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The president and chief executive officer of the Muscular Dystrophy Association provided insights on the agenda for the 2025 MDA conference, highlighting its significance as a premier event for advancing knowledge in neuromuscular disease treatment. [WATCH TIME: 4 minutes]

Previewing 2025 MDA Clinical & Scientific Conference Agenda: Donald S. Wood, PhD

Articles

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A Mother’s Fight Against Infantile Spasms: The Power of Instinct and Community

The epilepsy specialist and Cleveland Clinic’s Chief Research and Information Officer detailed the steps and teamwork required to implement a machine learning that predicts seizure outcomes in epilepsy surgery. [WATCH TIME: 4 minutes]

Interdisciplinary Team Needed to Apply Machine Learning in Epilepsy Surgery: Lara Jehi, MD, MHCDS

The professor of neurology at the University of Alabama at Birmingham Epilepsy Center commented on various topics related to infantile spasms amid Infantile Spasms Awareness Week.

NeuroVoices: Martina Bebin, MD, MPA, on Critical Aspects of Infantile Spasms Awareness

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Assistant professor of neurology at the Icahn School of Medicine at Mount Sinai.

The assistant professor of neurology at the Icahn School of Medicine at Mount Sinai provided an overview of a session on exercise and migraine presented at the 2024 Scottsdale Headache Symposium. [WATCH TIME: 5 minutes]

Overviewing Personalized Exercise Strategies for Migraine Management From AHS Scottsdale 2024: Anna Pace, MD

According to a new announcement, the FDA has approved AbbVie’s foscarbidopa/foslevodopa, marketed as Vyalev, as the first and only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of motor fluctuations in adults with advanced Parkinson disease (PD).

The company noted that timing for a patient's access to the therapy is dependent on their individual insurance plan, with coverage for Medicare patients expected in the second half of 2025.

“Overall, there is great excitement around the approval of Vyalev. While there are numerous options for the symptomatic treatment of PD, the options become limited as the disease progresses, and patients experience motor fluctuations despite their current treatment," Pavnit Kukreja, PharmD, senior director, neuroscience, US Medical Affairs, AbbVie, told 

 "Previously, only more invasive options, such as surgery, existed. Vyalev offers the ability to continuously deliver the gold standard, levodopa, without surgery, over the morning, day, and night."

The approval was supported by data from the phase 3 M15-736 study (NCT04380142) that assessed the efficacy of continuous subcutaneous infusion of foscarbidopa/foslevodopa, also known as ABBV-951, among adult patients with advanced PD compared with oral immediate-release carbidopa/levodopa (CD/LD IR), along with a 52-week, open-label M15-741 study (NCT03781167) which investigated the long-term safety and efficacy of the treatment. Results from the M15-736 study revealed that patients who received foscarbidopa/foslevodopa reported superior improvement in motor fluctuations, with increased ON time without troublesome dyskinesia and decreased OFF time, compared with oral CD/LD IR.

"The phase 3 study demonstrated superior efficacy over oral IR CD/LD with regards to improvement in On time without troublesome dyskinesia, and the adverse events were mostly mild to moderate and nonserious. We are committed to improving the lives of people impacted by PD and transforming the standard of care with this first-of-its-kind therapeutic option," Kukreja added. 

AbbVie submitted its new drug application (NDA) for ABBV-951

, with M15-736 serving as the basis for the submission.

 The study included 141 adult participants who were randomized 1:1 to either ABBV-951 solution (n = 74) as a continuous infusion under the skin plus oral placebo capsules for CD/LD or ABBV-951 as a subcutaneous infusion plus oral capsules containing CD/LD encapsulated tablets (n = 67).

"For too long, the Parkinson's community has had limited treatment options for advanced disease. Due to the progressive nature of the disease, oral medications are eventually no longer as effective at motor symptom control and surgical treatment may be required," 

, professor of neurology and director of the Parkinson's and Movement Disorder Center at the University of South Florida, said in a statement.

 "This new, non-surgical regimen provides continuous delivery of levodopa morning, day and night."

Led by Hauser, the double-blind, double-dummy, active-controlled study included a screening period (6-60 days), an oral CD/LD stabilization period (2-3 weeks), a double-blind treatment period (12 weeks) for a total of 13 scheduled visits. Eligible participants were at least 30 years old with a diagnosis of idiopathic and levodopa-responsive PD and had inadequately controlled motor fluctuations with an average OFF time of at least 2.5 h/day over 3 consecutive days.

ABBV-951 also showed a good safety profile in the phase 3 study, with most of the reported adverse events (AEs) either mild or moderate in a nature.

 Serious AEs occurred in 8% ABBV-951 group compared with 6% in the CD/LD group. Notably, there as 1 death recorded in the study, believed to be from a treatment-emergent AE while in the CD/LD group. At week 12, ABBV-951-treated patients showed a decrease of 2.75 hours in OFF time, with changes observed as early as the first week. In comparison, those in the oral CD/LD group demonstrated decreases of 0.96 hours during the same stretch (

 for its investigational 24-hour continuous foscarbidopa/foslevodopa pump. In the CRL, the agency requested additional information on the pump as part of its review, but did not request AbbVie to conduct additional efficacy and safety trials related to the drug.

 of foslevodopa/foscarbidopa (Produodopa), the first and only 24-hour infusion of levodopa-based therapy for patients with advanced PD more than a year after it received approval from the European Commission.

 Prior to the launch, the therapy had received authorization through the Decentralized Procedure in the third quarter of 2022, followed by a CE mark in November of 2023. 

The launch was supported by 3 studies: the phase 3 M15-741 study, the double-blind, active-controlled M15-736 study, and a phase 1 pharmacokinetic comparability study. Published in the 

 treated patients in M15-741 demonstrated a mean improvement of 3.8 (SD, 3.3) hours of ON time without dyskinesia and –3.5 (SD, 3.1) hours of normalized OFF time while on the therapy over a 52-week period. Additional, at that time, the percentage of patients experiencing morning akinesia dropped from 77.7% to 27.8%.

 (CRL) to the company's NDA for ABBV-951.

 In the CRL, the agency cited observations identified during inspection of a third-party manufacturer listed in the NDA. The inspection at the facility did not involve ABBV-951 or any of the company's medicine. The CRL did not identify any issues in terms of safety, efficacy, or labeling of ABBV-951, including the device. Furthermore, the letter did not request that the company perform additional efficacy and safety studies related to the drug or device-related testing.

"People living with advanced Parkinson's disease experience daily challenges as a result of uncertainty in managing motor fluctuations, especially as their disease progresses," Roopal Thakkar, MD, executive vice president, research & development, and chief scientific officer, AbbVie, said in a statement.

 "We are proud to bring this innovation to patients who may benefit from motor symptom control through continuous 24-hour administration of Vyalev."

REFERENCES
1. U.S. FDA Approves VYALEV™ (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson's Disease. News Release. AbbVie. Published October 17, 2024. Accessed October 17, 2024. https://news.abbvie.com/2024-10-17-U-S-FDA-Approves-VYALEV-TM-foscarbidopa-and-foslevodopa-for-Adults-Living-with-Advanced-Parkinsons-Disease
2. AbbVie submits new drug application to US FDA for investigational ABBV-951 (foscarbidopa/foslevodopa) for the treatment of advanced Parkinson disease. News release. AbbVie. May 20, 2022. Accessed October 17, 2024. https://www.prnewswire.com/news-releases/abbvie-submits-new-drug-application-to-us-fda-for-investigational-abbv-951-foscarbidopafoslevodopa-for-the-treatment-of-advanced-parkinsons-disease-301551779.html?tc=eml_cleartime
3. Soileau MJ, Aldred J, Budur K, et al. Safety and efficacy of continous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomized, double-blind, active-controlled, phase 3 trial. 

 2022;21(12):1099-1109. doi:10.1016/S1474-4422(22)00400-8.
4. AbbVie provides regulatory update on ABBV-951 (foscarbidopa/foslevodopa) new drug application. News release. AbbVie. March 22, 2023. Accessed October 17, 2024. https://news.abbvie.com/article_display.cfm?article_id=12567
5. AbbVie launches PRODUODOPA (foslevodopa/foscarbidopa) for people living with advanced Parkinson disease in the European Union. News release. January 9, 2024. Accessed October 17, 2024. https://www.prnewswire.com/news-releases/abbvie-launches-produodopa-foslevodopafoscarbidopa-for-people-living-with-advanced-parkinsons-disease-in-the-european-union-302028989.html
6. Aldred J, Freire-Alvarez E, Amelin AV, et al. Continuous subcutaneous foslevodopa/foscarbidopa in Parkinson’s disease: safety and efficacy results from a 12-month, single-arm, open-label, phase 3 study. 

 2023;12:1937-1958
7. AbbVie Provides U.S. Regulatory Update on ABBV-951 (Foscarbidopa/Foslevodopa). News Release. AbbVie. Published June 25, 2024. Accessed October 17, 2024. https://news.abbvie.com/2024-06-25-AbbVie-Provides-U-S-Regulatory-Update-on-ABBV-951-Foscarbidopa-Foslevodopa

The FDA has approved Vyalev, a subcutaneous 24-hour infusion therapy for advanced Parkinson's disease, offering a new non-surgical treatment option. Supported by phase 3 study data, Vyalev demonstrated superior improvement in motor fluctuations compared to oral carbidopa/levodopa. The therapy provides continuous levodopa delivery, addressing the limitations of oral medications in advanced stages. Most adverse reactions were mild or moderate, with infusion site events, hallucinations, and dyskinesia being the most common. Medicare coverage is anticipated in the latter half of 2025, subject to individual insurance plans.

In clinical trials, patients with Parkinson disease who were treated with foscarbidopa/foslevodopa experienced superior improvement in ON time without dyskinesia compared with oral immediate-release carbidopa/levodopa.

Clinical

FDA Approves AbbVie’s 24-Hour Foscarbidopa/Foslevodopa Pump for Advanced Parkinson Disease Treatment

A new multi-ethnic cohort study using novel ancestry-informed regression identified novel population-specific risk alleles associated with multiple sclerosis (MS) and successfully fine-mapped previously reported MS loci. These results suggest that novel ancestry-specific genetic variants impact the risk of MS, underscoring the advantage of a trans-ethnic approach for assisting with treatment decisions and prevention of MS in diverse ancestral populations.

All told, data of genome-wide genotypes were available for 4313 Hispanics patients (MS cases, n = 2201; controls, n = 2112) and 3085 African American patients (MS cases, n = 1584; controls, n = 1501). Investigators identified a novel genome-wide significant locus on chromosome 13q14.2 among alleles residing on an African haplotype. For alleles residing on a Native American haplotype, researchers identified a genome-wide significant signal within a known MS locus on chromosome 1p35.2.

"We believe this research, with novel approaches and analytical strategies like these, will help us to further elucidate the underlying molecular pathways involved in MS, which we hope in turn will pave the way for new targeted treatments for MS in all patient populations," lead author Jacob McCauley, PhD, professor at the University of Miami Miller School of Medicine, told 

2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress

, September 18-20, in Copenhagen, Denmark, researcher computed local ancestry with RFMixV2 and conducted genome-wide association with Tractor to acquire ancestry-specific effect-size estimates for alleles from an African, European, and Native American origin after TopMed imputation. Authors then performed a fixed-effects meta-analysis for the ancestry-specific tracts with summary statistics from a European cohort (MS cases, n = ~15K; controls, n = ~27K). Additionally, investigators utilized SuSieX for trans-ancestry fine-mapped in regions that showcased genome-wide significance.

Early Monoclonal Antibody Therapy Reduces Long-Term Disability in Pediatric Multiple Sclerosis

Researchers identified 2, when fine-mapping, of 95% credible sets that represented 2 distinct causal signals at 1p35.2. The first one identified was specific to Native American alleles, the top variant being missense mutation rs145088108, and the second one identified was specific to European alleles, the top variant being the previously identified rs10914539. Notably, investigators achieved 7 additional MS loci with fine-mapping of high resolution. 

These preliminary findings are some of the first to highlight the utility of a trans-ethnic approach to genetic variant discovery for MS risk and genetic fine-mapping efforts that benefited from the inclusion of diverse populations with shorter linkage disequilibrium blocks," McCauley said. "We anticipated that this work would provide novel insights, by leveraging the genetically complex ancestral background of these populations and complement the genetic studies that thus far have only been possible within the larger European ancestry analyses."

The findings also highlight the importance of exploring gene-environment interactions in further research in the future. Although the identified variants by investigators were largely population-specific, authors also underscored the need to assess how environmental and lifestyle factors might influence these and other genetic variants to impact MS risk which may be especially relevant in diverse populations with different socioeconomic backgrounds and diets. Thus, McCauley and colleagues of the Alliance for Research in Hispanic MS Consortium plan to perform functional studies to identify the causal pathways linked with the fine-mapped variants, and to lengthen their cohorts to discover additional ancestry-specific variants.

“The variants identified within this region could pave the way for new targeted treatments for MS, some of which may be population-specific. We must continue to refine our biological understanding of the disease and findings like these may be critical to help us understand the phenotypic diversity we observe across various global populations.,” McCauley added.

Click here for more coverage of ECTRIMS 2024.

REFERENCES
1. McCauley JL., et al. Novel ancestry-specific and putative causal genetic variants for multiple sclerosis identified by an ancestry-informed regression and trans-ethnic fine-mapping analysis. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark.
2. Ancestry-specific genetic variants linked to multiple sclerosis, new study shows. News Release. ECTRIMS. Published September 18, 2024. Accessed September 18, 2024.

A large-scale study presented at ECTRIMS 2024, conducted by the Alliance for Research in Hispanic MS Consortium, identified ancestry-specific genetic factors that influence the risk of developing multiple sclerosis.

Multi-Ethnic Study Identifies Ancestry-Specific Genetic Variants that Influence Risk of Multiple Sclerosis 

According to a new announcement, the FDA has issued a letter of support for using the α-synuclein seed amplification assay (αSyn-SAA) biomarker in clinical trials for Parkinson disease (PD) and related diseases. This decision comes following a multi-stakeholder collaboration between The Michael J. Fox Foundation for Parkinson's Research (MJFF) and the Critical Path Institute (C-Path) to advance PD therapeutics using this recently discovered biomarker.

In the letter, the agency highlighted that its support comes from evidence gathered in the Parkinson's Progression Markers Initiative (PPMI), a longitudinal observational study sponsored by MJFF. The FDA noted that its decision to encourage use of αSyn-SAA also relied on other global studies across industry and academia, which represented the large amount of data as well as the applied collaboration used to validate the tool.

“The biomarker, now with the support of the FDA, will lead to faster, more effective clinical trials for Parkinson’s disease. Researchers can design trials that target specific aspects of disease biology with confidence that participants in the study have similar, important biological features. We anticipate this will speed along potential therapies already in early stages of the pipeline, while also attracting new or sustained interest from drugmakers. Our laser-focused goal remains the same — placing better therapies and a cure in the hands of people and families with Parkinson's," Todd Sherer, PhD, MJFF's chief mission officer, told 

 "Working collaboratively together with partners — people and families living with PD, neuroscience and clinical leaders, industry experts, federal research funders (i.e., the National Institutes of Health), disease-focused nonprofit organizations and regulatory authorities — we are able to leverage the incredible amount of knowledge and expertise in the space. We believe bringing the field together is the fastest way to improve its outcomes.”

 showed that use of an αSyn-SAA technique had high diagnostic accuracy of PD, distinguished molecular subtypes, and detected the disease before primary symptoms.

 In total, data on αSyn-SAA was collected from 1123 participants from the PPMI cohort, including patients with a diagnosis of PD and at-risk patients with gene variants (GBA and LRRK2) linked to the disease. In the large-scale analysis, αSyn-SAA was shown to differentiate PD from controls with a sensitivity of 88% and specificity of 96%.

The research was co-led by authors Andrew Siderowf, MD, PPMI investigator and director, PD and Movement Disorders Center at the University of Pennsylvania, and Luis Concha, PhD, director, research and development at Amprion. In the study, samples of cerebrospinal fluid surrounding the brain and spinal cord were analyzed from each participant using αSyn-SAA.

GCase-Targeting Parkinson Drug GT-02287 Shows Target Engagement, Encouraging Safety in Early-Stage Study

In the study, approximately 93% of patients with no known genetic cause had a positive αSyn-SAA result. Results varied for patients with genetic forms of PD, with 96% having the GBA variant and a positive αSyn-SAA result, compared with 68% of patients with LRRK2. Most prodromal patients had positive αSyn-SAA results, suggesting they had α-synuclein aggregates despite no PD diagnosis. Fifty-five percent of women with PD with the LRRK2 variant had a positive αSyn-SAA result compared with 72% of men with PD who had the same the variant. Patients with the LRRK2 variant and a negative αSyn-SAA result tended to be older compared with than those with positive αSyn-SAA results.

Loss of sense of smell was the most strongly predicted clinical feature of a positive αSyn-SAA result. Among all participants with PD who had loss of smell, 97% had positive αSyn-SAA compared with 63% of patients whose sense of smell was unchanged. Also, in patients with REM sleep behavior disorder, positive αSyn-SAA results were present in 85% (28 out of 33 patients) of participants. There were no other clinical features associated with a positive αSyn-SAA result.

Patients who carried the LRRK2 or GBA variants but had no PD diagnosis or prodromal symptoms, nonmanifesting carriers (NMCs), had positive αSyn-SAA results (LRRK2, 9% [14 out of 159 patients]; GBA, 7% [11 out of 151 patients]). Most prodromal participants and NMCs with positive αSyn-SAA had brain scans that did not show a decline in the expected number of dopamine-producing nerve cells, suggesting buildup of α-synuclein aggregates could be an early mark of disease onset.

Since the tool can detect early biological changes related to PD and related diseases before symptoms appear, it could potentially enhance trials assessing therapies that are aimed at delaying or preventing disease onset. Additionally, it supports research into personalized therapies for patients at all stages of these conditions. The biomarker can further accelerate and streamline these trials by providing objective end points, ensuring participants have the relevant pathology, and tracking therapy-induced changes. This efficiency can reduce the risk for industry investment in developing potential blockbuster therapies, including preventive treatments.

“The new biomarker findings that have just emerged in the last two years are truly transforming how we're going to be doing drug development for the future of Parkinson's. We all know that this is a very complex neurodegenerative disease that has so much rapid progression and a huge unmet need for disease-modifying therapies," Diane Stephenson, PhD, executive director of Critical Path for Parkinson's Consortium at C-Path, told 

. "We now have a molecular tool that looks at a signature of what's going on in living individuals that tells you what is the underlying biology of the disease. Very similar to cancer, where we know the molecular features of the disease. We can now do this in Parkinson's where just two years ago, it was only possible by having autopsy postmortem tissues."

"With these new tools, we're able to identify a light that shows us who are the right people to treat with promising new disease-modifying therapies, not only when they're diagnosed, but years before the onset of symptoms," Stephenson said. "This landmark milestone that we achieved through this letter of support was so fast because of the data that was shared thanks to the generous support of The Michael J. Fox Foundation and thousands of patients from around the world who generated their samples. We pulled all that data together in a comprehensive submission to the FDA, and within three months they issued a letter of support. The data was reliable, robust, and showed consistency across multiple studies around the world.”

In January 2024, a multistakeholder team made up of academic researchers and clinicians, industry, nonprofits, regulators, and patients published the first biological staging system for Parkinson known as the neuronal alpha-synuclein disease integrated staging system (NSD-ISS).

 the system relies on the biomarker detected by SAA to identify the evolution of NSD into progressive stages.

 The agency’s letter of support recognizes the potential of NSD-ISS with data produced by αSyn-SAA to speed up the success of therapeutic development in PD.

, the proposed system is currently intended for research use only, with the goal to enhance trial design and improve drug development. Simuni, a professor of neurology and head of the division of movement disorder at the Northwestern University Feinberg School of Medicine, sat down with 

 to discuss the long-term impacts this staging system has on the PD research community. She provided clarity on the purpose behind the paper, the role of α-synuclein in PD, and the next steps in expanding drug development.

Tanya Simuni on PD Staging System

REFERENCES
1. FDA Issues 'Letter of Support' Encouraging Use of Synuclein-based Biomarker, αSyn-SAA, in Clinical Trials in Parkinson's and Related Diseases. News Release. The Michael J. Fox Foundation for Parkinson's Research. Published September 9, 2024. Accessed September 9, 2024. https://www.michaeljfox.org/publication/fda-issues-letter-support-encouraging-use-synuclein-based-biomarker-asyn-saa-clinical
2. Michael J. Fox Foundation Announces Significant Breakthrough in Search for Parkinson’s Biomarker. News Release. The Michael J. Fox Foundation for Parkinson’s Research. Published April 12, 2023. Accessed September 9, 2024. https://www.michaeljfox.org/research-news
3. Simuni T, Chahine LM, Poston K, et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23(2):178-190. doi:10.1016/S1474-4422(23)00405-2
4. New Biological Definition and Proposed Staging System for PD: What it means for Researchers, Industry Professionals and Clinicians. News Release. The Michael J. Fox Foundation for Parkinson’s Research. Published January 29, 2024. Accessed September 9, 2024. https://www.michaeljfox.org/news/new-biological-definition-and-proposed-staging-system-pd-what-it-means-researchers-industry 

The agency’s letter of support for using the α-synuclein seed amplification assay biomarker was supported by data observed in the Parkinson's Progression Markers Initiative cohort study. 

FDA Supports Alpha-Synuclein Seed Amplification Assay Biomarker for Clinical Trials in Parkinson Disease

In a phase 1, 2-part, open-label, fixed-sequence, single and multiple oral dose study newly published in 

Clinical Pharmacology in Drug Development

, results showed that the pharmacokinetics of vatiquinone (PTC Therapeutics) a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich ataxia (FA), can be adjusted by coadministration of cytochrome P450 isoform 3A4 (CYP3A4) inhibitor itraconazole or CYP3A4 inducer rifampin.

Coadministration of vatiquinone 400 mg with itraconazole 200 mg increased maximum observed concentration (C

) of vatiquinone and systemic exposure (AUC

) by approximately 3.5- and 2.9-fold, respectively. The coadministration of vatiquinone 400 mg with rifampin 600 mg decreased vatiquinone C

 by approximately 0.64- and 0.54-fold, respectively. Notably, the terminal half-life of vatiquinone was not influenced by neither itraconazole or rifampin.

“Vatiquinone has demonstrated a very well-established safety profile in children, including very young children with severe illnesses, as well as in adults in clinical studies," Matthew B. Klein, MD, MS, FACS, chief executive officer at PTC Therapeutics, told 

. "The pharmacology results shared in the publication should not impact the exposure, safety, or use of vatiquinone but can provide guidance for physicians when considering other medications that patients may be receiving."

In this study, investigators assessed the effect of itraconazole and rifampin on the single-dose PKs of vatiquinone. Researchers enrolled participants between 18 and 45 years of age, with a body mass index of 18.5-30 kg/m2. On the first day of each part of the study, patients only received a single dose of vatiquinone 400 mg, which was followed by a washout of 7 days. In Part 1, patients received itraconazole on days 8 through 11, and they received vatiquinone coadministered with itraconazole on day 12, followed by a last dose of itraconazole on day 13. In Part 2, patients received rifampin on days 8 through 21, and then received vatiquinone coadministered with rifampin on day 22, followed by a last dose of rifampin on day 23.

“The clinical study results confirm that the CYP3A4 enzyme plays an important role in vatiquinone metabolism and the effect on vatiquinone PK when coadministered with a potent CYP3A4 inhibitor or inducer. Additional work was performed to understand the impact of moderate CYP3A4 inhibitors and inducers on vatiquinone exposures via physiologically based pharmacokinetic modeling and will be presented elsewhere,” coauthor Lee Golden, MD, chief medical officer at PTC Therapeutics, and colleagues wrote.

Specific Biomarkers Detected for Staging and Treatment in Spinocerebellar Ataxia Type 3

Although 3 patients (13.04%) reported 4 treatment-emergent adverse events (TEAEs), investigators observed no treatment-emergent serious adverse events (TESAEs) during the study. Only 2 participants experienced temporary clinically significant elevations in hepatic enzymes. As for the reported TEAEs, they were in the Gastrointestinal System Organ Class (SOC) and, for 1 patient, also in the Nervous System SOC. 

Authors noted that all TEAEs were mild and resolved by the completion of the study or shortly thereafter. The reported TEAES were considered unrelated to vatiquinone although the elevated alanine transaminase and aspartate transaminase enzymes might have possibly been related to itraconazole, according to the principal investigator of the study.

“The results of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant,” Golden et al noted.

 According to a recent company update, PTC Therapeutics has plans to submit a new drug application (NDA) for vatiquinone for the treatment of FA in late 2024.

2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference

, held March 3-6, in Orlando, Florida, data from the placebo-controlled phase of the global phase 3 MOVE-FA trial (NCT04577352) assessing vatiquinone in patients with FA showed the treatment demonstrated clinically relevant benefits across multiple end points at 72 weeks.

In the analysis, investigators observed a –1.61 (

=.144) change in modified FA Rating Scale (mFARS)compared with the placebo at 72 weeks in the modified intent-to-treat (mITT) population, which consisted of 123 participants with FA. The researchers reported a sustained vatiquinone treatment benefit observed across all end points including the primary, secondary, and exploratory end points.

"The recently completed MOVE-FA placebo-controlled study results demonstrate a statistically significant and meaningful effect on the upright stability subscale of the disease rating scale – the most relevant and sensitive component of the disease rating scale for pediatric and young adult ambulatory patients," Klein said. "The results in the study support that vatiquinone could have an important effect in delaying loss of ambulation as well as other important and burdensome aspects of the disease."

Conducted by lead author David Lynch, MD, PhD, a neurologist and director of the Friedreich's Ataxia Program at Children's Hospital of Philadelphia, and colleagues, the trial included patients 143 aged at least 7 years, with an mFARS score of between 20 and 70 and the ability to ambulate at least 10 feet in 1 minute with or without assistance. The primary end point of the current analysis was placebo-corrected change from baseline in mFARS at 72 weeks. The intent-to-treat (ITT) population had a mean age of 18.7 years and the primary analysis population—the mITT population—included participants between 7 years and 21 years of age (mean, 14.6).

Investigators observed a nominally significant benefit recorded in the Upright Stability subscale (USS), a relevant metric of disease progression in younger ambulatory patients with FA, of mFARS, with a change of –1.26 (

 = .021). In addition, researchers observed nominally significant benefit in the Modified Fatigue Impact Scale, with a change of –5.05 (

 = .025). Overall, the authors noted that the treatment was safe and well tolerated among the participants, with no differences in treatment-related adverse events observed between treatment and placebo groups.

"The effects observed in this trial along with the established safety profile will form the basis of the planned vatiquinone NDA submission later this year," Klein added.

REFERENCES
1. Lee L, Thoolen M, Ma J, Kaushik D, Golden L, Kong R. Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone. Clin Pharmacol Drug Dev. Published online August 12, 2024. doi:10.1002/cpdd.1461
2. PTC Therapeutics Provides Corporate Update and Reports Second Quarter 2024 Financial Results. News Release. PTC Therapeutics. August 8, 2024. Accessed August 22, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-provides-corporate-update-and-reports-second-2
3. Lynch D, Duquette A, França MC, et al. Safety and Efficacy of Vatiquinone Treatment in Friedreich Ataxia Patients from MOVE-FA: a Phase 3, Double-blind, Placebo-controlled Trial. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster S79.

PTC Therapeutics has plans to submit a new drug application for vatiquinone, a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich ataxia, in late 2024.

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, a cell-based assay (CBA) developed by researchers allowed the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in routine laboratories. This CBA, using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs), can potentially open new viewpoints in establishing a diagnosis of complex diseases such as neuromyelitis optica spectrum disorder (NMOSD).

Using this 96-well CBA, investigators identified antibodies that recognized hiPSC-derived neural cells in 19 out of 99 patients. Antibodies were attached particularly to astrocytes in 9 cases, to neurons in 8 cases, and to both cell types in 2 cases, which were confirmed by microscopy single-cell analyses. Investigators observed that neural-specific antibody binding was more frequent in patients with inflammatory neurological diseases (IND, n = 15) compared with those who had non-IND (NIND, n = 4) (Fisher's exact test,

= .0005), further highlighting the significance of their comprehensive CBA.

"Our CBA using human iPSC-derived neurons and astrocytes allows to detect antibodies that would not be identified by traditional approaches. Indeed, these human central nervous system (CNS) cells naturally express antigens with the appropriate post-translational changes, which is not always the case with other methods reported to date. So, in the future, we envision that this CNS CBA has its place in the cases where an autoimmune neurological condition is strongly suspected, yet traditional detection assays give negative results,” senior author Renaud Du Pasquier, MD, told 

For instance, up to 46% of auto-immune encephalitis (AIE) and up to 16% of NMOSD are seronegative with current traditional assays. So, our CBA, by ascertaining the diagnosis of AIE or NMOSD in some patients, may decrease the area of uncertainty and thus help the physician in therapeutical management."

All told, human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 42 patients with IND and 57 patients with non-IND. Researchers noted that the IND group had 11 patients with established neural antibodies prior, 6 with seronegative NMOSD, 12 with suspension of autoimmune encephalitis/paraneoplastic syndrome (PNS), and 13 with other IND. Immunoglobulin G (IgG) binding to fixed CNS cells was identified utilizing fluorescently-labeled antibodies and evaluated by automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Authors used peripheral blood mononuclear cells (PBMC) as CNS-irrelevant control target cells. Researchers defined reactivity profile as positive through a Robust regression as well as an outlier removal test with a false discovery rate at 10% following each patient readout.

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Investigators also observed that 2 out of the 4 patients with aquaporin-4 antibody positive (AQP4+) NMOSD and 4 of 7 definite AIE/PNS with intracellular-reactive antibodies, as detected in diagnostic laboratories, tested also positive with the CBA. Notably, authors demonstrated antibody-reactivity in 2 out of the 6 patients who were seronegative NMOSD, 6 of 12 probable AIE/PNS, and 1 of 13 other IND. Flow cytometry utilizing hiPSC-derived CNS cells or PBMC-identified antibody binding among 13 patients versus no patients, respectively, which established the specificity of the recognized antibodies in the neural tissue.

"One of the most difficult aspects was establishing reliable protocols to generate large numbers of hiPSC-derived astrocytes and neurons. These protocols are needed to ensure consistency and high cell quality across experiments and different teams," Du Pasquier, who serves as a full professor and the head of the neurology department at CHUV/University of Lausanne, said. "After rigorous optimization, we successfully created protocols that consistently produce high-quality CNS cells. These protocols are now used by collaborators and other research teams worldwide, ensuring standardization and reliability across various labs."

"Another significant hurdle was automating the detection of antibody reactivity through fluorescence measurements including microscopy assessments. This step is crucial for determining whether autoantibodies in serum or CSF bind to astrocytes or neurons. Such optimization enables us to generate reliable results within a few days," Du Pasquier added.

Research indicated that up to 46% of patients diagnosed with presumed autoimmune limbic encephalitis tested negative for all currently identified central nervous system antigens.

Anna Pace, MD

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