Developing new and innovative treatments for disorders affecting the central nervous system is a long-standing issue in the landscape of CNS drug development. The complexity in the function of the brain and the spinal cord means development and trial success of new and effective CNS drugs is a long and often unsuccessful process.
Historically, failure rate for new CNS drugs was very high, due to the complex nature of these diseases and the biological, ethical, and technological limitations faced during the drug development process. Despite this, recent developments have been made in the field as our access to technology, and knowledge of these diseases grows.
In 2016, Alzheimer’s Disease International reported in their World Alzheimer’s report that around 47 million people struggle with dementia worldwide. Atlas of MS found in their 2020-2022 study that 2.9 million people worldwide are living with MS, and according to the Cerebral Palsy Alliance Research Foundation, 18 Million people globally have the condition. These statistics do not include individuals living with other CNS diseases such as bell’s palsy, epilepsy, and parkinson’s disease.
These statistics emphasise the urgent need for an increase in the success rate of new CNS drug development, and the importance of funding and understanding of CNS diseases.
This blog aims to review the current landscape of central nervous system disorders, including CNS drug development, CNS diagnosis technology, and CNS clinical trials. It will explore the hurdles faced in understanding these intricate diseases and the process of developing FDA-approved CNS drugs and treatments. We will also explore recent advancements and opportunities in this field as well as the forecasted future of CNS drug development.
CNS Drug Development – The Current Landscape
As we gain more understanding of these complex neurological and psychiatric disorders, we can better identify how to leverage modern technology to target these conditions. Pharmaceutical companies now have a better understanding than ever on how to best leverage both drug discovery as well as the precision of clinical trials. Leveraging technology such as gene editing and artificial intelligence are leading the new innovations of CNS understanding and treatment.
Some CNS diseases are currently more researched and understood than others. This in turn typically results in drugs and treatments for these diseases being more accessible.The current availability of drugs for a specific CNS disease usually depends on various factors, including:
- Disease Complexity
- Public Health Priority and Funding
- Availability of Clinical Trial Participants
- Understanding of Disease Mechanisms
Recent Pharmaceutical Advancements in CNS Drug Development
One of the most groundbreaking developments in CNS therapeutics in recent years is the emergence of gene therapies, such as Zolgensma. Gene therapy addresses the underlying genetic cause of CNS diseases, and seeks to tackle and modify these genetic mutations associated with CNS disorders. Early phase clinical trials of Zolgensma began in 2014, following the success of this clinical trial, the treatment was approved for adults and children with SMA type 1.
Another significant advancement in CNS therapeutics is the development of RNA-based therapeutics, such as antisense oligonucleotides (ASOs). ASO’s can target and regulate gene expression, blocking the translation of messenger RNA into proteins. In recent years ASOs have shown progress in the treatment of Huntington’s disease and Spinal Muscular Atrophy. Early clinical trials of these therapeutics showed a promise in reducing levels of the disease-causing protein. Despite this, Phase III clinical trials have been halted by an unblinded independent data monitoring committee, with no statement released of the reasoning of this.
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Recent Technology Advancements in CNS Diagnostics
Advancement in artificial intelligence and neuroimaging technology are also amplifying CNS drug therapeutics. Diagnostic imaging scans help identify CNS diseases, and advancements in these technologies allow for earlier and more accurate diagnosis.
MRI Scans
High-field and ultra-high field MRI scanners offer higher resolution and better signal-to-noise ratios, allowing for clearer identification of neurological abnormalities in patients. MRI technology has also adopted machine learning algorithms which helps enhance image analysis. These algorithms are particularly effective in identifying Altzheimer’s and Parkinson’s disease, as they can help better identify subtle changes in the brain.
PET Scans
PET scans have also undergone significant advancements in recent years. New radiotracers bind to cells and proteins associated with CNS diseases. Amyloid imaging has recently become an essential PET scan tool, which helps visualise changes in the brain that indicate Alzheimer’s disease.
Artificial Intelligence (AI)
In recent years, AI has been utilised to work collaboratively alongside neuroimaging tools and medical professionals to help identify and diagnose CNS conditions. Once diagnostic imaging scans have been done, AI’s pattern recognition helps identify changes and patterns in the brain, often with greater precision than a human could. This can result in faster and more accurate detection, shortening the wait time for patient diagnosis.
Wearable Devices
The advancements in wearable technologies, such as smartwatches and biosensors helps monitor the health of those with CNS disorders. This leads to faster response times to any changes or regression of a patient’s health. These devices can track metrics such as movement patterns, heart rate, and dopamine levels.
The Grand View Research estimates that the wearable medical devices market will have a revenue of $196 Billion by 2030, and will shape healthcare in the coming years.
What are the challenges of CNS Drug Development?
Complexity of the central nervous system
The complexity of the brain and the spinal cord make it particularly challenging when developing CNS drugs, compared to developing drugs for other therapeutic areas. The central nervous system is composed of different neurons, each with unique functions which interconnect to provide brain function. The intricacy of the central nervous system makes it difficult to identify and target specific CNS conditions.
Heterogeneity of CNS Symptoms
A lot of CNS disorders, such as Alzheimer’s and Multiple Sclerosis have several root causes, which affects how they can be treated. This requires more personalised treatments for each patient. The heterogeneity also affects the ability to achieve consistent results in CNS drug clinical trials, as it is challenging to find study groups which exhibit the same symptoms and disease progression. Heterogeneity is a key consideration when conducting any first in human clinical trial.
Neural Interaction
As the central nervous system operates through complex neural interactions, it is important that CNS drugs don’t disrupt these other neural pathways. It is a significant challenge to develop drugs which target specific pathways without these causing issues elsewhere in the central nervous system. For example, drugs to treat Parkinson’s disease and depression may aim to enhance neurotransmitter levels, leading to drastic side effects in other areas of the brain. It is important that the pharmacology of these drugs is thoroughly investigated to ensure they are safe and will not negatively affect other areas of the brain.
Lack of Animal Models
Animal models used in preclinical studies vastly differ from the complexity of the human central nervous system. This often makes them an unreliable indicator of if a new CNS drug will have a positive effect on treating these CNS diseases in humans. Animal models are useful in a lot of other therapeutic areas such as wound healing and cancer treatments, but the gap between animal models and the human brain remains a significant hurdle in CNS drug development.
H4 – The Blood-Brain Barrier (BBB)
The blood-brain barrier protects the brain from potentially harmful substances in the bloodstream. This can have significant effects on a drug’s ability to target areas of the brain as they fail to cross the blood brain barrier. Successful CNS drugs must contain specific properties that allow them to cross this barrier. Developing drugs which are both effective at treating CNS diseases and possess the physicochemical properties to penetrate the BBB is another obstacle faced during the drug development phase.
Clinical Trial Challenges and Complexities
Multifactorial Nature of CNS Disorders and Patient Variability
A lot of CNS disorders arise from a combination of genetic, environmental, and lifestyle factors. This adds another level of complexity when attempting to identify a single, definitive therapeutic target for clinical trials, making it difficult to define individuals which will benefit from the drug.
Limited Understanding of CNS Disorders
Despite recent advances in neuroscience, the complexity of the brain means understanding the precise mechanisms of many CNS disorders is still incomplete. This gap in knowledge makes it difficult to identify relevant and effective treatments in order to target these drugs. For example, the cause-and-effect in conditions such as schizophrenia and autism is still unknown. This gap in knowledge often leads to a trial-and-error approach in clinical trials, resulting in high failure rates.
As well as this, the quickly evolving understanding of many CNS conditions mean that endpoints and trial designs are constantly changing to keep up with new found information. This can add significant time and disruption to ongoing trials.
Ethical considerations of test patients
The vulnerable nature of many CNS patients is a significant ethical concern when conducting CNS clinical trials. Disorders such as Alzheimer’s and Schizophrenia can impair cognitive functions. This can affect the patient’s ability to give consent and to fully understand the trial’s procedures and potential risks This consideration can reduce the accessibility and diversity of patient recruitment in CNS clinical trials.
Market and Commercialisation Challenges
The CNS drug development journey involves rigorous and time-consuming approval processes to ensure drug safety and compliance to regulatory guidelines. Without proper advice from the outset, these can very easily involve setbacks in drug approval, delaying the accessibility of these treatments. Getting accurate advice from an experienced source at the start can allievate the risk of such delays occurring by ensuring study and trials designs are robust and will deliver the necessary data.
CNS Drug Development Opportunities
Artificial Intelligence
As well as being used in the diagnostic process of CNS diseases, new artificial intelligence is now being utilised in the drug development process. AI has generated molecular structures, which unlike past drugs, have the ability to cross the blood-brain barrier. Although still in the development phase, this process could lead to drugs that can more effectively target neurons in the brain.
Academic and Industry Collaborations
Collaborations have played a crucial role in recent years in the development of new CNS drugs. These collaborations allow for an amplification in expertise, research efforts, and research capabilities by academics and industry partners, providing more resources for new drug development. Academic and industry collaboration has been successful in developing treatment for schizophrenia in recent years.
Neuroimaging-based biomarkers
Neuroimaging-based biomarkers have been utilised in CNS drug development, aiding in determining the recommended dosing for new drugs. CNS diseases which have most benefited from these biomarkers are Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Neuroimaging-based biomarkers have been used in the diagnostic, drug development, and clinical research processes for these diseases.
Our understanding of CNS disorders is forever evolving. New technology advances and innovative approaches are constantly providing more hope for improved treatments and a higher success rate for clinical trials. By capitalising on emerging technology and dedicating research efforts, more can be done to effectively diagnose and treat these central nervous system disorders, resulting in better outcomes for CNS patients.