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Articles

Marketed as Amvuttra, the Alnylam Pharmaceuticals RNA-interference treatment is now approved for an additional patient population of 150,000 in the US, and more than 300,000 worldwide.

FDA Approves Vutrisiran for ATTR-CM, Expanding Indication in Amyloidosis

New biomarker data presented at the 2025 Muscular Dystrophy Association Clinical & Scientific Conference of RGX-202 in the phase 1/2 trial highlight strong microdystrophin expression.

Gene Therapy RGX-202 Shows Positive Interim Results in Duchenne Muscular Dystrophy Trial

Videos

The medical director of the Barlo Multiple Sclerosis Program at St Michaels Hospital discussed findings from phase 3 trials suggesting that baseline PRLs can predict disability accumulation and may serve as biomarkers for treatment response to tolebrutinib. [WATCH TIME: 6 minutes]

Using Baseline Paramagnetic Rim Lesion Count as Prognostic and Treatment Biomarkers in Multiple Sclerosis: Jiwon Oh, MD, PhD

A new analysis reported that givinostat, an oral histone deacetylase inhibitor recently approved for DMD, slowed disease progression by approximately 2 years compared with standard care.

Givinostat Delays Duchenne Muscular Dystrophy Progression by 2 Years, Simulation Model Shows

Marco Meglio, Assistant Managing Editor for 

, has been with the team since October 2019. Follow him on Twitter 

The MyacarinG study post-hoc analysis demonstrated rozanolixizumab's potential to significantly reduce ocular symptoms in gMG, with consistent improvements across multiple scoring systems.

Ocular Symptoms of Myasthenia Gravis Improved With Rozanolixizumab

Kathleen Costello discusses her new role as interim CEO of the CMSC. She has the support of Jeff Wilken, CMSC president, and Tina Trott, CMSC director.

Continuing the Vision of June Halper: What's Next for CMSC

Interim chief executive officer of the Consortium of Multiple Sclerosis Centers.

The interim chief executive officer at the Consortium of Multiple Sclerosis Centers invites healthcare professionals to the Consortium’s annual meeting from May 28–31 in Phoenix, Arizona. [WATCH TIME: 2 minutes]

What to Expect From the 2025 CMSC Annual Meeting: Kathleen Costello, CRNP, MSCN

The child neurologist and neuroimmunologist at Nationwide Children’s Hospital delved into the unique challenges and research objectives surrounding MOG antibody-associated disease. [WATCH TIME: 3 minutes]

Challenges and Research Priorities for Pediatric MOGAD: Kelsey Poisson, MD

NeurologyLive is your direct connection to the latest neurology news and interviews with expert neurologists in multimedia formats.

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Authors

The director of the Parkinson’s Disease and Movement Disorder Program at Emory University School of Medicine shared his perspective on the research and development of Parkinson therapies.

The Therapeutic Pipeline for Parkinson Disease: Stewart Factor, DO

The director of the Parkinson’s Disease and Movement Disorder Program at Emory University School of Medicine explained the various factors that make Parkinson so difficult to manage.

Managing Parkinson Disease Despite Motor and Nonmotor Challenges: Stewart Factor, DO

The director of the Movement Disorders Program and Vance Lanier Chair of Neurology at Emory University School of Medicine gave his perspective on the interim findings of a long-term safety study of apomorphine sublingual film.

Stewart Factor, MD: Long-Term Data on Apomorphine Sublingual Film in Parkinson

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

REFERENCES
1. Oh J, Fox RJ, Arnold DL, et al. LB1.1. Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT LB1.1
2. Fox RJ, Bar-Or A, Traboulsee A, et al. Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results from the Phase 3 HERCULES Trial. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 4027.
3. GEMINI 1 and 2 Trials. Presented at: ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Abstract 4026/O135

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.

Clinical

BTK Inhibitor Tolebrutinib Shows Greater Effectiveness in Multiple Sclerosis with Higher Paramagnetic Rim Lesion Counts

According to a new announcement, the FDA has approved suzetrigine (Vertex Pharmaceuticals), an oral selective NaV1.8 pain signal inhibitor, to treat patients who experience moderate-to-severe acute pain. Marketed as Journavx, the novel, non-opioid therapy becomes the first new class of medicine to treat acute pain in over 20 years.

The new drug application (NDA) for suzetrigine, formally known as VX-548, was based on data from a phase 3 program that included 2 randomized, double-blind, placebo-controlled trials; 1 post abdominoplasty surgery and 1 post bunionectomy surgery. The program also included a single arm safety and efficacy study that included patients with a wide range of surgical and non-surgical pain conditions.

"This is the first new and nonopioid pain class we've had at our disposal in over 20 years. It provides a selective, nonaddictive alternative to opioids for treatment of moderate to severe acute pain," Jessica Oswald, MD, MPH, steering committee member at Vertex and associate professor in pain management and emergency medicine at UC San Diego, told 

in a recent interview. "This offers an effective alternative to opioids, and it expands our nonopioid armamentarium. In the emergency department, I'm frequently stuck. I have patients with acute pain, and I have opioids, and I have to get creative with some of our available options. So this really provides one additional medication that I can use in my toolbox." 

Suzetrigine, which previously received breakthrough therapy, fast track, and priority review designations by the FDA, is contraindicated for concomitant use with strong CYP3A inhibitors. Additionally, patients should avoid food or drink containing grapefruit when taking the medication. 

"I think it will reduce a reliance on opioids, particularly in the perioperative and acute pain setting. I think NaV receptors are here to stay. I think suzetrigine, having its availability, will accelerate research into NaV inhibitors, and I think we're going to potentially see expanded applications for even potentially chronic pain," Oswald said. "Suzetrigine really highlights the importance of targeting peripheral receptors and potentially shifting future drug development strategies from more central acting drugs to the peripheral medications."

In the pivotal studies, suzetrigine met its primary end point of the time-weighted sum of the pain intensity difference from 0 to 48 hours, and demonstrated a clinically meaningful reduction in pain from baseline at 48 hours on the Numeric Pain Rating Scale (NPRS) after both abdominoplasty and bunionectomy surgeries. Compared with placebo, the mean difference in pain intensity from 0 to 48 hours for abdominoplasty was 48.4, and 29.3 for bunionectomy, showcasing a statistically significant improvement.

Among the patients in the single arm safety and efficacy study, 83.2% rated suzetrigine as good, very good, or excellent in treating pain based on the Patient Global Assessment (PGA) scale.

"I think the biggest studies are going to be your phase 3, NAVIGATE 1 and NAVIGATE 2 trials, which studied post-op abdominoplasty and bunionectomy. The NAVIGATE 1 and NAVIGATE 2 trials found that suzetrigine was superior to placebo for pain relief over 48 hours. It had comparable efficacy to opioids but not superior in all measures," Oswald said. "It had faster pain relief than placebo, with a median time being 2 hours, at a lower incidence of nausea, constipation and dizziness compared with opioids, and it was generally well tolerated, with no reports of respiratory depression or sedation. There was a real world study evaluating surgical and nonsurgical acute pain conditions and 83% of patients rated pain relief as 'good', 'very good' or 'excellent'."

All 3 studies revealed that suzetrigine was safe and well tolerated by participants, with majority of adverse events (AEs) being reported as mild-to-moderate. Findings from the 2 randomized controlled trials demonstrated that following abdominoplasty, 50% of patients who received suzetrigine experienced AEs, compared with 56.3% in the placebo group. After bunionectomy, 31% of patients who received the therapy reported adverse events, compared with 35.2% in the placebo group. Overall, the most common AEs observed in study participants on suzetrigine were itching, muscle spasms, increased blood level of creatine phosphokinase, and rash. 

"The common adverse events noted were headache, nausea and constipation. The company deemed these adverse events as generally mild to moderate in nature. There are no opioid related concerns. Notably, there is no respirator depression or sedation reported," Oswald added. "For monitoring considerations, I think hepatic or renal impairment patients may need additional consideration, though there was no major safety signals identified in the studies. I can see this being used as monotherapy or part of an opioid sparing strategy. I can see Suzette regime being ideal for opioid naive patients or those at risk for opioid related [adverse] effects."

An poster presented at ANESTHESIOLOGY 2024, the annual meeting of the American Society of Anesthesiologists, held October 18-22 in Philadelphia, Pennsylvania, demonstrated suzetrigine's positive effect across phase 3 clinical trial abdominoplasty and bunionectomy trials, underscoring the drug’s efficacy and safety across various pain conditions and settings. In these trials, 1118 participants underwent abdominoplasty, and 1073 participants underwent bunionectomy. All participants were aged between 18 and 80 years.

Participants who rated 4 or higher on the NPRS following surgery were randomized in a 2:2:1 ratio to receive either suzetrigine, hydrocodone bitartrate/acetaminophen (HB/APAP), or a placebo. The primary end point was the time-weighted sum of the pain intensity difference (SPID48) calculated from NPRS scores over 48 hours. A higher SPID48 value indicated a greater reduction in pain compared with baseline. Key secondary end points included the SPID48 for suzetrigine compared with HB/APAP, and the time required for suzetrigine to achieve a 2-point or greater reduction in NPRS compared to placebo. Safety was also assessed as a secondary end point.

Results showed that suzetrigine treatment significantly reduced pain compared with placebo. In the abdominoplasty trial, the least squares (LS) mean difference in SPID48 between suzetrigine and placebo was 48.4% (95% CI: 33.6, 63.1; 

 < .001). In the bunionectomy trial, the LS mean difference was 29.3% (95% CI: 14.0, 44.6; 

Neither trial demonstrated that suzetrigine was superior to HB/APAP in terms of SPID48. However, suzetrigine did exhibit a more rapid onset of meaningful pain relief than placebo in both trials. Additional findings demonstrated that the median time to achieve a 2-point or greater reduction in NPRS from baseline was significantly shorter with suzetrigine (119 minutes in the abdominoplasty trial and 240 minutes in the bunionectomy trial) compared with placebo (480 minutes in both trials; 

Suzetrigine was generally safe and well-tolerated in both trials, with AEs consistent with the post-surgical settings. The overall incidence of AEs was lower with suzetrigine compared with placebo or HB/APAP. Following abdominoplasty, the incidence of participants with any AEs was 50.0% with suzetrigine, 56.3% with placebo, and 60.7% with HB/APAP. Following bunionectomy, the rates were 31.0%, 35.2%, and 41.8%, respectively. No serious adverse events were related to suzetrigine.

In another poster presented at ANESTHESIOLOGY 2024, investigators conducted a phase 3, single-arm study to assess the safety and efficacy of suzetrigine for moderate-to-severe acute pain in a broader patient population.

 This patient population included both postoperative surgical patients and non-surgical patients with painful medical conditions. The study enrolled adults aged 18 to 80 with pain rated 4 or higher on the NPRS following surgery or presenting to a medical facility with newly developed moderate-to-severe acute pain within the past 48 hours. Participants received suzetrigine for 14 days or until pain resolved.

The primary objective was to assess safety and the secondary objective was to investigate the efficacy of suzetrigine in treating acute pain at the end of treatment as assessed by a patient global assessment. A total of 256 participants (222 surgical, 34 non-surgical) received suzetrigine. The most common surgical procedures were orthopedic, plastic and otorhinolaryngologic. The most common non-surgical conditions were sprains and strains of the upper and lower extremities.

Overall, in this second presented poster, suzetrigine was generally safe and well-tolerated in both surgical and non-surgical patients. Most AEs were reported as mild or moderate in severity, with headache being reported as the most common, occurring in 7% of participants. No serious AEs were related to suzetrigine, as noted by researchers. Majority of participants (83.2%) rated the efficacy of suzetrigine for treating pain as good, very good, or excellent at the end of the treatment period.

, researchers observed that suzetrigine reduced acute pain over a 48-hour period after abdominoplasty or bunionectomy with mild-to-moderate AEs at the highest dose. This previous trial was performed as 2 phase 2, randomized, double-blind, placebo-controlled studies. Participants included were aged between 18 years and 75 years with a pain score of at least 4 on the NPRS. Pain was also rated as moderate or severe on the Verbal Categorical Rating Scale in 4 hours after completion of the surgery and general anesthesia for those who underwent abdominoplasty and in 9 hours after removal of popliteal sciatic nerve block on postoperative day 1 in the bunionectomy trial.

For the abdominoplasty trial, 303 patients were included, with 81.5% who completed the treatment period. In the bunionectomy trial, 274 patients were included and 90.1% completed the treatment. The least-squares mean difference for the high-dose group and placebo group was 37.8 for participants in the abdominoplasty trial and 36.8 in the bunionectomy trial. For both studies, patients who received the lower doses displayed similar results as the placebo. Overall, investigators reported that headache and constipation were the most common adverse events reported with suzetrigine in this study.

"I think suzetrigine is a game changer in acute pain management. It's the first NaV 1.8 inhibitor we have available. It's the first NaV inhibitor we have available. It redefines a standard of care about providing nonopioid pain relief with fewer [adverse] effects. There are potential future applications in chronic pain, although more research is needed. It encourages a shift toward targeted, precision based pain treatment strategies, and its adoption in the clinical practice will be key to maximizing impact and reducing opioid prescribing," Oswald concluded in the interview. 

REFERENCES
1. FDA Approves Novel Non-Opioid Treatment for Moderate to Severe Acute Pain. FDA. Published January 30, 2025. Accessed January 30 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-non-opioid-treatment-moderate-severe-acute-pain
2. Vertex Announces FDA Acceptance of New Drug Application for Suzetrigine for the Treatment of Moderate-to-Severe Acute Pain. News Release. Vertex. July 30, 2024. Accessed January 30 2025. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-fda-acceptance-new-drug-application-suzetrigine
3. Vertex Announces Positive Results From the VX-548 Phase 3 Program for the Treatment of Moderate-to-Severe Acute Pain. News Release. Vertex. January 30, 2024. Accessed January 30 2025. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-positive-results-vx-548-phase-3-program
4. Bertoch T, D’Aunno D, McCoun J, et al. Randomized, placebo-controlled, phase 3 trials of suzetrigine, a non-opioid, pain signal inhibitor for treatment of acute pain after abdominoplasty or bunionectomy. Presented at American Society of Anesthesiologists 2024 Annual Meeting; October 18-22, 2024; Philadelphia, PA. Poster A1187.
5. McCoun J, Winkle P, Solanki D, et al. A phase 3, single-arm study of suzetrigine, a non-opioid, pain signal inhibitor for treatment of acute non-surgical conditions. Presented at American Society of Anesthesiologists 2024 Annual Meeting; October 18-22, 2024; Philadelphia, PA. Poster A2074.
6.Jones J, Correll DJ, Lechner SM, et al. Selective Inhibition of Na

. 2023;389(5):393-405. doi:10.1056/NEJMoa2209870

The FDA has approved suzetrigine, an oral selective NaV1.8 pain signal inhibitor, for moderate-to-severe acute pain, marking the first new class of non-opioid analgesics in over two decades. Clinical trials demonstrated its efficacy and safety, with significant pain reduction compared to placebo in abdominoplasty and bunionectomy surgeries. Suzetrigine showed a rapid onset of pain relief and was well-tolerated, with mild-to-moderate adverse events. It offers a promising alternative to opioids, addressing public health concerns related to opioid use in pain management.

Suzetrigine, a selective inhibitor of the NaV1.8 sodium channel, offers an alternative opioid treatment option for patients to treat moderate to severe pain without risk of addiction.

FDA Approves Vertex Pharmaceuticals' Suzetrigine for Acute Pain Management

 identified specific cerebrospinal fluid (CSF) lipids that distinguished multiple sclerosis (MS) from neuromyelitis optica spectrum disorder (NMOSD) and other neurological diseases with high accuracy, offering potential new biomarkers for diagnosis and disease monitoring. The research also reported correlations between CSF lipid levels and measures of disease activity, including Expanded Disability Status Scale (EDSS) scores and inflammatory cytokines.

In the study, researchers screened 353 lipid species in pooled CSF samples, quantifying 161 lipids across patients diagnosed with MS and NMOSD by clinical criteria as well as other inflammatory neurological diseases (OIND), and non-inflammatory neurological diseases (NIND). Significant differences emerged in the results, particularly in NMOSD, where 29 lipids—including sphingolipids and polyunsaturated lysophosphatidylcholines (LPCs)—were significantly elevated compared with MS.

"My understanding, from speaking to neuroimmunology specialists, is that diagnosis of AQP4 antibody-positive NMOSD is relatively clear-cut. The benefit of an alternative diagnosis will be distinguishing NMOSD from MS for AQP4 antibody-negative NMOSD, which I believe is somewhere in the range of 20-40% of NMOSD cases," senior author Anthony Don, PhD, a professor of medical biochemistry at the University of Sydney School of Medical Sciences, told 

in a recent interview. "We achieved very good differentiation of NMOSD from MS based on levels of just 3 lipids, and these lipids are easy to quantify with mass spectrometry systems that are used in clinical diagnostic labs. So an assay based on CSF or serum lipids would be quite easy to adapt for clinical practice, and low cost."

Further analysis showed that NMOSD cases exhibited higher levels of specific lipid classes, such as dihexosylceramides (Hex2Cer) and sphingomyelins (SM), compared with MS and NIND. A subset of OIND cases, including conditions like neurosarcoidosis and CNS lymphoma, also had elevated lipid levels similar with NMOSD. A machine-learning approach using partial least squares discriminant analysis and random forest analysis revealed that a combination of 3 lipids—GM3(d42:2), Hex2Cer(d18:1/22:0), and GM3(d38:1)—achieved 91% sensitivity and 91% specificity in differentiating NMOSD from MS. Notably, Hex2Cer(d18:1/22:0) alone distinguished NMOSD from MS with 73% sensitivity and 100% specificity at a threshold of 1.1 nmol/L CSF.

Dubai Study Highlights Disease Characteristics and Treatment Outcomes in NMOSD and MOGAD

Beyond diagnostic potential, the study examined how CSF lipids correlated with inflammatory cytokines and measures of disease activity. Several sphingolipids and LPC species were positively associated with inflammatory markers, including macrophage migration inhibitory factor (MIF), interleukin-6, and CXCL13, a chemokine involved in B-cell recruitment. Notably, 94 lipids were significantly correlated with MIF levels, with the strongest associations observed in SMs, Hex2Cers, and LPCs. Although MIF was elevated in NMOSD, it was also higher in patients with MS experiencing relapse compared with those in remission.

"Prior studies have not really looked at associations of lipid levels with inflammatory cytokines. We did this to determine if the increased levels of lipids in the CSF of [patients] with NMOSD reflect some kind of inflammatory signature and I was surprised by how strongly levels of many lipids in the CSF were correlated with the cytokine MIF. MIF is higher in [pateints] with NMOSD compared [with] MS or control [participants], so the correlation makes sense," Don explained. 

"Sphingolipid levels were higher in the CSF of [patients] with NMOSD but not MS (in fact they were higher in NMOSD compared [with] MS), so I’m not sure that CSF sphingolipids would be useful biomarkers for MS," Don added. "I think the finding of high levels of sphingolipids in the CSF of [patients] with NMOSD is clinically-relevant and should be explored as a biomarker of treatment response for that disease. Sphingolipids in the serum may be more poignant for MS and that will be discussed in a forthcoming paper."

In MS, gadolinium-enhancing (Gd+) lesions indicated active inflammation and blood-brain barrier disruption. In the study, 39 lipids, primarily phosphatidylcholine, triglycerides, and cholesterol esters (CEs), were significantly reduced in the CSF of patients with MS who had Gd+ lesions compared with those without. Notably, EDSS scores were inversely correlated with certain cholesterol esters, particularly CE(16:0), CE(22:5), and CE(22:6). Despite this correlation, the overall mean levels of these lipids did not significantly differ between disease groups.

"There is no obvious explanation for the inverse correlation between EDSS and CE(16:0), however we saw the association in 2 independent sample sets. Myelin is a vast reservoir of cholesterol, which cannot be broken down by the macrophages and microglia that degrade myelin in MS. Instead, they store the excess cholesterol that is released from the degraded myelin in the form of cholesterol esters," Don said. "Lower cholesterol ester levels in association with higher EDSS could reflect reduced cholesterol efflux from myelin plaques into the CSF as the disease progresses and plaques become chronic, or perhaps increased efflux across a leaky CSF-blood barrier. To determine if this correlation is relevant for monitoring treatment response, we would need to determine how CSF cholesterol ester levels vary over time and as a function of therapeutic response." 

Despite the study providing compelling set evidence that CSF lipids could serve as biomarkers for NMOSD and MS, authors acknowledged that several limitations exist. Researchers noted that the NMOSD sample size was relatively small, which prevented further stratification based on AQP4 antibody status. Additionally, the study did not include progressive MS cases, leaving questions about whether lipid differences extend beyond relapsing-remitting MS. Investigators also highlighted that the lack of healthy controls also meant that normal CSF lipid ranges could not be established.

All told, the current study underscored the potential of CSF lipids as biomarkers for differentiating NMOSD from MS and tracking disease activity. By identifying lipid profiles associated with inflammation and disability, these findings could pave the way for improved diagnostic and monitoring tools in neuroinflammatory diseases. Authors recommended that future research should validate these findings in larger cohorts and investigate whether lipid changes correlate with MRI measures of demyelination and therapeutic response.

"I think it is too early to talk about translation of CE(16:0) as a biomarker for MS. As mentioned [earlier], these lipids are not that challenging to measure with modern clinical mass spectrometers, but a plasma or serum biomarker would be better for MS and it is probably only a matter of time until we find a good one. I am not a clinical practitioner and they may have a different perspective," Don said.

REFERENCES
1. Shi L, Ghezzi L, Fenoglio C, et al. CSF sphingolipids are correlated with neuroinflammatory cytokines and differentiate neuromyelitis optica spectrum disorder from multiple sclerosis. J Neurol Neurosurg Psychiatry. 2024;96(1):54-67. Published 2024 Dec 16. doi:10.1136/jnnp-2024-333774
2. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2
3. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729

A study identified specific cerebrospinal fluid (CSF) lipids that differentiate multiple sclerosis (MS) from neuromyelitis optica spectrum disorder (NMOSD) and other neurological diseases, suggesting potential biomarkers for diagnosis and monitoring. Researchers screened 353 lipid species, finding significant differences, particularly in NMOSD. A machine-learning approach identified three lipids achieving high sensitivity and specificity in differentiating NMOSD from MS. CSF lipids correlated with inflammatory cytokines and disease activity measures. Despite promising results, limitations include small sample size and lack of healthy controls, necessitating further research for validation.

Cerebrospinal fluid lipid profiling revealed potential biomarkers for distinguishing NMOSD from MS and tracking disease activity, offering new insights into neuroinflammatory disease monitoring. 

Cerebrospinal Fluid Lipids Shows Promise as Biomarkers for Differentiating NMOSD and MS

Nearly 4 and a half years since its original submission, the FDA has approved Supernus Pharmaceuticals’ investigational agent SPN-830 (Onapgo) as the first and only subcutaneous apomorphine infusion device for the treatment of motor fluctuations in adults with advanced Parkinson disease (PD). The company also noted that it will make SPN-830 available in the second quarter of 2025 with a support team of experts, including a robust nurse education program, and access support at launch.

"People living with Parkinson's and their families are hungry for new treatment options, and the PMD Alliance community was thrilled to learn about SPN-830's approval. Every newly approved Parkinson's therapy is a win for our community," 

 in a recent interview. "The introduction of this therapy brings with it an increased need for education, and underscores the importance of clinician-patient communication. PMD Alliance produces resources and education to help patients understand their symptoms, for personal empowerment, but also to streamline clinic visits. Our annual healthcare provider conference, 

Advanced Therapeutics in Movement and Related Disorders (ATMRD)

, equips clinicians with the information to integrate new therapies into practice."

The therapy’s approval was based on data from the TOLEDO study (NCT02006121), a randomized, double-blind study in which treatment with the device was associated with a difference of –1.89 hours per day of OFF time for patients with PD in comparison with placebo. Published in the 

in 2018, the study randomly assigned 106 patients living with the disease to either 3-mg/hour to 8-mg/hour dose of apomorphine (n = 53) or placebo saline infusion (n = 53) during their wake hours for a 12-week period.

"Hope is strong after this approval, the third in less than a year. Combined with momentum from the 

 being signed into law, 2025 has the potential to be a banner year for people living with Parkinson's and the healthcare providers caring for them," Merriam said. 

In TOLEDO, the intervention group, with a mean final drug dose of 4.68 mg/hour, showed significant improvements, including a reduction in OFF time of –2.47 hours/day compared with –0.58 hours/day for placebo (

 = .0025), and an increase in ON time without troublesome dyskinesia of 2.77 hours/day versus 0.80 hours/day for placebo (

 = .0008). Additionally, 62% of the apomorphine group were responders compared with 29% in the placebo group (P = .0008).

"The approval of ONAPGO (SPN-830) is a significant milestone in Parkinson’s disease management. As advanced practice providers, we play a critical role in optimizing treatment plans and ensuring patients have access to the best available therapies," 

Association of Movement Disorder Advanced Practice Providers (AMDAPP)

 in an interview. "The long-awaited approval of ONAPGO opens another valuable tool in our clinical toolbox, giving us a new option to address motor fluctuations and improve “on” time for our patients. This therapy has the potential to be a game-changer, helping us provide more individualized and effective care to those living with Parkinson’s. Additionally, as more therapies like this are approved, it reinforces the need for continued innovation in drug development, particularly in delivering more consistent symptom control without relying solely on oral medications."

The timeline for SPN-830 dates back to September 2020, when Supernus sent its original new drug application (NDA) to the FDA.

 Shortly after, the FDA issued a refusal to file letter indicating that the NDA was not sufficiently complete to permit a substantive review. Nearly a year later, in December 2021, the company resubmitted its NDA; however, it was once again met with resistance, as the FDA 

In the CRL, the agency noted that it required additional information and analyses related to the device, including labeling, product quality and manufacturing, device performance, and risk analysis. At the time, no additional efficacy or safety clinical studies were required. Notably, the FDA mentioned in the letter that the application's approval would require inspections that could not be completed in a timely manner, primarily because of travel restrictions amid the COVID-19 pandemic.

 for SPN-830 in October 2023 which was subsequently accepted by the FDA less than a month later.

 In April 2024, the FDA issued another CRL for the device, citing 2 areas that required additional review or more information.

 The first was related to product quality while the second related to the master file for the infusion device, which is proprietary to the device manufacturer. Supernus went back to make adjustments and thus, towards the latter half of 2024, the company announced that the FDA accepted its resubmission of the NDA for SPN-830, giving it a PDUFA date of February 1, 2025.

"The approval of SPN-830 is incredibly exciting! Extensive data supports its effectiveness, as it has been used in other regions for decades—dating back 29 years in Europe. As more treatment options become available for people living with Parkinson’s disease, we, as clinicians, can better tailor treatment plans to each individual’s unique needs and best interests," Erin Zinn, MSN, APRN-CNP, ANP-BC, CMRD, director of Operations & Strategy at AMDAPP, told 

. "SPN-830 represents yet another groundbreaking option for managing PD. This is an exciting time in the movement disorders community, with new advancements offering hope for improved quality of life for those with Parkinson’s."

Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the First Half of 2025

At the end of the treatment period in TOLEO, patients on SPN-830 experienced a mean reduction in OFF time of –2.47 hours per day (SD, 3.70) compared with –0.58 hours per day (SD, 2.80) for those on placebo (

Supernus Pharmaceuticals' SPN-830 (Onapgo) has been approved by the FDA as the first subcutaneous apomorphine infusion device for advanced Parkinson's disease, reducing motor fluctuations. The approval was based on the TOLEDO study, which demonstrated significant reductions in OFF time and increases in ON time without dyskinesia. Despite initial regulatory challenges, the device will be available in 2025. SPN-830 offers a non-invasive alternative to manage motor symptoms, bypassing gastrointestinal issues associated with oral medications, and providing more predictable symptom control.

SPN-830 is a wearable subcutaneous infusion device designed to deliver continuous treatment throughout the waking day, ensuring more consistent control of OFF time.

Stewart Factor, DO

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