In September 2009, PTC entered into an agreement with Roche for the development of orally bioavailable small molecules for central nervous system diseases. In 2020, PTC announced the FDA approval of Evrysdi™ (risdiplam) for the treatment of spinal muscular atrophy (SMA) in adults and children 2 months and older, in partnership with the SMA Foundation and Roche.PTC acquired the Bio-e platform in 2019. The Bio-e platform utilizes expertise in electron-transfer chemistry to modulate key biological processes beyond the reach of current drug development approaches. The lead compounds from the Bio-e platform, PTC743 and PTC857, target the enzyme 15-lipoxygenase – a key enzymatic hub that regulates the inflammation and oxidative stress that underpin mitochondrial disease and CNS pathology. Two pivotal studies will investigate the safety and efficacy of PTC743: a Phase 2/3 trial in refractory mitochondrial epilepsy and a Phase 3 trial in Friedreich’s ataxia..
AIM:AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS:AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3-4 of each treatment period (Part 2). RESULTS:Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, n = 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was -437.0 (28.0) and -256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of -180.4 μmol/L (95% CI: -229.5, -131.4; p < 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports. CONCLUSIONS:Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed. The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; https://www.isrctn.com/ISRCTN79102999).
OBJECTIVE:This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. SUBJECTS AND METHODS:Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. RESULTS:We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. CONCLUSION:Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
Abstract Background and Aims Familial chylomicronemia syndrome (FCS) is an ultra-rare genetic disorder caused by pathogenic variants in fivegenes (LPL, APOA5, APOC2, LMF1, and GPIHBP1), characterized by severe hypertriglyceridemia and a high risk ofacute pancreatitis. The available evidence, derived mainly from European and North American cohorts, identifiesLPL as the most frequently implicated gene (Hegele et al.), with limited representation of Latin Americanpopulations. The aim of this study was to characterize the genetic and demographic profile of patients with FCSacross six Latin American countries and to compare these findings with those reported in the literature. Methods This was a retrospective study of 83 patients with genetically confirmed FCS. Anonymized data from the PTCTherapeutics Diagnostic Program, collected between 2020 and 2025, were analyzed. Results A total of 83 cases from Colombia, Costa Rica, Ecuador, Guatemala, Mexico, and Panama were included, with amean age of 33.2 ± 20.5 years and a female predominance (63.0%). LPL was the most frequently affected gene (55.4%), followed by APOA5 (15.7%), GPIHBP1 (12.0%), LMF1 (12.0%), and APOC2 (3.6%). Differences wereobserved across countries, with greater genetic heterogeneity in Ecuador. Compared with the literature, the LatinAmerican cohort showed a lower proportion of LPL-associated cases and a greater relative contribution of non-LPLgenes. Conclusions FCS in Latin America appears to exhibit greater genetic heterogeneity than that described in European and NorthAmerican cohorts, underscoring the need for further characterization.
