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Articles

Priya Kishnani, MD, division chief of Medical Genetics at Duke University, reflects on Pompe disease’s historical and scientific evolution, from early enzyme therapy to next-generation treatment strategies and newborn screening breakthroughs.

Newborn Screening, Enzyme Delivery, and the Future of Pompe Disease Treatment

New data from the HELIOS trial shows AMX0035 improves glycemic control and stabilizes symptoms in Wolfram syndrome, paving the way for future studies.

AMX0035 Continues to Stabilize and Improve Wolfram Syndrome at 48 Weeks, Phase 2 HELIOS Trial Shows

FDA approves study to test Capsida's CAP-002 gene therapy for STXBP1-DEE, offering hope for improved seizure control and developmental outcomes in affected patients.

FDA Clears IND to Study Gene Therapy CAP-002 in STXBP1 Developmental Epileptic Encephalopathy

The director of the Tuberous Sclerosis Program at Cleveland Clinic provided clinical commentary on a novel clustering analysis in TSC, revealing how phenotype-genotype insights can lead to more personalized treatment and surveillance.

NeuroVoices: Ajay Gupta, MD, on Phenotyping Tuberous Sclerosis Complex Into Disease Clusters

Marco Meglio, Assistant Managing Editor for 

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

Staff neurologist, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic

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Experts discussed how aging impacts multiple sclerosis management, treatment decisions, and overall patient health. [WATCH TIME: 5 minutes]

The Role of Aging in Multiple Sclerosis Care

This closing episode looks ahead to the future of SMA care, examining how updated best practices aim to accelerate access, optimize outcomes, and fuel ongoing progress.

Looking Ahead: How Consensus Guidelines Will Shape the Future of SMA Care

Experts discussed the current and future applications of AI and machine learning in multiple sclerosis research and clinical care, highlighting both opportunities and limitations. [WATCH TIME: 9 minutes]

AI and Machine Learning in MS: Promise and Practicality for Clinical Practice

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Panelists discuss how early recognition of dyskinesia symptoms, ongoing patient-clinician communication, and individualized treatment strategies are key to effectively managing Parkinson disease and improving patients’ quality of life.

Video: Dyskinesia and Patient Communication in Parkinson Disease

Dyskinesia and Patient Communication in Parkinson Disease

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.

Clinical

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

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 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.

Bisena Bulica, DO

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