Therapeutic advances in Multiple sclerosis.pptx

Therapeutic advances in Multiple sclerosis.

1. Therapeutic advances in M ultiple sclerosis By Dr. Anuhya Krishna

2. Introduction Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. T reatment of MS has evolved over the past three decades with development of new, high efficacy disease modifying therapies targeting various mechanisms Emerging therapies include CNS-penetrant Bruton’s tyrosine kinase inhibitors and autologous hematopoietic stem cell transplantation as well as therapies aimed at remyelination or neuroprotection.

3. C linical subtypes include Clinically isolated syndrome (CIS), R elapsing-remitting MS (RRMS ), P rimary progressive MS (PPMS ), S econdary progressive MS (SPMS) A dditional caveat of modifying MS subtypes as “active” or “not active” based clinical relapse and/or MRI activity. Activity = clinical relapses and/or MRI ( Gd -enhancing MRI lesions ; new/ enlarging T2 lesions )

4. Innate immune cells with prominent roles in MS include myeloid-derived macrophages and microglia . Adaptive immune cells involved in MS include CD4 + T cells, in particular Th1 cells , against myelin proteins and CD8+ cytotoxic T cells B-cells play a key role in the pathogenesis of MS by means of Pro inflammatory cytokine and chemokine production, antibody formation , and antigen presentation to T cells Progressive MS is suspected to result from cumulative injury due to chronic inflammation and neurodegeneration stemming from multiple pathogenic mechanisms including activated microglia, oxidative stress , mitochondrial dysfunction .

5. Therapeutic Goals Treatment of the MS patient should be directed toward these fundamental goals: Treat acute relapses Decrease the frequency of relapses and prevent progression / accumulation of disability Relief and modification of symptoms Support family and patient ( economic / social ) A meta-analysis of various DMTs demonstrated that all studied DMTs reduced relapse rate within 2 years D emonstrated that earlier treatment with a DMT reduced onset of disability .Especially , that earlier high-efficacy therapy may be more successful at reducing disability .

6. Disability occurs via Relapse associated worsening ( RAW) and progression independent of relapse activity ( PIRA)

7. Disease modifying therapy

8. Injectable Interferons . Glatiramer acetate . Infusion Therapies Natalizumab . Alemtuzumab . Ocrelizumab . Oral Therapies Fingolimod . Siponimod . Teriflunomide . Dimethyl fumarate Cladribine

9. MOA ( Interferon and GA )- Inhibits pro inflammatory cytokines, such as interferon gamma, tumor necrosis factor-and increases interleukin 10 MOA of Interferon and GA - Inhibits proinflammatory cytokines, such as interferon gamma, tumor necrosis factor-and increases interleukin 10

10. MOA- Monoclonal antibody targeting the alpha 4 integrins ,

11. MOA- Monoclonal antibody that lyses cells expressing CD52- various cells express it

12. MOA- Lytic monoclonal antibody targeting CD20 molecule on surface of B cells

13. MOA- Modulates sphingosine-1-phosphate receptors, lymphocytes unable to migrate out of lymphoid tissue;

14. MOA - Inhibits dihydroorotate dehydrogenase , thereby inhibiting lymphocyte proliferation

15. MOA - Activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which enhances response to oxidative stress

16. Mechanism-inhibits topoisomerase II ., Side effects - has serious and sometimes life-threatening risks -cardiotoxicity ; the Potentially fatal secondary leukemia had been reported several times in patients with MS Now it is rarely use for MS .

17. Cladribine – an oral cytotoxic drug was FDA approved Side effects and monitoring – infection . Antiherpes prophylaxis is given to those with lymphocyte counts less than 200 cells/ mL. Before use, exclude those with active or latent human immunodeficiency virus (HIV ), tuberculosis , hepatitis B, hepatitis C, and other acute infection. Patients who are antibody negative to VZV should be vaccinated before treatment . may increase the risk of malignancy; oral cladribine is contraindicated for those with an active malignancy. contraindicated for use in pregnancy and lactation. Effective contraception should be used while taking cladribine . Because oral cladribine may reduce the effectiveness of oral contraceptives, a barrier contraceptive should be added during and for at least 4 weeks after each treatment course. Adenosine nucleoside analog

18. Hematopoietic stem cell transplant An off treatment designed to induce long-term suppression of MS AHSCT has predominantly been employed as a rescue therapy after an escalation sequence in which more than one line of treatment has failed. Application of AHSCT to MS is intended to eliminate the aberrant adaptive immune system the hope that immune tolerance will be re‑established. Side effects - Transient alopaecia and amenorrhoea

19. Outline of the AHSCT procedure. procedure starts with mobilization of HSCs from the bone marrow by injection of cyclophosphamide intravenously and granulocyte-colony stimulating factor (G‑CSF) subcutaneously. The autologous graft harvested from the peripheral blood by leukoapheresis , and which can undergo CD34 selection to enrich HSCs or can be unmanipulated , is cryopreserved for subsequent use. Ablation of the immune and, to a variable extent, myeloid system is most commonly achieved by high-dose conditioning with a combination of cytotoxic drugs. The autologous haematopoietic graft is then reinfused (transplantation), and antithymocyte globulin (ATG) is often administered with the conditioning regimen to deplete T cells; owing to the long half-life of ATG, it will also deplete and prevent the engraftment of any T cells present in the autologous graft ( in vivo graft T cell depletion). Different levels of supportive care are required during the procedure ( BEAM ( bis-chloroethylnitrosourea , etoposide, cytosine arabinoside and melphalan )

20. Proposed model of therapeutic mechanisms of AHSCT . Ablative conditioning leads to radical depletion of pathogenic immune cells. During the 6 months after autologous haematopoietic stem cell transplantation (AHSCT), homeostatic expansion of the T cell repertoire produces CD8+ and, in smaller numbers, CD4+ T cells, and antigens are encountered through infection and reimmunization . These processes are associated with potentiation of immune regulation. Subsequently, and most effectively at 1–2 years after transplantation, immune renewal via thymopoiesis leads to increased numbers of naive CD4+ and CD8+ T cells. In parallel, naive B cell reconstitution possibly restores the B cell repertoire and antibody diversity.

21. Bruton’s Tyrosine Kinase Inhibitors ( BTKi ) Bruton’s tyrosine kinase inhibitors ( BTKi ) are emerging oral treatments for MS. BTKs are are expressed in B cells, monocytes, neutrophils, and mast cells and are important for B cell maturation, proliferation, antigen presentation and differentiation to plasma cells. In myeloid cells (monocytes, granulocytes), BTK is important for cytokine and inflammatory mediator production and phagocytosis . BTK expressed in microglia, which are implicated in neuro inflammation of progressive as well as relapsing phenotypes, making it an attractive target for both forms of MS

22. Currently FDA approved BTKi – Ibrutinib (2013) Acalabrutinib (2017) Zanubrutinib (2020)

23. I brutinib F irst BTKi authorized by the FDA in 2013. Non selective , S/E-skin and dermatological problems, allergic reactions, fever, lymphadenopathy, edema, albuminuria, diarrhea, bleeding, infection, headaches, and atrial fibrillation  Drug resistance emerges in 60% of patients   Acalabrutinib   Unlike I brutinib, A calabrutinib possesses a high degree of selectivity and could minimize the incidence of the targeted side effects fast oral absorption rate, a shorter half-life, and fewer side effects

24.   Zanubrutinib -   Irreversible second-generation BTK inhibitor, more selective to BKT , hence less side effects Dose-160 mg twice a day or 320 mg once a day Tirabrutinib and Orelabrutinib are approved by japan and china approved FDA respectively.

25. Different BTKi which are In trials are Evobrutinib Fenebrutinib Remibrutinib Tolebrutinib Orelabrutinib - phase II trial Phase III trial

26. Evobrutinib is a highly selective irreversible oral BTKi In trials, there is reduction in reduce T1 gadolinium-enhancing lesions without a significant difference in the annualized relapse rate between placebo and low and high Evobrutinib doses Tolebrutinib vs Placebo , it was shown to reduce T1 gadolinium-enhancing lesions in a dose-dependent manner at 12 weeks

27. Remyelination and Neuroprotective Strategies In a double-blind, randomized, placebo-controlled trial in the United Kingdom studied the effect of three neuroprotective medications ( amiloride 5mg, fluoxetine 20mg, riluzole 50mg) on the percentage brain volume change at 96 weeks as well as T2 lesion burden, functional evaluations and time to first relapse in patients with SPMS, with no significant different in the primary or secondary outcomes Metformin, a common medication used in diabetes mellitus, has been studied as a potential therapy to improve the regenerative potential of oligodendrocyte progenitor cells. At present a study is on going

28. Thank you