The Challenges of Conducting Rare Disease Clinical Trials
Regulation, governance and funding can be extra barriers for small biotech firms trying to make an impact.
Designing and running clinical trials to test the effectiveness and safety of a new drug is an extremely complex process. Doing this for rare diseases – defined in the United Kingdom as diseases affecting fewer than 1 in 2,000 people – presents additional challenges for researchers and biotechnology companies to overcome.
SynaptixBio is a UK-based biotechnology company pursuing new treatments for a type of rare and deadly genetic brain disorders, known as leukodystrophies. These disorders damage the white matter of the brain and spinal cord by affecting the myelin sheath which insulates nerve fibers, leading to a progressive decline in motor and cognitive abilities.
SynaptixBio recently announced that it had identified a promising candidate drug for treating one leukodystrophy, H-ABC, that will soon head into clinical trials.
To learn more about the unique obstacles that come with rare disease clinical trials, the effect of leukodystrophies on patients and what more can be done to support rare disease research, Technology Networks spoke with Uwe Meya, MD, chief medical officer at SynaptixBio.
What unique challenges are involved in running clinical trials for rare diseases?
Uwe Meya, MD (UM):
Developing a drug for a rare disease is risky. The costs of development may be as high or higher than creating a drug for a more common disorder, the pool of patients for clinical trials is limited and the market is small.
Economic incentives present a sizable obstacle. Since rare diseases impact very few patients, pharmaceutical companies and institutional investors often hesitate to look at the expensive R&D required to find life-saving drugs, instead focusing on more mass-market candidates.
Although regulatory incentives help, the cost and time frames for rare disease drug development can still be prohibitive.
One of the most pressing issues for rare disease treatment innovation is data scarcity and fragmentation. Rare diseases, by definition, affect smaller populations, making it difficult to collect sufficient clinical data for accurate analysis.
The data that does exist is often siloed across hospitals, research centres or pharmaceutical companies, making comprehensive analysis and collaboration difficult. Without access to unified, high-quality datasets, advanced technologies like AI tools and machine learning can have limited impact.
From a governance and ethical perspective, rapid innovation must be balanced with patient safety and privacy. New diagnostic tools or treatments powered by AI need rigorous oversight, particularly when using sensitive patient data. Mistakes and data breaches can erode public trust and impose slow adoption.
Structurally, it is smaller biotechs that are more commonly involved in finding or designing drugs for rare diseases, but this creates the problem that they are likely less able to invest in such advanced tools.
AB:
SynaptixBio is heavily involved in developing therapies that can be used to treat leukodystrophies, particularly H-ABC. Can you tell us more about this rare genetic disorder?
UM:
H-ABC stands for “hypomyelination with atrophy of the basal ganglia and cerebellum”. It results in impaired myelin production and damage to the basal ganglia and the cerebellum.
Myelin is a part of the brain that builds the sheaths around the axons (the long branches of the neurons that reach out for connections with another neuron). Because of its appearance, this is called “white matter”. When an individual does not have enough myelin, they are said to have “hypomyelination,” where “hypo” means less than expected.
Myelin is to neurons in the brain like the insulation around the electrical cords in your house. It enhances the efficiency of communication between cells in the brain and supports the health of cells in the brain. Myelin is made by cells called oligodendrocytes. In H-ABC, researchers think these special cells do not do their job properly, leading to insufficient development of myelin.
The basal ganglia, also called deep gray nuclei, are collections of neurons deep in the brain. They help coordinate how smoothly movements are executed, their coordination and their speed. In H-ABC, researchers think these special cells get sick and die, leading to atrophy of these structures.
The cerebellum is a structure at the base of the brain that helps regulate information coming from the brain as it exits to the spinal cord and vice versa. It helps regulate balance and the smoothness of movements. In H-ABC, the impacts on these structures are similar to those in the basal ganglia.
H-ABC is caused by a mutation in a gene called TUBB4A and is part of a larger disease group called TUBB4A-related leukodystrophy. TUBB4A makes a special structural protein called tubulin, and tubulins come together to build microtubules. Microtubules serve to provide structure to cells and to move components in the cell.
Individuals with deleterious changes to one of the copies of the TUBB4A gene are thought to make an abnormal copy of the normal tubulin protein, interfering with normal microtubule function.
AB:
How does H-ABC affect people with the disorder?
UM:
People with TUBB4A-related leukodystrophy show progressive deterioration of motor skills, which extends to walking, sitting, using their hands, but also speech and swallowing.
The symptoms and progress of H-ABC differ depending on when the disease first appears.
When symptoms begin in the first few months of life, children mostly never reach early motor milestones like head control, sitting or walking. The effect of the disease also tends to be severe and its progress more rapid. In these cases, symptoms may include:
- A small head (microcephaly)
- Uncontrolled, jerky eye movements (nystagmus) and poor vision
- Problems with swallowing and speech
- Low muscle tone (hypotonia)
- Poor coordination or clumsiness (ataxia)
- Muscle and limb stiffness (spasticity)
- Involuntary movements, including twisting, writhing and abnormal postures (dystonia and choreoathetosis)
- Seizures
When symptoms begin later, in early childhood, children start losing their previously achieved milestones and the progression may be slower. In these cases, the primary symptom is progressively greater trouble with movement, including:
- Stiffness of the arms and legs (spasticity)
- Gait problems and other problems with coordination (ataxia)
- Involuntary movements, including twisting, writhing and abnormal postures
- Learning difficulties
AB:
SynaptixBio recently announced the choice of a candidate drug for upcoming clinical trials – an antisense oligonucleotide (ASO), SB H-19642. How does this candidate work? How do ASOs compare to gene therapy?
UM:
SynaptixBio’s approach is based on “gene silencing” – a technique that stops the expression of a mutated gene without altering the gene itself. This is achieved using antisense oligonucleotides (ASOs), short strands of synthetic nucleotides that bind to the mutated RNA and prevent the formation of the mutated protein. Similar approaches are being explored for treating Alzheimer’s disease, Parkinson’s disease and motor neuron diseases, such as amyotrophic lateral sclerosis.
Around 80% of rare diseases are monogenic, caused by a mutation in a single gene, so the ability to stop that mutation from forming toxic proteins is a hugely promising avenue of investigation. This gene silencing approach is different from gene editing in that the gene itself is untouched; only its expression as a protein is affected.
ASOs are highly targeted and may produce much fewer side effects than gene editing. Perhaps most importantly, ASOs target the molecular causes of disease, rather than just treating the symptoms. This is what makes them game-changing.
AB:
What more could be done to better support efforts to discover treatments for rare diseases?
UM:
The situation can be improved with more reliable investment and funding, with more collaborative and coordinated research with specialist institutions and with education campaigns to enhance diagnostic rates. We enjoy working with patient advocacy groups, which play an important role for trial design and patient awareness, and we look forward to even more frequent collaboration.
