Обновленная информация о новых методах склероза: от мрачного поражения до сцинтилляционного успеха.

INTRODUCTION

Since the introduction of interferon beta-1b in 1993, tremendous progress was made in developing highly effective, well tolerated and generally well tolerated treatments for relapsing multiple sclerosis (MS) [ 1 ]. In recent years, increasing evidence supports the notion that highly effective treatments should be used shortly after diagnosis in most patients to prevent disability [ 2 ]. Today for many MS patients, who are diagnosed in a timely manner and started on high efficacy treatments, living with MS will be associated with a far lower medical and social burden than ever before. Substantial unmet needs persist especially for those with progressive forms of MS for whom treatment options are limited. The recent positive result from a phase 3 study in nonrelapsing progressive MS has brought hope that even progressive forms of MS might become readily treatable conditions. Strategies for enhancing repair and reversing neurological disability via remyelination, axonal sprouting and other trophic support remain in early development. This review is an update on current clinical trials of unapproved disease modifying medical treatments that have either recently completed or are underway in relapsing and progressive forms of MS. Symptomatic management, physical or cognitive rehabilitation techniques, and established therapies will not be discussed except when used in combination with novel medical interventions.

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Materials and methods

A search on clinicaltrials.gov was performed using the search term “multiple sclerosis” and filtered by: “interventional”, “not yet recruiting”, “recruiting” and “active, not recruiting”. The search generated a total of 517 trials that were reviewed by the authors to identify medical treatments in development without regulatory approval.

BRUTON'S TYROSINE KINASE INHIBITORS

Bruton's tyrosine kinase (BTK) was identified as the gene associated with X-linked agammaglobulinemia (XLA or Bruton's agammaglobulinemia) (Table 1 ). Ogden Bruton described XLA in 1952 [ 3 ] and was honored by having the causative gene named after him following its discovery in 1993 [ 4 ]. Young male children living with XLA present with recurrent infections of the sinuses, ears, lungs and skin [ 5 ]. In XLA, pro-B cells fail to mature into pre-Bells and do not produce antibodies. Affected boys have low immunoglobulins levels and have lymphoid hypoplasia. Interestingly, patients living with XLA do not get autoimmune diseases including MS.

Table 1 Bruton's tyrosine kinase inhibitors in development Bruton's tyrosine kinase inhibitors Compound Phase NCT Number Sponsor Study population
N
Results Evobrutinib 3 3 NCT04338022 NCT04338061 Merck Serono RMS 1124 1166 negative Tolebrutinib 3 3 3 3 NCT04410978 NCT04410991 NCT04411641 NCT04458051 Sanofi RMS RMS nrSPMS PPMS 974 899 1131 767 negative negative positive ongoing Fenebrutinib 2 3 3 3 NCT05119569 NCT04586023 NCT04586010 NCT04544449 Genentech/Roche RMS RMS RMS PPMS 109 751 746 985 positive ongoing ongoing ongoing Remibrutinib 3 3 NCT05156281 NCT05147220 Novartis RMS 800 (est) 800 (est) ongoing ongoing Orelabrutinib 2 NCT04711148 Beijing InnoCare Pharma Tech Co., Ltd. RMS 160 positive BIIB091 2 NCT05798520 Biogen RMS 275 (est) ongoing est, estimated recruitment target; nrSPMS, nonrelapsing secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis.

Bruton's tyrosine kinase inhibitors in development

est, estimated recruitment target; nrSPMS, nonrelapsing secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis.

BTK is a tyrosine kinase involved in downstream signaling from the pre-B cell receptor. BTK is a Tec family kinase and is expressed in all hematopoietic cell lines except for T cells and terminally differentiated plasma cells. Because microglia are myeloid cells, they also express BTK. In B cells, receptor activation causes intracellular signaling through BTK resulting in transcriptional regulation that governs diverse processes including antibody production, cytokine secretion, maturation, chemotaxis, adhesion, and trafficking. BTK inhibition is a proved treatment for chronic lymphocytic leukemia and mantle cell lymphoma [ 6 ]. As small molecules, BTKIs may have advantages over monoclonal antibodies or other biologics especially for CNS conditions because they have the potential for CNS penetrance. Many BTKIs were developed to covalently bind their receptor and reduce the steady-state concentration needed for their pharmacologic effects.

Evobrutinib was the first BTKI to show therapeutic potential in a phase 2 study in RMS [ 7 ] and was investigated in twinned phase 3 study ( NCT04338022 , NCT04338061 ) [ 8 ]. These studies tested the hypothesis that evobrutinib would be superior to teriflunomide in reducing MS relapses. Unfortunately, there was no significant difference between evobrutinib and teriflunomide on any outcome. Important lessons learned from this unsuccessful development program include consistent use of active comparators from phase 2 to phase 3, determination and assessment of an optimal therapeutic dose in phase 2, and in-vivo determination of CNS drug concentrations that are likely to have the anticipated physiologic effects.

The next BTKI to complete phase 3 studies was tolebrutinib that is a highly CNS penetrant BTKI [ 9 ] and showed activity on gadolinium-DPTA lesion formation in RMS [ 10 ]. Three phase 3 trials with tolebrutinib were completed: two head-to-head trials in RMS vs. teriflunomide ( NCT04410978 , NCT04410991 ) [ 11 ▪▪ ] and one in nonrelapsing secondary progressive MS (nrSPMS) vs. placebo ( NCT04411641 ) [ 12 ▪▪ ]. A trial in primary progressive MS (PPMS) is ongoing ( NCT04458051 ). Like evobrutinib, the twinned trials in RMS failed to show superior risk reduction of MS relapses compared to teriflunomide. However, in contrast to evobrutinib, tolebrutinib was nominally superior to teriflunomide in prevention of confirmed disability progression (CDP). The study of tolebrutinib in nrSPMS met its primary endpoint on prevention of CDP and showed a beneficial effect on confirmed disability improvement. This study is particularly important because it is the first drug to show a clear treatment effect on CDP and CDI in nrSPMS in a phase 3 trial. Tolebrutinib is currently being considered for approval by the FDA. Tolebrutinib is associated with potentially life-threatening drug-induced liver injury and will likely require intensive monitoring of liver functions, at least initially if it is to be used safely in clinical practice.

Fenebrutinib is a peripherally acting, reversibly binding BTKI that is under investigation in twinned phase 3 studies in RMS vs. teriflunomide ( NCT04586023 , NCT04586010 ) as well as a phase 3 study in PPMS vs. ocrelizumab ( NCT04544449 ) [ 13 ]. The studies in RMS are expected to complete in fourth quarter 2025, and the trial in PPMS is expected to complete in early 2026. Fenebrutinib showed beneficial effects on new lesion formation in a placebo-controlled phase 2 trial in RMS ( NCT05119569 ).

Remibrutinib is a peripherally acting, covalent binding BTKI being compared head-to-head vs. teriflunomide in twinned phase 3 study in RMS ( NCT05156281 NCT05147220 ). These studies are actively recruiting study participants. A study of remibrutinib following treatment with anti-CD20 monoclonal antibody (MAb) in RMS is being planned. Orelabrutinib is a CNS penetrant BTKI under investigation in a phase 2 study, placebo-controlled trial in RMS ( NCT04711148 ) and a study in PPMS is being planned. BIIB-091 is a BTKI being studied either alone or in combination with diroximel fumarate in a phase 2 RMS study ( NCT05798520 ).

Given that four phase 3 trials showed no difference in either evobrutinib or tolebrutinib vs. teriflunomide on reducing the risk of relapse in RMS, it seems that the phase 3 trials of fenebrutinib and remibrutinib will probably not show superiority over teriflunomide on relapse prevention. That tolebrutinib showed effects on CDP beyond that of teriflunomide perhaps suggests that the more CNS penetrant BTKIs could have an advantage over peripherally acting BTKIs. The CNS targets responsible for the reduction in CDP and improvement in CDI are not yet unidentified and preclinical studies suggest that CNS microglial cells, macrophages and B cells could all be beneficially affected through BTK inhibition.

MYELIN REPAIR AND PROTECTION

Remyelination of denuded axons offers tantalizing hope to restore neurologic deficits caused by demyelination as well as to protect axons from subsequent transection. Although some MS plaques remyelinate, oligodendroglial precursor cells can be found in MS plaques but appear to be unable to remyelinate presumably due to inhibitory signals [ 14 ]. Multiple strategies have tried to promote remyelination some through overcoming inhibitory signals, others by providing cofactors for enzymes critical for myelin formation and still others through stimulating OPC differentiation. To date, no drug has shown a clinically meaningful impact on myelin repair in phase 3 trials. Drugs that have been tested and failed include opicinumab, a MAb directed against LINGO-1 (an inhibitory signaling molecule); elezanumab, an antirepulsive guidance molecule A MAb, (another inhibitory molecule for myelination and axonal sprouting); RHIgM22a, a putative myelin-inducing MAb,; MD-1003, pharmaceutical grade, high-dose, biotin which is a co-factor for carboxylases crucial for myelin production; bexarotene, a retinoic acid RXR-gamma receptor agonist; and domperidone, a prolactin secretion stimulant [ 15 – 18 ] (Table 2 ).

Table 2 Remyelinating therapies Remyelinating and neuroprotective therapies Compound Phase NCT number Sponsor Study population
N
Results Clemastine fumarate 2 NCT02521311 UCSF AON in RMS 90 (est) Ongoing Clemastine fumarate + metformin 2 NCT05131828 Cambridge University Hospitals NHS Foundation Trust RMS 70 (est) Ongoing Metformin 2 NCT05298670 German University in Cairo RMS 80 (est) Ongoing Metformin 2 NCT05893225 University Hospital, Antwerp PMS 120 (est) Ongoing Bazedoxifene acetate 2 NCT04002934 UCSF Postmenopausal women with RMS 62 (est) Ongoing Testosterone undeconoate 2 NCT03910738 University Hospital, Strasbourg, France Men with RMS 40 (est) Ongoing PIPE-307 2 NCT06083753 Contineum Therapeutics/Johnson& Johnson RMS with VEP latency delay 168 Ongoing PIPE-791 2 NCT06683612 Contineum Therapeutics PMS, HC, IPF 28 (est) Ongoing CNM-Au8 2 NCT03536559 Clene Nanomedicine Chronic optic neuropathy in RMS 73 Terminated CNM-Au8 2 NCT03993171 Clene Nanomedicine MS, PD 30 (est) Ongoing OCS-05 2 NCT04762017 Oculis AON 36 Completed AON, acute optic neuritis; AON, acute optic neuritis; est, estimated recruitment target; HC, healthy control; IPF, idiopathic pulmonary fibrosis; PD, Parkinson's disease; PMS, progressive MS; RMS, relapsing multiple sclerosis; VEP, visual evoked potential.

Remyelinating therapies

AON, acute optic neuritis; AON, acute optic neuritis; est, estimated recruitment target; HC, healthy control; IPF, idiopathic pulmonary fibrosis; PD, Parkinson's disease; PMS, progressive MS; RMS, relapsing multiple sclerosis; VEP, visual evoked potential.

Clemastine fumarate, a CNS penetrant antihistamine, was identified using an in-vitro screen of FDA-approved drugs that could promote myelin formation. Preclinical studies of clemastine showed robust evidence of remyelination in some models and a phase 2 trial in chronic optic neuropathy revealed a physiologically detectable reduction in full field visual evoked potential latency, an effect consistent with possible remyelination [ 19 , 20 ]. Current trials with clemastine fumarate include an acute optic neuritis trial ( NCT02521311 ), a combination treatment trial with metformin ( NCT05131828 ), a glycemic control medication that might also promote remyelination. Several additional studies with metformin are underway: an add-on study with interferon beta-1a ( NCT05298670 ), a placebo-controlled, add-on to standard-of-care study in progressive MS ( NCT05893225 ), and a placebo-controlled trial in progressive MS ( NCT05349474 ). Given the well established safety profile of metformin and clemastine, these studies hold considerable promise that repurposing these medications will be well tolerated. Bazedoxifene acetate is a selective estrogen receptor modulator that is FDA approved for use to prevent postmenopausal osteoporosis when applied in combination with conjugated estrogens. Like clemastine, baxzedoxifene was identified using an in-vitro screen of CNS penetrant drugs that could promote myelin differentiation in vitro. Bazedoxifene is being studied in a phase 2 study in postmenopausal women with MS ( NCT04002934 ). Based on results from the Cuprizone preclinical model of CNS demyelination, testosterone undeconoate is being studied to promote OPC maturation in a phase 2 trial of men with RMS using measures of myelin integrity by diffusion tensor imaging and thalamic atrophy ( NCT03910738 ). PIPE-307 was developed after clemastine's mechanism of action in promoting myelin differentiation was found to be antagonism of the M1 muscarinic receptors of oligodendroglial precursor cells. PIPE-307 is highly selective for the M1 receptor and was well tolerated in healthy volunteers despite being intravenously administered. A phase 2 study is RMS to evaluate PIPE-307's effect on full field PET latency is underway ( NCT06083753 ). PIPE-791 is a lysophosphatidic acid receptor antagonist that promotes OPC differentiation in vitro and promoted myelin repair in preclinical models. PIPE-791 is being studied in a phase 1b trial in progressive forms of MS (PMS), healthy volunteers and persons with idiopathic pulmonary fibrosis ( NCT06683612 ).

CNM-Au8 (nanocrystalline gold) was studied in a phase 2 trial of chronic optic neuropathy in RMS where it was hoped that its ability to catalyze nicotinamide adenine dinucleotide hydride (NADH) to the energetic co-factor NAD+ might stimulate myelin production ( NCT03536559 ) [ 21 ]. The trial was terminated early due to failure to fully recruit during the Covid-19 pandemic. A single-center, study conducted in MS and Parkinson's disease showed a potentially beneficial effect of CNM-Au8 on 31P-MR spectroscopy imaging for the combined cohort [ 22 ] and a phase 2 study of CNM-Au8 in MS investigating this endpoint is underway ( NCT03993171 ).

OCS-05 is an intravenously infused peptidomimetic small molecule that is hypothesized to have neuroprotective properties in acute optic neuritis (AON). A phase 2 trial compared OCS-05 vs. placebo in conjunction with standard of care corticosteroids. Positive results showing decreased thinning of the ganglion cell-inner plexiform layer and the retinal nerve fiber layer as measured by optical coherence tomography as well as benefits on low contrast letter acuity were reported ( NCT04762017 ).

IMMUNE MODULATORS

Vidofludimus calcium (IMU-838) is a next-generation small molecule inhibitor of dihydro-orotate dehydrogenase (DHODH), the same enzyme targeted by teriflunomide, but has improved specificity that could lead to an improved adverse effect profile [ 23 ]. Compared to teriflunomide, vidofludimus calcium more effectively inhibits DHODH and T cell proliferation. Following a successful phase 2 study [ 24 ], vidofludimus calcium is currently being investigated in twinned, phase 3 trials in RMS ( NCT05134441 , NCT05201638 ) and in a phase 2 trial in PMS ( NCT05054140 ) (Table 3 ).

Table 3 Immune modulators in development Immune modulators Compound Phase NCT Number Sponsor Study Population
N
Results Vidofludimus calcium 3 3 3 NCT05134441 NCT05201638 NCT05054140 Immunic AG RMS RMS PMS 1050 (est) 1050 (est) 450 (est) ongoing ongoing ongoing Masitinib 3 NCT05441488 AB Science PMS 800 (est) ongoing Frexalimab 3 3 NCT06141473 NCT06141486 Sanofi RMS nrSPMS 1400 (est) 858 (est) ongoing ongoing Foralumab 1 2 NCT05029609 NCT06292923 Tiziana Life Sciences LTD nrSPMS 0 54 (est) withdrawn ongoing IMCY-0141 2 NCT05417269 Imcyse SA RMS 150 (est) ongoing Simvastatin 3 NCT03387670 University College, London SPMS 964 negative est, estimated recruitment target; nrSPMS, nonrelapsing secondary progressive multiple sclerosis; PMS, progressive MS; RMS, relapsing multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Immune modulators in development

est, estimated recruitment target; nrSPMS, nonrelapsing secondary progressive multiple sclerosis; PMS, progressive MS; RMS, relapsing multiple sclerosis; SPMS, secondary progressive multiple sclerosis.

Masitinib mesylate is a selective tyrosine kinase (c-kit) inhibitor that targets mast cell and microglia and has been in development as a DMT for MS since 2012 [ 25 ]. A phase 3 trial ( NCT01433497 ) demonstrated clinical efficacy in slowing disease progression in primary progressive and clinically inactive secondary progressive MS [ 26 ]. A follow-up phase 3 trial including MR outcomes in PMS is actively recruiting ( NCT05441488 ).

CD40 ligand is upregulated on activated T lymphocytes in persons with MS. Further, polymorphisms associated with MS risk are present in the CD40 gene. Antagonism of the interaction of CD40 with CD40 ligand weakens the adaptive immune response which could have beneficial properties in MS. CD40 ligand inhibition was previously studied in MS [ 27 ]. However, studies with a first generation CD40 ligand MAb were stopped due to thromboembolic events [ 28 ]. Frexalimab is a second generation CD40 ligand MAb that was Fc engineered to abrogate platelet activation triggered by immune complex stimulation of FcγRIIa. A phase 2 study in RMS showed that frexalimab reduced the accumulation of contrast enhancing lesions seen on T1-weighted imaging following gadolinium-DPTA contrast administration compared to placebo over 12 weeks [ 29 ▪ ]. Frexalimab is being studied in phase 3 trials in relapsing MS ( NCT06141473 ) and nonrelapsing SPMS ( NCT06141486 ).

Foralumab (TZLS-401) is a human, anti-CD3 MAb that modulates CD3 function without inducing lymphopenia and is delivered in a stabilized liquid form intranasally. Foralumab completed a phase 1 trial in SPMS that showed encouraging results for a therapeutic effect on PET MRI in ( NCT05029609 ). Foralumab is now under investigation in a phase 2 study of nonactive SPMS ( NCT06292923 ).

IMCY-0141 is a synthetic peptide based on myelin oligodendrocyte glycoprotein (MOG), a key constituent of myelin. IMCY-0141 is proposed to stimulate the expansion of antigen-specific cytolytic CD4 + T cells that abrogate an autoimmune response to the MOG antigen. IMCY-0141 is being studied in a phase 2 study in RMS ( NCT05417269 ). Given that the dominant auto-antigens in MS have yet to be identified (if even dominant auto-antigens contribute to MS pathogenesis) beneficial effects of IMCY-0141 may be difficult to detect. Because MOG is the dominant auto-antigen in MOG antibody-associated disease (MOGAD) it seems that IMCY-0141 might be more successfully studied in MOGAD compared to MS.

Simvastatin is an HMG-CoA reductase inhibitor that is proposed to have neural protective and anti-inflammatory effects in MS [ 30 ]. Following the success of a multicenter study in SPMS [ 31 ] a multicenter, placebo controlled, phase 3 trial of simvastatin in SPMS investigated its impact on CDP ( NCT03387670 ). Unfortunately, this study failed to show a beneficial effect of simvastatin compared to placebo on CDP [ 32 ▪ ].

B CELL TARGETING THERAPIES

The development of anti-CD20 MAbs as DMTs for MS has led to a sea change in medical management: as a class, anti-CD20 MAbs now are the most commonly prescribed DMTs [ 1 , 33 ]. Several strategies are seeking to build upon this success Table 4 .

Table 4 B cell targeting therapies in development B cell therapies Compound Phase NCT number Sponsor Study population
N
Results LYS3541860 2 NCT06220669 Eli Lily RMS 200 (est) ongoing RO7121932 1b NCT05704361 Roche MS 129 ongoing Ixazomib 1 NCT03783416 Queen Mary University of London MS 72 (est) ongoing Obexelimab 2 NCT06564311 Zenas BioPharma (USA), LLC RMS 93 (est) ongoing Telitacicept 2 NCT04625153 RemeGen Co., Ltd. RMS 30 (est) ongoing est, estimated recruitment target; RMS, relapsing multiple sclerosis.

B cell targeting therapies in development

est, estimated recruitment target; RMS, relapsing multiple sclerosis.

LY3541860 is a nondepleting, anti-CD19 MAb antibody that inhibits B cell activation, proliferation and differentiation [ 34 ]. LY3541860 is being studied in a phase 2 trial of RMS with the goal to reduce accumulation of new T1 gadolinium-enhancing lesions over 9 months of this placebo-controlled study ( NCT06220669 ).

RO7121932 is a type 2 anti-CD20 MAb that is coupled to transferrin-based brain shuttle technology to allow active uptake of the MAb into the CNS compartment. RO7121932 causes programmed cell death of B cells independently of complement activation or cellular cytotoxicity mechanisms and therefore has the potential to directly eradicate CNS resident B cells. RO7121932 is being studied in a phase 1 study of MS patients that will evaluate first a single ascending dose of intravenously or subcutaneously administered investigational product followed by a multiple ascending dose study in MS participants ( NCT05704361 ). This product is being developed to test the hypothesis that eradication of CNS resident B cells will further reduce MS CDP beyond that of the peripherally restricted anti-CD20 MAbs.

Ixazomib is FDA approved for treatment of multiple myeloma and is a plasma cell targeting proteasome inhibitor. Ixazomib is being studied in a phase 1 study in MS to determine whether treatment will reduce or eradicate the intrathecal production of gammaglobulins in the spinal fluid of MS patients ( NCT03783416 ).

Obexelimab a bispecific MAb engineered to bind CD19 and the Fc gamma receptor IIb, thereby mimicking the antigen-antibody complex, to inhibit B cells, plasmablasts and plasma cells. Obexelimab is being developed in IgG4-mediated disease and systemic lupus erythematosus [ 35 , 36 ]. Obexelimab is being studied in a phase 2 trial in RMS vs. placebo with the goal of showing a reduction in cumulative gadolinium-enhancing lesions identified on T1 brain MRI over 24 weeks ( NCT06564311 )

Telitacicept (RC18) is a Recombinant Human B Lymphocyte Stimulator Receptor:Immunoglobulin Fc Fusion Protein, which inhibits BLyS (B cell activation factor) and APRIL (a B cell proliferation-inducing ligand) thereby blocking B cell proliferation [ 37 ]. Telitacicept is being studied in a phase 2, placebo-controlled 48-week study in RMS with the goal of demonstrating an impact on MS relapses and gadolinium-enhancing lesions identified on T1 brain MRI ( NCT04625153 ).

It seems possible that all these strategies could achieve success in their respective early phase 1 and 2 studies. The challenge they all will face is demonstration of superior efficacy and/or safety compared to anti-CD20 MAbs. Given the extraordinarily robust effects of anti-CD20 MAbs in RMS, head-to-head trials will require very large numbers of participants to show evidence of superiority over a proved anti-CD20 MAb. It seems doubtful that there will be sufficient participants for recruitment in multiple head-to-head trials and consideration should be given to a multiarm, parallel group study design wherein each product will be compared to a common control [ 38 ].

MICROBIOME AND DIETARY SUPPLEMENTS

Studies on the gut microbiome showed differences in the composition of microflora between MS patients and controls [ 39 ]. The gut microflora can potentially interact with dendritic cells and lymphocytes within the lamina propria thereby eliciting proinflammatory or anti-inflammatory host responses. These observations led to the hypothesis that perhaps altering the gut microflora could be beneficial in MS [ 40 ]. Early phase studies exploring fecal matter transplantation (FMT) in MS were halted due to safety concerns ( NCT04096443 , NCT03594487 ). A phase 1 study examining the impact of vancomycin on the gut microflora in MS is currently underway ( NCT05539729 ) (Table 5 ).

Table 5 Supplements and microbiome influencing treatments in development Supplements and microbiome targeting treatments Compound Phase NCT number Sponsor Study population
N
Results Vancomycin 1 NCT05539729 Icahn School of Medicine at Mount Sinai MS 12 (est) ongoing N-acetyl cysteine 2 NCT05122559 UCSF PMS 98 (est) ongoing Nicotinamide riboside 2 NCT05740722 Haukeland University Hospital PMS 300 (est) ongoing Conjugated linoleic acid + probiotics 2 NCT05920018 Universität Münster RMS 100 (est) ongoing est, estimated recruitment target; PMS, progressive MS; RMS, relapsing multiple sclerosis.

Supplements and microbiome influencing treatments in development

est, estimated recruitment target; PMS, progressive MS; RMS, relapsing multiple sclerosis.

N-acetyl cysteine (NAC) is a glutathione precursor whose antioxidant properties could be neuroprotective. NAC is being studied in a placebo-controlled, add-on to standard of care, phase 2 study of PMS whose goal is to reduce measures of brain and spinal cord atrophy ( NCT05122559 ).

Nicotinamide riboside is a dietary supplement that could potentially increase production of NAD+ which in turn may be beneficial as a neuroprotectant and aid in myelin production. Nicotinamide riboside is being studied in a 30-month long placebo-controlled trial of PMS whose goal is to show an impact of this supplement on prevention of worsening disability ( NCT05740722 ).

Conjugated linoleic acid (CLA) is thought to have anti-inflammatory properties. CLA (Tonalin FFA 80) in combination with probiotics (Vivomixx/VSL#3) are being investigated as add-on therapy in a placebo-controlled phase 2 trial in RMS who are treated with auto-injected interferon or glatiramer acetate ( NCT05920018 ).

Demonstrating therapeutic benefit of dietary supplements or specific diets has been very challenging in MS and currently there are no supplements or diets that are proved to be beneficial. Demonstrating a consistent therapeutic benefit of vitamin D supplementation has been challenging although a recently reported trial in CIS showed a therapeutic effect of high dose vitamin D in reducing the risk of clinical or radiographic disease activity [ 41 ]. Nevertheless, the advantage of these approaches is clear: they are very low cost when compared to traditional medical DMTs, they are often very well tolerated, are orally administered and can be taken in combination with approved DMTs.

CELLULAR THERAPIES

Immune depletion with subsequent repopulation of autologous stem cells (autologous hematopoietic stem cell transplantation, AHSCT) appears to induce remission in relapsing MS possibly through eradicating memory cells but does not appear to have sustained benefits in PPMS [ 42 ]. A single-arm, uncontrolled study in relapsing MS is open for recruitment in Russia ( NCT05832515 ). Two randomized controlled trials are recruiting RMS participants: one comparing AHSCT vs. alemtuzumab, cladribine or ocrelizumab ( NCT03477500 ) and the other vs. best available therapy ( NCT04047628 ). These randomized controlled trials are much needed to understand whether this risky treatment outperforms commonly available highly effective treatments over both the short and longer term (Tables 6 and 7 ).

Table 6 Cell-based treatments in development Cell-based therapies Treatment Phase NCT number Sponsor Study population
N
Results AHSCT 1 NCT05832515 St. Petersburg State Pavlov Medical University MS 200 (est) ongoing AHSCT vs. Alemtuzumab 3 NCT03477500 Haukeland University Hospital RMS 100 (est) ongoing AHSCT vs. Best Available Therapy 3 NCT04047628 National Institute of Allergy and Infectious Diseases (NIAID) RMS 156 (est) ongoing Allogenic Adipose Tissue-derived MSC 1 NCT06592703 Rennes University Hospital PPMS 10 (est) ongoing Allogeneic Umbilical Cord MSC 1/2a NCT05532943 Ever Supreme Bio Technology Co., Ltd. RMS 41 (est) ongoing Allogeneic Adult Umbilical Cord Derived MSC 1 NCT05003388 The Foundation for Orthopaedics and Regenerative Medicine MS 15 (est) ongoing IMS001 human embryonic cell derived MSC 1 NCT04956744 ImStem Biotechnology MS 30 (est) ongoing Intrathecal MSC 1/2 NCT04749667 Haukeland University Hospital PMS 18 (est) ongoing Adipose derived MSC 2 NCT05116540 Hope Biosciences Stem Cell Research Foundation RMS 24 positive Intrathecal Donated Human Umbilical Cord Blood Mononuclear Cells 1 NCT04943289 Duke University PPMS 20 (est) ongoing AHSTC, autologous hematopoietic stem cell; est, estimated recruitment target; MSC, mesenchymal stem cell; PMS, progressive forms of MS; PPMS, primary progressive MS; RMS, relapsing multiple sclerosis.

Cell-based treatments in development

AHSTC, autologous hematopoietic stem cell; est, estimated recruitment target; MSC, mesenchymal stem cell; PMS, progressive forms of MS; PPMS, primary progressive MS; RMS, relapsing multiple sclerosis.

Table 7 CAR T treatments in development KYV-101 (CD19 CAR T) 1 NCT06138132 Stanford University PMS 12 (est) ongoing KYV-101 (CD19 CAR T) 1 NCT006451159 UCSF PMS 10 (est) ongoing KYV-101 (CD19 CAR T) 2 NCT06384976 Kyverna PMS 120 (est) ongoing CC-97540 (CD19 CAR T) 1 NCT06220201 Juno Therapeutics, Inc., Bristol-Myers Squibb MS 98 (est) ongoing YTB323 (CD19 CAR T) 1/2 NCT06617793 Novartis RMS 28 (est) ongoing Azercabtagene zapreleucel 1 NCT06680037 TG Therapeutics, Inc. PMS 32 (est) ongoing C-CAR168 (BCMA CAR T) 1 NCT06249438 Renji Hospital RMS, SLE, IMNM, NMOSD, gMG 30 (est) ongoing CT103A (BCMA CAR T) 1 NCT04561557 Tongji Hospital MS, NMOSD, gMG, CIDP, IIM, AE, MOGAD, POEMS 36 (est) ongoing AE, autoimmune encephalitis; BCMA, B cell maturation antigen; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; est, estimated recruitment target transplantation; gMG, generalized myasthenia gravis; IIM, idiopathic inflammatory myopathies; IMNM, immune-mediated necrotizing myopathy; MOGAD, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease; NMOSD, neuromyelitis optica spectrum disorders; POEMS, Syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes); SLE, systemic lupus erythematosus.

CAR T treatments in development

AE, autoimmune encephalitis; BCMA, B cell maturation antigen; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; est, estimated recruitment target transplantation; gMG, generalized myasthenia gravis; IIM, idiopathic inflammatory myopathies; IMNM, immune-mediated necrotizing myopathy; MOGAD, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease; NMOSD, neuromyelitis optica spectrum disorders; POEMS, Syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes); SLE, systemic lupus erythematosus.

Mesenchymal stem cells (MSCs) administered either intravenously or through intrathecal transplantation are being investigated as possible neuroregenerative or neuroprotective treatments in MS ( NCT06592703 , NCT05532943 , NCT05003388 , NCT04956744 ). These studies are uncontrolled and what their added value to our understanding of MS will be is unclear. One trial used a blinded, cross-over study design and will assess evoked potentials in progressive MS ( NCT04749667 ). A phase 2, randomized, blinded, placebo-controlled trial of intravenously infused, adipose-derived, MSCs met its primary endpoint improving quality of life measures of both physical and mental health in RMS ( NCT05116540 ). Similar to MSC trials, a phase 1 study is using donated umbilical cord blood cells (DUOC-01) for intrathecal injection in PPMS ( NCT04943289 ).

Chimeric antigen receptor T cell (CAR T) cells are patient-derived T cells that are genetically modified to target a single antigen, expanded in vitro and then infused into a lymphodepleted patient. CAR T has revolutionized the treatment of certain types of cancer. CAR T cells directed against CD19, a B cell-surface antigen, showed apparently striking clinical benefits in treatment-refractory patients living with systemic lupus erythematosus, systemic sclerosis, myositis and myasthenia gravis [ 43 , 44 ]. These observations suggested that perhaps deeper tissue depletion of B cells by CAR T treatment might be more effective than depletion of B cells by anti-CD20 monoclonal antibodies. CD19 CAR T cells were used on a compassionate use basis in MS. Several phase 1 CAR T trials targeting B cells either directed against CD19 ( NCT06138132 , NCT06451159 , NCT06384976 , NCT06220201 , NCT06617793 , NCT06680037 ) or B cell maturation antigen (BCMA, NCT06249438 , NCT04561557 ) are underway. The ability of CAR T cells to traverse the blood-brain barrier may be particularly relevant in PMS [ 45 ]. That BCMA directed CAR T therapy used for treatment of multiple myeloma is associated with Parkinsonism and multiple cranial neuropathies will likely limit utility of BCMA as a target for autoimmune neurological disease [ 46 ].

Cellular approaches to induce self-tolerance

A phase 2 study of autologous tolerogenic dendritic cells derived from peripheral blood is being investigated as an add-on treatment to moderately effective treatments ( NCT04530318 ). The dendritic cells are loaded with immunogenic peptides and through their interactions with antigen-specific T lymphocytes are hypothesized to induce regulatory T cells. A major potential limitation to this approach is that the antigenic targets in MS remain unknown. A single-arm study is investigating the safety of autologous monocyte-derived dendritic cells that are tolerized with Vitamin-D3 and loaded with myelin peptides prior to intranodal injection ( NCT02903537 ). A phase 1 study of ABA-101 is underway in participants with PMS who carry the major MS susceptibility allele, HLA-DRB1∗1501. ABA-101 is a tissue-specific TCR-Treg cell therapy created by engineering a patient's own Tregs to express a T cell receptor (TCR) that specifically recognizes immunogenic CNS myelin fragments.

IDP-023 is made from allogenic g-natural killer cells (NK): a NK cell subset that develop through epigenetic imprinting in response to cytomegalovirus infection. g-NK cells have enhanced capacity to target tumors and, when used in combination with anti-CD20 mAbs, can potently deplete B cell. IDP-023 is being investigated in combination with ocrelizumab and interleukin-2 (to help expand the g-NK cells in vivo ) in a phase 1b study of treatment-refractory PMS ( NCT04956744 ).

Lastly, a single-center, phase 1 study using autologous EBV-reactive CD8 T cells in clinically isolated syndrome remains open for recruitment ( NCT02912897 ) despite the failure of the phase 1/2 ATA-188 clinical trial program to show any beneficial effect in progressive MS ( NCT03283826 ).

CONCLUSION

The effective treatment of relapsing MS is one of the great success stories of modern medicine. Many patients who in years past would have been destined for irreversible severe disability and social isolation can now live relatively unencumbered by the worst aspects of progressive MS. Nonetheless, there remain major unmet needs for treatments that reduce disability worsening in progressive forms of MS as well as for restoration of lost function. Our understanding of the biology that inhibits neuronal CNS repair is in its infancy and strategies that can overcome these limits are sorely needed for repair of existing deficits. Further, our collective understanding of the cellular and molecular mechanisms underlying disease progression remains limited. Until these mechanisms are better understood, therapeutic development will continue to be limited by hypotheses that are obtuse rather than targeted. Nevertheless, the finding that tolebrutinib reduces CDP in nrSPMS is a major breakthrough that doubtless will result in development of additional BTKIs with improved safety and efficacy profiles. That microglia could be an important therapeutic target in MS opens potential for further investigation into the roles these innate immune system cells have in MS.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

B.A.C.C. received personal compensation has received personal compensation for consulting from Alexion, Avotres, Biogen, Boston Pharma, EMD Serono, Hexal/Sandoz, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, and TG Therapeutics and received research support from Genentech and Kyverna.

H.-P.H. received personal compensation for serving on steering and data monitoring committees from BayerHealthcare, Biogen, BMS Celgene, Boehringer Ingelheim, GeNeuro, Merck KG Darmstadt, Novartis, Roche, TG Therapeutics, VielaBio.