficacy of CFZ533 as an add-on therapy to standard of care in patients with moderate to severe MG Primary outcome: change in QMG score Sites: Europe, Canada, Russia, Taiwan

4 Lymphocyte Classes Downloaded from: StudentConsult (on 22 September :54 PM) 2005 Elsevier

5 CFZ533 suppresses B cell Activation Figure 10-1 Phases of the humoral immune response. The activation of B cells is initiated by specific recognition of antigens by the surface Ig receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B cell clone. Progeny of the clone may produce IgM or other Ig isotypes (e.g., IgG), may undergo affinity maturation, or may persist as memory cells. Downloaded from: StudentConsult (on 22 September :59 PM) 2005 Elsevier

6 Clinical Trial Update Rituximab Phase II Trial of Rituximab In Myasthenia Gravis NIH NINDS Treatment refractory patients Includes patients with AChR and MuSK Antibody MG Primary outcome: percent of subjects that can reduce their prednisone dose by 75% at 1 year Close to completing recruitment

7 B cell Activation Figure 10-1 Phases of the humoral immune response. The activation of B cells is initiated by specific recognition of antigens by the surface Ig receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B cell clone. Progeny of the clone may produce IgM or other Ig isotypes (e.g., IgG), may undergo affinity maturation, or may persist as memory cells. Downloaded from: StudentConsult (on 22 September :59 PM) 2005 Elsevier

8 Clinical Trial Update Conti-Fine BM et al. J Clin Invest. 2006;116(11): Eculizumab Objective: evaluate the Safety and Efficacy of Eculizumab in Subjects With Refractory Generalized MG Primary outcome: change from baseline in MG-ADL Completed enrollment First MG trial to complete enrollment on time Results will be presented in July at the International Congress on Neuromuscular Diseases, Toronto Potential to be first immunotherapy approved for MG in the US

9 Highlights from the 2015 Scientific Session Liu WB et al., Epidemiology and Clinical Characteristics of Myasthenia gravis patients in China High percentage (49.97%) of juvenile MG patients X Huang et al., Clinical features of Juvenile Myasthenia Gravis in southern China 1699 Juvenile MG patients. Majority (93.2%) of the juvenile patients only had ocular symptoms at onset, usually respond well to immunosuppression Message: MG in China appears to have distinct features compared with the U.S. and genetics may play a large role. Understanding these differences may lead to a better understanding of disease pathology and hopefully better treatment.

10 Highlights from the 2015 Scientific Session MM Dimachkie et al., Open Label study of subcutaneous immunoglobulin (SCIg) in myasthenia gravis: Study Design and Progress Update ZA Siddiqi et al., A Pilot Trial to Assess the Feasibility and Efficacy of Subcutaneous Immunoglobulin in Patients with Myasthenia Gravis Exacerbation Preliminary Results

11 Immunomodulatory Therapy: IVIG Pooled immunoglobulin proteins from many healthy individuals Response within 2 weeks Often administered over 2-5 days in health care facility Can be administered at home Message: several studies are in progress looking at the feasibility, safety and efficacy of SCIg for chronic MG treatment.

12 Highlights from the 2015 Scientific Session AC Guidon et al., Myasthenia Gravis Following Nivolumab and Pembrolizumab/Ipilimumab Therapy Two patients who developed MG during nivolumab (anti-pd1) and pembrolizumab/ipilimumab (anti-pd1/anti-ctla-4) therapy Message: Checkpoint blockade drugs for the treatment of advanced cancer may significantly improve patient outcomes with these cancers. However, several cases of MG have been now documented. This is important for clinicians/patients to know and may also yield insights into the mechanism of disease for at least some cases of autoimmune MG.

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15 Antigen-specific immunotherapy for MG appears promising Results in animal models Onset of chronic EAMG could be prevented Established EAMG could be rapidly reversed Treated rats exhibited long-term resistance to reinduction of EAMG, suggesting a lasting cure Next steps Further animal studies, including naturally occurring animal MG Using formulation appropriate for humans

16 7 patients (Ottawa, CA) Autologous HSCT Mean age 44 =autolo gous+stem+c ell+transplant&sourc e=lnms&tb m=isch&sa=x&ved =0ahUKEwjKgcuA7LvMAhVJN j4khbdodqaq_auic SgD &biw=1600&bih=841&dpr=1.2#imgrc=zvc2yq2z9laalm%3a

17 Autologous stem cell transplant in MG Results: All patients achieved complete stable remission with no residual MG symptoms and no MG therapies Three patients experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT (resolved) Conclusion: may be an option for very refractory generalized MG patients, though emerging therapies may supplant this therapy as an option.

18 American Brain Foundation MGFA Clinician-Scientist Development Award Michael Hehir M.D. (U. Vermont) Immunosuppressive Cost Unit: A Novel Method to Assess the Value and Cost of Immunosuppressant Side Effects Research Goal: develop a novel, weighted scale, called the Immunosuppressive Cost Unit (ICU), to quantify and compare the value and burden of immunosuppressive agents used to treat autoimmune neuromuscular diseases. Currently, side effects are usually quantified as a rate and there is no weighting or importance assigned to side effects from the patient perspective.

19 ICU methods Several phases: Phase 1: severe side effects are being assigned a value (near completion). Phase 2: mild/moderate side effects. Phase 3: prospectively evaluate 40 patients every 3 months for 1 year

20 Immunosuppressive Cost Unit Important concept that values the patient perspective If successful, similar scales could be developed for other immunosuppressive medications Could be applied to other autoimmune diseases

21 Thank You Thank You