Breakthrough Clinical Results

GeneDx announced data from the SeqFirst study, conducted in partnership with Seattle Children's, demonstrating the effectiveness of rapid exome sequencing (rES) and rapid genome sequencing (rGS) as a first-tier test for non-critical pediatric inpatients. The study showed that implementing rES/rGS reduced the average time to a precise genetic diagnosis from almost ten months to 13 days. Despite increased utilization, the diagnostic yield remained high (over 40%), comparable to critical care settings. This supports broader adoption of rapid genomic testing in non-critical care to improve patient outcomes and lower healthcare costs. The study highlights the significant reduction in time to diagnosis, enabling earlier interventions and better care planning for children with rare and undiagnosed conditions.

Incidence and Prevalence

Global Estimates of Rare Disease Prevalence

Rare diseases represent a heterogeneous group of approximately 7000-8000 conditions that are characterized by their low prevalence. Despite the individual rarity of each condition, collectively, rare diseases present a significant global health challenge, affecting millions of people worldwide.

Global Prevalence

Current estimates indicate that rare diseases affect approximately 10% of the global population, which places a significant burden on individuals, families, and society. More specifically, there are more than 6000 different rare diseases that affect nearly 300 million people worldwide.

Regional Studies and Demographics

In a comprehensive nationwide retrospective observational cohort study conducted in England using electronic health records of more than 58 million people, researchers identified 894,396 individuals with at least one rare disease. This provides important data from a large population sample.

In Brazil, estimates suggest that between 7 to 12 million Brazilians may be affected by rare diseases, highlighting the substantial impact in different regions of the world.

Demographic Variations

Research has revealed significant demographic variations in rare disease prevalence:

• 49 rare diseases are significantly more frequent in female individuals than in male individuals
• 62 rare diseases are significantly more frequent in male individuals than in female individuals

Ethnic variations were also observed: - 47 rare diseases are significantly more frequent in Asian or British Asian individuals than in White individuals - 22 rare diseases are significantly more frequent in Black or Black British individuals than in White individuals

Challenges in Prevalence Estimation

Despite the collective prevalence, the prevalence of each rare disease is low, resulting in limited biomedical resources dedicated to research for individual rare diseases. There is currently no international alignment on how to define and describe rare diseases, which affects accurate global prevalence estimation.

Treatment Landscape

The vast majority (95%) of patients with rare conditions lack effective treatment or a cure, highlighting the significant unmet medical need in this area.

In conclusion, while rare diseases individually affect small populations, their collective impact is substantial, affecting hundreds of millions of people globally with significant variations across demographic groups and regions.

Economic Burden

Key Unmet Needs for Rare Diseases

Global Impact and Diagnostic Challenges

Rare diseases collectively impact approximately 300 million individuals globally despite affecting small population segments individually. A significant unmet need is the delayed diagnosis experienced by rare disease patients. This is largely due to lack of knowledge among clinicians, particularly emergency physicians, with 98.2% of surveyed emergency physicians feeling their knowledge about rare diseases was insufficient. The diagnostic journey for people living with undiagnosed rare diseases (PLURDs) remains arduous and often inconclusive, with limited awareness of rare disease incidence and professional resources.

Treatment Access and Therapeutic Gaps

More than 90% of rare diseases lack effective therapies despite legislative efforts like the 1983 US Orphan Drug Act. Similarly, no approved treatments exist for almost 95% of rare diseases, and existing treatments are cost-intensive for patients. Orphan drugs face significant challenges in marketing authorization, reimbursement, and have high costs creating affordability barriers for both patients and healthcare systems. There is also limited availability of treatments in developing countries.

Between 1990 and 2022, 491 novel orphan drugs were approved, with 65% approved for a single rare disease, 15% for multiple rare diseases, and 20% for both rare and common diseases. Only 10% of orphan drugs received a subsequent indication approval for a pediatric population of an orphan disease, highlighting the gap in pediatric rare disease treatment.

Genetic Nature and Personalized Medicine Needs

More than 70% of rare diseases are genetic in nature, with patient-specific mutations. This creates a need for personalized and patient-specific preclinical models to develop effective, speedy, and affordable therapeutic options. Complex in vitro models (CIVMs), including induced pluripotent stem cells (iPSCs), organoids, and organs-on-chips are emerging as powerful human-based pre-clinical systems. Knowledge of specific cell types affected by genetic alterations in rare diseases is crucial for advancing diagnostics and treatments.

Healthcare System Challenges

Rare disease management suffers from a lack of multidisciplinary approach, insufficient specialists, and inadequate infrastructure. There are limited newborn screening programs, poor care coordination across services, and inadequate psychosocial support for patients. The availability of specialized centers and genomic sequencing (WES/WGS) varies across countries due to healthcare systems, economic status, and government policies.

Population Inequities

Significant inequities exist related to place of residence, race/ethnicity disparities in care, gender differences in treatment access, socioeconomic status affecting care quality, age-related inequities, and disability-related barriers.

Research and Development Challenges

The traditional drug development and reimbursement pathway is not fit for purpose for N-of-1 individualized therapies. There is a lack of international alignment on how to define and describe rare diseases and a need for a global reference to establish mutual understanding. Some regions face a shortage of core authors and high-quality literature, with limited collaboration among research teams in certain countries.

Emerging Solutions

Promising approaches include gene therapies for treating severe disorders including rare diseases, physical activity (PA) as a potential strategy to improve overall well-being and quality of life, artificial intelligence for drug discovery, repurposing, and clinical trial optimization, and molecular farming approaches for affordable orphan drug production. Other recommended solutions include enhanced collaboration between stakeholders, separate registration processes for orphan drugs, multidisciplinary teams, and expanded genetic diagnostic techniques in clinical practice.