https://doi.org/10.1177/17562864241233041 https://doi.org/10.1177/17562864241233041 journals.sagepub.com/home/tan 1 Ther Adv Neurol Disord 2024, Vol. 17: 1–17 DOI: 10.1 77/ 17562864241233041 © The Author(s), 2024. Article reuse guidelines: sagepub.com/journals- permissions Creative Commons CC BY: This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the Sage and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). TherapeuTic advances in neurological disorders Plain language summary A review of Bruton’s tyrosine kinase inhibitors in multiple sclerosis Why was this study done? This study was done to find out about current knowledge on a type of drug, called Bruton’s tyrosine kinase inhibitors, or BTK inhibitors. There are currently six BTK inhibitors being studied as a possible new drug for treating multiple sclerosis (MS). Some of these six drugs are also being studied as a possible new drug for chronic spontaneous urticaria, rheumatoid arthritis and systemic lupus erythematosus. These are all autoimmune conditions, where the immune system mistakenly attacks parts of the body. Clinician scientists wanted to understand what is currently known about BTK inhibitors, how they work in the laboratory and how safe they could be for treating autoimmune conditions. This could help us understand more about BTK inhibitors in MS. What did the scientists do? The scientists assessed existing research on these six BTK inhibitors, through a process known as a literature review. These were results from ongoing clinical trials, and information collected through studying BTK inhibitors in A review of Bruton’s tyrosine kinase inhibitors in multiple sclerosis Laura Airas, Robert A. Bermel, Tanuja Chitnis, Hans-Peter Hartung , Jin Nakahara, Olaf Stuve , Mitzi J. Williams, Bernd C. Kieseier and Heinz Wiendl Abstract: Bruton’s tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium- enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration. Correspondence to: Heinz Wiendl Department of Neurology, University Hospital Muenster, Albert- Schweitzer-Campus 1, Building A 1, Muenster 48149, Germany wiendl@uni-muenster.de Laura Airas Division of Clinical Neurosciences, University of Turku, Turku, Finland Neurocenter, Turku University Hospital, Turku, Finland Robert A. Bermel Mellen Center for MS, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA Tanuja Chitnis Brigham Multiple Sclerosis Center, Harvard Medical School, Boston, MA, USA Hans-Peter Hartung Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany Brain and Mind Center, University of Sydney, Sydney, NSW, Australia Department of Neurology, Palacký University Olomouc, Olomouc, Czech Republic Jin Nakahara Department of Neurology, Keio University School of Medicine, Tokyo, Japan Olaf Stuve Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA Neurology Section, VA North Texas Health Care System, Dallas, TX, USA Peter O’Donnell Brain 1233041 TAN0010.1177/17562864241233041Therapeutic Advances in Neurological DisordersL Airas, RA Bermel review-article20242024 Review TherapeuTic advances in neurological disorders Volume 17 2 journals.sagepub.com/home/tan laboratories. The researchers pieced together all these findings, to produce this paper that summarizes the results. What did the scientists find? The scientists found that most studies of BTK inhibitors for MS are still ongoing. So far, BTK inhibitors seem to show reasonable safety in most studies, but it is too early to know. The researchers also found out about how BTK inhibitors work in the lab, about what could happen if the drugs are taken for a long time and how they could impact female reproductive health. What do these findings mean? These findings will help other scientists learn more about BTK inhibitors in MS. Trials with BTK inhibitors for MS are still ongoing, but piecing together all the current findings gives a picture of what we know and what still needs to be done. Keywords: BTK inhibitors, disease-modifying therapies, long-term administration, multiple sclerosis, safety, selectivity Received: 7 June 2023; revised manuscript accepted: 29 January 2024. Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA Mitzi J. Williams Joi Life Wellness MS Center, Atlanta, GA, USA Bernd C. Kieseier Department of Neurology, Medical Faculty, Heinrich- Heine-University, Düsseldorf, Germany Novartis Pharma AG, Basel, Switzerland Introduction Bruton’s tyrosine kinase (BTK) is a non-receptor, cytoplasmic tyrosine kinase expressed by, and crit- ical for, the development of B-cells and myeloid cells, located both peripherally and within the cen- tral nervous system (CNS).1,2 Inhibitors of BTK, such as ibrutinib, acalabrutinib and zanubruti- nib,3,4 are approved for the treatment of B-cell malignancies, suggesting efficacy upon B-cell inhi- bition.2,3 In mature B-cells, BTK is a signal trans- ducer downstream from toll-like receptor 45 and B-cell receptor.6 B-cell activation is an integral pathogenic mechanism of chronic autoinflamma- tory conditions; thus, efficacy in B-cell inhibition could establish a relevance for BTK inhibitors in the management of autoinflammatory condi- tions.1 Furthermore, BTK is expressed in the myeloid cells, specifically the macrophages,7 den- dritic cells,8 mast cells9 and microglia,10 acting downstream from Fcγ and Fcε receptors,2,10 estab- lishing its relevance in diverse autoinflammatory mechanisms of pathogenesis. However, ibrutinib, acalabrutinib and zanubrutinib have exhibited sig- nificant off-target effects, including increased risk of haemorrhage, infection and atrial fibrillation.4,11 This generation of BTK inhibitors may, therefore, be unsuitable for long-term use, as required for chronic inflammatory conditions, owing to their challenging safety profiles. Therefore, develop- ment of the next generation of BTK inhibitors, with improved specificity and resultant tolerability is needed. Currently, second-generation BTK inhibitors are under investigation for multiple autoimmune conditions, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), chronic spontaneous urticaria (CSU) and multi- ple sclerosis (MS).1,12 Incorporating learning from ongoing clinical trials, this review will evaluate the potential of second-generation BTK inhibitors, their improved selectivity and anticipated safety profile in the treatment of MS. MS is a chronic, immune-mediated disease of the CNS, leading to demyelination and axonal dam- age.13 This translates into clinical disability for people living with MS.13,14 Second-generation BTK inhibitors are under clinical development for relapsing MS (RMS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and one in secondary progressive MS (SPMS), sum- marized in Table 1. In MS pathogenesis, T-cells, B-cells and myeloid cells of the immune system play a key role in damaging the CNS and, as such, they have been of much interest as a therapeutic target in the development of disease-modifying treatments (DMTs).13,15 Immune-mediated mechanisms of inflammation are of much impor- tance in MS progression; thus, targeting these mechanisms is integral in the development of prospective DMTs for multiple MS subtypes.16 The efficacy of recent B-cell depleting DMTs in MS management has further highlighted the role and importance of B-cells in the pathogen- esis of this disease.17 An unmet need for new treatments remains, despite the availability of multiple DMTs for MS.18 Owing to the hetero- geneity of MS, the use of specific DMTs may be limited among individuals, depending upon L Airas, RA Bermel et al. journals.sagepub.com/home/tan 3 Table 1. Current clinical development and characteristics of BTK inhibitors for MS. Trial information BTK inhibitor characteristics BTK inhibitor Lead developer Current phase of development Subtype of studied MS BTK binding mechanism Half-life (h)a IC50 in vitro (nM)b BIIB091 Biogen II RMS Non-covalent 0.66 87 Evobrutinib Merck KGaA III RRMS, SPMS with relapses Covalent 2 47.7 Fenebrutinib Roche III RMS, PPMS Non-covalent 4.2–9.9 5.3 Orelabrutinib Innocare II RRMS Covalent 1.5–4 1.6 Remibrutinib Novartis III RMS Covalent 1–2 5.5 Tolebrutinib Sanofi/Principia III RMS, SPMS, PPMS Covalent 1.5–2 0.9 aHalf-life data obtained from pharmacodynamic clinical trials, evobrutinib,19 fenebrutinib,20 remibrutinib21 and tolebrutinib.22 bIC50 data for evobrutinib, fenebrutinib, remibrutinib and tolebrutinib were obtained from comparative analyses research article;1 data for orelabrutinib23 were obtained from recent clinical trials; data for BIIB091 were obtained from in vitro studies.24 BTK, Bruton’s tyrosine kinase; MS, multiple sclerosis; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis. comorbidities, life situation, drug tolerance and toxicities14,18; thus, further treatments need to be developed. Specific DMT use may also include patient preferences owing to tolerability and administration methods. Second-generation BTK inhibitors may hold some potential, with prospective transience of treatment effects, potential for flexible dosing and oral administra- tion differing from current B-cell depleting therapeutics.1 Evidence identification Literature for this review was identified through a provisional scoping search, followed by tar- geted literature searches through the Embase database via the Ovid platform for clinical trial information, publications and conference post- ers. This process followed best practice guidance in the development of narrative reviews.25 Literature searching focused on three themes using pre-defined eligibility criteria and identi- fied evidence relating to BTK inhibition in auto- immune conditions, MS and BTK inhibitor safety profiles. Search terms included ‘Bruton’s tyrosine kinase inhibitor’ and ‘multiple sclerosis’, ‘autoimmune’ and associated drug safety terms. This was also conducted for the six BTK inhibi- tors in phase II or III trial for MS, using the search terms ‘Multiple Sclerosis’ and ‘BIIB091’, ‘evobrutinib’, ‘fenebrutinib’, ‘orelabrutinib’, ‘remibrutinib’ and ‘tolebrutinib’. The titles and abstracts of search results were screened by a sin- gle reviewer for relevance for these sections. BTK-relevant mechanisms of MS pathogenesis Inhibitors of BTK have several proposed mecha- nisms of action, which may be relevant to the pathogenesis of MS,2,26 as summarized in Figure 1. Pre-clinical models have been utilized to investi- gate the role of BTK in MS. Treatment with the BTK inhibitor evobrutinib (Merck KGaA) dose- dependently inhibited maturation of B-cells, anti- gen-triggered activation and the release of pro-inflammatory cytokines in animal models of MS. This resulted in reduced disease severity in mice, highlighting the potential importance of BTK signalling pathways in MS pathogenesis. Furthermore, leptomeningeal inflammation, which was associated with poor clinical outcomes in MS, has been modelled in experimental auto- immune encephalomyelitis (EAE) mice.27 Mice treated with evobrutinib showed a significant improvement in meningeal inflammation, com- pared with vehicle, exhibiting a 30% reduction and a 5% increase, respectively.27 Remibrutinib (Novartis) treatment in EAE models strongly reduced B-cell-dependent inflammation and exhibited BTK occupancy in the brain and peripheral immune system.28 TherapeuTic advances in neurological disorders Volume 17 4 journals.sagepub.com/home/tan In Xenopus transgenic models, approximately 75% of immune cells expressing BTK were microglia, and the remainder astrocytes, suggesting a high bioavailability of BTK in the CNS of this model system.15 Microglia initiate demyelination and immune filtration in MS pathogenesis during the early phases of the condition, while in later stages they can promote both neurodegeneration and remyelination.34 Microglia BTK could be an important therapeutic target, if the pro-inflamma- tory function could be curtailed in early phases of the condition and the pro-remyelinating function promoted. In the Xenopus transgenic model, in vivo BTK inhibition resulted in a 1.7-fold improvement in remyelination, compared with untreated controls.10 Furthermore, in vitro and in vivo mouse models demonstrated that BTK expression is increased upon microglia activation and treatment with the BTK inhibitor evobrutinib reduces the expression of inflammatory surface markers, implicating a BTK inhibition effect upon microglia functionality.10,28 The role of BTK in systemic immune activation, as well as its poten- tial impact on microglia suggests that BTK inhibi- tion represents a promising treatment pathway for MS. This may be pertinent in MS subtypes, such as PPMS and SPMS, in which progression inde- pendent of relapse activity, partly driven by micro- glial activation, may be a key contributor.35 Clinical insights of BTK mode of action in MS There are six BTK inhibitors currently under development for the treatment of MS. These include: BIIB091 (Biogen, Cambridge, Massachusetts, United Stated), evobrutinib (Merck KGaA, Darmstadt, Germany), fenebrutinib (Roche, Basel, Switzerland), orelabrutinib Figure 1. Simplified mechanisms of MS pathogenesis relevant to BTK inhibition. Proposed, simplified, MS-relevant BTK molecular mechanism of action following inhibition. In myeloid cells, BTK is activated through Fcγ receptor signalling and then signals through Plc-γ2 to activate the NFĸβ and NFAT pathway, leading to transcriptional activation. In B-cells, BTK is activated through B-cell receptor signalling; BTK inhibition may increase pro- inflammatory cytokine production. BTK is expressed in myeloid cells, with important roles in their function,2,6 including brain- specific microglia, and peripheral macrophages.29 In MS pathogenesis, B-cells can undergo antigen-triggered activation, a BTK-mediated pathway, to release pro-inflammatory cytokines including IFNƴ and TNFα.2 Release of pro-inflammatory cytokines can lead to the differentiation of pro-inflammatory CD4+ T-cells, implicated in demyelination.30 Pro-inflammatory cytokine release from B-cells also leads to macrophage polarization, promoting transformation to the pro-inflammatory M1 phenotype.5 These have been implicated in myelin phagocytosis, resulting in foam cells, which have been found in active neuronal lesions in MS.31,32 BTK is also expressed in the microglia, CNS-specific macrophages, leading to microglial activation.33 Activated microglia are also implicated in demyelination and are abundant in active neuronal MS lesions.10,33 Inhibition of BTK may have potential in the mediation of these mechanisms,10 thus it is of interest for novel MS therapeutics. BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; CNS, central nervous system; IFNƴ, interferon gamma; MS, multiple sclerosis; NFAT, nuclear factor of activated T cells; NFκβ, nuclear factor kappa-light-chain-enhancer of activated B cells; TNFα, tumour necrosis factor alpha. L Airas, RA Bermel et al. journals.sagepub.com/home/tan 5 (Innocare, Beijing, China), remibrutinib (Novartis, Basel, Switzerland) and tolebrutinib (Sanofi, Paris, France). A summary of different clinical trials, tar- get population and BTK inhibitor characteristics are provided in Table 1. Early phase clinical trials have revealed that BTK inhibitors can be detected in the cerebrospinal fluid (CSF) after oral administration. It still needs to be established to what extent CSF concentra- tion reflects BTK tissue occupancy in the CNS and prediction of clinical efficacy. Tolebrutinib exhibited dose-dependent peripheral BTK occu- pancy in the blood and entered the CSF in phase I trials.22 In a phase IIb trial of tolebrutinib, a dose-dependent reduction in new gadolinium- enhancing lesions in the brain could be demon- strated,36 indicating the potential efficacy of BTK inhibition in modulating CNS inflammatory activity.37 A phase II trial of evobrutinib, which was placebo- and dimethyl fumarate- controlled, illustrated that participants receiving 75 mg dosage of evobrutinib had significantly fewer gadolinium-enhancing lesions upon MRI 12–24 weeks after treatment initiation compared with the placebo group.38 Similarly, 12 week interim analyses of an orelabru- tinib phase II trial demonstrated reductions in gadolinium-enhancing lesions in participants receiving orelabrutinib compared with placebo.39 Future clinical studies will seek to demonstrate additional clinical benefits in MS. Great therapeu- tic focus will rest upon the modulation of micro- glia and myeloid cells by BTK inhibitors. This is particularly pertinent when BTK expression is considered, because in vivo models have suggested that, proportionally, there is higher expression and potentially bioavailability of BTK in the microglia compared with astrocytes.10 Targeting of micro- glia alongside B cells could be beneficial as effec- tors of MS pathogenesis.34 Second-generation BTK inhibitor binding mechanisms For long-term use in chronic autoinflammatory conditions, such as MS, the binding mechanisms of BTK inhibitors need to be considered. First- generation BTK inhibitors currently approved for use in oncology or second-generation BTK inhib- itors under investigation in MS, with the excep- tion of BIIB091 and fenebrutinib, are covalent inhibitors.4 Covalent inhibitors of BTK target the SH3 pocket of BTK, irreversibly binding to cysteine 481 (Cys481) and, therefore, blocking kinase activation.40 First-generation BTK inhibi- tor ibrutinib is a covalent inhibitor, utilized in the treatment of B-cell malignancies, mantle cell lym- phoma (MCL) and chronic lymphoid leukaemia (CLL).3 In a subset of people with CLL or MCL, resistance to ibrutinib has been noted, reducing the potency of BTK inhibition,41,42 highlighting a potential challenge in long-term BTK inhibitor use. Notably, resistance to therapeutics is rela- tively common in oncology, owing to the enhanced proliferative rate of malignant cells, selection pressure caused by therapeutics and resultant selective advantage for resistance muta- tions.3,6,43 This may not be the case in the use of BTK inhibitors for non-malignant autoimmune conditions such as MS. However, resistance should be considered and monitored in the devel- opment of covalent BTK inhibitors for long-term use. Non-covalent inhibitors reversibly bind to differ- ent BTK-specific pockets.41,44 As an example of a non-covalent BTK inhibitor, BIIB091 (Biogen) is an orthosteric, reversible adenosine triphosphate competitor, which sequesters tyrosine 551, an important BTK phosphorylation site, leading to an inactive conformation.44 A phase II trial exam- ining BIIB091 in RMS is planned and yet to recruit, while fenebrutinib is undergoing a phase III clinical trial for people with RMS or PPMS,45 ClinicalTrials.gov identifiers: NCT05798520, NCT04586010, NCT04544449. The transient binding mechanics displayed by non-covalent BTK inhibitors may provide advantages in terms of long-term administration41,44; however, the distinction between covalent and non-covalent BTK inhibitors is not yet fully understood, nor have these differences been established in the context of MS. Second-generation BTK inhibitor selectivity Overall, the second-generation BTK inhibitors under investigation for the treatment of MS have low half maximal inhibitory concentration (IC50) values for BTK binding, as described in Table 1, suggesting high selectivity. A recent in vitro com- parative study, investigating B-cell inhibition fur- ther implicated this previously observed high selectivity, with IC50 values after 1 h of 18 nM for remibrutinib, 320 nM for evobrutinib, 74 nM for tolebrutinib, 185 nM for orelabrutinib and 15 nM TherapeuTic advances in neurological disorders Volume 17 6 journals.sagepub.com/home/tan for fenebrutinib.46 Subsequent kinome screening at 1 µM illustrated a ranking from the least to most off-target kinase binding. The least off-tar- get binding was shown by remibrutinib, followed by fenebrutinib, evobrutinib, orelabrutinib and tolebrutinib.46 These data suggest varied but promising selectivity, which may have down- stream implications in the off-target side effects and safety profile of these BTK inhibitors. BIIB091 was not included in these analyses, but has an in vitro IC50 value of 87 nM in stimulated B cells and 106 nM in myeloid cells.24 The IC50 for many of the BTK inhibitors has been reported for closely related kinases of the tyrosine-protein kinase (TEC) family, of which BTK is a member, including TEC, interleukin- 2-inducible T-cell kinase (ITK), cytoplasmic tyrosine-protein kinase (BMX) and tyrosine-pro- tein kinase (TXK).1 Tolebrutinib has a compara- ble IC50 for TEC, BMX and TXK, but an IC50 more than 350-fold higher for ITK, when com- pared with BTK and TEC.1 Conversely, fenebru- tinib shows an improved cross selectivity profile, exhibiting IC50 values above 1000 nM for TEC, ITK and TXK.1 Similarly and despite its compa- rably high IC50 value for BTK, evobrutinib has IC50 values greater than 1000 nM for ITK and 100 nM for TKX, respectively.1 Data on cross selectivity for these kinases are not available for remibrutinib and orelabrutinib. However, a screen for BTK inhibition of 218 off-target kinases demonstrated that in terms of IC50 values, fenebrutinib is over 130-fold more selective than evobrutinib and tolebrutinib. Furthermore, fene- brutinib dissociation from BTK has been shown to be slow, with a residence time of 18.3 h, impli- cating high stability.47 The clinical relevance of differences in selectivity and stability among inhibitors may also translate in ongoing clinical trials, but this is yet to be fully investigated. In comparison, the first-generation BTK inhibi- tor ibrutinib shows an >80% occupancy of all of these closely related TEC kinases, along with important receptor and intracellular kinases such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor recep- tor 4 (HER4) and Janus kinase 3.4 Off-target effects of HER2 and HER4 inhibition include atrial fibrillation,4 which has been reported in ibrutinib treatment.12 Commonly reported adverse events (AEs) in ibrutinib treatment are rash and diarrhoea, previously thought to be through inhibition of EGFR; however, recent data have illustrated this to be inconclusive.4 Ibrutinib is currently the only BTK inhibitor approved by the US Food and Drug Administration utilized for autoimmunity in ster- oid-resistant chronic graft versus host disease (cGvHD).48 A phase II clinical trial for cGvHD demonstrated high efficacy, with 67% of partici- pants showing an objective response rate.12 However, low-grade infection AEs were com- mon, experienced by 69% of participants,12 while two participants in an evaluable population of 42 died as a result of AEs, pneumonia and bron- chopulmonary aspergillosis.12 These infectious complications may be due to immunosuppression during ibrutinib treatment. Furthermore, treat- ment with ibrutinib has been illustrated to impair the immune response to influenza, hepatitis C and zoster vaccines in people with CLL.49,50 The effect of treatment upon immune response to both infections and vaccines may be a key consid- eration in the development of second-generation BTK inhibitors for MS.51 Encouragingly, second-generation BTK inhibi- tors including evobrutinib, fenebrutinib and remibrutinib under trial for MS broadly show <50% occupancy of TEC kinases.4 These data suggest that recently developed BTK inhibitors demonstrate a promising selectivity profile; however, this is yet to be fully established. Off- target effects, which could be attributed to bind- ing to other members of the TEC kinase family, may manifest during clinical trials of BTK inhibitors. The TEC kinases have similar roles to BTK, with high expression in myeloid cells,1 implicating the possibility of immunity-related AEs. However, after the challenging safety pro- files of first-generation BTK inhibitors, there is likely to be a cautious approach to safety in the use of second-generation BTK inhibitors for MS, along with a range of autoimmune conditions. Concentration of BTK inhibitors in the CNS and adjacent CSF Much of the pharmacokinetic and pharmacody- namic data available for second-generation BTK inhibitors are based on blood absorption and L Airas, RA Bermel et al. journals.sagepub.com/home/tan 7 peripheral target occupancy, with little data avail- able regarding the concentration of BTK inhibi- tors in the CSF. Furthermore, pharmacokinetic studies undertaken in phase I do not reflect dos- ages given in phase II and III trials. A phase I trial of tolebrutinib demonstrated that 2 h after a first dose of 120 mg, there was a mean CSF con- centration of 1.87 ng/mL across four healthy participants.22 However, this time point is in conflict with the half-life of tolebrutinib of between 90 and 120 min; therefore, the study team highlighted that the actual CSF concentra- tion may be higher; thus, further research on this with more sensitive time points and lower dos- ages utilized in clinical development is needed.22,52 Subsequent studies in healthy vol- unteers suggested that tolebrutinib remains pre- sent at bioactive levels in the CSF 4 h after dosing, when given at dosages of 60 or 120 mg.53 Similarly, CSF concentration has been meas- ured for evobrutinib, reaching a mean concen- tration of 3.21 ng/mL 2 h post dose, across nine participants with RRMS.54 A previous study also highlighted that tolebrutinib administration resulted in alterations in CSF protein levels in people with MS, compared with untreated peo- ple with MS.55 This further suggests tolebrutinib presence in the CSF in people with MS. The presence of BTK inhibitors in the CSF impli- cates potential adjacent CNS relevant mecha- nisms of action to be further elucidated. The suitability of second-generation BTK inhibi- tors for the management of MS will be illumi- nated through further dissection of the CSF exposure through determination of drug concen- tration. The extent to which CSF concentration reflects tissue occupancy in the CNS and subse- quently predicts clinical efficacy still needs to be established. Safety summary of second-generation BTK inhibitors in MS Transferable insights may be obtained regarding safety, efficacy and mechanisms of action, which could be relevant to MS, through understanding the development and trial results of BTK inhibi- tors in other autoimmune conditions. Phase II and III clinical trials investigating the efficacy of BTK inhibitors for diverse autoimmune condi- tions are currently underway. The key safety and efficacy findings of these trials can be found in Table 2. Ta bl e 2. S um m ar y of B TK in hi bi to rs u nd er c lin ic al tr ia l f or a ut oi m m un e co nd iti on s. Tr ia l i nf or m at io n Su m m ar y of k ey fi nd in gs A ut oi m m un e co nd it io n B TK in hi bi to r Le ad d ev el op er C ur re nt p ha se of d ev el op m en t Sa fe ty Ef fi ca cy C hr on ic sp on ta ne ou s ur tic ar ia R em ib ru tin ib N ov ar tis III • N o do se -l im iti ng to xi ci tie s ob se rv ed in d os ag es up to 6 00 m g pe r da y in p ha se I • H ig h to le ra bi lit y ex hi bi te d • P ha rm ac od yn am ic d at a su pp or t h ig h se le ct iv ity • D os e- de pe nd en t i m pr ov em en ts in s ym pt om s fo llo w in g 12 w ee ks o f t re at m en t i n ph as e IIb Fe ne br ut in ib R oc he II- di sc on tin ue d • W el l t ol er at ed , w ith s m al l p ro po rt io n of m ild A Es • M os t c om m on A Es w er e ur tic ar ia , na so ph ar yn gi tis a nd h ea da ch e • R ed uc tio n of a ut oa nt ib od ie s, s ug ge st in g B TK ta rg et e ng ag em en t • Im pr ov em en t o f d is ea se a ct iv ity b y w ee k 8 at se le ct ed d os ag es • Fi nd in gs fr om in te ri m a na ly se s of e ff ic ac y da ta le ad to tr ia l d is co nt in ua tio n R he um at oi d ar th ri tis Ev ob ru tin ib M er ck K G aA IIb • H ig h to le ra bi lit y ex hi bi te d, w ith c om pa ra bl e tr ea tm en t- em er ge nt A Es a m on g gr ou ps • P ha se II b tr ia ls fa ile d to r ea ch th e pr im ar y en dp oi nt o f A C R 20 , a m ea su re in di ca tin g a > 20 % im pr ov em en t o f p ar tic ip an ts ’ R A s ym pt om s Fe ne br ut in ib R oc he II • C lin ic al tr ia l a nd O LE a na ly se s fo r fe ne br ut in ib in m ul tip le a ut oi m m un e co nd iti on s su gg es ts h ig h to le ra bi lit y • P ha se II s tu di es h ig hl ig ht ed fa vo ur ab le s af et y pr of ile • D os e- de pe nd en t i m pr ov em en ts in A C R 50 , a m ea su re in di ca tin g a > 50 % im pr ov em en t o f pa rt ic ip an ts ’ R A s ym pt om s • Tr ia ls in p op ul at io n, u nr es po ns iv e to T N F th er ap eu tic s or m et ho tr ex at e, ta ki ng m et ho tr ex at e in c om bi na tio n w ith fe ne br ut in ib sh ow ed im pr ov em en ts in A C R 50 (C on tin ue d) TherapeuTic advances in neurological disorders Volume 17 8 journals.sagepub.com/home/tan Tr ia l i nf or m at io n Su m m ar y of k ey fi nd in gs A ut oi m m un e co nd it io n B TK in hi bi to r Le ad d ev el op er C ur re nt p ha se of d ev el op m en t Sa fe ty Ef fi ca cy Sy st em ic lu pu s er yt he m at os us Ev ob ru tin ib M er ck K G aA II- • W el l t ol er at ed a nd fa vo ur ab le s af et y pr of ile sh ow n • Fa ile d to m ee t p ri m ar y ef fic ac y en dp oi nt s Fe ne br ut in ib R oc he II- di sc on tin ue d • W as w el l t ol er at ed • Fa ile d to m ee t p ri m ar y ef fic ac y en dp oi nt s • R ed uc tio n of to ta l I gG a nd Ig M a nt ib od y le ve ls b y w ee k 48 , s ug ge st in g ta rg et e ng ag em en t Su m m ar y of k ey s af et y an d ef fic ac y fin di ng s in c lin ic al tr ia ls o f B TK in hi bi to rs fo r au to im m un e co nd iti on s. T he se B TK in hi bi to rs a re a ls o un de r tr ia l f or M S. D at a ob ta in ed to p op ul at e Ta bl e 2 w er e ob ta in ed fr om c lin ic al tr ia l f in di ng s, p ub lis he d pr im ar y re se ar ch a rt ic le s an d co nf er en ce p ro ce ed in gs . F ur th er d et ai ls c an b e fo un d in th e re fe re nc es a s fo llo w s. C hr on ic s po nt an eo us u rt ic ar ia : r em ib ru tin ib ,21 ,5 6 f en eb ru tin ib , C lin ic al Tr ia ls .g ov id en tif ie r: N C T0 36 93 62 5, N C T0 31 37 06 9. 57 R A : e vo br ut in ib ,58 fe ne br ut in ib .5 9, 60 ,6 1, 62 S ys te m ic lu pu s er yt he m at os us : e vo br ut in ib ,1, 19 ,6 3 f en eb ru tin ib , C lin ic al Tr ia ls .g ov id en tif ie r: N C T0 31 37 06 9. 1, 64 AC R 20 , A m er ic an C ol le ge o f R he um at ol og y re sp on se c ri te ri a 20 ; A C R 50 , A m er ic an C ol le ge o f R he um at ol og y re sp on se c ri te ri a 50 ; A E, a dv er se e ve nt ; B TK , B ru to n’ s ty ro si ne k in as e; Ig G , i m m un og lo bu lin G ; I gM , i m m un og lo bu lin M ; O LE , o pe n- la be l e xt en si on ; R A , r he um at oi d ar th ri tis ; T N F, tu m ou r ne cr os is fa ct or . Ta bl e 2. ( C on tin ue d) Ta bl e 3. S um m ar y of s af et y an d ef fic ac y of B TK in hi bi to rs in M S cl in ic al tr ia ls . Tr ia l i nf or m at io n K ey fi nd in gs B TK in hi bi to r Le ad d ev el op er C ur re nt p ha se o f de ve lo pm en t Su bt yp e of M S Sa fe ty Ef fi ca cy B IIB 09 1 B io ge n II R M S • P ha se II tr ia ls a re n ot y et r ec ru iti ng • P ha se II tr ia ls a re n ot y et r ec ru iti ng Ev ob ru tin ib M er ck K G aA III R R M S, S P M S w ith r el ap se s • P ha se II tr ia ls d em on st ra te d si m ila r A E in ci de nc e ac ro ss pl ac eb o an d ev ob ru tin ib d os es ; ho w ev er , g ra de 3 –4 A Es w er e hi gh es t i n th e 75 m g da ily a nd 75 m g tw ic e da ily g ro up s. T hi s w as c om pa ra bl e w ith th e di m et hy l fu m ar at e gr ou p • P ha se II tr ia ls h av e de m on st ra te d a do se -d ep en de nt re du ct io n in th e ex pa ns io n of s lo w ly e xp an di ng le si on s in p ar tic ip an ts w ith R R M S • H ig h ev ob ru tin ib d os ag es c om pa re d w ith lo w d os ag es le ad to s ig ni fic an t r ed uc tio ns in s lo w ly e xp an di ng le si on s in p ar tic ip an ts w ith R R M S > 8. 5 ye ar s po st - di ag no si s an d ba se lin e ED SS s co re o f > 3. 5 (C on tin ue d) L Airas, RA Bermel et al. journals.sagepub.com/home/tan 9 Tr ia l i nf or m at io n K ey fi nd in gs B TK in hi bi to r Le ad d ev el op er C ur re nt p ha se o f de ve lo pm en t Su bt yp e of M S Sa fe ty Ef fi ca cy Fe ne br ut in ib R oc he III R M S, P P M S • O LE s tu di es h av e su gg es te d re du ce d fr eq ue nc y of A Es , t he m os t co m m on b ei ng n as op ha ry ng iti s, na us ea a nd h ea da ch e, fo llo w in g co nt in ua tio n of tr ea tm en t • H ig h to le ra bi lit y sh ow n in p ha se II tr ia ls , w ith n o in cr ea se d in ci de nc e of in fe ct io n co m pa re d w ith p la ce bo • Ef fic ac y en dp oi nt s fo r ph as e III w ill in cl ud e se ns iti ve m ea su re m en t o f M S sy m pt om at ic p ro gr es si on O re la br ut in ib In no ca re II R R M S • R ep ur po se d on co lo gy d ru g fo r B -c el l m al ig na nc ie s. S af et y da ta fr om o nc ol og y su gg es ts h ig h in ci de nc e of A Es , b ut w el l t ol er at ed • P ha se II tr ia ls a re o ng oi ng • In te ri m a na ly se s at 1 2 w ee ks h av e ill us tr at ed a d os e- de pe nd en t r ed uc tio n of n ew b ra in le si on s R em ib ru tin ib N ov ar tis III R M S • Fa vo ur ab le s af et y pr of ile a nd h ig h to le ra bi lit y sh ow n in C SU • P ha se II fi nd in gs c ur re nt ly u na va ila bl e • R ec ru iti ng p ar tic ip an ts w ith R M S fo r ph as e III tr ia ls To le br ut in ib Sa no fi/ P ri nc ip ia III R M S, S P M S, P P M S • N o se ri ou s A Es in p ha se I tr ia ls . M ild A Es o cc ur ri ng in > 10 % o f pa rt ic ip an ts w er e he ad ac he a nd di ar rh oe a • P ha se II b: th er e w er e no di sc on tin ua tio ns r el at in g to tr ea tm en t • P ha se II b de m on st ra te d do se -d ep en de nt r ed uc tio ns of g ad ol in iu m -e nh an ci ng le si on s af te r 12 w ee ks o f tr ea tm en t i n pa rt ic ip an ts w ith R M S • P ha se II I t ri al s un de rw ay fo r pa rt ic ip an ts w ith R M S, SP M S an d P P M S Su m m ar y of k ey s af et y an d ef fic ac y fin di ng s in c lin ic al tr ia ls o f B TK in hi bi to rs fo r th e tr ea tm en t o f M S. D at a ob ta in ed to p op ul at e Ta bl e 3 ha ve b ee n ob ta in ed fr om c lin ic al tr ia l fin di ng s, p ub lis he d pr im ar y re se ar ch a rt ic le s an d co nf er en ce p ro ce ed in gs . F ur th er d et ai ls c an b e fo un d in th e re fe re nc es a s fo llo w s: B IIB 09 1, e vo br ut in ib ,65 ,6 6 f en eb ru tin ib ,59 ,6 7 or el ab ru tin ib ,68 ,3 9, 69 r em ib ru tin ib ,56 ,7 0 t ol eb ru tin ib .2 2, 36 C lin ic al Tr ia ls .g ov id en tif ie rs : N C T0 57 98 52 0, N C T0 43 38 02 2, N C T0 43 38 06 1, N C T0 40 32 15 8, N C T0 45 86 02 3, N C T0 47 11 14 8, N C T0 51 47 22 0, N C T0 44 10 97 8, N C T0 44 10 99 1, N C T0 44 11 64 1 an d N C T0 44 58 05 1. A E, a dv er se e ve nt ; B TK , B ru to n’ s ty ro si ne k in as e, C SU , c hr on ic s po nt an eo us u rt ic ar ia ; E D SS , E xp an de d D is ab ili ty S ta tu s Sc al e; M S, m ul tip le s cl er os is ; O LE , o pe n- la be l e xt en si on ; P P M S, p ri m ar y pr og re ss iv e m ul tip le s cl er os is ; R M S, r el ap si ng m ul tip le s cl er os is ; R R M S, r el ap si ng -r em itt in g m ul tip le s cl er os is S P M S, s ec on da ry p ro gr es si ve m ul tip le s cl er os is . Ta bl e 3. ( C on tin ue d) TherapeuTic advances in neurological disorders Volume 17 10 journals.sagepub.com/home/tan As described in Table 1, there are six BTK inhibi- tors under investigation for MS. These are cur- rently in phase II or III trials and have a targeted focus in treating people with RMS or RRMS, ClinicalTrials.gov identifiers: NCT05798520, NCT04586010, NCT04544449, NCT04338022, NCT04338061, NCT04410978, NCT04410991, NCT04411641, NCT04458051, NCT04711148, NCT04586023 and NCT05147220. Two phase III trials are underway for BTK inhibitors in PPMS and one phase III trial in non-relapsing SPMS, ClinicalTrials.gov identifiers: NCT04544449, NCT04458051 and NCT04411641. Current clinical trial developments and efficacy endpoints are summarized in Table 3, owing to the differ- ences in MS population, endpoints and current stages between trials. The safety profiles of each BTK inhibitor will be summarized and con- trasted. It is important to caveat that in terms of trial design, trial stage, patient populations, phar- macokinetic and pharmacodynamic properties, there are substantial differences between each BTK inhibitor; thus, they cannot be directly com- pared, or findings extrapolated in terms of safety. Tolebrutinib showed favourable safety exposure and pharmacodynamics in a phase I trial.22 For all participants, the drug was well tolerated with no serious AEs, while the pharmacokinetic pro- file exhibited rapid absorption and favourable CSF concentrations.22 Following on from this, a phase IIb trial of tolebrutinib treating RMS fur- ther highlighted the favourable safety profile, with no AE-related discontinuations reported in 130 participants.36 Safety signals in a phase III trial of reversible drug-induced liver injury in June 2022 placed the programme on partial hold and paused recruitment in trials across MS subtypes,52 including RMS, SPMS and PPMS, but trials have since resumed,71 ClinicalTrials.gov identifiers: NCT04410978, NCT04410991, NCT04411641 and NCT04458051. The majority of drug- induced liver injuries occurred in individuals with concurrent, predisposing medical conditions and resolved following treatment discontinuation.52 The safety challenges encountered in the phase III trial could potentially account for the reduced selectivity profile of tolebrutinib when compared with other second-generation BTK inhibitors in development.46 RMS is also the planned focus of a phase II trial of BIIB091, which is not yet recruit- ing ahead of initiation, ClinicalTrials.gov identi- fier: NCT05798520. Phase I safety data for BIIB091 are not yet publicly available, ClinicalTrials.gov identifier: NCT03943056. Similarly, orelabrutinib is a BTK inhibitor for B-cell malignancies and is currently under phase II trial for the treatment of RRMS only,68 ClinicalTrials.gov identifier: NCT04711148. A retrospective study highlighted that it is well tol- erated in the treatment of CNS lymphoma.69 Evobrutinib is undergoing phase III trial for the treatment of RRMS or SPMS with relapses and has shown promising safety profiles in earlier phases, ClinicalTrials.gov identifiers: NCT04338022, NCT04338061 and NCT04032158. The first in- human phase I study of evobrutinib in terms of safety, tolerability and pharmacokinetics was undertaken with the view to develop it as a pro- spective therapeutic for SLE, RA and RRMS, demonstrating a favourable safety profile.19 A recent analysis of evobrutinib AEs illustrated that this BTK inhibitor is well tolerated in people with MS, utilizing data from phase II trials of evobru- tinib for MS, RA and SLE from more than 1000 participants.65 The proportion of participants across all autoimmune conditions experiencing AEs was comparable between evobrutinib and placebo groups, with an incidence of 66.2% and 62.4%, respectively.65 A remibrutinib phase III clinical trial is also recruiting for people with RMS, ClinicalTrials. gov identifier: NCT05147220. Remibrutinib is a covalent BTK inhibitor, which has shown high in vitro target occupancy, suggesting high selectivity and potency.70 Like alternative BTK inhibitors, remibrutinib has shown a favourable safety profile across dosages in CSU.56 In 267 participants with CSU, no dose-dependent pattern in AEs was exhibited and most AEs were mild to moderate in severity.72 Remibrutinib has shown high efficacy in the treatment of CSU in a phase IIb study.56 Daily dosages of up to 600 mg were investigated in phase I, with no dose-limiting toxicities exhib- ited and high tolerability demonstrated.21 With dosages equal to or higher than 30 mg, blood BTK occupancy was greater than 95% for at least 24 h, further suggesting high selectivity and potency.21 This is supportive of the favourable safety profile exhibited and phase III trial of remi- brutinib for CSU started in late 2021.56 A phase III study of fenebrutinib is currently recruiting people with RMS and PPMS, ClinicalTrials.gov identifier: NCT04586010, NCT04544449. High dosages of fenebrutinib L Airas, RA Bermel et al. journals.sagepub.com/home/tan 11 were well tolerated, with no increase in infection rate, while AEs became less frequent following consistent administration in open-label extension (OLE) studies.59 In part, it could be speculated that this favourable safety profile, even at high dosages, could be due to the high selectivity of fenebrutinib demonstrated in vitro.1 These data supported the continuation of fenebrutinib trials in MS, enabling the initiation of phase III tri- als.59,67 Phase II trials and OLEs of fenebrutinib demonstrated a promising safety profile in a range of autoimmune conditions, including RA, SLE and CSU.59 Like remibrutinib, fenebrutinib has undergone a phase II trial for the treatment of CSU, ClinicalTrials.gov identifier: NCT03693625. However, this trial was discontinued in 2020, fol- lowing an interim efficacy analysis, ClinicalTrials. gov identifier: NCT03137069. Despite this, fene- brutinib for the treatment of CSU exhibited high tolerability, with a small proportion of mild AEs, the most common being urticaria, nasopharyngi- tis and headache,57 ClinicalTrials.gov identifier: NCT03693625 and NCT03137069. The poten- tial discrepancy between these two second-gen- eration BTK inhibitors for CSU treatment in terms of efficacy suggests that there could be dif- ferences among inhibitors in their suitability for treating specific autoimmune conditions. Although BTK inhibitors are receiving substan- tial attention as novel DMTs for MS, the results of ongoing phase III trials will be pivotal in evalu- ating whether the BTK inhibitors described dem- onstrate the desired benefit–risk profiles. Phase I and II trials have been promising; however, fur- ther conclusions cannot be drawn until the com- pletion of phase III trials, which will enable a more thorough dissection of BTK inhibitor safety and efficacy. Potential implications of BTK inhibitor administration in female reproductive health Worldwide, it is estimated that between 66% and 78% of people with MS are female, the aver- age age of MS diagnosis across sexes is 32 years.73 Therefore, in the development of novel DMTs for MS, it is important to consider female needs in relation to reproductive health and choices. A recent study in a healthy female study popula- tion investigating remibrutinib suggested that when administered at a dose of 100 mg twice daily, it does not substantially interfere with expo- sure of the combined oral contraceptive pill (COCP), containing 30 µg ethinylestradiol/150 µg levonorgestrel.74 There was no change in ethi- nylestradiol exposure, but a slight increase in lev- onorgestrel exposure.74 Furthermore, the incidence of AEs was higher when the COCP was administered alone (26.7%), than when both the COCP and remibrutinib were taken (22.2%),74 suggesting second-generation BTK inhibitor administration may not have pharmacodynamic or safety implications in COCP use. However, extrapolation of these data to a population with MS, across individual BTK inhibitors, hormonal contraceptive methods or COCP types should not be undertaken; thus, further research is needed. First-generation BTK inhibitors such as ibrutinib are not recommended for use during pregnancy, with highly effective contraception required dur- ing administration, while second-generation BTK inhibitors have similar guidelines, ClinicalTrials. gov identifier: NCT04338022, NCT04338061, NCT04032158, NCT04410978, NCT04410991, NCT04411641, NCT04458051, NCT04711148, NCT04586023 and NCT05147220. To date, there have been no peer-reviewed articles detail- ing instances of pregnancy during BTK inhibitor clinical development and the effects of the drugs on a developing fetus are not known. As described in Table 1, BTK inhibitors have a short half-life, ranging from 1 to 9.9 h.19–21 This may make treat- ment with BTK inhibitors a flexible option for MS management, until close to stopping contra- ception for pregnancy planning. Post-partum and if breastfeeding is chosen, the concentration of MS DMTs in breastmilk and implications in infant exposure need to be considered.75 It is cur- rently unknown whether second-generation BTK inhibitors are present in breastmilk,75 with par- ticipants who are pregnant or breastfeeding excluded from clinical trials. Further insights from prospective future OLE studies and real- world evidence may enable further elucidation of the implications of BTK inhibitors in the repro- ductive choices of people with MS. TherapeuTic advances in neurological disorders Volume 17 12 journals.sagepub.com/home/tan Potential implications of long-term BTK inhibitor administration Despite the promising safety profiles of second- generation BTK inhibitors observed to date in MS trials, there are several adverse reactions that have previously been associated with first-genera- tion BTK inhibitor administration.4 While not affecting all people taking BTK inhibitors, sev- eral adverse reactions are of concern when long- term administration is considered. Most notably, these include atrial fibrillation, derma- tological toxicities, spontaneous bleeding and invasive fungal infection.4 Infectious complica- tions could be due to potential immunosuppres- sion, as previously discussed.12,48–50 Currently, it is unclear whether these effects are BTK inhibitor class-related and most prevalent in early therapeutics used short-term in the treat- ment of B-cell malignancies. Alternatively, non- infection-related reactions could be due to off-target effects.76 The BTK inhibitors cur- rently under development have been purported to have a higher selectivity than those of the pre- vious generation, as detailed throughout this review. Owing to the early development stage of second-generation BTK inhibitors for the treat- ment of MS, more clinical trial data are required to fully elucidate the safety profile in this patient population. Importantly, OLE studies and long- term administration will further enable the assessment of long-term impacts of BTK inhibi- tor administration and the safety profile of these treatments. The effects of mid- to long-term use of BTK inhibitors in the treatment of MS are currently unknown. In humans, loss of function muta- tions and deletions of the BTK gene are respon- sible for the rare genetic condition X-linked agammaglobulinaemia, characterized by pri- mary immunodeficiency, due to reduced circu- lation of B-cells and hypogammaglobulinaemia.77 The role of BTK in the maintenance of immu- nity should be considered in the development of inhibitors for long-term use, along with poten- tial implications for immunosuppression from long-term administration. Conclusion So far, the benefit–risk profile of second-genera- tion BTK inhibitors in the treatment of MS is encouraging. BTK inhibitors can enter the CSF, thus highlighting the potential for access to cells of the adaptive and innate immune system, both in the CNS and periphery concurrently. Furthermore, preclinical models have suggested modulation of immune cells in demyelination and myelin repair following BTK inhibition, but this is yet to be understood in humans and may be illuminated by future clinical studies. The results of ongoing phase II and III trials will help to further elucidate the clinical efficacy and immune responses of BTK inhibition, along with understanding BTK inhibitor’s safety profile under chronic use, which will be observed more fully during OLE studies. It is yet to be established where in the therapeutic pathway BTK inhibitors would occupy, but this will be informed through ongoing clinical devel- opment and subsequent real-world evidence stud- ies. The introduction of BTK inhibition was perceived as a major breakthrough in oncology; it is hoped that these drugs will bring a similar incre- mental value to the therapeutic armamentarium in fighting MS. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Author contributions Laura Airas: Conceptualization; Writing – review & editing. Robert A. Bermel: Conceptualization; Writing – review & editing. Tanuja Chitnis: Conceptualization; Writing – review & editing. Hans-Peter Hartung: Conceptualization; Writing – review & editing. Jin Nakahara: Conceptualization; Writing – review & editing. Olaf Stuve: Conceptualization; Writing – review & editing. Mitzi J. Williams: Conceptualization; Writing – review & editing. Bernd C. Kieseier: Conceptualization; Writing – review & editing. Heinz Wiendl: Conceptualization; Writing – review & editing. L Airas, RA Bermel et al. journals.sagepub.com/home/tan 13 Acknowledgements The authors are grateful to Rachael Chandler PhD (Oxford PharmaGenesis, Oxford, UK), for providing medical writing support. These services were funded by Novartis Pharma AG. Authors had full control of the content and made the final decision for all aspects of this article. Funding The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This review was funded by Novartis Pharma AG (Basel, Switzerland). Competing interests LA has obtained institutional research support from Aatos Erkko Foundation, Finnish Academy, Merck, Novartis, Sanofi Genzyme and US National MS Society, and compensation for lec- tures and advising from Janssen, Merck, Novartis, Roche, Sanofi Genzyme and Viracta is. TC has received compensation for consulting from Banner Life Sciences, Biogen, Bristol Myers Squibb, Novartis Pharmaceuticals, Roche Genentech and Sanofi Genzyme. She has received research support from the National Institutes of Health, National MS Society, US Department of Defense, Sumaira Foundation, Brainstorm Cell Therapeutics, Bristol Myers Squibb, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Novartis Pharmaceuticals, Octave Bioscience, Roche Genentech, Sanofi Genzyme and Tiziana Life Sciences. JN received honoraria from Abbvie, Alexion, Amgen, Asahi-Kasei, Biogen, Bristol Myers, Chugai, CSL-Behring, Daiichi-Sankyo, Eisai, Kyorin, Mitsubishi-Tanabe, Novartis, Otsuka, Roche, Takeda and Teijin; received research supports from Biogen, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, EA Pharma, Eisai, JB, MEXT, Mitsubishi-Tanabe, Otsuka, Shionogi, Sumitomo Pharma, Takeda and Teijin; serves as a paid scientific advisor to Alexion, Biogen, Chugai, Horizon, Roche and Novartis; serves as a local principal investigator for Novartis (remibrutinib) and Sanofi (tolebrutinib) and serves as a member of scientific steering commit- tee for Novartis (remibrutinib). OS is an Associate Editor at Therapeutic Advances in Neurological Disorders; therefore, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process. In addition, OS has served on data monitoring committees for Genentech-Roche, Pfizer, Novartis and TG Therapeutics without monetary compensation, advised EMD Serono and VYNE, receives grant support from EMD Serono, is a 2021 recipient of a Grant for Multiple Sclerosis Innovation (GMSI), Merck KGaA, is funded by a Merit Review grant (federal award document num- ber (FAIN) BX005664-01) from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Deve- lopment, and by RFA-2203-39314 (PI) and RFA-2203-39305 (co-PI) grants from the National Multiple Sclerosis Society (NMSS). HW has received honoraria for acting as a mem- ber of Scientific Advisory Boards from Abbvie, Alexion, Argenx, Bristol Myers Squibb/Celgene, Janssen, Merck, Novartis. He receives speaker honoraria and travel support from Alexion, Biogen, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Genzyme, Merck, Neurodiem, Novartis, Roche Pharma AG, TEVA, WebMD Global. He is acting as a paid consultant for Abbvie, Actelion, Argenx, Biogen, Bristol Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen, Lundbeck, Merck, NexGen, Novartis, PSI CRO, Roche, Sanofi, Swiss Multiple Sclerosis Society, UCB, Worldwide Clinical Trials. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics Inc., Argenx, Biogen, CSL Behring, F. Hoffmann-La Roche, Genzyme, Merck KGaA, Novartis Pharma, Roche Pharma, UCB Biopharma. Availability of data and materials Not applicable. ORCID iDs Hans-Peter Hartung https://orcid.org/0000- 0002-0614-6989 Olaf Stuve https://orcid.org/0000-0002- 0469-6872 Heinz Wiendl https://orcid.org/0000-0003- 4310-3432 TherapeuTic advances in neurological disorders Volume 17 14 journals.sagepub.com/home/tan References 1. Ringheim GE, Wampole M and Oberoi K. 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