AMWA Member Blair Hesp explores the challenges associated with developing a prophylactic treatment for age-related neurodegenerative disease.
The graveyard for clinical trials investigating treatments for age-related neurodegenerative disease is becoming more cluttered by the day. Buried in this graveyard are both therapies designed to relieve symptoms and those aimed at slowing disease progression, but by the time they are administered these therapies are inevitably too little, too late given the level of neuronal damage that has occurred by the time most patients become symptomatic.
One of the main problems with identifying the early stages of neurodegenerative disease is the brain’s remarkable ability to re-wire itself and continue to function relatively normally despite a loss of neuronal capacity. For example, patients with Parkinson’s disease have often lost >80% of the dopaminergic neurons in their substantia nigra by the time they present with symptomatic disease.
Accordingly, new treatment options for neurodegenerative disease are focusing on an “early intervention” strategy using disease-modifying drugs that attempt to slow disease progression. However, early intervention is a relative term, especially given that the vast majority of the damage has already been done. Perhaps “earlier intervention” is a more appropriate term for a rear guard action aimed at slowing the advance of age-related neurodegenerative disease.
“One of the main problems with identifying the early stages of neurodegenerative disease is the brain’s remarkable ability to re-wire itself…”
Given this knowledge, it is not unreasonable to consider whether treatment with disease-modifying therapies for age-related neurodegenerative disorders may need to begin decades before outwardly visible symptoms appear to be efficacious. So, could prophylactic treatment against age-related neurodegenerative disease ever be a realistic proposition? Would it even be feasible to initiate a clinical trial that would investigate this possibility?
Who do you treat?
There are a myriad of ethical questions here. How do you identify appropriate candidates for a clinical trial investigating the pharmacological prevention of age-related neurodegenerative disease? A selection of patients with a familial history of neurodegenerative disease, or identified as being genetically high-risk, could be used as a surrogate for the general population, but perhaps, as shown with many cancer therapies, this may be too simplistic. Alternatively, it may be necessary to wait for new genotypic or phenotypic markers of future neurodegenerative disease to be identified as a large-scale interventional study involving a general population sample would surely not be justifiable.
Furthermore, with the advances of modern medicine, it may be expected that an increasing proportion of the population will live to an age at which they develop an age-related degenerative disease. But, would the benefit of preventing or limiting age-related degenerative disease in the minority justify medicating the majority?
When do you treat?
Any patients enrolled in a study examining prophylaxis against age-related neurodegenerative disease will most likely be medicated over a number of years, if not decades, before any treatment benefit could be identified. However, it would not be unreasonable for any treatment detriment to be identified in the meantime. In this case, do you stop the trial and under what circumstances?
“…could prophylactic treatment against age-related neurodegenerative disease ever be a realistic proposition?”
Also, when do you start prophylactic treatment for age-related neurodegenerative disease? Middle age may be too late, but prophylactically treating patients in their 20s or 30s may leave a generation resigned to daily pill-popping. In addition, how would an ‘at-risk’ population be defined and would treatment be truly prophylactic or initiated upon observing a sign of brain pathology?
How would you measure outcomes?
As cancer therapies have become increasingly effective, there has been an increasing focus on surrogate endpoints in clinical trials, such as progression-free survival and response rate, as opposed to the gold standard endpoint of overall survival. This is partially because of outcomes being confounded by later treatments and partially because of the practical considerations associated with increasing median survival times.
Investigating the prophylaxis of age-related neurodegenerative diseases would offer the same challenges, but on an even longer time scale. Likewise, would it be appropriate to measure future disability and quality of life or overall survival as a primary endpoint when attempting to prevent neurodegenerative disease? How do you control for confounding factors? Could surrogate biochemical endpoints form the basis of prophylactic treatment? Currently, markers associated with neurodegenerative disease, such as beta-amyloid plaques or tau protein in Alzheimer’s disease, have been found to be of questionable value as surrogate endpoints, so can we be confident of the value of surrogate endpoints in neurological disease?
“…prophylactically treating patients in their 20s or 30s may leave a generation resigned to daily pill-popping. ”
Who will pay?
Merely investigating the concept of prophylaxis for age-related neurodegenerative disease is an extremely expensive proposition. Trials for cancer therapies are already looking to use surrogate markers for efficacy because median survival times are now routinely extending to a number of years. Furthermore, it is quite possible that by the time a new treatment is identified, and confirmed as being efficacious, intellectual property rights for the treatment are likely to have expired, so the proposition of a low commercial return on an extremely large investment is unlikely to be shouldered by the private sector, or at least not without significant public sector funding or intellectual property concessions.
Likewise, would the cost of medicating a large population over an extended period of time to reduce future costs associated with age-related neurodegenerative disease justify the opportunity cost of fewer resources being available for current medical needs?
Is prophylactic treatment for age-related neurodegenerative disease a realistic proposition?
The reality appears to be that prophylactic treatment of age-related neurodegenerative disorders is unlikely to be ethically or economically feasible without a clear and readily identifiable benefit being likely for those treated. Therefore, a reactionary “early intervention” in response to symptomatic markers of age-related neurodegenerative disease is likely to remain our best option for making the best out of a bad situation when fighting age-related neurodegenerative disease.
This post originally appeared on Pharmaphorum.
Blair Hesp is the Managing Director of Kainic Medical Communications Ltd., a New Zealand-based agency that specialises in providing on-demand professional medical writing support to overseas medical communications agencies and New Zealand-based biotechnology companies. Blair has a PhD in Pharmacology from the University of Otago and a New Zealand Diploma in Business, and has been recognised as one of New Zealand’s most innovative marketing and communications professionals. In addition to several years’ experience working in the Global and European medical communications industry in the United Kingdom, he has also spent several years working in the international intellectual property industry.