Rare diseases Flashcards
What is a rare disease
Rare disease is a disorder that affects fewer than 5 individuals in 10,000 of the population (as defined by the European union)
What is an orphan drug
Orphan drug is a drug developed to treat rare or a neglected disease.
Orphan drug designation in the EU is based on: The prevalence of disease, The disease; life-threatening, serious or chronic no approved treatment available
How do rare diseases impact the study design. Give examples of the challenges
The study design and drug supply chain is the greatest challenge that rare disease drug development faces
Clinical trial design is challenging;
Small patient population = low disease incidence = small sample size = Statistically underpowered
Geographically dispersed (fewer patients/country) (multicentre study £££)
Limited disease reporting and understanding
Insufficient natural history data
Small # case studies > limited/no follow-up
No validated disease relevant endpoints
Clinical obstacles
Heterogeneous presentation
Advanced disease (diagnostic delays)
Experts are few and geographically dispersed
What is Mitochondrial neurogestrointestinal encephhalomyopathy (MNGIE)
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the nuclear thymidine phosphorylase (TYMP) gene.
What are the clinical presentations of MNGIE
Gastrointestinal Symptoms: chronic abdominal pain, malabsorption
Neurological Symptoms:
Peripheral Neuropathy
Ocular Symptoms: loss of vision
What are the 2 experimental approaches for MNGIE treatment
Direct removal of the elevated metabolites via Haemodialysis (no clinical improvements)
Introduction of deficient thymidine phosphorylase:
Erythrocyte encapsulated thymidine phosphorylase (EE-TP):
What information is included in the investigational medicinal product dossier (IMP/IMPD)
Chemistry
Manufacturing process
Tests performed to ensure quality/purity of study drug
What is the result of mutations in the TYMP gene
Mutations in the TYMP gene lead to a deficiency in thymidine phosphorylase activity, resulting in elevated thymidine levels in the blood and tissues.
The biochemical consequences of mutations in the nuclear TYMP gene in MNGIE include:
Mitochondrial DNA Depletion
Mitochondrial Dysfunction:
The mitochondrial dysfunction associated with MNGIE is a consequence of impaired nucleotide metabolism and mitochondrial DNA depletion. Mitochondrial dysfunction affects cellular energy production and contributes to the multisystemic symptoms observed in MNGIE, such as gastrointestinal dysfunction and neurological impairment.
Accumulation of Toxic Intermediates:
The accumulation of thymidine and deoxyuridine can result in the formation of toxic intermediates. These intermediates may interfere with cellular processes and contribute to the pathophysiology of MNGIE.
What is Erythrocyte encapsulated thymidine phosphorylase (EE-TP)
Thymidine phosphorylase is an enzyme involved in the catabolism of thymidine, a component of DNA
TP is encapsulated in autologous erythrocytes ex vivo
This is then intravenously administered to patients
Plasma thymidine/deoxyuridine permeate erythrocyte membrane via nucleoside transporters
Thymidine/uracil exit cell for excretion/metabolism
What is orphan drug designation based on in the EU?
The prevalence of disease
The disease; life-threatening, serious or chronic no approved treatment available
How can the orphan drug space be accessed effectively?
Improve understanding of underlying: disease pathology
Conduct natural history studies
Clinical trial endpoints
Surrogate endpoint measures
Identify drug targets
Identify therapeutic approaches
Understand how patients and their families are impacted by the disease:
Clinical trial design (procedures)
End point measures
Increase disease awareness:
Among healthcare professionals
Patient identification
Improve diagnosis
Recruit patients earlier on in disease course
What does the MHRA point of care (POC) manufacture framework propose?
Proposes:
POC manufacturing sites
Local manufacture of drug & release
Authorised person at each site
Transmit manufacturing data to Central control site
List the advantages of the POC framework:
Reduces costs + no shipping costs, faster production time & flexible patient scheduling
Explain the role of the TYMP gene and the result of a mutation in the gene
The TYMP gene encodes the enzyme thymidine phosphorylase, which is involved in the catabolism of thymidine, a DNA building block. Mutations in the TYMP gene lead to a deficiency in thymidine phosphorylase activity, resulting in elevated thymidine levels in the blood and tissues.
