MYASTHENIA GRAVIS power point .pptx sms mc jaipur

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1. PRESENTED BY - DR ADITI JAIN EMERGING DRUGS FOR MYASTHENIA GRAVIS

2. INTRODUCTION An antibody mediated autoimmune disorder affecting the function of the neuromuscular junction, leading to fluctuating weakness of ocular, facial, bulbar, limb, and respiratory muscles MG onset peaks at ages 30 and 50. Estimated mortality rate 2% Incidence is 0.3 to 2.8 per 100,000, with a median prevalence of 10 per 100,000 globally. Many patient with MG benefit from standard treatment - but still 8.5 -15% still having varying degree disability because of insufficiently controlled clinical symptoms or unacceptable side effects. we consider the broad spectrum of emerging therapeutics, including B cell depletion, complement and T cell inhibition, and neonatal Fc receptor (FcRn) antagonists.

3. PATHOPHYSIOLOGY - Ach rc antibody - IGG1 and IGG3 Cause 85% generalized weakness Musk antibody - IGG4 - no activation of complement system Interactions between MuSK and low density lipoprotein receptor related protein 4 (LRP4)cause clustering of AChRs.

4. NEW TREATMENTS - Myasthenia gravis have been treated with pyridostigmine, corticosteroids, immunosuppressants (eg, azathioprine and mycophenolate mofetil), Intravenous immunoglobulins or plasmapheresis in myasthenia gravis crisis or severe myasthenia gravis symptoms. The international consensus guidance recommends early consideration of thymectomy in patients with (AChR+gMG), aged 18-50 years, (Association of British Neurologists younger than 45 years

5. B cell depleting agents Neonatal fc receptor inhibition Complement inhibition Interleukin 6 inhibition

6. B cell depletion- RITUXIMAB - chimeric monoclonal antibody against CD20 MuSK+MG - early treatment option who have had an unsatisfactory response to initial immunotherapy. ( The 2020 update of the international myasthenia gravis consensus guidelines) For AChR+gMG, the efficacy of rituximab is unclear, but remains an option if patients fail other immunosuppressive treatments Inebilizumab, -anti-CD19 monoclonal antibody, targets and depletes pro-B cells, plasmablasts, and plasma cells.- phase 3 trial

7. Neonatal Fc receptor antagonist

8. Efgartigimod alfa —(ADAPT TRIAL) , the FDA approved,(n December 2021) an IgG1 Fc fragment, for the treatment of AChR+gMG. Dose -(10 mg/kg every two weeks v 10 mg/kg every seven days for four infusions, with repeated cycles every four weeks) Rozanolixizumab- FDA approval for the treatment of AChR+gMG in June 2023 - s/c infusion Batoclimab and Nipocalimab - phase 3 trial

9. WHAT THIS STUDY ADDS The phase 3 FLEX trial of batoclimab This drug can be used in rapid reduction of symptoms during flares, prevention of myasthenic exacerbation/crisis long-term maintenance of remission using the lowest effective dose.

10. Complement inhibitors - Eculizumab- (REGAIN TRIAL) recombinant monoclonal anti- body that binds to C5, inhibits enzymatic cleavage to C5a and C5b, and ultimately prevents formation of the membrane attack complex.( FDA approved ) Reserved for those with refractory symptoms. Complication - increase risk of infection - Neissseria meningitidis Meningococcal vaccination with ACYW conjugate and serogroup B vaccine at least two weeks before the first drug infusion

11. Ravulizumab (CHAMPION TRIAL) long acting C5 complement inhibitor well tolerated and has the benefit of dosing every eight weeks, compared with every two weeks for eculizumab Zilucoplan ( RAISE TRIAL) small 15 amino acid macrocyclic peptide binds to C5 with high affinity, preventing the cleavage of C5 and assembly of the membrane attack complex. Self administered s/c

12. T cell directed treatment Satralizumab: monoclonal antibody against interleukin 6 receptor to inhibit IL-6 signaling and T cell activation. (phase 3 trial) for AChR+gMG- Tocilizumab Another IL-6 receptor antagonist under phase 2 trial for AChR+gMG Chimeric Antigen Receptor (CAR) T cell therapy

13. MEDICATION BRAND NAME APPROVAL YEAR MECHANISM OF ACTION ADMINISTRATION Eculizumab SOLIRIS 2017 Complement inhibition weekly intravenous (IV) infusions for four weeks, followed by maintenance doses every two weeks. Efgartigimod VYVGART 2021 Neonatal fc receptor antagonist IV infusion treatment a week for four weeks with a break between cycles. Ravulizumab ULTOMIRIS 2022 first long-acting complement inhibitor, Induction by IV infusion, maintenance doses are given every eight weeks. Rozanolixizumab Rystiggo®) 2023 first FDA-approved treatment for both anti-AChR and anti-MuSK antibody-positive myasthenia gravis . Neonatal fc receptor antagonist subcutaneous infusion once a week for six weeks. Zilcuplan ZILBRYSQ 2023 Block complement system Daily s/c injection

14. PREGNANCY AND MG Avoid pregnancy during the first two years following onset of gMG due to the increased risk of myasthenic crisis during this period Thymectomy should be considered prior to pregnancy or postponed until after pregnancy Pyridostigmine and prednisone in low doses are considered safe during pregnancy, Azathioprine and cyclosporine -relatively safe during pregnancy -third trimester warrant cautious blood monitoring as medication-induced leukopenia in the mother is a risk factor for neonatal leukopenia. Mycophenolate mofetil is teratogenic and should not be used during pregnancy , at least 6 weeks prior to conception Eculizumab treatment during pregnancy is relatively safe for mothers and their babies. given during pregnancy if absolutely needed. Plasmapheresis can be used in case of exacerbations or when intensified therapy is needed.

15. THANK YOU…