PTC Therapeutics (United States)

Aromatic ʟ-amino acid decarboxylase (AADC) deficiency is a rare pediatric neurotransmitter disorder that typically necessitates lifelong care, and that carries a risk of childhood mortality. Eladocagene exuparvovec gene therapy is designed to restore AADC production. Study GT-002 (NCT04903288) is a phase 2, multicenter, open-label trial assessing the pharmacodynamics, safety, and efficacy of eladocagene exuparvovec administered to the putamen bilaterally in pediatric patients with AADC deficiency using a magnetic resonance (MR)-compatible cannula. Patients received eladocagene exuparvovec at 1.8 × 1011 vector genomes via the SmartFlow MR-compatible cannula in a single operative session. Endpoints include the change from baseline in cerebrospinal fluid homovanillic acid levels, motor milestone achievement, and safety. Here we report results from 48 weeks of follow-up. Mean (SD) cerebrospinal fluid homovanillic acid levels increased from baseline (22.5 [32.3] nmol/L; n = 13) to week 48 (55.3 [45.6] nmol/L; change from baseline: 28.3 [13.7] nmol/L; p = 0.0003; n = 9), indicating de novo dopamine production. At baseline (n = 13), all patients showed severe motor developmental delay; at week 48 (n = 12), nine achieved full head control, four could sit unassisted, two could stand with support, and two could walk independently to a toy. Overall, 260 treatment-emergent adverse events were reported in 13 patients; 259 were deemed unrelated and one likely unrelated to the MR-compatible cannula. No treatment-emergent adverse events led to study withdrawal and no deaths occurred. This study provides further evidence of the favorable pharmacodynamic, efficacy, and safety profile of eladocagene exuparvovec in children with AADC deficiency; intraputaminal administration using an MR-compatible cannula was well tolerated. Study GT-002 (NCT04903288) provides further evidence of the favourable pharmacodynamic, efficacy and safety profile of eladocagene exuparvovec gene therapy in children with AADC deficiency over 48 weeks and demonstrates that intraputaminal administration using an MR-compatible cannula was well tolerated, allowing for real-time MRI confirmation of cannula placement and infusate coverage, and for accurate dosing to the putamen.

SUMMARY & CONCLUSIONSIn the realm of reliability testing, one of the fundamental challenges lies in the identification and selection of the most critical failure modes and corresponding performance parameters. With a vast array of potential failure mechanisms and performance metrics, engineers often struggle to pinpoint those that truly reflect real-world degradation and field performance. Traditionally, this selection process is guided by expert judgment and established references such as the NSWC Mechanical Handbook, and other well-defined handbooks. However, practical constraints including limited time, budget, and test resources make exhaustive testing for all potential failure modes unfeasible.This paper introduces the Critical Failure Mode Prioritization (CFMP) methodology for reliability test design. Unlike traditional approaches that rely heavily on expert opinion and static reference standards, CFMP integrates real-world operating conditions and focuses on prioritizing the most significant and probable failure modes. By leveraging tools such as Parameter Diagram (P-Diagram), Design Failure Mode and Effects Analysis (DFMEA), actual field usage data, and historical field failure data, this methodology moves beyond subjective biases. It identifies and models failure modes based on their occurrences, Mean Time to Failure (MTTF), and percentage of contributions, thereby enhancing the relevance and accuracy of the testing process.The key distinction of the CFMP approach lies in its ability to handle products with multiple failure modes and mechanisms. It emphasizes identifying the critical failure mode or mechanism that could lead to system failure as early as possible. This method is more comprehensive, focusing on end-to-end processes and prioritizing sub-assembly and system-level testing from the end user's perspective, rather than primarily from an engineer’s point of view.This paper addresses the highly relevant topic of prioritizing different failure modes in reliability testing. It mentions relevant exemplary data, especially on the side of requirements.Moreover, the CFMP methodology is grounded in core reliability engineering principles. By incorporating physics-of-failure (POF) analysis to explore optimal failure mechanisms, degradation modeling to forecast failure progression, and preventive maintenance strategies for proactive decision-making, CFMP ensures that test conditions are aligned with actual usage profiles. This results in more accurate, relevant, and efficient testing, directly supporting the prediction of field performance and facilitating better-informed decisions.

ABSTRACT Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG trinucleotide repeats in the ATXN3 gene. This mutation induces a toxic gain-of-function of the ATXN3 protein, leading to neurodegeneration, particularly in the cerebellum and brainstem. Despite extensive research, no disease-modifying treatments are available for SCA3 patients. In this study, we developed and tested a novel therapeutic strategy using recombinant adeno-associated virus (rAAV) to deliver bicistronic artificial microRNAs designed to selectively silence the mutant ATXN3 allele. Through in vitro screening, we identified a lead construct (miATXN3-10x2) that effectively and specifically silenced the mutant allele by targeting of a single nucleotide polymorphism (SNP) associated with the repeat expansion. This construct was packaged into rAAV9 and delivered via intra-cerebellar administration into two mouse models of SCA3, resulting in robust suppression of mutant ATXN3 in the cerebellum. To assess long-term efficacy, we performed intra-cisterna magna (ICM) injections of rAAV9-miATXN3-10x2 in a severe SCA3 transgenic mouse model. Widespread distribution of viral vectors and miATXN3 copies was observed in disease-relevant brain regions. Treated animals exhibited significant and sustained improvements in motor function at 5, 8, and 11 weeks post-injection. Histological analyses showed a reduction in mutant ATXN3 aggregates and a trend toward preventing shrinkage of cerebellar molecular layer. These findings were supported by dose-dependent reductions in mutant ATXN3 mRNA levels and decreased expression of neuroinflammatory markers in the cerebellum. Additionally, a significant increase of the neuronal marker NeuN was also observed in treated animals. Finally, transcriptomic profiling of the cerebellum demonstrated that treated transgenic animals exhibited an improved transcriptomic signature, shifting toward a wild-type profile. In conclusion, our findings highlight the therapeutic potential of a single administration of rAAVs encoding bicistronic artificial microRNAs for allele-specific gene silencing in SCA3. This study provides compelling preclinical evidence supporting the translation of this approach into clinical applications for SCA3 patients.

Aim: To report the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) from the phase III, 72-week, placebo-controlled period of Study 041. Materials & methods: Inclusion criteria: boys with nmDMD aged ≥5years, on a stable corticosteroid regimen for ≥12months, and baseline 6-minute walk distance (6MWD) ≥150m. Randomization: 1:1, ataluren (40mg/kg/day):placebo. Primary end point: slope of 6MWD change (average rate of change). Secondary end points: changes in 6MWD, time to 10% persistent worsening in 6MWD, North Star Ambulatory Assessment score, timed function tests and safety. Study populations: intention-to-treat; patients aged ≥7 to ≤16years with baseline 6MWD ≥300m and stand from supine ≥5s; patients with baseline 6MWD 300-400m. Results: In the intention-to-treat population (n=359), over 72weeks, ataluren reduced the rate of 6MWD decline by 21% (p = 0.0248), reduced the average 6MWD change (p = 0.0248), delayed time to 10% persistent worsening in 6MWD (p = 0.0078), and reduced North Star Ambulatory Assessment total score decline (p = 0.0235), change in 10m walk/run time (p=0.0422) and change in time to climb four stairs (p = 0.0293) versus placebo. In the 6MWD 300-400m subgroup (n=169), ataluren reduced the rate of 6MWD decline by 30% (p = 0.0310) versus placebo. Ataluren treatment benefits were seen in secondary end points in this subgroup, except for change in time to descend four stairs. In the 6MWD ≥300m and time to stand from supine ≥5s subgroup (n=185), there was a 9% slower rate of 6MWD decline for ataluren versus placebo over 72weeks (p = 0.3626). Ataluren reduced change in time to climb four stairs (p = 0.0179) versus placebo in this subgroup; no treatment benefits were seen for other secondary end points. Ataluren was well tolerated (serious adverse events: ataluren, 7.1%; placebo, 6.8%); no deaths occurred. Conclusion: Long-term ataluren treatment has a favorable benefit-risk profile, slowing motor function decline in the largest phase III nmDMD study to date.

Introduction: Vatiquinone is a first-in-class, small molecule designed to maintain mitochondrial function in the disorders like Friedreich’s ataxia (FA). Vatiquinone inhibits 15-lipoxygenase, consequently decreasing oxidative stress and neuroinflammatory response pathways. Methods: Population pharmacokinetic modeling analysis was conducted to characterize vatiquinone pharmacokinetic profiles in healthy volunteers and patients and explore the effects of covariates on vatiquinone exposures. Results: A two-compartment model with parallel zero- and first-order absorption was developed and verified. The values of essential parameters were: absorption fraction through the first-order process, 74.4%; absorption rate constant, 0.20 h−1; delay time, 2.79 h; zero-order absorption duration, 6.03 h; apparent volume of distribution, 180.75 L for the central and 4852.69 L for the peripheral compartment; and apparent clearance, 162.72 L/h. Strong CYP3A4 inducers could reduce exposure by 50%; strong CYP3A4 inhibitors could increase it by 252%. Vatiquinone exposure was 19% lower in patients with Friedreich’s ataxia versus healthy volunteers. A medium-fat meal increased exposure up to 25-fold versus a fasted status. Body weight and body mass index had significant clinical relevance to exposures. Conclusions: A two-compartment model effectively described the pharmacokinetic profiles of vatiquinone after oral administration. Covariates significantly impacted exposures, including body weight, meals, disease status, comedications and body mass index.

BackgroundAromatic L-amino acid decarboxylase deficiency (AADCd) is a rare genetic disorder characterized by movement disorders, motor and autonomic dysfunction, and developmental delays. The gene therapy eladocagene exuparvovec has become available in some regions; pooled clinical trial results demonstrate continuous long-term improvement in motor development and cognitive function. We sought to characterize clinically meaningful change in motor function, as measured by Total Peabody Developmental Motor Scales-Second Edition (PDMS-2) score, and assess correlations with cognition and language domains of the Bayley-III and motor milestone (MM) achievement.MethodsData from N = 30 patients from three single-arm clinical studies of eladocagene exuparvovec were analyzed. Anchor-based estimation of the meaningful score difference (MSD) of Total PDMS-2 score was conducted using mean-difference and receiver operating characteristic curve (ROC) approaches. MM achievement served as the anchor defining meaningful change.ResultsAn MSD of 40 points for Total PDMS-2 score was selected for analysis as it yielded specificity > 0.95 using the ROC approach, and generally aligned with the mean-difference approach. Cumulative incidence analysis reflected that 50% of patients treated with eladocagene exuparvovec may achieve the MSD of 40-point change in Total PDMS-2 score at 6 months, and 86% at 18 months. Correlations between measures were of large magnitude and improved over time (Month 6: r = 0.599 [p = 0.0032]; Month 18: r = 0.796 [p = 0.0002]; Month 60: r = 0.861 [p = 0.0007]).ConclusionsThe MSD of 40 points for Total PDMS-2 score enables the interpretation of changes observed in patients with AADCd, and suggests that treatment with eladocagene exuparvovec leads to significant improvements in motor and cognitive function.

Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.

<bold>Background:</bold> Multiple pro-inflammatory mediators implicated in the pathogenesis of moderate to severe asthma signal via the JAK/STAT pathway. KN-002 is a potent pan-JAK inhibitor formulated as a dry powder for oral inhalation. <bold>Methods:</bold> This Phase 1b, randomized, double-blinded, placebo-controlled study (<ext-link>NCT05006521</ext-link>) evaluated the safety and pharmacokinetics (PK) of KN-002 after 10-day administration of 4 mg BID to subjects with moderate to severe asthma using ICS/LABA therapy. Adverse Events (AEs) were recorded at each visit with hematology/chemistry samples collected at screening, Days 1-3, 6, 9-12 and 17. Intensive PK sampling was assessed on Days 1 and 10 (predose, 0.5, 1, 2, 3, 4, 6, 8, and 12 hrs [Day 1] plus 24 and 48 hrs post dose [Day 10]) and predose on Days 2 to 9. <bold>Results:</bold> 23 subjects (17 KN-002:6 placebo) received treatment. No serious/severe AEs were reported and no subjects withdrew. 10 (58.8%) KN-002 and 2 (33.3%) placebo reported AEs. The most common AE was headache; 3 [17.6%] KN-002 and 1 [16.7%] placebo. Two AEs, mild sore throat and moderate headache, were reported as possibly related to KN 002; both resolved without dosing change. Clinical laboratory outcomes revealed no findings of clinical concern. Steady state PK was achieved by Day 3 with minimal accumulation upon repeat dosing. Plasma levels were below pharmacologically active concentrations. The KN-002 safety/PK profile was consistent with that reported in subjects with ICS naïve mild asthma. <bold>Conclusions:</bold> Inhaled KN-002 was well tolerated by subjects with moderate to severe asthma using ICS/LABA. Outcomes support the Phase 2 development in subjects with uncontrolled asthma using medium to high dose ICS/LABA treatment.