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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

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Neurology News Network. for the week ending April 19, 2025. [WATCH TIME: 3 minutes]

Valtoco Gains Expanded Indication, FDA Approves Digital Therapeutic for Migraine, Phase 1 Study of AMX0114 in ALS Begins

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The resident in the Department of Neurology at NYU Langone Health discussed the preliminary findings of a 9-month study on lecanemab recently presented at the 2025 AAN Annual Meeting. [WATCH TIME: 2 minutes]

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The associate professor of neurology at Mayo Clinic spoke about the findings of a population-based cohort study seeking to investigate the incidence of levodopa-induced dyskinesia in atypical parkinsonism.

Rodolfo Savica, MD, PhD: Dyskinesias in Atypical Parkinsonism

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.

Clinical

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

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.

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. 

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. 

Rodolfo Savica, MD, PhD

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