Neuromyelitis Optica News Gloria von Geldern, MD Assistant Professor of Neurology University of Washington Multiple Sclerosis Center Multiple Sclerosis Regional Summit June 13, 2020 Disclosures ▪ No conflict of interest ▪ Off-label treatments will be mentioned Current research funding Patient-Centered Outcomes Research Institute (PCORI) What is New in NMO? Natalia Rost, MD Chair scientific committee AAN Neuromyelitis Optica (NMO) Neuromyelitis Optica Spectrum Disease (NMOSD) ▪ Inflammatory disorder of the central nervous system ▪ Predominantly involving optic nerves and spinal cord ▪ Severe demyelination and axonal damage ▪ Rare disease: 0.5-10/100,000, ~8,000 patients in the US ▪ Black > Asian > White ▪ Female > Male Flanagan et al., 2016 Bukhari et al. 2017 Hor et al. 2018 (Guthy-Jackson Charitable Foundation) Multiple Sclerosis vs NMO Pittock and Lucchinetti 2016 History 1894: Clinical case descriptions 2004: AQP4 antibody identified by Devic and Gault by Lennon, Weinshenker et al. Eugene Devic (1858–1930) Lancet2004; 364: 2106–12; Journal of Neuroinflammation 2013, 10:8 Diagnostic Criteria Wingerchuk et al. 2015 Myelin Oligodendrocyte (MOG) Antibody ▪ More common in men and whites ▪ Bilateral optic neuritis, caudal myelitis ▪ Better recovery compared to AQP4-Ab pos NMO ▪ MRI brain without NMO findings ▪ Assay now commercially available at Mayo Sato et al. 2014; van Pelt et al. 2016 Auto-Antibody to Aquaporin 4 Water channel protein in ▪ Astrocytic foot processes at the blood-brain barrier ▪ Spinal cord grey matter ▪ Periaqueductal and periventricular regions ▪ Mueller cells in the retina Amiry-Moghaddam and Otterson 2003 Bystander Oligodendrocyte Injury Tradtrantip et al 2017 Pathology Extensive demyelination Perivascular & parenchymal Complement activation Axonal injury, necrosis eosinophils & granulocytes rosette and rim pattern Jacob et al. 2013 Treatment ▪ Relapse treatment: IVMP (with prolonged oral taper), plasma exchange ▪ Symptom management ▪ Disease modifying/preventative therapy Treatment: Relapse Prevention What we knew before: ▪ MS DMTs may worsen NMO interferons, natalizumab, fingolimod ▪ Small prospective or retrospective series: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate, mitoxantrone Mandler et al. 1998; Constanzi et al. 2011; Cree et al. 2005; Jacob 2009 Kimbrough et al. 2012; Papeix et al. 2007; Kleiter et al. 2012; Min et al. 2012 Immunosuppressive Treatments of NMO until 2019 Sellner et al. 2010 What is New in NMO? Natalia Rost, MD Chair scientific committee AAN Emerging Therapy Mechanisms: Pathophysiology of AQP4-IgG associated NMO Mayo Clin Proc. 2017;92(4):663-679 3 Treatments in 4 Trials Eculizumab Satralizumab Satralizumab Inebilizumab (Anti-C5) (Anti-IL6R) (Anti-IL6R) (Anti-CD19) PREVENT SAKURA-SKY SAKURA-STAR N-MOmentum Participants 143 (143) 83 (55) 95 (64) 230 (212) (AQP4 positive) Additional Yes Yes No No immuno- suppression Relapse reduction 94% 62% 55% 73% (79% in AQP4+) (74% in AQP4+) (77% in AQP4+) Disability NS NS NS OR=0.371 reduction (p=0.007) Eculizumab (Soliris®) First FDA approved medication for NMOSD: June 27, 2019 Infusion ▪ Induction: 900mg IV weekly x4 ▪ Maintenance: 1,200mg IV every 2 weeks ▪ Supplemental dosing for patients receiving plasmapheresis or fresh frozen plasma infusion Also approved (2007) for paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (HUS), myasthenia gravis Eculizumab (Soliris®): Mechanism of Action Complement Inhibitor (monoclonal antibody) Binds C5 → prevents cleavage into C5a and C5b Inflammation and Regeneration 36 (11), 2016 Eculizumab (Soliris®): Efficacy Phase 3 Trial (PREVENT) 143 patients (all AQP4+) most on AZA, MMF, steroids relapses 2% vs 35% RR 0.04, 95% (CI 0.01-0.15 ) Pittock et al. 2019 Eculizumab (Soliris®): Risks and Side Effects Boxed warning: meningococcal infection ▪ REMS program required ▪ Meningococcal vaccine at least 2 weeks prior to starting treatment ▪ In unvaccinated patients 2 weeks of antibacterial prophylaxis Cost: $ 500,000 a year Inebilizumab (Uplizna®) Second FDA approved medication for NMOSD: June 11, 2020 Infusion 300mg IV x2 (2 weeks apart) every 6 months? Inebilizumab (Uplizna®): Mechanism of Action CD19-Inhibitor (monoclonal antibody) Depletes B cells, including plasmablasts B-cell development Inebilizumab Rituximab Büdingen et al. 2015 Inebilizumab (Uplizna®): Efficacy 230 patients 3:1 placebo Trial was stopped early after 6.5 months due to decreased relapses in treatment arm (12 vs 39%) HR 0.27 (95% CI 0.15-0.50) Cree et al. Lancet 2019; 394: 1352–63 Indelizumab (Uplizna®) May Reduce Relapse Severity Weinshenker et al. ECTRIMS 2019 (Poster 358) Inebilizumab (Uplizna®): Risks and Side Effects Infections: ▪ Respiratory infections ▪ Hep B reactivation ▪ (Low risk of) PML Infusion reactions Satralizumab (brand name?) Not approved, currently under review by FDA Subcutaneous 120mg every 2 weeks x3 then every 4 weeks Similar to Tocilizumab (Actemra): Approved for rheumatoid arthritis, giant cell arteritis Currently investigated for Covid-19 (cytokine release syndrome) Satralizumab: Mechanism of Action IL6R-Inhibitor (monoclonal antibody) Prevents cytokine IL-6 from triggering inflammation ▪ IL-6 increases survival of plasmablasts (that produce Ab) ▪ IL-6 may lead to imbalance of T cells ▪ IL-6 can increase blood brain barrier permeability Kishimoto, Innovative Medicine, 2015 Satralizumab: Efficacy 83 patients over 107 weeks AQP4+ 20 vs 43% relapses HR 0.38 (95% CI 0.16-0.88) 55 patients AQP4+ 11 vs 43% HR 0.21 (95% CI 0.06-0.75) AQP4- Yamamura et al. NEJM 2019; Traboulsee et al Lancet Neurology 2020 Satralizumab: Risks and Side Effects Boxed warning: ▪ Serious and fatal opportunistic infections (invasive fungal, bacterial, viral) ▪ Tuberculosis → test for latent tuberculosis before and during therapy Summary of Phase 3 Studies Trial challenges: ▪ Many sites ▪ Few relapses ▪ Different proportion AQP4 positive patients ▪ Different inclusion criteria ▪ Different definition of relapse All three agents are: ▪ Highly effective ▪ Similar safety profile How to Use the New Treatments? New (FDA approved) therapies vs. previously used agents? ▪ In patients who are stable on current treatments ▪ In new patients ▪ In patients who fail other treatments → Individualized treatment decisions Take Home Points 3 new preventative treatments for NMDOSD ▪ Large placebo-controlled trials ▪ Highly effective in AQP4 positive patients Future Directions ▪ Comparative efficacy (with old and new therapies) ▪ When to use which agent ▪ Long-term safety data ▪ Treatment for AQP4-negative patients (anti-MOG) ▪ Biomarkers predicting relapses (GFAP?) Neuroimmunology Care at UW MS Center Located at NWH campus.