Pharmacological treatment options for inhibiting progression independent of relapse activity in multiple sclerosis Review article
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Published:
Sep 30, 2024
Keywords:
multiple sclerosis, progression independent of relapse activity, PIRA, pharmacotherapy, disease-modifying drugs, neurodegeneration, remyelination
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Abstract
The article presents an overview of current pharmacotherapeutic options for inhibiting relapse-independent progression in multiple sclerosis. It discusses the paradigm shift in multiple sclerosis treatment, which stems from the growing awareness of progression independent of relapse activity. The mechanisms of action and clinical trial results for several drugs, including ocrelizumab, siponimod, natalizumab, ibudilast, simvastatin, biotin, masitinib, and others, are presented. The complexity of progression independent of relapse activity pathophysiology translates into the need for a multidirectional therapeutic approach. Developing effective therapies is challenging due to the complexity of pathomechanisms in the course of the disease and the need for long-term observations. The evolution of methods for assessing disease progression and the importance of identifying reliable biomarkers are also discussed. A promising direction is the possibility of using combination therapies and personalization of treatment.
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References
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5. Lublin FD, Häring DA, Ganjgahi H et al. How patients with multiple sclerosis acquire disability. Brain. 2022; 145(9): 3147-61.
6. Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2019; 9: 3116.
7. Sugimoto K, Nishioka R, Ikeda A et al. Activated microglia in a rat stroke model express NG2 proteoglycan in peri-infarct tissue through the involvement of TGF-β1. Glia. 2014; 62(2): 185-98.
8. Mei F, Lehmann-Horn K, Shen YAA et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife. 2016; 5: e18246.
9. Sedel F, Bernard D, Mock DM et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016; 110: 644-53.
10. Friese MA, Craner MJ, Etzensperger R et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med. 2007; 13(12): 1483-9.
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12. Magliozzi R, Howell OW, Nicholas R et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Annals of Neurology. 2018; 83(4): 739-55.
13. Ontaneda D, Thompson AJ, Fox RJ et al. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. The Lancet. 2017; 389(10076): 1357-66.
14. Barro C, Benkert P, Disanto G et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018; 141(8): 2382-91.
15. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383(6): 546–57.
16. Gärtner J, Hauser SL, Bar-Or A et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022; 28(10): 1562-75.
17. Bar-Or A, Hauser SL, Cohen JA et al. Early Initiation of Ofatumumab Delays Disability Progression in People With Relapsing Multiple Sclerosis: 6-Year Results From ALITHIOS Open-Label Extension Study. In 2024.
18. Gingele S, Jacobus TL, Konen FF et al. Ocrelizumab Depletes CD20+ T Cells in Multiple Sclerosis Patients. Cells. 2018; 8(1): 12.
19. Montalban X, Hauser SL, Kappos L et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376(3): 209-20.
20. Wolinsky JS, Arnold DL, Brochet B et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 998-1009.
21. Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. British J Pharmacology. 2012; 167(5): 1035-47.
22. Kappos L, Bar-Or A, Cree BAC et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. The Lancet. 2018; 391(10127): 1263-73.
23. Benedict RHB, Tomic D, Cree BA et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021; 96(3): e376-86.
24. Arnold DL, Piani-Meier D, Bar-Or A et al. Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler. 2022; 28(10): 1526-40.
25. Polman CH, O’Connor PW, Havrdova E et al. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med. 2006; 354(9): 899-910.
26. Kapoor R, Ho PR, Campbell N et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. The Lancet Neurology. 2018; 17(5): 405-15.
27. Giovannoni G, Cutter G, Sormani MP et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Multiple Sclerosis and Related Disorders. 2017; 12: 70-8.
28. Gibson LCD, Hastings SF, McPhee I et al. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. European Journal of Pharmacology. 2006; 538(1-3): 39-42.
29. Fox RJ, Coffey CS, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379(9): 846-55.
30. Fox RJ, Coffey CS, Cudkowicz ME et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemporary Clinical Trials. 2016; 50: 166-77.
31. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006; 6(5): 358-70.
32. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. The Lancet. 2014; 383(9936): 2213-21.
33. Chan D, Binks S, Nicholas JM et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. The Lancet Neurology. 2017; 16(8): 591-600.
34. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13): 1719-31.
35. Cree BAC, Cutter G, Wolinsky JS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 988-97.
36. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. Bauer JA, editor. PLoS ONE. 2009; 4(9): e7258.
37. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Neurol Neuroimmunol Neuroinflamm. 2022; 9(3): e1148.
38. Chataway J, De Angelis F, Connick P et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. The Lancet Neurology. 2020; 19(3): 214-25.
39. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radical Biology and Medicine. 1995; 19(2): 227-50.
40. Marracci GH, Jones RE, McKeon GP et al. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2002; 131(1-2): 104-14.
41. Spain R, Powers K, Murchison C et al. Lipoic acid in secondary progressive MS: A randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017; 4(5): e374.
42. Loy BD, Fling BW, Horak FB et al. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complementary Therapies in Medicine. 2018; 41: 169-74.
43. Mei F, Fancy SPJ, Shen YAA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014; 20(8): 954-60.
44. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. The Lancet. 2017; 390(10111): 2481-9.
45. Hartley MD, Altowaijri G, Bourdette D. Remyelination and Multiple Sclerosis: Therapeutic Approaches and Challenges. Curr Neurol Neurosci Rep. 2014; 14(10): 485.
46. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology. 2015; 14(2): 183-93.
47. Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012; 8(11): 647-56.
48. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. The Lancet Neurology. 2015; 14(2): 208-23.
49. Sormani M, Signori A, Siri P et al. Time to first relapse as an endpoint in multiple sclerosis clinical trials. Mult Scler. 2013; 19(4): 466-74.
50. Goldman MD, LaRocca NG, Rudick RA et al. Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data. Neurology. 2019; 93(21): e1921-31.
51. De Stefano N, Stromillo ML, Giorgio A et al. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016; 87(1): 93-9.
52. Kappos L, De Stefano N, Freedman MS et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis. Mult Scler. 2016; 22(10): 1297-305.
53. Khurana V, Sharma H, Afroz N et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Euro J Neurology. 2017; 24(9): 1099-107.
2. University of California, San Francisco MS-EPIC Team; Cree BAC, Hollenbach JA, Bove R et al. Silent progression in disease activity–free relapsing multiple sclerosis. Annals of Neurology. 2019; 85(5): 653-66.
3. Kappos L, Wolinsky JS, Giovannoni G et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020; 77(9): 1132.
4. Giovannoni G, Popescu V, Wuerfel J et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022; 15: 175628642110667.
5. Lublin FD, Häring DA, Ganjgahi H et al. How patients with multiple sclerosis acquire disability. Brain. 2022; 145(9): 3147-61.
6. Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis. Front Immunol. 2019; 9: 3116.
7. Sugimoto K, Nishioka R, Ikeda A et al. Activated microglia in a rat stroke model express NG2 proteoglycan in peri-infarct tissue through the involvement of TGF-β1. Glia. 2014; 62(2): 185-98.
8. Mei F, Lehmann-Horn K, Shen YAA et al. Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife. 2016; 5: e18246.
9. Sedel F, Bernard D, Mock DM et al. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology. 2016; 110: 644-53.
10. Friese MA, Craner MJ, Etzensperger R et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med. 2007; 13(12): 1483-9.
11. Scolding NJ, Pasquini M, Reingold SC, Cohen JA; International Conference on Cell-Based Therapies for Multiple Sclerosis; International Conference on Cell-Based Therapies for Multiple Sclerosis; International Conference on Cell-Based Therapies for Multiple Sclerosis. Cell-based therapeutic strategies for multiple sclerosis. Brain. 2017; 140(11): 2776-96.
12. Magliozzi R, Howell OW, Nicholas R et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Annals of Neurology. 2018; 83(4): 739-55.
13. Ontaneda D, Thompson AJ, Fox RJ et al. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. The Lancet. 2017; 389(10076): 1357-66.
14. Barro C, Benkert P, Disanto G et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018; 141(8): 2382-91.
15. Hauser SL, Bar-Or A, Cohen JA et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383(6): 546–57.
16. Gärtner J, Hauser SL, Bar-Or A et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022; 28(10): 1562-75.
17. Bar-Or A, Hauser SL, Cohen JA et al. Early Initiation of Ofatumumab Delays Disability Progression in People With Relapsing Multiple Sclerosis: 6-Year Results From ALITHIOS Open-Label Extension Study. In 2024.
18. Gingele S, Jacobus TL, Konen FF et al. Ocrelizumab Depletes CD20+ T Cells in Multiple Sclerosis Patients. Cells. 2018; 8(1): 12.
19. Montalban X, Hauser SL, Kappos L et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017; 376(3): 209-20.
20. Wolinsky JS, Arnold DL, Brochet B et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 998-1009.
21. Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. British J Pharmacology. 2012; 167(5): 1035-47.
22. Kappos L, Bar-Or A, Cree BAC et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. The Lancet. 2018; 391(10127): 1263-73.
23. Benedict RHB, Tomic D, Cree BA et al. Siponimod and Cognition in Secondary Progressive Multiple Sclerosis: EXPAND Secondary Analyses. Neurology. 2021; 96(3): e376-86.
24. Arnold DL, Piani-Meier D, Bar-Or A et al. Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial. Mult Scler. 2022; 28(10): 1526-40.
25. Polman CH, O’Connor PW, Havrdova E et al. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis. N Engl J Med. 2006; 354(9): 899-910.
26. Kapoor R, Ho PR, Campbell N et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. The Lancet Neurology. 2018; 17(5): 405-15.
27. Giovannoni G, Cutter G, Sormani MP et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Multiple Sclerosis and Related Disorders. 2017; 12: 70-8.
28. Gibson LCD, Hastings SF, McPhee I et al. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. European Journal of Pharmacology. 2006; 538(1-3): 39-42.
29. Fox RJ, Coffey CS, Conwit R et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018; 379(9): 846-55.
30. Fox RJ, Coffey CS, Cudkowicz ME et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemporary Clinical Trials. 2016; 50: 166-77.
31. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006; 6(5): 358-70.
32. Chataway J, Schuerer N, Alsanousi A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. The Lancet. 2014; 383(9936): 2213-21.
33. Chan D, Binks S, Nicholas JM et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. The Lancet Neurology. 2017; 16(8): 591-600.
34. Tourbah A, Lebrun-Frenay C, Edan G et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016; 22(13): 1719-31.
35. Cree BAC, Cutter G, Wolinsky JS et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Neurology. 2020; 19(12): 988-97.
36. Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. Bauer JA, editor. PLoS ONE. 2009; 4(9): e7258.
37. Vermersch P, Brieva-Ruiz L, Fox RJ et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Neurol Neuroimmunol Neuroinflamm. 2022; 9(3): e1148.
38. Chataway J, De Angelis F, Connick P et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. The Lancet Neurology. 2020; 19(3): 214-25.
39. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radical Biology and Medicine. 1995; 19(2): 227-50.
40. Marracci GH, Jones RE, McKeon GP et al. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2002; 131(1-2): 104-14.
41. Spain R, Powers K, Murchison C et al. Lipoic acid in secondary progressive MS: A randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017; 4(5): e374.
42. Loy BD, Fling BW, Horak FB et al. Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. Complementary Therapies in Medicine. 2018; 41: 169-74.
43. Mei F, Fancy SPJ, Shen YAA et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014; 20(8): 954-60.
44. Green AJ, Gelfand JM, Cree BA et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. The Lancet. 2017; 390(10111): 2481-9.
45. Hartley MD, Altowaijri G, Bourdette D. Remyelination and Multiple Sclerosis: Therapeutic Approaches and Challenges. Curr Neurol Neurosci Rep. 2014; 14(10): 485.
46. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology. 2015; 14(2): 183-93.
47. Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012; 8(11): 647-56.
48. Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. The Lancet Neurology. 2015; 14(2): 208-23.
49. Sormani M, Signori A, Siri P et al. Time to first relapse as an endpoint in multiple sclerosis clinical trials. Mult Scler. 2013; 19(4): 466-74.
50. Goldman MD, LaRocca NG, Rudick RA et al. Evaluation of multiple sclerosis disability outcome measures using pooled clinical trial data. Neurology. 2019; 93(21): e1921-31.
51. De Stefano N, Stromillo ML, Giorgio A et al. Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016; 87(1): 93-9.
52. Kappos L, De Stefano N, Freedman MS et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis. Mult Scler. 2016; 22(10): 1297-305.
53. Khurana V, Sharma H, Afroz N et al. Patient-reported outcomes in multiple sclerosis: a systematic comparison of available measures. Euro J Neurology. 2017; 24(9): 1099-107.