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Avidity Biosciences advances del-brax for FSHD, initiating a pivotal Phase 3 study while exploring accelerated FDA approval pathways.

FDA Accelerated Approval Open for FSHD Agent Del-Brax, With Newly Initiated Phase 3 Study to Confirm Efficacy

Daniel Mikol, MD, PhD, chief medical officer at NervGen Pharma, provided clinical perspective on recently announced positive findings from a phase 1b/2a trial testing NVG-291 as a treatment for  spinal cord injury.

Insights on NervGen Pharma’s Positive Phase 1b/2a Data for NVG-291 in Spinal Cord Injury

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Once-Nightly Oxybate Reduces Sleep-Related Eating, Samelisant Improves Excessive Daytime Sleepiness, Tirzepatide's Impact on OSA and Obesity

Take 5 minutes to catch up on NeurologyLive®'s highlights from the week ending June 13, 2025. 

NeurologyLive® Friday 5 — June 13, 2025

Director of the Center for Brain and Mind Health at Yale University.

The director of the Center for Brain and Mind Health at Yale University discussed new findings in thrombolytic therapy, stroke monitoring, neuroprotection, and imaging technologies presented at ESOC 2025. [WATCH TIME: 7 minutes]

Advances in Therapeutics and Imaging from European Stroke Organization Conference 2025: Kevin Sheth, MD

Associate Professor; Director of Outpatient Operations, Jefferson Headache Center; Co-Chief, Division of Headache, Jefferson University Hospital



The director of outpatient care at Jefferson Headache Center reflected on advances in migraine care and the ongoing outpatient challenges in treating this widespread yet under-recognized condition. [WATCH TIME: 3 minutes]

Evolving Perceptions and Care Challenges in Migraine: Michael Marmura, MD

The neurosurgeon at Northwestern Medicine discussed diagnostic approaches, evolving treatment strategies, and the importance of timely referral in managing peripheral nerve injuries. [WATCH TIME: 3 minutes]

Emerging Considerations in Peripheral Nerve Injury and Surgical Intervention: Kevin Swong, MD

Marco Meglio, Assistant Managing Editor for 

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The neuroscientist and physician at Mount Sinai explored the role of sleep-dependent brain clearance in Alzheimer disease and how emerging research is challenging longstanding assumptions.

NeuroVoices: Andrew Varga, MD, on Debating Whether Brain Cleansing Prevents Alzheimer Disease

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Neuromuscular expert Matthew Alexander, PhD, explores the evolving landscape of targeted therapies in muscular dystrophies, from fibrosis and glycosylation to combination strategies with gene therapy.

From Fibrosis to Function: Exploring New Pathways in Muscular Dystrophy Research

The associate professor of pediatric neurology and genetics at the University of Alabama Birmingham provided clinical insights on the key signaling pathways currently being targeted in the treatment of muscular dystrophies. [WATCH TIME: 4 minutes]

Exploring New Avenues for Treating Muscular Dystrophies With Targeted Therapies: Matthew Alexander, PhD

, a retrospective cohort study using MSBase registry data that compared 360 definitions of progression independent of relapse activity (PIRA) in patients with relapsing-remitting multiple sclerosis (MS) reported substantial differences in PIRA incidence and persistence depending on definition parameters.The study suggests that a proposed standardized definition could improve consistency and comparability across future MS research.

Overall, the analysis comprised 33,303 patients with clinically definite relapsing-remitting MS from 186 centers in 43 countries, drawn from a total pool of 87,239 patients in the MSBase registry between July 2004 and July 2023.

 Conducted by lead author Jannis Müller, MD, MSc, former research fellow of the CORe team at the RMH Neuroimmunology Centre in Melbourne, and colleagues, patients included in the analysis had an average of 15.1 visits across 8.9 years, and 84.2% were diagnosed with relapsing-remitting MS.

Investigators tested PIRA incidence and persistence using combinations of criteria such as baseline disability, confirmation period, magnitude of worsening, and freedom from relapse at both worsening and confirmation time points. Across all definitions, researchers reported that PIRA incidence ranged from 0.141 to 0.658 events per decade, and persistence ranged from 0.753 to 0.919 over at least 5 years.

"PIRA is an emerging concept in MS, which is becoming increasingly more important. This is because the contemporary therapies are very effective at reducing the risk of MS relapses, but less so at reducing progression of disability. To quantify how much disability in MS is attributable to relapses and how much is [because of] PIRA is important for development of new therapies and correct use of the current therapies," 

, professor of neurology and applied statistician at University of Melbourne and Royal Melbourne Hospital, told 

in a recent interview. "For example, a new class of therapies - BTK-inhibitors - seem to be more effective at reducing progression than the risk of relapses. If that impression proves to be correct, then we should know who has developed disability in the absence of relapses and whether we can prevent such disability in the future."

Psychological Perspective on the Role of Mental Health in MS Rehabilitation and Care

All told, participants included 24,152 women (72.5%) and 9151 men (27.5%), with a mean age of 36.4 years at their first visit and a median Expanded Disability Status Scale (EDSS) score of 2.0. Investigators noted that the definitions of PIRA varied by how baseline disability was treated (e.g., fixed or rebaselined after events), confirmation duration (6, 12, or 24 months), and relapse-free periods surrounding worsening and confirmation events.

Additional findings showed that both the baseline strategy and the length of the confirmation period significantly impacted PIRA detection. Among the tested definitions, 1 yielded a balanced estimate of both incidence and persistence. This definition meant that it required significant EDSS worsening from a baseline reset after each PIRA, relapse, or improvement; no relapse since the last EDSS assessment; and confirmation with EDSS scores that remained above the worsening threshold for 12 months, without relapse in 30 days prior.

"PIRA is a clinically apparent worsening of disability in the absence of relapses. It occurs in both relapsing and progressive forms of MS. However, there seems to be a layer of progression that is not clinically apparent. To identify such progression, we need more sophisticated methods," Kalincik said. "I do not think there is presently one test that can identify silent progression in MS. At the RMH Neuroimmunology Centre, and with support from MS Australia, industry and donors, we are presently developing a set of tests and analyses, which will enable to identify silent progression in individuals with MS and prevent its transition into overt disability."

Investigators acknowledged several limitations of the study, including the use of the EDSS, which may have overlooked nonmotor symptoms and introduced variability. The comparison framework may not have fully captured interactions among criteria, and treatment status was not considered, which could have influenced PIRA estimates. The definition also depended on standardized relapse identification and may have missed cases where relapse and progression overlapped. Additionally, imaging and biomarker data were not included, which might have improved the assessment of PIRA.

“In present clinical practice, PIRA as at best acknowledged, but rarely results in therapeutic decisions. This is because our instruments to slow down or prevent PIRA are limited. However, with emergence of new therapies, our focus on PIRA is increasing. I believe that in the near future PIRA will become a treatable target, and its accurate identification will then be of high importance," Kalincik said.

REFERENCES
1. Müller J, Sharmin S, Lorscheider J, et al. Standardized Definition of Progression Independent of Relapse Activity (PIRA) in Relapsing-Remitting Multiple Sclerosis. 

. Published online April 14, 2025. doi:10.1001/jamaneurol.2025.0495
2. Kalincik T, Butzkueven H. The MSBase registry: Informing clinical practice.

. 2019;25(14):1828-1834. doi:10.1177/1352458519848965

A retrospective cohort study using MSBase registry data analyzed 360 definitions of progression independent of relapse activity (PIRA) in relapsing-remitting multiple sclerosis (MS). The study found significant variability in PIRA incidence and persistence based on definition parameters, suggesting a standardized definition could enhance research consistency. The analysis included 33,303 patients, with findings indicating that baseline disability and confirmation period significantly impact PIRA detection. Limitations included reliance on the EDSS and lack of imaging data. A proposed PIRA definition aims to balance sensitivity and specificity for long-term disability worsening.

A recent large cohort analysis of global MS registry data reported that the incidence and persistence of progression independent of relapse activity varied widely depending on how it was defined.

Clinical

Observed Differences in PIRA Definition Call for More Standardized Agreement on Term 

A recently published systematic review reported that serum neurofilament light chain (sNfL) levels were elevated in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), particularly during clinical attacks and in those with brain lesions, but had limited ability to predict relapse or differentiate MOGAD from related demyelinating diseases.

Multiple Sclerosis and Related Disorders, 

the review analyzed 23 original research articles comprising data from 422 patients with MOGAD from Embase, MEDLINE, Scopus, and CINAHL databases. In most studies, sNfL levels were higher in patients with MOGAD (n = 292) than in healthy controls (n = 3172), with 1 study reporting elevated levels only during relapse.

 Additionally, patients with MOGAD who experienced recent attacks with brain lesions (samples, n = 69) had higher sNfL levels than those without lesions (samples, n = 78).

Conducted by senior author Giulia Fadda, MD, assistant professor of neurology in the Department of Medicine at the University of Ottawa, and colleagues, 3 out of 5 studies in the analysis reported higher median sNfL concentrations following clinical attacks (samples, n = 69) compared with remission (samples, n = 83). However, authors reported that onset sNfL levels did not predict relapse risk, with similar levels in relapsing (n = 15) and monophasic (n = 18) cases.

"This is an evolving and promising field. While the clinical utility of sNfL in MOGAD is not yet fully defined, its potential is increasingly recognized. sNfL levels at presentation have limited utility in distinguishing MOGAD from other demyelinating disorders, but combining them with other biomarkers may enhance diagnostic accuracy," Fadda told 

"Because sNfL levels tend to rise during acute attacks compared to remission, they may help differentiate true relapses from pseudorelapses. However, their sensitivity in this context still needs to be better defined, and initial findings suggest that it might be lower in isolated optic neuritis presentations than in cases involving the brain or spinal cord. Further research is needed to clarify how sNfL levels relate to long-term outcomes and imaging markers of CNS damage in MOGAD. Standardized testing protocols will be essential to improve comparability across studies and support future clinical application."

Across the included studies in the analysis, authors noted that the sNfL levels during attacks were comparable between MOGAD (n = 94) and patients with multiple sclerosis (MS; n = 256), and between MOGAD (n = 149) and aquaporin-4-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD; n = 214). Notably in 2 studies, researchers reported that the sNfL levels were higher at disease onset than in subsequent attacks (n = 133).

Indirect Immunofluorescence May Aid in Detecting Anti-MOG Antibodies in NMOSD, MOGAD

"I believe it is unlikely that sNfL will play a major role in differentiating brain versus optic nerve phenotypes in MOGAD beyond what clinical assessment already provides. However, its value as a prognostic biomarker may vary by phenotype, likely being more informative in cases involving the brain or spinal cord, and less so in isolated optic neuritis, where axonal damage may be more localized and less reliably reflected in serum levels," Fadda said.

All told, a positive correlation was observed between sNfL levels and attack severity measured by disability scales (n = 202), although no such correlation was revealed with acute or residual visual acuity (eyes, n = 45) or retinal thickness among optic neuritis cases (eyes, n = 11). Authors also noted that the serum glial fibrillary acidic protein /sNfL ratio was reported as useful in distinguishing MOGAD from MS and AQP4+ NMOSD in 2 studies (MOGAD: n = 56, AQP4+ NMOSD: n = 66, MS: n = 31).

“While one of the greatest clinical utilities of sNfL in MS is as a sensitive marker of subclinical disease activity and in confirming treatment response, because subclinical attacks are rare in MOGAD, sNfL is less likely to serve that same role in this population. Instead, its main potential in MOGAD may lie in assessing attack severity and predicting the likelihood of clinical recovery," Fadda said. "Studies to date have primarily examined correlations between sNfL levels and acute-phase clinical disability scores, while their relationship between sNfL and residual neurological deficits, T2 lesion burden on MRI, or gray matter volume changes remains largely unexplored."

"These could be important for identifying patients who might benefit from more aggressive acute treatment. Predicting a relapsing disease course remains a major unmet need in MOGAD. Notably, two small studies did not found an association between higher sNfL levels at onset and relapse risk, but it remains to be determined whether longitudinal sNfL measurements during remission,and changes from that baseline, could offer greater predictive value. Interestingly, one study found that the sNfL/MOG antibody ratio could predict monophasic versus relapsing disease, a result that merits further validation," Fadda noted.

REFERENCES
1. Labib M, Thebault S, Booth RA, et al. The utility of serum neurofilament light chain in MOGAD: Current insights and future directions. Mult Scler Relat Disord. Published online April 5, 2025. doi:10.1016/j.msard.2025.106410
2. Huang KY, Wu CL, Chang YS, et al. Elevated plasma neurofilament light chain in immune-mediated neurological disorders (IMND) detected by immunomagnetic reduction (IMR). Brain Res. 2023;1821:148587. doi:10.1016/j.brainres.2023.148587

Serum neurofilament light chain (sNfL) levels are elevated in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), especially during clinical attacks and in those with brain lesions. However, sNfL levels have limited predictive value for relapse and cannot effectively differentiate MOGAD from other demyelinating diseases. The review analyzed 23 studies involving 422 MOGAD patients, revealing that sNfL levels during attacks were similar to those in multiple sclerosis and aquaporin-4-positive neuromyelitis optica spectrum disorder. Future research should focus on larger cohorts and standardized methodologies.

A review highlighted the role of serum neurofilament light chain as a potential biomarker in MOG antibody-associated disease, with findings pointing to associations with attack severity.

Serum Neurofilament Light Chain Limited in Predicting MOGAD Attacks but Correlates With Attack Severity

According to a new announcement, the FDA has approved Soleno Therapeutics'  diazoxide choline (DCCR) extended-release tablets, marketed as Vykat XR, for the treatment of Prader-Willi syndrome (PWS) for patients 4 years and older who have hyperphagia. Thus, DCCR, a novel, proprietary extended-release dosage form containing diazoxide choline — the crystalline salt of diazoxide — is administered once daily and becomes the first therapy to treat hyperphagia in PWS.

In November 2024, the FDA extended its review period for the new drug application (NDA) of DCCR extended-release tablets for PWS.

 The extension was triggered by recent responses to the agency's information requests, which were classified as a major amendment to the NDA. As a result, the PDUFA goal date was pushed back by 3 months to allow the FDA sufficient time to complete its review, including the newly submitted data. Notably, the agency did not highlight any concerns related to safety, efficacy, or manufacturing in its correspondence.

“My immediate reaction was relief - I have been working with PWS for [over] 25 years to try to find an answer to the life-limiting issue of hyperphagia in this syndrome, so I was grateful that we now have an effective medication. I was one of the [principal investigators] for the study and had 33 patients on trial at my site, so got to see firsthand how well this medication worked for patients,” Jennifer Miller, MD, professor of pediatric endocrinology at the University of Florida, told 

in a recent interview. "I think it will change the treatment landscape by offering hope to patients and families with this condition. The concept of having a starving child and not being able to feed them is devastating for parents to contemplate. For physicians it offers the possibility of treatment in a space where there is currently none. That is huge."

The NDA is supported by data from the phase 3 DESTINY-PWS trial (NCT03440814) of DCCR tablets in PWS, which did not achieve its primary end point of significantly improving hyperphagia compared with placebo. However, notable improvements were observed in patients with severe baseline hyperphagia and in a pre-COVID analysis.

The 13-week, randomized, double-blind, placebo-controlled trial included 127 participants aged 4 years and older with PWS and hyperphagia. The primary outcome measured changes from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Secondary end points assessed global impression scores, body composition, behaviors, and hormone changes.

DCCR treatment did not yield a statistically significant reduction in hyperphagia in the overall population (least-square mean [LSmean] [SE]: -5.94 [0.879] vs -4.27 [1.145]; 

 = .198). However, in participants with severe hyperphagia, DCCR demonstrated a significant reduction (LSmean [SE]: -9.67 [1.429] vs -4.26 [1.896]; 

 .012). Two of the 3 secondary end points showed positive results, including improvements in the Clinical Global Impression of Improvement (CGI-I; 

Importantly, a pre-COVID analysis revealed statistically significant improvements across all primary and secondary end points, including hyperphagia (

 = .015), caregiver-reported global change (

= .003). DCCR was generally well-tolerated, with 83.3% of participants in the DCCR group experiencing a treatment-emergent adverse event (TEAE) compared with 73.8% in the placebo group — a difference that was not statistically significant.

Additional efficacy was confirmed during the 16-week randomized withdrawal phase of Study 2-RWP (NCT03714373), a phase 3 multicenter, double-blind, placebo-controlled trial.

 Participants who were switched to a placebo experienced a statistically significant increase in hyperphagia compared with those who continued taking DCCR. Before entering the randomized withdrawal phase, all participants had received DCCR in either a double-blind or open-label setting for an average of 3.3 years.

Soleno submitted its NDA to the FDA on June 27, 2024, which was accepted with priority review in August 2024. In the Untied States, diazoxide choline has received breakthrough and fast track designations, along with orphan drug designation in both the U.S. and E.U. for the treatment of PWS. The company noted that it anticipates DCCR to be available in the U.S. beginning in April 2025.

"The data was always positive from my perspective (even though did not reach statistical significance initially due to COVID interrupting the trial) -watching it was remarkable," Miller said. "I have been involved in basically every clinical trial in PWS and have never seen anything like this in terms of efficacy and duration of efficacy. Remarkable! In terms of [adverse] effects - this is a huge message I want the community to know! The drug reduces insulin release from the beta cells of the pancreas so for people with PWS who are older and obese and have insulin resistance or pre-diabetes there is a huge risk for development of type 2 diabetes."

Building on previous data from the 13-week DESTINY PWS trial, a 1-year analysis of DCCR administration further supported its potential to address key complications of PWS.

 This extended study included 125 participants aged 4 years and older who were enrolled in the original phase 3 trial and its open-label extension, receiving DCCR for up to 52 weeks. The primary end point, change in hyperphagia measured b HQ-CT, showed a significant reduction (mean [SE]: -9.9 [0.77]; 

 < .0001). Notably, patients with more severe baseline hyperphagia (HQ-CT > 22) experienced even greater improvements.

Beyond hyperphagia, DCCR administration led to marked reductions in aggression, anxiety, and compulsivity (all, 

 < .0001). Metabolic parameters also improved, with significant decreases in leptin, insulin, and insulin resistance, alongside a rise in adiponectin levels (all, 

 < .004). Additionally, lean body mass increased significantly (

 < .0001), reflecting positive changes in body composition.

Clinician and caregiver assessments indicated a meaningful reduction in overall disease severity (both, 

 < .0001), suggesting DCCR may ease the burden on families managing the complex symptoms of PWS. Common TEAEs included hypertrichosis, peripheral edema, and hyperglycemia, though only 7.2% of participants discontinued because of adverse events.

Following promising results from the DESTINY PWS trial and its open-label extension, a comparative analysis offered additional evidence that long-term administration of DCCR tablets could lead to meaningful improvements in PWS symptoms.

 In this study, participants from the phase 3 and open-label extension DCCR trials were compared with a matched cohort from the PATH for PWS natural history study to better understand how DCCR impacts the progression of the syndrome over time.

The analysis included participants aged 5 years and older with similar baseline characteristics, focusing on changes in hyperphagia as measured by the HQ-CT (range 0–36). At 26 weeks, the DCCR-treated group showed a significantly greater reduction in hyperphagia scores compared to the natural history cohort (LSmean [SE]: -8.3 [0.75] vs -2.5 [0.43]; 

 < .001). This difference remained significant at 52 weeks (LSmean [SE]: -9.2 [0.77] vs -3.4 [0.47]; 

 < .001), even under a worst-case sensitivity analysis where missing scores were imputed with the highest possible value.

Behavioral improvements extended beyond hyperphagia. Using the Prader-Willi Syndrome Profile questionnaire (PWSP), significant reductions were observed across all measured domains at both 26 weeks (

 ≤ .003) in the DCCR-treated cohort compared to the natural history group. These findings suggested that DCCR may positively influence aggression, anxiety, compulsivity, and overall disease burden.

REFERENCES
1. Soleno Therapeutics Announces U.S. FDA Approval of VYKAT(TM) XR to Treat Hyperphagia in Prader-Willi Syndrome. News Release. Soleno Therapeutics. Published March 26, 2025. Accessed March 27, 2025. https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-us-fda-approval-vykattm-xr-treat
2. Soleno Therapeutics Announces FDA Extension of Review Period for DCCR (Diazoxide Choline) Extended-Release Tablets in Prader-Willi Syndrome. News Release. Soleno Therapeutics. Published November 26, 2024. Accessed March 26, 2025. https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-fda-extension-review-period-dccr
3. Miller JL, Gevers E, Bridges N, et al. Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial. 

. 2023;108(7):1676-1685. doi:10.1210/clinem/dgad014
4. Miller JL, Gevers E, Bridges N, et al. Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study. 

. 2024;32(2):252-261. doi:10.1002/oby.23928 
5. Strong TV, Miller JL, McCandless SE, et al. Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study. 

. 2024;16(1):22. Published 2024 Apr 26. doi:10.1186/s11689-024-09536-x

The FDA has approved Soleno Therapeutics' diazoxide choline extended-release tablets, Vykat XR, for treating hyperphagia in Prader-Willi syndrome (PWS) patients aged 4 and older. Despite not meeting the primary endpoint in the phase 3 DESTINY-PWS trial, significant improvements were noted in patients with severe hyperphagia and in pre-COVID analyses. Long-term studies showed reductions in hyperphagia, aggression, anxiety, and metabolic parameters. Vykat XR, with breakthrough and fast track designations, is expected to be available in the U.S. by April 2025.

The FDA has recently granted approval to Soleno Therapeutics' DCCR tablets as the first treatment for hyperphagia in Prader-Willi syndrome.

FDA Approves Diazoxide Choline Extended-Release Tablets for Hyperphagia in Prader-Willi Syndrome

A post-hoc, late-breaking analysis of several phase 3 trials assessing tolebrutinib (Sanofi), an investigational Bruton tyrosine kinase (BTK) inhibitor, suggested that the agent has greater efficacy in patients with multiple sclerosis who have higher number of paramagnetic rim lesions (PRLs).

The research comprised data from the HERCULES study of patients with non-relapsing secondary progressive MS (nrSPMS) as well as GEMINI 1 and 2, two identical trials of patients with relapsing MS (RMS). In HERCULES, treatment with tolebrutinib demonstrated a 54% attenuated risk in 6-month confirmed disability worsening (CDW) among patients with at least 4 baseline PRLs, the highest quartile group observed. In GEMINI, a similar risk mitigation was observed with a 46% and 49% risk reduction in participants with 1-3 and at least 4 PRLs, respectively.

These data were presented by lead author 

, staff neurologist and medical director of the Barlo Multiple Sclerosis Program, St. Michaels Hospital, University of Toronto, at the 

2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum

, held February 27-March 1, in West Palm Beach, Florida. Overall, the analysis comprised 653 of the original 3004 patients across the studies who had PRL imaging data available.

Oh and colleagues manually identified PRLs on SWI images generated from 3D-gradient echo phase images (6 echoes ranging from 4.9 to 41 ms, 0.8-mm isotropic resolution). In HERCULES, 40% of participants had 0 PRLs at baseline, 36% had 1-3 PRLs, and 24% had at least 4 PRLs, with similar distributions observed in the GEMINI study. All told, results revealed a numerically similar risk of 6-month CDW associated with the GEMINI trials and of 6-month CDP for the HERCULES trial among tolebrutinib-treated patients with PRLs in both studies vs participants without PRLs.

"This finding has several clinical and clinical trial implications, particularly for trial design in the future. If we want to enrich clinical trial populations for people more likely to accumulate disability, pearls could be considered as a measure to help with this—though, of course, these findings need to be validated," Oh told 

"To get a better idea, we need to assess the longitudinal data, but this does suggest that what we’re thinking about the relationship between 'pearls' and disability holds up prospectively," Oh said. "That’s important because many smaller studies have shown a correlation between an individual’s pearl count and motor as well as cognitive disability. The fact that this was demonstrated in a two- to three-year clinical trial is significant—showing prospectively that having a certain number of pearls greatly increases the risk of developing disability is a critical finding."

BTK Inhibitor Orelabrutinib Shows Promising Efficacy in Phase 2 Study of Relapsing-Remitting Multiple Sclerosis

An investigational agent, tolebrutinib was awarded breakthrough therapy designation for patients with nrSPMS in December 2024 using 

 as the basis for the decision. After randomly assigning patients 2:1 to either tolebrutinib or placebo, results showed that those time to onset of CDP, the primary end point, was reduced by 31% for those on active treatment in comparison with placebo (HR, 0.69; 95% CI, 0.55-0.88; 

= .0026). On a secondary end point, the number the patients who experienced confirmed disability improvement increased by nearly 2-fold, 10%, for those treated with tolebrutinib relative to the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal 

"Like any research study, this has several strengths, particularly that it was conducted within multiple large phase 3 clinical trials and evaluated pearls prospectively. However, before drawing definitive conclusions, it’s important to validate these relationships in other clinical trials. We also need to assess whether this apparent accentuated treatment effect holds in other relevant clinical trials," Oh said. "There are multiple other BTK inhibitors and experimental therapies under evaluation that may target some of the disease mechanisms relevant to MS progression. Validation in external studies and different settings is necessary before we can definitively say that 'pearls' should be used as prognostic or treatment effect biomarkers."

HERCULES and GEMINI differed in a few ways, with the former including patients with nrSPMS and the latter comprising those with RMS. In HERCULES, patients were randomly assigned to either tolebrutinib or placebo whereas in the GEMINI trials, participants were randomized in both studies 1:1 to receive either tolebrutinib and placebo daily or 14mg teriflunomide (Aubagio; Sanofi) and placebo. In GEMINI, tolebrutinib failed to meet its primary end point of reducing annualized relapse rate (ARR) in comparison with teriflunomide; however, it did show positive data on a key secondary end point of pooled 6-month CDW, significantly delaying the time to onset of worsening.

"As for the effect of tolibrutinib on 'pearls', I don’t think we can say definitively without the longitudinal data. However, the fact that individuals with a greater number of pearls seemed to show a better treatment effect suggests that tolibrutinib, which we know can penetrate the central nervous system at bioactive concentrations, may beneficially affect cells relevant to progressive disease biology," Oh said.

Tolebrutinib also currently remains in development for patients with primary progressive MS, a subgroup of MS with significant therapeutic needs. The ongoing phase 3, randomized, 

 (NCT04458051), which primarily tests effects of the agent in delaying disability progression, is expected to have data released in the second half of 2025. Spanning 277 study locations, the study also has several secondary objectives, including MRI lesions, cognitive performance, physical function, and quality of life.

Tolebrutinib, a highly selective, oral, irreversible BTK inhibitor, targets the BTK enzyme in immune cells, particularly B cells. What distinguishes tolebrutinib from other BTK inhibitors is its targeting of BTK with a high degree of selectivity, which helps to minimize off-target effects and reduce adverse events, particularly in the central nervous system. Because of its irreversible build, it binds permanently to the BTK enzyme, which may provide sustained therapeutic effects with a potentially lower risk of relapse in conditions like MS.

Click here for more 2025 ACTRIMS Forum coverage

Tolebrutinib, an investigational Bruton tyrosine kinase inhibitor, shows promise in treating multiple sclerosis (MS), particularly in patients with higher numbers of paramagnetic rim lesions (PRLs). Data from phase 3 trials, HERCULES and GEMINI, indicate significant risk reduction in disability progression among patients with PRLs. Tolebrutinib received breakthrough therapy designation for non-relapsing secondary progressive MS based on these findings. Despite not meeting the primary endpoint in GEMINI, it demonstrated positive secondary outcomes. Ongoing studies, like PERSEUS, continue to explore its efficacy in primary progressive MS.

In both HERCULES and GEMINI trials, tolebrutinib reduced the risk of 6-month confirmed disability worsening, especially in participants with at least 4 baseline paramagnetic rim lesions.

Matthew Alexander, PhD

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