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A potentiometric electronic tongue was applied to study the release of valsartan from pharmaceutical formulations, i.e., minitablets uncoated and coated with Eudragit E. Special attention was paid to evaluate the influence of medium temperature and composition, as well as to compare the performances of the sensor arrays working in various hydrodynamic conditions. The drug dissolution profiles registered with the ion-sensitive electrodes were compared with standard dissolution tests performed with USP Apparatus 2 (paddle). Moreover, the signal changes of all sensors were processed by principal component analysis to visualize the release modifications, related to the presence of the coating agent. Finally, the importance and influence of the experimental conditions on the results obtained using potentiometric sensor arrays were discussed.

People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq ® ) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.

IntroductionIn 2020, the new nationwide protocol of prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). The study aimed to: (1) assess the safety of switching from pdFVIII to rFVIII, (2) assess the safety and efficacy of pharmacokinetically based (PK-based) personalized prophylaxis in severe hemophilia A.Patients and methods151 children and adolescents receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of the optimal model of prophylaxis was performed in all patients. Two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed, with parents leaving the choice to their decision. Parents reported all episodes of bleeds. Screening for inhibitor was performed every 3 months. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks.Results141/151 (93.4%) patients completed the study. 34 patients decided to continue standard prophylaxis with rFVIII (Group I), whereas 107 were switched to PK-based prophylaxis (Group II). The risk of inhibitor development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitor with its spontaneous elimination. The retrospective analysis of bleeds during the last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis had historically lower ABR and AJBR than those who started PK-based personalized prophylaxis. After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period. However, the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis.Conclusion(1) Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, (2) PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA.

Treatment of haemophilia A with FVIII replacement has evolved over the past decades to adapt to the needs of patients. octanate®, a plasma-derived, double virus-inactivated, von Willebrand factor (VWF)-containing FVIII concentrate, has been used in clinics worldwide for over 20 years. First licensed in 1998 in Germany, octanate® is approved in over 80 countries for the prevention and treatment of bleeding and for surgical prophylaxis in patients with haemophilia A, and in over 40 countries for immune tolerance induction (ITI). The manufacturing process for octanate® was developed to ensure high viral safety and effectively eliminates both enveloped and nonenveloped viruses. Over the past 20 years, the excellent safety and efficacy of octanate® have been demonstrated in pivotal clinical trials in adult and paediatric previously treated patients (PTPs) for on-demand treatment, prophylaxis and as surgical cover. Importantly, octanate® has displayed low immunogenicity in previously untreated patients (PUPs), with only 9.8% of PUPs developing FVIII inhibitors. octanate® has also shown to be highly effective in inhibitor elimination when used as ITI therapy. In a population of patients with high risk of ITI failure, success was achieved in 79.2% of patients (70.8% complete success), even when using exceptionally stringent success criteria. No relapses were observed. Here we present an overview of the clinical data with octanate® that support its use in a range of patient populations and clinical indications.

Abstract Background The thalassemia syndromes are classified according to the globin chain or chains whose production is affected. β-thalassemias are caused by point mutations or, more rarely, deletions or insertions of a few nucleotides in the β-globin gene or its immediate flanking sequences. These mutations interfere with the gene function either at the transcriptional, translational or posttranslational level. Methods Two cases of Polish patients with hereditary hemolytic anemia suspected of thalassemia were studied. DNA sequencing and mRNA quantification were performed. Stable human cell lines which express wild-type HBB and mutated versions were used to verify that detected mutation are responsible for mRNA degradation. Results We identified two different frameshift mutations positioned in the third exon of HBB. Both patients harboring these mutations present the clinical phenotype of thalassemia intermedia and showed dominant pattern of inheritance. In both cases the mutations do not generate premature stop codon. Instead, slightly longer protein with unnatural C-terminus could be produced. Interestingly, although detected mutations are not expected to induce NMD, the mutant version of mRNA is not detectable. Restoring of the open reading frame brought back the RNA to that of the wild-type level. Conclusion Our results show that a lack of natural stop codon due to the frameshift in exon 3 of β-globin gene causes rapid degradation of its mRNA and indicate existence of novel surveillance pathway.

Simoctocog alfa (human-cl rhFVIII, Nuwiq®) is a 4th generation recombinant FVIII (rFVIII), without chemical modification or fusion with any other protein/fragment. Nuwiq® is produced in a human embryonic kidney cell line (HEK293F), which ensures human-specific post-translational protein processing. Nuwiq® was evaluated in seven prospective clinical studies in 201 adult and pediatric previously treated patients (PTPs) with severe hemophilia A. The NuProtect study in 110 previously untreated patients (PUPs) is ongoing. The mean half-life of Nuwiq® was 15.1–17.1 h in PTP studies with adults and adolescents, and 12.5 h in children aged 2–12 years. Clinical trials in PTPs demonstrated the efficacy and safety of Nuwiq® in the prevention and treatment of bleeds and as surgical prophylaxis. In the NuPreviq study of pharmacokinetic (PK)-guided personalized prophylaxis in 66 adult PTPs, 83% of patients had no spontaneous bleeds during 6 months of personalized prophylaxis and 57% were treated ⩽2 per week. No FVIII inhibitors were detected in PTPs after treatment with 43,267 injections and >80 million IU of Nuwiq®. Interim data for 66 PUPs with ⩾20 exposure days to Nuwiq® in NuProtect demonstrated a low cumulative high-titer inhibitor rate of 12.8% [actual incidence 12.1% (8/66)] and convincing efficacy and safety.