What drugs are in development for Multiple Sclerosis?

Introduction to Multiple Sclerosis

Definition and Symptoms
Multiple sclerosis (MS) is a chronic, immune-mediated, and often neurodegenerative disorder of the central nervous system (CNS) that principally affects the brain, spinal cord, and optic nerves. It is characterized by focal inflammatory demyelination with subsequent axonal injury. This results in clinical symptoms that may include motor weakness, sensory disturbances, visual impairment, spasticity, ataxia, cognitive dysfunction, and fatigue. MS presentations can vary markedly between patients, with most individuals initially suffering from a relapsing-remitting pattern that over time can transition into a progressive phase involving continuous neurological deterioration. The heterogeneous nature of the disease—in terms of age‐of‐onset, relapse frequency, rate of progression, and individual clinical presentation—complicates both the diagnosis and management of MS.

Current Treatment Landscape
At present, multiple therapies are already approved and widely used in clinical practice. They mainly focus on modifying immune functions. Classic drugs include various interferon formulations, glatiramer acetate, oral agents like fingolimod, teriflunomide, and dimethyl fumarate, as well as monoclonal antibodies for high‑efficacy treatment such as natalizumab, ocrelizumab, and alemtuzumab. These therapies help reduce relapse rates and slow down the conversion to progressive disability, yet they do not efficiently address neurodegenerative aspects or repair myelin damage completely. Given these limitations, ongoing research and development efforts search for drugs that target additional disease components, including direct neuroprotection, remyelination, and modulation of innate immune cells like microglia.

Drug Development Pipeline

The drug development pipeline for MS spans the continuum from early exploratory work to late-stage clinical development. Advances in our understanding of MS immunopathology and neurodegeneration have prompted a reexamination of targets and encouraged the development of a range of new molecules and biologicals.

Early-Stage Development Drugs
Early-stage development typically focuses on target identification, proof-of-concept in preclinical models, and optimization of drug candidates for potency and safety. In this stage, high-throughput screening methods and advanced molecular techniques are used to identify potential small molecules and biological modifiers.

• Small molecules with neuroprotective or remyelinating properties are being evaluated. For example, research is underway to develop compounds that enhance remyelination by either boosting endogenous repair mechanisms or by directly promoting oligodendrocyte differentiation. One promising avenue involves antioxidant compounds derived from natural sources or synthetically optimized derivatives to relieve oxidative stress—a key contributor to neurodegeneration in MS.

• Novel immunomodulatory targets are also under investigation in early-stage development. Some preclinical studies have identified targets such as Bruton's tyrosine kinase (BTK). BTK inhibitors such as fenebrutinib are now being optimized to achieve sufficient blood–brain barrier penetration to modulate both peripheral and CNS immune responses. Early data indicate that compounds in this class can decrease inflammatory lesion formation and target slowly expanding lesions (SELs) that correlate with progression. Other innovative candidates include agents targeting the SYK kinase signaling pathway; recent studies suggest that enhancing SYK activity in microglia promotes clearance of myelin debris, thereby providing a potential neuroprotective effect.

• Cell-based therapies have also emerged as early-stage candidates. Mesenchymal stem cell-derived neural progenitor cell (MSC-NP) therapy is being explored for its capability to modulate microglia activity and promote remyelination. In preclinical studies, MSC-NPs have been shown to secrete factors such as TGF-β that shift microglia toward a pro-regenerative profile, potentially reducing chronic inflammation within the CNS.

• Gene expression–based approaches are emerging as a method to identify molecules capable not only of modulating immune responses but also of supporting neuronal repair. Some preclinical candidates in this regard focus on identifying and modulating genes that are differentially expressed in MS lesions versus healthy tissue. Early drug candidates target the regulation of these genes to restore beneficial pathways in the CNS.

Late-Stage Development Drugs
Late-stage development is characterized by the optimization of drug candidates that have demonstrated acceptable safety profiles and promising efficacy in early clinical studies. At this stage, drugs are entering or are already in Phase II or Phase III trials.

• BTK inhibitors remain among some of the most promising candidates in late development. Fenebrutinib, for example, is undergoing late-stage trials to evaluate its effect on both relapsing and progressive forms of MS. Data suggest that fenebrutinib can favorably affect MRI markers of brain inflammation and lesion formation.

• Other monoclonal antibodies targeting pathways not completely addressed by current therapies are in late-stage development. One emerging approach involves targeting the CD80/CD86 co-stimulatory pathway. Drugs such as abatacept and belatacept, which have been used in transplant medicine for immunomodulation, are being repurposed for MS treatment after genomic studies indicated that the CD80/CD86 signaling pathway plays a role in the breakdown of self-tolerance in MS. These agents are currently in clinical trials evaluating their efficacy in reducing disease activity and preventing disability progression.

• Selective sphingosine 1-phosphate receptor modulators continue to progress through the pipeline. While the first-generation compounds like fingolimod are already approved, newer agents such as siponimod, ozanimod, and ponesimod are being developed with improved receptor subtype selectivity and safety profiles. Phase III studies have shown siponimod to have beneficial effects on disability progression in secondary progressive MS, while optimized dosing strategies for ozanimod and ponesimod are being tested in ongoing large-scale trials.

• Novel small molecules targeting neuronal and glial functions are also at the late stage. For example, LABP‑66 is an orally active candidate that targets the NLRX1 pathway in the CNS. By modulating the immunometabolic control of CD4+ T cells, microglia, and neurons, LABP‑66 aims to provide both neuroprotection and immunomodulation, offering a potentially improved option for MS patients.

• In addition, drugs that target cytokine expression and the innate immune response are entering late-stage clinical testing. Some compounds aim to rebalance cytokine production and thereby reduce neuroinflammation without the broad immunosuppression associated with many current MS therapies. These compounds are designed to stabilize the inflammatory milieu in the CNS, potentially limiting both relapse frequency and disease progression.

Mechanisms of Action

Understanding the mechanisms of action is key to appreciating how new drugs in development may provide improved treatment for MS—not only by controlling immune-mediated damage but also by promoting repair and neuroprotection.

Novel Therapeutic Targets
New drug candidates for MS are targeting a broader range of pathways than traditional immunomodulators. In addition to targeting adaptive immune cells such as T cells and B cells, many promising drugs aim at CNS-resident cells to facilitate repair and protect neurons.

• BTK inhibitors such as fenebrutinib target the B cell receptor signaling pathway and modulate innate immune cells like microglia. This approach is based on the concept that BTK is involved in both peripheral B-cell activation and brain-centric inflammatory responses. By inhibiting BTK, these drugs aim to reduce formation of new lesions as well as slow down chronic lesion expansion—a key indicator of disease progression.

• There is growing interest in targeting co-stimulatory molecules such as CD80 and CD86 that modulate the interaction between antigen-presenting cells and T cells. Drugs such as abatacept and belatacept work by blocking these co-stimulatory signals, thereby reducing T-cell–mediated attack on myelin. This strategy reflects a novel immunomodulatory approach that differs from conventional cytokine-targeting therapies.

• The NLRX1 pathway has recently emerged as a potential target due to its role in regulating cellular metabolism and immune responses. LABP‑66, which modulates the NLRX1 pathway, may help shift the balance toward enhanced autophagy and improved mitochondrial function in immune cells, leading to decreased production of inflammatory cytokines and improved neuronal survival.

• Another new target involves SYK kinase signaling in microglia. Studies indicate that boosting SYK activity could accelerate the clearance of myelin debris from chronic lesions, thereby promoting remyelination and halting neurodegenerative processes in progressive MS. Targeting SYK offers a distinct angle from conventional immunosuppression and supports the concept of endogenous CNS repair.

• Cell-based therapies such as MSC-NP treatment work via mechanisms distinct from small molecule drugs. MSCs secrete a range of immunomodulatory and neurotrophic factors (including TGF-β) that can alter microglial activation from a pro-inflammatory to a pro-regenerative phenotype. This mechanism could reduce ongoing damage while promoting remyelination and axonal repair.

Mechanisms of New Drugs
The new molecules being developed are designed to address both the inflammatory and neurodegenerative components of MS. Their mechanisms of action are often multifaceted, combining several potentially complementary effects:

• Many small molecules act not only as immunomodulators but also as direct neuroprotectants. For instance, selective sphingosine 1‑phosphate receptor modulators (siponimod, ozanimod, ponesimod) change lymphocyte trafficking while potentially exerting effects on CNS cells such as oligodendrocytes. Improved receptor selectivity may reduce side effects such as cardiac arrhythmias, a known side effect of earlier therapies like fingolimod.

• BTK inhibitors work by interfering with the signaling needed for B-cell activation and cytokine production, and emerging evidence suggests that this class of drugs also acts on microglia, reducing the chronic inflammatory milieu in the brain.

• Agents targeting costimulatory signals (abatacept, belatacept) block the necessary second signals for full T-cell activation. As a result, these drugs attempt to re-establish immune tolerance and temper the autoimmune response with potentially fewer side effects than broad immunosuppressive agents.

• LABP‑66 modulates the NLRX1 pathway to influence energy metabolism in immune cells. By favoring oxidative phosphorylation and reducing pro-inflammatory differentiation, the molecule may reduce CNS inflammation as well as support myelin preservation and repair.

• MSC-based therapies function via paracrine signaling, where secreted factors modify the local inflammatory environment and promote remyelination—a mechanism that is distinctly regenerative compared to classical “stop relapse” strategies.

Clinical Trials and Research

New drugs and novel therapeutic strategies in MS are being evaluated through rigorous clinical trials and research studies worldwide. Information from “synapse” documents, which represent reliable and structured reports, provide significant insight into both current and emerging candidates.

Key Clinical Trials
Several large-scale and targeted trials are in progress:

• BTK inhibitors have been the focus of multiple Phase II and Phase III trials, with fenebrutinib being a prime example. In a Phase III trial, fenebrutinib demonstrated significant reduction of T1 and T2 brain lesions—a marker for inflammation and disease burden—and is expected to further assess disability progression.

• Trials targeting sphingosine 1‑phosphate receptors have involved head-to-head comparisons aimed at optimizing efficacy and minimizing side effects. Siponimod has already shown promising effects in reducing disability progression in secondary-progressive MS in the EXPAND study, and similar trials for ozanimod and ponesimod are ongoing.

• Clinical trials for cell-based therapies, particularly using MSC-NP injections, are already showing encouraging data regarding safety and preliminary efficacy. These studies evaluate not only functional outcomes but also shifts in biomarkers such as pro-regenerative marker expression in microglia.

• Trials involving CD80/CD86 targeting therapies are also being conducted. Early-phase trials with abatacept and belatacept have been initiated in MS patients, aiming to determine whether interfering with costimulatory pathways can reduce relapse frequency and slow progression without significant immunosuppressive adverse effects.

• Other Phase II/III trials evaluate novel compounds such as LABP‑66, where the primary endpoints include not only reduction in relapse frequency but also measures of neuroprotection and remyelination, such as imaging markers and cognitive function assessments. Such trials represent a holistic approach to MS therapy by targeting both inflammation and neurodegeneration.

• Several trials are now integrating biomarker-based endpoints—using genomic and proteomic indicators—to assess therapeutic responses more objectively. These studies aim to overcome the limitations of traditional clinical endpoints by subcategorizing patients into molecular endophenotypes with differing response profiles, which may eventually lead to more individualized treatment protocols.

Research Outcomes and Data
The outcomes of these clinical trials are often reported in terms of both clinical relapse rates and MRI-based outcomes. As follows:

• BTK inhibitor trials have demonstrated a reduction in slowly expanding lesions (SELs) which correlate with long-term progression, suggesting that these drugs can target both acute inflammation and chronic neurodegeneration.

• Data from sphingosine 1‑phosphate receptor modulator trials reveal that newer agents achieve a balance between efficacy (significantly reducing lesion counts and relapse rate) and safety (by decreasing cardiac risks), compared to earlier modulator drugs.

• Analysis of costimulatory pathway–targeting agents has shown that blockade of CD80/CD86 results in reduced T-cell activation, with early trials noting trends toward an improved relapse profile even though longer-term efficacy data are needed.

• Research on cell-based therapies, particularly MSC-NP therapies, has provided important evidence that modulating microglial function can achieve beneficial outcomes both in terms of clinical measures and biomarker changes in the CNS. For example, shifts towards a regenerative microglial phenotype have been accompanied by improvements in motor and cognitive functions in early-phase trials.

• Emerging imaging techniques and assessments of biomarkers—such as neurofilament light chain (NfL) levels—are also providing insights into the neuroprotective effects of these novel therapies. Reductions in NfL during clinical trials serve as an important correlate of slowed neurodegeneration, thereby supporting the efficacy of drugs beyond just reducing relapses.

Future Directions and Challenges

Despite the promise of many novel therapies, several challenges remain. Future research will need to address both emerging therapeutic opportunities and obstacles inherent in the development and evaluation of new MS drugs.

Emerging Therapies
The future of MS therapy is likely to feature a combination of approaches rather than a “one-size-fits-all” therapy. Several promising avenues include:

• Combination therapies involving both immunomodulatory and neuroprotective agents are expected to become more common. For example, combinations of BTK inhibitors with agents that promote remyelination (such as MSC-based therapies) may offer synergistic benefits by simultaneously addressing inflammation and repair.

• Personalized medicine approaches are gaining traction, as ongoing research aims to identify molecular biomarkers that predict which drugs work best for which patients. By using genomic and proteomic data, MS patients may eventually be divided into subgroups that respond preferentially to specific mechanisms of action—whether that be through costimulatory blockade, S1P receptor modulation, or neuroprotective small molecules.

• New small molecules designed to cross the blood–brain barrier are of significant interest. Agents targeting intracellular pathways such as SYK or NLRX1 have the potential to exert effects directly within the CNS. These drugs may help clear myelin debris, promote endogenous repair mechanisms, and protect neurons from inflammatory damage, thereby addressing the unmet need for treatments in progressive MS forms.

• Immunometabolic rebalancing is emerging as a crucial area. Studies focusing on how mitochondrial function and cellular metabolism affect immune cell phenotypes have led to the identification of targets such as NLRX1. The development of molecules like LABP‑66 capitalizes on these findings, offering a potential dual benefit of immunomodulation and neuroprotection with an oral dosing regimen—an attractive feature for improving patient adherence.

• There is also growing interest in drug repurposing efforts. Agents like abatacept (originally used in other immunological conditions) are being investigated for MS because of their ability to modulate T-cell costimulation, and such repurposing is supported by genetic and genomic data linking the CD80/CD86 pathway to MS.

Challenges in MS Drug Development
Even with promising candidates in the drug pipeline, several challenges still hamper the development process:

• MS is a heterogeneous disease; thus, designing clinical trials that capture the diversity of patient responses remains complex. Differences in disease phenotype, genetic predisposition, and environmental influences necessitate large sample sizes and/or stratified trial designs, which can be both expensive and time-consuming.

• Most clinical endpoints in MS have traditionally focused on relapse rates and MRI lesion counts; however, these may not fully capture neurodegeneration and disability progression, particularly in progressive forms of the disease. The need for more sensitive biomarkers and outcome measures is pressing, as these are required to truly determine the efficacy of a drug in halting CNS progression.

• Penetration of the blood–brain barrier remains a significant hurdle. Many drugs that work peripherally fail to achieve therapeutic concentrations within the CNS. New molecules need to be designed with chemical properties that allow sufficient CNS uptake, but balancing this with safety profiles is challenging.

• While many drugs have shown efficacy in relapsing-remitting MS, treatments for progressive MS remain far less successful. The compartmentalization of inflammation within the CNS and the irreversible nature of accumulated damage necessitate therapies that can promote repair and remyelination—areas where current drugs fall short.

• Safety concerns are a constant challenge. For example, broad immunosuppression can lower relapse rates but at the cost of increased infection risks or other adverse effects like cardiac issues (seen with older sphingosine 1‑phosphate modulators). New therapies must aim for maximal benefit with minimal side effects, a balance that is difficult to achieve when attempting to target multiple mechanisms simultaneously.

• Regulatory and translational issues also play a role. As promising early-stage drugs transition into late-stage trials, ensuring robust data on long-term safety and efficacy is critical. This involves not only regulatory approval processes but also the integration of new outcome measures that are acceptable to regulatory agencies worldwide.

Detailed Conclusion

In summary, the landscape of drugs in development for multiple sclerosis is both broad and dynamic and reflects significant advances in our understanding of the disease’s dual nature—comprising both inflammatory and neurodegenerative components. At the early-stage level, candidates include novel small molecules, antioxidants, and cell-based therapies that target fundamental aspects of CNS repair and immune regulation. Drugs such as BTK inhibitors (e.g., fenebrutinib), SYK-enhancing molecules, and MSC-NP therapies are in preclinical or early clinical development with promising initial efficacy and safety data.

In late-stage development, efforts are primarily directed at optimizing and validating these novel approaches through rigorous Phase II and III clinical trials. Novel immunomodulatory strategies include selective sphingosine 1‑phosphate receptor modulators (siponimod, ozanimod, ponesimod), and agents targeting costimulatory molecules like CD80/CD86 (abatacept and belatacept) are progressing further in the pipeline. Additionally, innovative molecules such as LABP‑66, which target immunometabolic pathways (NLRX1), represent a new wave of drugs that may overcome limitations of current therapies by providing both neuroprotection and effective immune modulation.

Mechanistically, the new drugs are designed to work on several fronts. They not only address peripheral immune activity (reducing relapses by modulating B cells, T cells, and costimulatory signals) but also aim to directly affect CNS-resident cells, such as microglia and oligodendrocytes, to facilitate the clearance of debris, promote remyelination, and ultimately protect neuronal integrity. Clinical trials, as indicated by robust MRI and biomarker data, are beginning to validate these approaches. They provide encouraging evidence that the new agents can reduce both acute inflammatory activity and the progression of established chronic damage.

Looking forward, the future of MS therapeutic development involves overcoming several challenges. These include the need for more sensitive and specific clinical outcome measures, enhanced CNS penetration of drugs, and the design of combination or personalized treatment regimens based on extensive genomic and proteomic profiling. The increasing use of advanced imaging and biomarker endpoints in clinical trials will help refine our understanding of drug efficacy, especially in progressive forms of the disease, where conventional measures have so far fallen short. Equally, the translational challenge of moving from promising preclinical data to patient benefit remains significant. Researchers must navigate regulatory hurdles, ensure long-term safety, and tailor therapies to the heterogeneous MS patient population to derive maximum benefit with minimal side effects.

In conclusion, while current approved treatments have significantly changed the course of relapsing-remitting MS, the evolving drug development pipeline—informed by cutting-edge molecular insights and advanced clinical trial designs—offers hope for future therapies that address not only acute inflammation but also neurodegeneration and remyelination. Emerging drugs such as BTK inhibitors, costimulatory blockers, novel S1P modulators, and agents targeting intracellular pathways (e.g., NLRX1 and SYK) represent promising strategies that are likely to reshape the MS treatment landscape over the coming years. Each of these agents brings its own set of potential benefits and challenges. As clinical trials progress and more data become available, these new therapies could eventually translate into more personalized, safer, and more effective treatment regimens—ultimately transforming the quality of life for patients with multiple sclerosis.