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Targeting shared molecular etiologies to accelerate drug development for rare diseases.

ABSTRACT: Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable. Grouping rare disease patients for clinical trials based on the underlying molecular etiology, rather than the traditional, symptom-based definition of disease, has the potential to greatly increase the number of patients gaining access to clinical trials. Basket clinical trials based on a shared molecular drug target have become common in the field of oncology and have been accepted by regulatory agencies as a basis for drug approvals. Implementation of basket clinical trials in the field of rare diseases is seen by multiple stakeholders-patients, researchers, clinicians, industry, regulators, and funders-as a solution to accelerate the identification of new therapies and address patient's unmet needs.

SUBMITTER: Zanello G

PROVIDER: S-EPMC10331571 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Targeting shared molecular etiologies to accelerate drug development for rare diseases.

Zanello Galliano G Garrido-Estepa Macarena M Crespo Ana A O'Connor Daniel D Nabbout Rima R Waters Christina C Hall Anthony A Taglialatela Maurizio M Chan Chun-Hung CH Pearce David A DA Dooms Marc M Brooks Philip John PJ

EMBO molecular medicine 20230627 7

Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable. Grouping rare disease patients for clinical trials based on the underlying molecular etiology, rather than the traditional, symptom-based d ...[more]

PMID: 37366158

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Project description:BACKGROUND:Thirty thousand infants are born every year with congenital hearing impairment in mainland China. Racial and regional factors are important in clinical diagnosis of genetic deafness. However, molecular etiology of hearing impairment in the Tibetan Chinese population living in the Tibetan Plateau has not been investigated. To provide appropriate genetic testing and counseling to Tibetan families, we investigated molecular etiology of nonsyndromic deafness in this population. METHODS:A total of 114 unrelated deaf Tibetan children from the Tibet Autonomous Region were enrolled. Five prominent deafness-related genes, GJB2, SLC26A4, GJB6, POU3F4, and mtDNA 12S rRNA, were analyzed. Inner ear development was evaluated by temporal CT. A total of 106 Tibetan hearing normal individuals were included as genetic controls. For radiological comparison, 120 patients, mainly of Han ethnicity, with sensorineural hearing loss were analyzed by temporal CT. RESULTS:None of the Tibetan patients carried diallelic GJB2 or SLC26A4 mutations. Two patients with a history of aminoglycoside usage carried homogeneous mtDNA 12S rRNA A1555G mutation. Two controls were homozygous for 12S rRNA A1555G. There were no mutations in GJB6 or POU3F4. A diagnosis of inner ear malformation was made in 20.18% of the Tibetan patients and 21.67% of the Han deaf group. Enlarged vestibular aqueduct, the most common inner ear deformity, was not found in theTibetan patients, but was seen in 18.33% of the Han patients. Common molecular etiologies, GJB2 and SLC26A4 mutations, were rare in the Tibetan Chinese deaf population. CONCLUSION:The mutation spectrum of hearing loss differs significantly between Chinese Tibetan patients and Han patients. The incidence of inner ear malformation in Tibetans is almost as high as that in Han deaf patients, but the types of malformation vary greatly. Hypoxia and special environment in plateau may be one cause of developmental inner ear deformity in this population.

Project description:BackgroundThe ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports.MethodsThe applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters.Results and discussionDirect applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters.ConclusionNovel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes.

Project description:BackgroundMore effective incentives are needed to motivate paediatric oncology drug development, uncoupling it from dependency on adult drug development. Although the current European and North-American legislations aim to promote drug development for paediatrics and rare diseases, children and adolescents with cancer have not benefited as expected from these initiatives and cancer remains the first cause of death by disease in children older than one. Drug development for childhood cancer remains dependent on adult cancer indications and their potential market. The balance between the investment needed to execute a Paediatric Investigation Plan (PIP) in Europe and an initial Paediatric Study Plan (iPSP) in the US, coupled with the potential financial reward has not been sufficiently attractive to incite the pharmaceutical industry to develop drugs for rare indications such as childhood cancer.MethodsWe propose changes in the timing and nature of the rewards within the European Paediatric Medicine Regulation (PMR) and Regulation on Orphan Medicinal Products (both currently under review), which would drive earlier initiation of paediatric oncology studies and provide incentives for drug development specifically for childhood indications.ResultsWe suggest modifying the PMR to ensure mechanism-of-action driven mandatory PIP and reorganization of incentives to a stepwise and incremental approach. Interim and final deliverables should be defined within a PIP or iPSP, each attracting a reward on completion. A crucial change would be the introduction of the interim deliverable requiring production of paediatric data that inform the go/no-go decisions on whether to take a drug forward to paediatric efficacy trials.ConclusionAdditionally, to address the critical gap in the current framework where there is a complete lack of incentives to promote paediatric-specific cancer drug development, we propose the introduction of early rewards in the Orphan Regulation, with a variant on the US-Creating Hope Act and its priority review vouchers.

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Targeting shared molecular etiologies to accelerate drug development for rare diseases.

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Targeting shared molecular etiologies to accelerate drug development for rare diseases.

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