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Articles

The complement system is critical in immune defense and tissue homeostasis, but its dysregulation can contribute to autoimmune neurological disorders and neurodegenerative diseases like Alzheimer, ALS, and multiple sclerosis.

Understanding the Critical and Emerging Role of Complement in Neurological Disorders

Vatiquinone, a small molecule inhibitor, demonstrated its efficacy and safety across a range of age groups with Friedreich ataxia, with effects seen on disease progression and specific subscales of the mFARS.

PTC Formally Submits NDA for Vatiquinone as Treatment for Adults and Children With Friedreich Ataxia

IJMSC Insights offers a closer look at the latest research and the people behind it from the community of the International Journal of Multiple Sclerosis Care (IJMSC) and the Consortium of Multiple Sclerosis Centers (CMSC).

IJMSC Insights: Ahmed Zayed Obeidat on the Intersection of Art and Medicine

As new treatments become available, it may be essential to achieve a timely and accurate diagnosis to enable patients and their family to make informed decisions and retain the greatest level of autonomy.

Newly Published Guideline on Diagnosing Alzheimer and Related Cognitive Disorders for Clinical Practice

Assistant professor of pediatrics at the University of Michigan.

Videos

A duo of experts discussed the importance of addressing barriers such as provider comfort, access to genetic counselors, and insurance coverage to reduce diagnostic latency and standardize genetic testing for epilepsy. [WATCH TIME: 5 minutes]

Improving Access and Reducing Latency in Genetic Testing for Epilepsy: Julie Ziobro, MD, PhD; John Schreiber, MD

Assistant professor of neurosurgery and neuroscience at Mayo Clinic Arizona

The assistant professor of neurosurgery and neuroscience at Mayo Clinic Arizona discussed an ongoing early-stage study assessing the therapeutic potential of NRTX-1001 nerve cell therapy in drug-resistant unilateral mesial temporal lobe epilepsy. [WATCH TIME: 5 minutes]

Studying Nerve Cell Therapy NRTX-1001 to Treat Mesial Temporal Lobe Epilepsy: Jonathan Parker, MD, PhD

, has been with the team since September 2022. Follow her on Twitter 

The program assembles a collaborative team of in-house and external experts in research, clinical care, and regulatory affairs to navigate gene therapy programs through the drug development process.

FDA Grants MDA Kickstart Program Rare Pediatric Disease Designation and Orphan Drug Designation in Congenital Myasthenic Syndrome

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

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Professor of neurology at University of Florence.

The professor of neurology at University of Florence talked about a study presented at ECTRIMS 2024 that validated definitions of progression independent of relapse activity in early relapsing MS. [WATCH TIME: 5 minutes]

Defining Progression Independent of Relapsing Activity and Insights into Early Multiple Sclerosis Progression: Emilio Portaccio, MD

A newly published study showed that pediatric patients from Black and low-income backgrounds with neuromyelitis optica spectrum disorder (NMOSD) experience significantly worse health outcomes compared with their nonHispanic White and more affluent peers. Published in 

, these findings highlight the interplay of race, socioeconomic factors, and healthcare disparities in managing this rare autoimmune condition of the optic nerve and spinal cord.

Among 38 cases of aquaporin-4-positive (AQP4+) NMOSD diagnosed in pediatric patients, researchers observed that Black or African American (AA) patients had an average Expanded Disability Status Scale (EDSS) score of 2.46 compared with 0.33 in nonHispanic White patients (

 = 0.003). Notably, this minority pediatric patient population also had 2.37 more hospital admissions 

 = 0.002) and spent 28.40 additional inpatient days 

 = 0.002) within 2 years of their diagnosis in comparison with their nonHispanic White counterparts.

“Higher attack severity and mortality have been reported in Black/African American adults with NMOSD, and our study corroborates that similar disparities likely exist in children. Historically, these disparate clinical outcomes were attributed to presumed genetic factors, which disregards the fact that race and ethnicity are social constructs," lead author Kelsey E. Poisson, MD, codirector of the Neuroimmunology Program at Nationwide Children’s told 

 "Black/African American children in our study had a higher degree of socioeconomic disadvantage, which may contribute to poorer outcomes. Given the trend in our study toward more delayed diagnosis in Black/African American children, a more severe burden of disease may develop, requiring longer inpatient hospitalization and ultimately resulting in higher disability."

In this study, researchers analyzed the cases of pediatric patients diagnosed with AQP4+ NMOSD based on 2015 international consensus criteria from 3 tertiary pediatric care centers in the United States between 2009 and 2021.

 Using socioeconomic data linked to the patients' addresses, the investigators assessed the influence of race, ethnicity, and socioeconomic status on disease progression and healthcare utilization over a 2-year period post-diagnosis. Authors noted that the data collection included clinical measures, hospitalization records, and neighborhood-level indicators from data in the U.S. Census.

Cerebral Lesions Considered Important Predictor of Cognitive Deficits in MOGAD

Additional findings showed that pediatric patients with AQP4+ NMOSD who had public insurance experienced a higher relapse rate than those on private insurance (

 = 0.046). Results also revealed that a significantly higher EDSS correlated with pediatric patients who lived in census tracts with a lower median income, higher deprivation index, and higher proportion of population on assisted income, in poverty, and with vacant housing (all, 

< 0.05) at 2 years and at the most recent follow-up. Thus, these results emphasize the role of social determinants in exacerbating health disparities beyond initial diagnosis.

"These neighborhood characteristics illustrate the daily living conditions of our patients and are also influenced by the inequitable distribution of resources through structural racism," Poisson, who also serves as an assistant professor of Clinical Pediatrics and Neurology at The Ohio State University College of Medicine, said. "Living in more disadvantaged neighborhoods can affect health outcomes through environmental exposures, poor access to transportation and healthy food, lack of adequate health insurance and medication adherence, and lower health literacy."

The current study faced several limitations including the exclusion of patients without 2-year follow-up data, which might have made the results biased toward those with better access to care. Furthermore, incomplete documentation may have prevented accurate assessment of delays in initiating disease-modifying therapy. Health care utilization data was also limited for patients seeking care outside study centers, and the sample was less representative of White patients because of regional recruitment biases. Additionally, the assessed neighborhood-level socioeconomic data might not fully capture individual or household-level disparities.

“Ultimately we need larger studies that enable us to pursue sub-analyses on identified disparities in minoritized populations to determine the influence of social determinants of health within these sub-populations,"  Poisson said. "Given that this will be very difficult due to the rarity of AQP4+ NMOSD in children, we simultaneously need to be screening to identify those that are at-risk and offering interventions such as care navigation services, transportation assistance, legal advocacy for unsafe housing, and further caregiver education to promote health literacy about NMOSD."

REFERENCES
1. Poisson KE, Nguyen L, Horn PS, et al. Racial, Ethnic, and Socioeconomic Disparities in Pediatric Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. Pediatr Neurol. Published online October 11, 2024. doi:10.1016/j.pediatrneurol.2024.09.028
2. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729

A recent study highlights significant health disparities in pediatric patients with aquaporin-4-positive neuromyelitis optica spectrum disorder (NMOSD), particularly affecting Black and low-income children. These patients experience worse outcomes, including higher disability scores, more hospital admissions, and longer inpatient stays compared to their nonHispanic White peers. Socioeconomic factors, such as public insurance and living in disadvantaged neighborhoods, exacerbate these disparities. The study underscores the need for larger research efforts and targeted interventions to address social determinants of health and improve outcomes for at-risk populations.

A new study revealed stark racial and socioeconomic disparities in pediatric neuromyelitis optica spectrum disorder outcomes, underscoring the need for targeted interventions.

Clinical

Race, Socioeconomic Status Play Major Role in Disparities Seen in Pediatric NMOSD Outcomes

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.

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.

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.

Emilio Portaccio, MD

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