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Research Priorities and Clinical Insights in Lennox-Gastaut Syndrome

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Drugs often involve multiple daily doses with complex dosing regimens, but interventions that have been applied generically to patients with chronic diseases can be applied to these cases as well.

Parkinson Medication Adherence is Suboptimal

The FDA has approved a new autoinjector formulation for lecanemab (Leqembi; Eisai), an antiamyloid therapy indicated for patients with early-stage Alzheimer disease (AD) and mild cognitive impairment (MCI) from AD. With the decision, the subcutaneous autoinjector (SC-AI) becomes the first-ever at-home, self-administered option for ongoing AD treatment, improving convenience and access for patients in the United States.

The new SC-AI, approved based on data from the pivotal phase 3 Clarity AD trial (NCT03887455), provides quicker administration for patients, lasting about 15 seconds total. In clinical trial settings, it demonstrated comparable exposure, improved tolerability, enhanced amyloid clearance, and better user-friendliness in patient, caregiver, and healthcare surveys. In addition, there is a belief that this new SC-AI will have significant societal cost savings, lowering treatment and administration expenses.

"This FDA action demonstrates continued progress in the field of Alzheimer's treatment," said Maria C. Carrillo, PhD, chief science officer and medical affairs lead at Alzheimer's Association, said in a statement.

 "We are seeing the evolution of amyloid targeting antibody treatments, including improvements in drug delivery and acknowledgment that this class of treatments continues to demonstrate clinical benefit beyond the 18-month clinical trial data."

"), the subcutaneous autoinjector contains 360 mg/1.8 mL (200 mg/mL), administered over approximately 15 seconds. Its specific indication is for maintenance dosing to treat AD in patients with MCI or the mild dementia stage of the disease. Following an 18-month course of lecanemab-irmb IV treatment at 10 mg/kg every 2 weeks, patients can either continue those infusions at 10 mg/kg every 4 weeks or begin on this new weekly 360-mg subcutaneous injection with the autoinjector.

"The expectation with subcutaneous delivery of Alzheimer's treatment is that patients and care partners find it easier, simpler and more convenient to use, and that it reduces the need to travel for hospital or infusion center visits, compared to intravenous infusion," Carrillo said in a statement.

 "The result is that more people will continue taking their medicine and experiencing treatment benefits."

, enrolled 1795 patients with confirmed amyloid pathology and followed them for 18 months of treatment with lecanemab. Although the drug was initially approved in its biweekly IV form, a subsequent analysis led by Reisa Sperling, MD, a neurologist at Brigham and Women’s Hospital, examined outcomes with the SC-AI formulation.

Results showed that after 6 months, patients receiving SC-AI achieved 14% greater amyloid plaque clearance compared with IV dosing. Pharmacokinetic analyses further confirmed that subcutaneous administration achieved drug exposure within accepted bioequivalence limits (80%–125%), supporting Eisai’s selection of a dose that delivers efficacy comparable to the IV formulation while potentially offering patients a more convenient treatment option.

Study investigators believe this new SC-AI formulation may improve the risk of amyloid-related imaging abnormalities (ARIA), a concern for amyloid-targeting treatments like lecanemab. In Clarity AD, the rates of ARIA-edema, ARIA-hemorrhage, and ARIA-H alone with intravenous lecanemab, the original formulation, were 12.6%, 17.3%, and 8.9%, respectively. In comparison, the corresponding rates for those on SC-AI were 16.7%, 22.2%, and 8.3%, though interpretation was limited by smaller sample size.

NeuroVoices: Howard Fillit, MD, on AAIC 2025 Highlights in Alzheimer Disease Prevention, Biomarkers, and Therapeutics

"This shift to subcutaneous maintenance dosing is a crucial step toward making Leqembi more accessible for patients, similar to how diabetes and GLP-1 medications are delivered, and represents the first step towards the day when patients can bypass infusions altogether," 

, cofounder and chief science officer of the Alzheimer's Drug Discovery Foundation (ADDF), said in a statement. “This milestone lessens the burden on patients and caregivers by reducing the logistical challenges of receiving Alzheimer’s treatment, while also bringing us closer to the day when patients can more easily receive a combination of drugs, potentially administered from home."

Typically, IV therapies impose more significant burdens on costs and payers, providers, patients, and caregivers. A U.S. cost comparison model study, published this summer in 

, showed that SC-AI may offer substantial societal savings by lowering treatment costs, minimizing time demands, and relieving quality of life (QOL) burdens for patients and caregivers.

In the analysis, costs were estimated from a societal perspective over 4 years, including a per-patient, head-to-head analysis and population-level assessment accounting for population size, current treatment rates, and SC uptake. All told, SC-AI was estimated to yielded per-patient savings of $72,891–$80,925 over 4 years compared with IV administration, corresponding to annual savings of $18,223–$20,231 at willingness-to-pay thresholds of $150,000 and $200,000 per quality-adjusted life-year gained, respectively.

The analysis estimated that 1,259,263 patients in the U.S. with early AD would be eligible for treatment with lecanemab, with 62,963 patients receiving treatment. In the IV scenario, all treated patients were assigned to the IV regimen; in the SC scenario, 31,093 (49.4%) were assigned to the SC administration, while 31,870 (50.6%) were assigned to the IV regimen.

The projected savings with SC-AI lecanemab were driven by reductions of $40,638 in treatment costs, $8151 in administration time, and $24,102–$32,136 in QOL related expenses per patient. When modeled at the population level over four years, this translated into $3.16–$3.71 billion in total societal savings, including $1.26 billion from treatment costs, $253 million from administration time, and $1.65–$2.20 billion from QOL-related improvements.

"We’ve long known that Alzheimer’s is not a one-target disease, and the future lies in precision combination therapies tailored to each patient based on their individual biomarker profiles," Fillit said in a statement.

 "Subcutaneous delivery is more than an upgrade – it’s a gateway to the next generation of Alzheimer’s care, accelerating our ability to bring effective, multi-modal treatment regimens to the millions of patients who need them."

REFERENCES
1. FDA Approves LEQEMBI® IQLIK™ (lecanemab-irmb) Subcutaneous Injection for Maintenance Dosing for the Treatment of Early Alzheimer's Disease. News release. August 29, 2025. Accessed August 29, 2025. https://www.prnewswire.com/news-releases/fda-approves-leqembi-iqlik-lecanemab-irmb-subcutaneous-injection-for-maintenance-dosing-for-the-treatment-of-early-alzheimers-disease-302542371.html
2. Alzheimer’s Association Welcomes FDA Action Approving Leqembi Weekly Subcutaneous Maintenance Dosing. News Release. Alzheimer’s Association. Published August 29, 2025. Accessed August 29, 2025. https://www.alz.org/news/2025/fda-action-approving-leqembi-subcutaneous-maintenance-dosing
3. Irizarry M, Li D, Dhadda S, Hersch S, Reyderman L, Kramer L. Preliminary update on lecanemab safety in Clarity AD open-label extension, including subcutaneous formulation. Presented at: CTAD conference; October 24-27, 2023; Presentation 4.
4. FDA Approval of Leqembi Subcutaneous Formulation Charts Path to Combination Therapies for Alzheimer’s Disease. News Release. Alzheimer's Drug Discovery Foundation. Published August 29, 2025. Accessed September 2, 2025. https://www.alzdiscovery.org/news-room/announcements/fda-approval-of-leqembi-subcutaneous-formulation-charts-path-to-combination-therapies-for-alzheimers-disease
5. Monfared AAT, Barrows S, Fox L, et al. Societal Costs and Efficiency of Subcutaneous versus Intravenous Lecanemab in Early Alzheimer’s Disease: A U.S. Cost Comparison Model. 

Published online July 4, 2025. doi:10.1007/s40120-025-00790-2

The FDA has approved a new subcutaneous autoinjector formulation for lecanemab, an anti-amyloid therapy for early-stage Alzheimer's disease and mild cognitive impairment. This at-home, self-administered option enhances convenience and access for patients. The autoinjector, based on the Clarity AD trial, offers quicker administration, improved tolerability, and better user-friendliness. It also shows potential for significant societal cost savings by reducing treatment and administration expenses. Pharmacokinetic analyses confirm bioequivalence with the IV formulation, supporting its efficacy and convenience for patients.

The autoinjector, branded as Leqembi Iqlik, contains a 360 mg/1.8 mL dose administered over 15 seconds. It is expected to enhance Alzheimer treatment accessibility and offer cost savings for patients.

Clinical

FDA Approves Lecanemab Autoinjector, Marking First At-Home Treatment for Alzheimer Disease

A new indirect treatment comparison study showed that lecanemab (Leqembi; Eisai) had significantly lower risks of amyloid-related imaging abnormality (ARIA) outcomes overall and in subgroups of interest compared with donanemab (Kisulna; Eli Lilly). These results, which also showed lower mortality related to ARIA or intracerebral hemorrhage (ICH) in lecanemab, reinforce the importance of understanding comparative real-world safety profiles to better inform treatment decisions for patients with Alzheimer disease (AD).

Researchers reported that treatment with lecanemab demonstrated significantly lower risk of any ARIA, ARIA with edema/effusions (ARIA-E) or ARIA with microhemorrhage or superficial siderosis (ARIA-H), compared with donanemab with a risk difference-in-difference of -10.1% (95% CI, -15.3% to -5.0%). Presented at the 

2025 Alzheimer’s Association International Conference

, held July 27-30, in Toronto, Canada, authors noted that the risk difference-in-difference for ARIA-E (-10.7%; 95% CI, -14.5% to -6.9%) and ARIA-H (-10.1%; 95% CI, -15.0% to -5.2%) were also significantly lower with lecanemab treatment.

The study, presented by Anna Burke, MD, the director of Alzheimer’s and Memory Disorders Division at Barrow Neurological Institute Barrow, comprised an indirect treatment comparison of ARIA outcomes and mortality rates to understand safety differences. For the analysis, researchers used ARIA rates in the FDA-approved labels, FDA review documents, or peer-reviewed publications. The study outcomes included ARIA-E, ARIA-H, ICH at least 1cm, APOE4 status, all-cause death, and additional ARIA outcomes in the overall clinical trial population over 18 months. Investigators utilized Anchored Bucher indirect treatment comparisons to compare rates of ARIA outcomes between lecanemab and donanemab, with placebo as the common comparator.

In the subgroup of APOE4 carriers, risk difference-in-differences were -11.1% for ARIA-E (95% CI, -16.0%, -6.2%), and -14.4% for ARIA-H (95% CI, -20.5% to -8.2%), favoring lecanemab. Notably, lecanemab had also a significantly lower risk of microhemorrhage (-7.5%; 95% CI, -12.1% to -2.9%), and superficial siderosis (-8.8%; 95% CI, -12.0% to -5.6%). Additionally, the incidence of ICH (0.3%; 95% CI, -0.5%, 1.1%) and mortality (-1.0%; 95% CI, -2.4%, 0.5%) were not significantly different between the 2 treatments. Authors noted that lecanemab displayed a significantly lower risk of death with concurrent ARIA or ICH (-0.5%; 95% CI, -0.9%, 0.0%) compared with donanemab.

Combination Vascular Risk Therapies Tied to Slower Cognitive Decline, Less Dementia Pathology

Following the initial abstract submission to AAIC 2025, Eisai incorporated data from TRAILBLAZER-ALZ 6 (NCT05738486) after the release of the trial’s 18-month findings and the recent update to donanemab’s titration schedule in its label. A network meta-analysis that factored in the revised donanemab dosing from TRAILBLAZER-ALZ 6 supported the results of the Bucher indirect comparison, showing a lower incidence of ARIA in patients treated with lecanemab compared with donanemab.

Lecanemab and donanemab, 2 antiamyloid antibodies, received FDA approval for the treatment of early AD and entered clinical practice in July 2023 and July 2024, respectively. In another study on lecanemab and donanemab presented at AAIC 2025, results revealed that early adopters of the approved antiamyloid therapies were, on average, more socially advantaged compared with the general dementia patient population, despite exhibiting high rates of cardiovascular risk and cardiovascular complication.

Using data from Epic Cosmos, the retrospective study analyzed 3242 patients who received lecanemab and 160 who received donanemab infusions between July 1, 2023 and November 29, 2024. In the comparator group, researchers included 1,907,655 patients who took oral dementia medications including donepezil, rivastigmine, galantamine, or memantine. Findings from the study showed that patients who received antiamyloid therapy were younger, more likely to be White and non-Hispanic, a man, commercially insured or on Medicare, and less likely to be on Medicaid. Authors also noted that these patients were also more likely to reside in socioeconomically advantaged ZIP codes.

Presented by Jay B. Lusk, MD, MBA, a preventive medicine resident at the University of North Carolina at Chapel Hill, the study reported that the average 10-year atherosclerotic cardiovascular disease (ASCVD) risk score for patients who received antiamyloid therapy was 19.9. Additionally, authors noted that 36.9% of patients had an ASCVD risk score greater than 10 in 12 months, and 84.6% had a systolic blood pressure above 135 mmHg in the year prior to therapy. A total of 1,345 patients (37.5%) had a history of major adverse cardiac and cerebrovascular events (MACCE) before therapy. In 12 months of initiating therapy, 95 patients (2.7%; 95% CI, 2.1–3.2%) had a new MACCE diagnosis, and 58 patients (1.7%; 95% CI, 1.3–2.1%) received a new diagnosis of a cerebrovascular event.

Click here for more coverage of AAIC 2025.

REFERENCES
1. Burke A et al. Indirect treatment comparison of ARIA outcomes for lecanemab compared to donanemab based on reported results. Presented at: 2025 Alzheimer’s Association International Conference; July 27-31; Toronto, Canada. Abstract 103048.
2. Lusk JB et al. Characteristics and safety outcomes of patients treated with lecanemab or donanemab in routine clinical practice: a nationwide study. Presented at: 2025 Alzheimer’s Association International Conference; July 27-31; Toronto, Canada. Abstract 98805.

Lecanemab demonstrated significantly lower risks of amyloid-related imaging abnormalities (ARIA) and associated mortality compared to donanemab in a recent study. This indirect treatment comparison utilized data from FDA-approved labels and peer-reviewed publications, highlighting lecanemab's favorable safety profile, particularly in APOE4 carriers. Despite similar intracerebral hemorrhage and mortality rates, lecanemab showed reduced risks of microhemorrhage and superficial siderosis. Additionally, early adopters of anti-amyloid therapies were more socially advantaged, with higher cardiovascular risk profiles, compared to the general dementia patient population.

Although the FDA-approved therapies lecanemab and donanemab both slow progression in early Alzheimer disease, a new study presented at AAIC 2025 highlighted differences in their safety profiles.

Indirect Comparison Study Hints at Lower ARIA and ICH-Related Mortality Risk in Lecanemab Over Donanemab

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Multiple Sclerosis and Related Disorders, 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 = .015), caregiver-reported global change (

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The 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.

Donald G. Grosset, BSc, MBChB, MD

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