Expanded Access: Opening Doors to Personalized Medicine for Rare Disease patients and patients with Neurodegenerative Diseases

Abstract

In neurodegenerative diseases a select set of neuron population displays early vulnerability and undergo progressive degeneration. The heterogeneity of the cerebral cortex and the heterogeneity of patient populations diagnosed with the same disease offer many challenges for developing effective and long-term treatment options. Currently, patients who are considered to have a “rare” disease are left with no hopes for cure, and many of the neurodegenerative diseases progress fast without any effective solutions. However, as our understanding of disease mechanisms evolve, we begin to realize that the boundaries between diseases are not as sharp as once believed. There are many patients who develop disease due to common underlying causes and mechanisms. As we move forward with drug discovery effort, it becomes obvious that we will have to shift our focus from finding a cure for a disease, to finding solutions to the disease causing cellular mechanisms so that patients can be treated by mechanism-based strategies. This paradigm shift will lay the foundation for personalized medicine approaches for neurodegenerative disease patients as well as patients diagnosed with a rare disease.

Introduction

Our brain is complex and heterogeneous. There are thousands of different neuron types in our cerebral cortex, all with a different pattern of connectivity and function. Understanding the cellular and molecular basis of neuronal diversity is needed not only to reveal how our brain develops, but also to understand why diseases emerge. Especially for neurodegenerative diseases, which were originally described based on clinical evaluation of patients and their symptoms, revealing the underlying causes of disease pathology is required for developing proper treatment options.

The concept of selective vulnerability was first suggested when it became clear that not all neurons in the brain responded to stress to the same degree and to the same extent (1). Likewise, a cell-type specific vulnerability and progressive degeneration was observed mainly in a select set of neuron populations in the brain, leaving other neurons and cells mostly unaffected (2). Understanding the basis of this selective neuronal vulnerability is an active area of research. In Alzheimer’s Disease (AD), for example, mainly the hippocampal neurons display progressive degeneration, whereas neurons in the motor cortex remain healthy. Likewise, in motor neuron disease patients, even though the neurons of the motor neuron circuitry undergo degeneration, the neurons of the hippocampus and other brain regions retain their health and connectivity. This is why AD patients retain their ability to move their body, and the motor neuron disease patients continue to remember effectively, albeit cannot perform voluntary movement.

The selective neuronal vulnerability affects different neurons and different circuitries. Therefore, the behavioral outcome varies among patients of different diseases. The original characterization of diseases was made based on observational clinic, and paying attention to the neuronal circuitries that are affected. For example, Dr. James Parkinson published his essay on the shaking palsy in 1817, describing the first patient based on detailed clinical diagnosis, which are currently used today. Interestingly, when the first patient diagnosis was made, we had very little knowledge or understanding of the neuronal connectivity and circuitry mapping. Yet, the same disease characterizations are still in effect today and patients continue to be diagnosed with similar clinical measures that are developed in the late 1900s. All drug related rules, regulations, drug discovery platform designs, expectations to move into clinic and all clinical outcome measures are built onto the baseline clinical information generated more than 100 years ago, and based on the information that was available at the time. However, many things have changed and improved since the last century, but unfortunately the advances in medicine and science have not been properly reflected on how we assess patients and define diseases.

There could be immense heterogeneity among patients who are diagnosed with the same disease. This is in part due to the different mechanisms that are responsible for neuronal vulnerability. For example, even though the outcome is neuronal death, a neuron may die due to different reasons, such as problems in axonal transport, mitochondrial dysfunction, increased ER-stress, mRNA instability, DNA damage, protein folding defects, protein aggregation, problems with lipid homeostasis, among many others. Therefore, patients diagnosed with the same disease do not have to have the same underlying cause that leads to their clinical diagnosis. In fact, many of the underlying causes are shared among patients who are diagnosed with different diseases. These could be considered as converging paths or converging mechanisms. For example, problems with unfolded protein response, autophagy, inflammation and mitochondrial defects are observed in many patients, who are categorized in different disease clusters (Figure 1).

Figure 1:

Patients are currently grouped in diseases based on clinical phenotypes. For each disease, subsets of patients share one or more common underlying cause with patients from other diseases, which collectively contribute to degeneration of selected neuronal populations. For example, some Alzheimer’s, Parkinson’s and ALS patient may have problems with unfolded protein response (UPR), autophagy, inflammation, and mitochondrial dysfunction. Therefore, developing treatment strategies based on common underlying causes broadens the spectrum and begin to offer personalized treatment strategies. Here, treating mitochondrial problems is used as an example. Drugs or compounds that treat other causes would also be as important as correcting mitochondrial defects.

An example of converging paths could be at the site of mitochondria, one of the most important organelle for generation of energy, and controlling many of the key cellular functions. Problems with mitochondria are observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients, dopaminergic neurons of Parkinson’s Disease (PD) patients, hippocampal neurons of Alzheimer’s Disease (AD) patients, and in many diffrent patients with rare diseases (3, 4). At first this may seem to contradict with the selective neuronal vulnerability hypothesis because we know that different neuron populations are primarily affected in different diseases. So how is it possible that that they degenerate due to common causes? The answer to that question lies in the fact that even problems, such as mitochondrial dysfunction, can be varied. For example, in one case the integrity of the inner membrane may be affected, in an other case, the ATP-production machinery may not be functioning, the lipid β-oxidation could be defective, the ultrastructural integrity may be comprimised. In fact, stating that there is mitochondrial problem is an over simplification. Likewise, other common disease mechanisms also are multi-faceted and complex. To make things even more complicated, just remember that not a single problem but a combination of multiple problems may be in effect. For example, protein misfolding and accumulation, ER Stress, inflammation, axonal transport defects, and changes in lipid homeostasis may contribute albeit at unique levels and intensities in different patients.

Failures in clinical trials, especially during Phase 3, speak volumes to the heterogeneity of the patient population and how we must change our unfounded expectation that one drug will cure all patients within that disease. Because different patients develop disease due to a plethora of underlying causes, it is very unlikely that one drug will improve the condition of heterogeneous patient populations within the same disease group. It is also important to remember that to date there are more than 140 genes identified to be either causative or associated with ALS and the proteins that are coded by these genes represent a very wide variety of proteins, many with unrelated functions. Therefore, the diseases are more complex than we think both at a genetic and mechanism level. This complexity may be challenging, but it also helps identify common causes, converging paths, and upstream regulators, which could be druggable targets for a larger population of patients. (5)

Unfortunately, grouping people based on disease names generates the false expectation that diseases as distinct entities and patients within each disease group are very similar in nature. This now emerges as a roadblock for future success in drug discovery efforts and for developing effective treatment strategies for neurodegenerative diseases in particular.

Another disadvantage of grouping patients based on disease names is the generation of the “rare disease” definition, which covers patients who either could not be categorized with the known diseases, and need to have their own disease name to be categorized under a different disease code identifier. However, this is very problematic and comes with many limitations and setbacks. First, because the number of patients is very limited the drug companies will not show interest in developing drugs because there will never be “enough” number of patients to complete meaningful Phases of clinical trials. In reality, the total numbers of patients who have been considered a “rare disease patient” are not few in numbers. When combined, they may make the largest disease population. Yet, with the current approach, it is very unlikely that any effective treatment will ever be developed to improve their condition.

As we build a better understanding about the underlying causes and cellular defects that lead to selective vulnerability of distinct neuron populations, it is our obligation to change our way of thinking about neurodegenerative diseases. Why can we not develop a better strategy that would help classify patients based on the cellular problems that lead to the selective vulnerability of their neurons? Is it really impossible to see beyond disease names, and begin to appreciate the mechanisms, the cellular events that are perturbed in patients? Especially in the 21st centuary, and with all the new information, we should be able to look beyond disease names. The underlying causes as well as the converging and diverging paths define the pathalogical condition of patients. So why not focus more on the mechanisms that are perturbed and try to find solutions to them as we try to eradicate neurodegenerative diseases?

If we manage to shift focus onto mechanisms, then there will be no patient left behind. Most importantly, it will also allow personalized medicine approaches to be developed, so that solutions will be tailored around the needs of the patient and we will be able to help one patient at a time, by appreciating their personal differences.

Currently, physicians could prescribe FDA (Food and Drug Administration)-approved drugs that are used for other diseases and this is called “off label use”. Even though there may be problems with insurance coverage, this is an important step for considering drugs that are approved for other diseases, and for mechanisms that may be related to the condition of the patient.

Most interestingly, however, FDA of USA developed a program called “Expanded Access”, which allows patients to have access to compounds that have passed Phase 1 and 2 stages of clinical trials, with proven safety and afficacy and no toxicity to patients (6). These compounds, because they have not yet passed Phase 3 of clinical trials, cannot be considered an FDA-approved “drug”. However, because information is available on their target engagement, mode of action and the pathways they modulate, and because they lack toxicity, FDA gave permission for them to be considered, based on the needs of the patient and based on the recommendations of the patient’s physician. In support of this move, on June 1^st 2020, a new bill, the A.C.T. for ALS H.R 7071, was introduced to earmark funds to finance access to investigational drugs for ALS and other rapidly progressing neurodegenerative diseases so that FDA’s Expanded Access Program would receive financial support. These developments further suggest that both FDA and the US goverment are moving in the direction of building personalized medicine approaches especially for patients with fast progressing and debiliating diseases.

Expanded Access to patients may appear to be a small step, but it has immense implications both for drug discovery and for developing personalized treatment strategies. In the near future, we may be able to develop clinical trials not in the name of a disease, but in the name of a mechanism. This will allow many different patients, who have been previously earmarked with different disease names, to be included into the studies that are developed based on a specific and shared disease mechanism. This would especially be a good news for “rare disease” patients, because their disease spectrum did not fit well into the previously described and characterized diseases. Therefore, even though they share many common mechanisms with the patients of other diseases, they were never similar enough to the other patients, and thus were excluded. This mechanism-based approach will be more inclusive and will encompass patients from many different diseases, some of the rare disease patients, and interestingly, it may even include patients beyond the spectrum of neurodegeneration, and potentially cancer patients.

In fact, the cancer field is about 10 years ahead of neurosciences. Previously, cancer drug discovery efforts were paying more attention to the tissue and categorizing cancers mostly based on the tissue of origin, such as breast cancer, ovarian cancer, prostate cancer. However, as we begin to learn the different kinds of cancers and their mode of propagation and tumorigenicity, the tissue became less important, while revealing the type of melanomas became the key aspect of understanding cancer pathology. Likewise, developing drugs for the mode of action, the mechanisms of propagation became more relevant (7). In line with this change in perception, the cancer drug discovery field has demonstrated an exponential growth and improvement. In less than 10 years, many forms of cancer are now kept under control and many patients, regardless of the tissue their cancer was first identified, are included in drug discovery studies as long as the underlying causes of their tumor malignancies were similar.

As we begin to reveal the underlying causes of selective neuronal vulnerability in neurodegenerative disease patients, a new algorithm will be developed to stratify them. It is possible that in the near future, the mechanism will be more important and relevant than the disease name. We will be able to identify patients based on the perturbed and altered mechanism in the disease and will begin to develop personalized medicine approaches that are tailored around the needs of the patient.

Since the mode of action for many of the FDA-approved drugs are already known, it is possible that we will witness an immense wave of drug repurposing studies that investigate whether a drug that was previously approved for one disease, now also have implications for patients that are grouped under a different disease name. It is important to remember that an earlier version of edaravone, the second ALS drug that received FDA approval, was originally identified as an antioxidant drug targeting peroxyl radicals and many types of reactive oxygen species, and was used primarily after acute ischemic stroke (8). Therefore, we foresee immense research efforts investigating whether current drugs and their derivatives, could be reporposed for other diseases and conditions.

For example, and just as an example, if a drug was approved to improve the integrity of mitochondria and thus increase their health and function, then the same drug may also be utilized for a subset of patient population within different diseases, as long as these patients also become diseased due to mitochondrial defects in their vulnerable neurons. So, the goal of drug discovery shifts from curing any particular disease, to curing the health of diseased neurons. This is an immense shift in critical thinking, and this vision lays the foundation of the path that is going to move us forward (Figure 1).

Thanks to the pace of discoveries in the field of biomarkers, soon clinicians will be able to assess and understand why their patients develop the disease, and will prescribe drugs to treat the underlying cause. Since each patient develops pathology due to different underlying factors, the prescription of one patient will in fact be very different from another patient diagnosed with the same disease. Each patient will be prescribed what his or her degeneration neurons require to get better, and as neurons become healthier, the circuitries they belong to will become more integrated and functional. This improvement in function will be reflected to patient’s behavior and overall health.

Conclusion

The scientific developments of the 20^th and now 21^st century, made us realize how complex the diseases are and that it is not possible to group patients under the umbrella of any given disease. Many patients develop disease manifestations due to common cellular pathologies, and the boundaries among diseases are fluid and dynamic. Therefore, our approach needs to be more inclusive and expanded so that patients from other diseases can also be included in treatment strategies as long as they share the common underlying cause.

We will have to shift our focus from disease to mechanism and develop personalized medicine strategies in the near future so that no patient will be left behind, and solutions can be tailored around the medical needs of each patient. Yes, this is challenging, but this is the path forward. Paving the way for a personalized and effective treatment strategy is our obligation to patients.

Abbreviations:

AD

Alzheimer’s Disease

PD

Parkinson’s Disease

ALS

amyotrophic lateral sclerosis

ER

endoplasmic reticulum

FDA

Food and Drug Administration