Analysis of the first ten years of FDA's rare pediatric disease priority review voucher program: designations, diseases, and drug development.

BACKGROUND: The Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program. RESULTS: We used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data. CONCLUSIONS: The RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development-from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

FDA orphan products clinical trial grants: assessment of outcomes and impact on rare disease product development.

BACKGROUND: The Office of Orphan Products Development (OOPD) of the United States (U.S.) Food and Drug Administration (FDA) has awarded over 700 grants to conduct clinical trials of medicals products for rare diseases since 1983, leading to over 70 marketing approvals. However, despite recent progress in rare disease product development, thousands of rare diseases still have no approved treatments. An assessment of this clinical trial grants program was undertaken to provide an in-depth analysis of the characteristics and outcomes of the program. Results of this analysis will be used to inform future goals of the program, as well as internal data collection to continue to maximize the program's impact in supporting rare disease product development. RESULTS: Between fiscal years 2007-2011, OOPD funded 85 clinical trial grants. These grants spanned 18 therapeutic areas, included all pre-approval phases (Phases 1-3), and approximately 75% of the grants studied small molecule drugs. Nine (11%) product approvals, of seven drugs and two devices, were at least partially supported by grants funded within this 5-year timeframe. Four of the seven drugs approved were new molecular entities (NMEs). The average time from funding to approval was seven years. We also found a suggested association between collaboration with multiple types of stakeholders and the success of grants, where we defined success as either positive or negative study findings or a future marketing approval. CONCLUSIONS: The clinical trials funded by OOPD provided valuable information for future product development, and there were a notable number of approvals that occurred using the support of the grants program. There was a suggested association between collaboration and successful outcomes. Efficient and innovative trial designs and collaboration among stakeholders appear vital to continue to effectively bring products to rare disease patients. Ongoing program assessments will ensure that the funding continues to be used to optimally meet the treatment needs of the rare disease community.

Antiseizure effects of TrkB kinase inhibition.

OBJECTIVE: The principal molecular targets of conventional antiseizure drugs consist of ligand-gated and voltage-gated ion channels and proteins subserving synaptic function. Inhibition of the receptor tyrosine kinase TrkB limits epileptogenesis, but its effect on individual seizures is unknown. We sought to determine whether inhibition of TrkB kinase exerts an antiseizure effect. METHODS: We utilized the kindling model in combination with an inducible conditional knockout of the TrkB gene (Act-CreER TrkB(flox/flox) mice treated with tamoxifen), and also with a chemical-genetic approach in which mice carry a TrkB kinase with a phenylalanine to alanine substitution of residue 616 (TrkB(F) (616A) ), which allows inhibition of the kinase by a blood-brain barrier permeable small molecule, 1'-naphthylmethyl-4-amino-1-tert-butyl-3-(p-methylphenyl)pyrazolo[3,4-d]pyrimidine (1NMPP1). RESULTS: Following induction of kindling, reduction of TrkB protein levels in Act-CreER TrkB(flox/flox) mice treated with tamoxifen was associated with reduced severity of behavioral seizures evoked by stimulation. Treatment with 1NMPP1 for 2 weeks following induction of kindling reversibly elevated both focal electrographic and generalized seizure thresholds in TrkB(F) (616A) , but not wild-type (WT), mice. In contrast to kindled animals, treatment of naive TrkB(F) (616A) mice for 2 weeks had no detectable effect on electrographic seizure threshold (EST). SIGNIFICANCE: This study provides proof of concept of a novel molecular target for antiseizure drugs, namely the receptor tyrosine kinase TrkB.

Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy.

Temporal lobe epilepsy is the most common and often devastating form of human epilepsy. The molecular mechanism underlying the development of temporal lobe epilepsy remains largely unknown. Emerging evidence suggests that activation of the BDNF receptor TrkB promotes epileptogenesis caused by status epilepticus. We investigated a mouse model in which a brief episode of status epilepticus results in chronic recurrent seizures, anxiety-like behavior, and destruction of hippocampal neurons. We used a chemical-genetic approach to selectively inhibit activation of TrkB. We demonstrate that inhibition of TrkB commencing after status epilepticus and continued for 2 weeks prevents recurrent seizures, ameliorates anxiety-like behavior, and limits loss of hippocampal neurons when tested weeks to months later. That transient inhibition commencing after status epilepticus can prevent these long-lasting devastating consequences establishes TrkB signaling as an attractive target for developing preventive treatments of epilepsy in humans.

Altered Purkinje cell miRNA expression and SCA1 pathogenesis.

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disorder caused by polyglutamine repeat expansions in Ataxin-1. Recent evidence supports a role for microRNAs (miRNAs) deregulation in SCA1 pathogenesis. However, the extent to which miRNAs may modulate the onset, progression or severity of SCA1 remains largely unknown. In this study, we used a mouse model of SCA1 to determine if miRNAs are misregulated in pre- and post-symptomatic SCA1 cerebellum. We found a significant alteration in the steady-state levels of numerous miRNAs prior to and following phenotypic onset. In addition, we provide evidence that increased miR-150 levels in SCA1 Purkinje neurons may modulate disease pathogenesis by targeting the expression of Rgs8 and Vegfa.

The cellular and synaptic location of activated TrkB in mouse hippocampus during limbic epileptogenesis.

Understanding the mechanisms of limbic epileptogenesis in cellular and molecular terms may provide novel therapeutic targets for its prevention. The neurotrophin receptor tropomyosin-related kinase B (TrkB) is thought to be critical for limbic epileptogenesis. Enhanced activation of TrkB, revealed by immunodetection of enhanced phosphorylated TrkB (pTrkB), a surrogate measure of its activation, has been identified within the hippocampus in multiple animal models. Knowledge of the cellular locale of activated TrkB is necessary to elucidate its functional consequences. Using an antibody selective to pTrkB in conjunction with confocal microscopy and cellular markers, we determined the cellular and subcellular locale of enhanced pTrkB induced by status epilepticus (SE) evoked by infusion of kainic acid into the amygdala of adult mice. SE induced enhanced pTrkB immunoreactivity in two distinct populations of principal neurons within the hippocampus-the dentate granule cells and CA1 pyramidal cells. Enhanced immunoreactivity within granule cells was found within mossy fiber axons and giant synaptic boutons. By contrast, enhanced immunoreactivity was found within apical dendritic shafts and spines of CA1 pyramidal cells. A common feature of this enhanced pTrkB at these cellular locales is its localization to excitatory synapses between excitatory neurons, presynaptically in the granule cells and postsynaptically in CA1 pyramidal cells. Long-term potentiation (LTP) is one cellular consequence of TrkB activation at these excitatory synapses that may promote epileptogenesis.

Conditional deletion of TrkC does not modify limbic epileptogenesis.

The neurotrophin receptor, tropomyosin-related kinase B (TrkB), is required for epileptogenesis in the kindling model. The role of a closely related neurotrophin receptor, TrkC, in limbic epileptogenesis is unknown. We examined limbic epileptogenesis in the kindling model in TrkC conditional null mice, using a strategy that previously established a critical role of TrkB. Despite elimination of TrkC mRNA, no differences in development of kindling were detected between TrkC conditional null and wild type control mice. These findings reinforce the central role of TrkB as the principal neurotrophin receptor involved in limbic epileptogenesis.

Cross-sector sponsorship of research in eosinophilic esophagitis: a collaborative model for rational drug development in rare diseases.

Like many rare diseases, eosinophilic esophagitis (EoE) is a poorly understood disorder, and assessment tools to accurately determine disease activity, remission, and natural history have long been inadequate. Clinical outcome end points able to assess the effectiveness of candidate therapeutic agents in clinical trials have been a particular deficiency and are urgently needed. With no approved therapy available to patients and with the prevalence of EoE on the increase, collaborative approaches to drug development are becoming ever more important. We describe a collaborative effort mobilized across institutions, including both the public and private sectors, that was initiated within the past 18 months expressly to address the need for further clinical research into the cause and treatment of EoE. Collaborators include the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition; the International Gastrointestinal Eosinophilic Researchers; and the US Food and Drug Administration. This effort has resulted in the elucidation of several parameters essential for effective EoE registration trials, including the need for clinically meaningful end points that measure changes in clinical symptoms in addition to the assessment of intraepithelial mucosal eosinophilia. The development and use of biomarkers, particularly in early-phase drug development, have become an important focus for investigations that might reduce clinical reliance on serial invasive monitoring. The concerted efforts described here to develop rational therapeutics and drug development paradigms in EoE also appear to provide a model for effective collaboration in the context of drug development for rare diseases and perhaps more generally for public health initiatives.

Adeno-associated virus type 5 reduces learning deficits and restores glutamate receptor subunit levels in MPS VII mice CNS.

A major challenge in treating lysosomal storage diseases with enzyme therapy is correcting symptoms in the central nervous system (CNS). This study used a murine model of mucopolysaccharidosis type VII (MPS VII) to test whether pathological and functional CNS defects could be corrected by expressing beta-glucuronidase via bilateral intrastriatal injection of adeno-associated virus type 5 (AAV5betagluc) vectors. After injecting AAV5betagluc, different brain regions expressed active beta-glucuronidase, which corrected lysosomal storage defects. Compared to age-matched littermates, adult MPS VII mice were impaired in spatial learning and memory, as measured by the repeated acquisition and performance chamber (RAPC) assay. AAV5betagluc-treated MPS VII mice improved significantly in the RAPC assay, relative to saline-injected littermates. Moreover, our studies reveal that cognitive changes in MPS VII mice correlate with decreased N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptor expression. Importantly, AAV5betagluc delivery restored glutamate receptor levels. Together, these data demonstrate that AAV5 vectors deliver a therapeutically effective beta-glucuronidase gene to the CNS and further suggest a possible mechanism underlying spatial learning defects in MPS VII mice.

Functional correction of CNS phenotypes in a lysosomal storage disease model using adeno-associated virus type 4 vectors.

Lysosomal storage diseases (LSDs) represent a significant portion of inborn metabolic disorders. More than 60% of LSDs have CNS involvement. LSD therapies for systemic diseases have been developed, but efficacy does not extend to the CNS. In this study, we tested whether adeno-associated virus type 4 (AAV4) vectors could mediate global functional and pathological improvements in a murine model of mucopolysaccharidosis type VII (MPS VII) caused by beta-glucuronidase deficiency. Recombinant AAV4 vectors encoding beta-glucuronidase were injected unilaterally into the lateral ventricle of MPS VII mice with established disease. Transduced ependyma expressed high levels of recombinant enzyme, with secreted enzyme penetrating cerebral and cerebellar structures, as well as the brainstem. Immunohistochemical studies revealed close association of recombinant enzyme and brain microvasculature, indicating that beta-glucuronidase reached brain parenchyma via the perivascular spaces lining blood vessels. Aversive associative learning was tested by context fear conditioning. Compared with age-matched heterozygous controls, affected mice showed impaired conditioned fear response and context discrimination. This behavioral deficit was reversed 6 weeks after gene transfer in AAV4 beta-glucuronidase-treated MPS VII mice. Our data show that ependymal cells can serve as a source of enzyme secretion into the surrounding brain parenchyma and CSF. Secreted enzymes subsequently spread via various routes to reach structures throughout the brain and mediated pathological and functional disease correction. Together, our proof-of-principal experiments suggest a unique and efficient manner for treating the global CNS deficits in LSD patients.