Pediatric Rare Diseases Development in the Pharmaceutical Industry: An International Consortium for Innovation and Quality in Pharmaceutical Development, Clinical Pharmacology Leadership Group-Pediatrics Working Group, Rare Diseases Subteam Whitepaper Examining the Current Landscape and Recommendations for the Future.

Many new opportunities surround rare pediatric disease drug development, thanks to key advances in regulatory thinking and in the scientific community. As rare disease drug development brings challenges to the developers in terms of limited understanding of natural history, heterogeneity in drug response, as well as difficulty recruiting patients in pivotal trials, there has never been a greater need for quantitative integration. To understand how International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) member companies approach pediatric rare disease drug development, the rare pediatric subteam of the Clinical Pharmacology Leadership Group (CPLG) sponsored Pediatrics Working Group conducted a baseline survey to assess the four main pillars of this quantitative innovation, namely, biomarkers and surrogate end points, statistical methodologies, model-informed drug development, as well as public-private partnerships. The survey was administered by IQ and yielded 13 evaluable responders from represented companies. This article presents the key findings from this baseline identifying survey, highlighting the key blind spots, and providing insightful expert opinions to address those gaps. In summary, we call an urgent attention to the community on the opportunities to enhance integration and within-industry learnings from this analysis on aspects related to platform studies, end-to-end quantitative integration, and sharing of trial-level placebo data for better understanding of disease progression and more efficient trial designs. We collectively hope that these findings will stimulate discussion and debate around cross-industry sharing and collaboration to better delineate principles and further enhance the efficiency of rare pediatric disease drug development.

Effect of biodegradable and conventional microplastic exposure in combination with seawater inundation on the coastal terrestrial plant Plantago coronopus.

Coastal ecosystems face a multitude of pressures including plastic pollution and increased flood risk due to sea level rise and the frequency and severity of storms. Experiments seldom examine multiple stressors such as these, but here we quantified the effect of microplastics (polyethylene terephthalate (PET): a durable plastic and polybutylene adipate terephthalate (PBAT): a biodegradable polymer), in combination with simulated seawater inundation on the coastal species Plantago coronopus. After 35-days exposure to plastic (0.02 g.Kg-1, <300 µm diameter), P. coronopus were flooded to pot height with artificial seawater for 72-h, drained and grown for a further 24-days. Plant mortality, necrosis and photosynthetic efficiency (Fv/Fm) were recorded throughout, with root:shoot biomass and scape production (flower stalks) quantified at harvest. There were significant interactions between microplastics and seawater on the root:shoot ratio; a measure of resource allocation. The allocation to belowground biomass increased significantly under the PET + inundation treatment compared to the PBAT + inundation and the no plastic + inundation treatments, with potential consequences on the capture of water, nutrients and sunlight, which can affect plant performance. Plant necrosis significantly increased, and Fv/Fm declined as a result of seawater inundation. While not significant, plant Fv/Fm responses were influenced by microplastics (17% and 7% reduction in PBAT and PET exposure respectively compared to the no plastic control). Plants mediated this stress response with no discernible treatment-specific effects detected in Fv/Fm 14-days after seawater introduction. Plastic exposure significantly influenced potential reproductive output, with lower average scape numbers across PBAT treatments, but higher in PET treatments. This study highlights the complex interactions and potential for microplastics to present an elevated risk when in combination with additional stressors like seawater flooding; establishing the threat presented to ecosystem resilience in a changing world is a priority.

Effects of foetal size, sex and developmental stage on adaptive transcriptional responses of skeletal muscle to intrauterine growth restriction in pigs.

Intrauterine growth restriction (IUGR) occurs both in humans and domestic species. It has a particularly high incidence in pigs, and is a leading cause of neonatal morbidity and mortality as well as impaired postnatal growth. A key feature of IUGR is impaired muscle development, resulting in decreased meat quality. Understanding the developmental origins of IUGR, particularly at the molecular level, is important for developing effective strategies to mitigate its economic impact on the pig industry and animal welfare. The aim of this study was to characterise transcriptional profiles in the muscle of growth restricted pig foetuses at different gestational days (GD; gestational length ~ 115 days), focusing on selected genes (related to development, tissue injury and metabolism) that were previously identified as dysregulated in muscle of GD90 fetuses. Muscle samples were collected from the lightest foetus (L) and the sex-matched foetus with weight closest to the litter average (AW) from each of 22 Landrace x Large White litters corresponding to GD45 (n = 6), GD60 (n = 8) or GD90 (n = 8), followed by analyses, using RT-PCR and protein immunohistochemistry, of selected gene targets. Expression of the developmental genes, MYOD, RET and ACTN3 were markedly lower, whereas MSTN expression was higher, in the muscle of L relative to AW littermates beginning on GD45. Levels of all tissue injury-associated transcripts analysed (F5, PLG, KNG1, SELL, CCL16) were increased in L muscle on GD60 and, most prominently, on GD90. Among genes involved in metabolic regulation, KLB was expressed at higher levels in L than AW littermates beginning on GD60, whereas both IGFBP1 and AHSG were higher in L littermates on GD90 but only in males. Furthermore, the expression of genes specifically involved in lipid, hexose sugar or iron metabolism increased or, in the case of UCP3, decreased in L littermates on GD60 (UCP3, APOB, ALDOB) or GD90 (PNPLA3, TF), albeit in the case of ALDOB this only involved females. In conclusion, marked dysregulation of genes with critical roles in development in L foetuses can be observed from GD45, whereas for a majority of transcripts associated with tissue injury and metabolism differences between L and AW foetuses were apparent by GD60 or only at GD90, thus identifying different developmental windows for different types of adaptive responses to IUGR in the muscle of porcine foetuses.

Pediatric oncology drug development and dosage optimization.

Oncology drug discovery and development has always been an area facing many challenges. Phase 1 oncology studies are typically small, open-label, sequential studies enrolling a small sample of adult patients (i.e., 3-6 patients/cohort) in dose escalation. Pediatric evaluations typically lag behind the adult development program. The pediatric starting dose is traditionally referenced on the recommended phase 2 dose in adults with the incorporation of body size scaling. The size of the study is also small and dependent upon the prevalence of the disease in the pediatric population. Similar to adult development, the dose is escalated or de-escalated until reaching the maximum tolerated dose (MTD) that also provides desired biological activities or efficacy. The escalation steps and identification of MTD are often rule-based and do not incorporate all the available information, such as pharmacokinetic (PK), pharmacodynamic (PD), tolerability and efficacy data. Therefore, it is doubtful if the MTD approach is optimal to determine the dosage. Hence, it is important to evaluate whether there is an optimal dosage below the MTD, especially considering the emerging complexity of combination therapies and the long-term tolerability and safety of the treatments. Identification of an optimal dosage is also vital not only for adult patients but for pediatric populations as well. Dosage-finding is much more challenging for pediatric populations due to the limited patient population and differences among the pediatric age range in terms of maturation and ontogeny that could impact PK. Many sponsors defer the pediatric strategy as they are often perplexed by the challenges presented by pediatric oncology drug development (model of action relevancy to pediatric population, budget, timeline and regulatory requirements). This leads to a limited number of approved drugs for pediatric oncology patients. This review article provides the current regulatory landscape, incentives and how they impact pediatric drug discovery and development. We also consider different pediatric cancers and potential clinical trial challenges/opportunities when designing pediatric clinical trials. An outline of how quantitative methods such as pharmacometrics/modelling & simulation can support the dosage-finding and justification is also included. Finally, we provide some reflections that we consider helpful to accelerate pediatric drug discovery and development.