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Developing disease-modifying therapies for neurodegenerative diseases remains a pressing need.

The incidence of neurodegenerative disease is ramping up in the U.S. and elsewhere as much of the global population ages. One out of three seniors dies with Alzheimer’s disease or another form of dementia, according to the Alzheimer’s Association.

Parkinson’s disease is also becoming more widespread. Between 2015 and 2040, the number of people with Parkinson’s could nearly triple, rising from 6.3 to 17.5 million.

But developing drugs that can slow or stop the progression of such diseases poses a significant challenge for drug developers. Eli Lilly’s donanemab, for instance, showed promise earlier this year in treating Alzheimer’s in a Phase 2 study summarized in NEJM.

Another Alheimer’s candidate, aducanumab from Biogen, has also shown promise, although late last year, an FDA advisory committee concluded that more data were needed to demonstrate its efficacy.

Developing disease-modifying therapies (DMTs) for Parkinson’s disease poses a similar challenge.

To learn more about the prospects of such DMTs for the two most common neurodegenerative diseases, we reached out to Sarah Elsayed, neurology analyst at GlobalData and her colleague, Alessio Brunello, who is a managing pharma analyst at the data analytics and consulting firm.

Drug Discovery & Development: What are the main challenges in developing disease-modifying therapies for Parkinson’s disease (PD)?

Elsayed: According to GlobalData’s recent research, the lack of a disease-modifying agent and the high failure in PD clinical trials come down to the following points.

  • To date, the underlying pathophysiology of PD is not fully understood, and as a result, developing novel targets is extremely slow. The lack of pathological or imaging-based biomarkers has also complicated identifying pathologic differences between PD patients, affecting their accurate recruitment in new trials.
  • Phase 3 clinical trials for PD typically require hundreds of patients, and assessments are limited to observational methods. This includes a combination of physician and patient self-assessments. While PD is a particularly difficult disease to assess, even within a single patient, these clinical trials are designed in a way that can only capture a single snapshot of what may be a rollercoaster of motor fluctuations for an individual patient, as symptoms may vary significantly throughout the day, and from one assessment to another.
    • Finally, the neuroprotective or disease-modifying effects of drugs are complex to measure in clinical trials. This is due to several factors, including the need to test these drugs on early or even pre-symptomatic patients, the need to have cerebrospinal fluid (CSF) and imaging-based biomarkers in addition to the clinical endpoints, and the need to evaluate these drugs over longer-duration trials.

Accordingly, key opinion leaders (KOLs) suggested that the improved understanding of the mechanisms underlying PD neuropathology will allow for the future development of new neuroprotective and disease-modifying therapies. This will also drive more advancements in diagnosing PD patients at earlier stages through predictive biomarkers and genetic testing.

The advancement of the biomarkers, including genetic testing for risk factors at very early stages of the disease, is expected to impact the understanding of the brain’s responses and the potential disease-modifying/neuroprotective properties of therapies. KOLs believed that having pipeline agents aimed at certain gene mutations is the key to testing specific genetic subtypes of the PD population and developing effective personalized medications (precision medicine) in the future. An example of that is testing for the GBA or the LRRK2 gene, which was found to be a common gene in PD patients (5–10%).

Predictive biomarkers of PD progression will have multiple implications in DMTs, including improvements in early diagnosis. This will allow interventions at the earliest possible detection, improved clinical trial design, and an ability to predict patient prognosis. In addition to clinical benefits, biomarkers will likely catalyze scientific advancements in basic research towards a better understanding of the disease pathophysiology.

Finally, advanced technology can also play a role in improving clinical trials through the digital tracking of motor symptoms, specifically in advanced-stage patients who have debilitating symptoms and mobility problems. An application of digital tracking technology has been recently used in Roche’s PRX-002 trial, PASADENA, where digital tools enabled the remote and frequent assessment of participants in the trial. The positive signals on motor functions were confirmed using Roche’s PD Mobile Application v2, a smartphone app designed to measure core motor signs of PD, including several motor function tests and passive monitoring.

Drug Discovery & Development: What are some of the central challenges to developing a disease-modifying therapy for Alzheimer’s disease (AD)? 

Brunello: Similar to Parkinson’s disease, the drug development efforts for AD were met with a high failure rate, which could be due to the lack of identifying potential therapeutic targets, coupled with the need for reliable biomarkers and accurate clinical trial designs. The amyloid hypothesis has been the major explanation for the pathogenesis of AD for 20 years, but after amyloid-beta (Aβ)-targeting drugs ended in failure, researchers also started to explore other potential treatment options such as tau proteins and vaccines, even though these approaches were not successful either. The long list of Phase 3 clinical trial failures has raised doubts about the approach. Not all scientists are convinced that Aβ is the primary cause of AD, casting doubts about the potential of these drugs to be successful clinically and commercially. Also, recent studies indicated that the main factor involved in the development and progression of the disease is tau and not Aβ.

Despite that, the amyloid-beta hypothesis remains central in the development of anti-AD drugs. Therefore, combination therapy is likely the way to go for the Aβ inhibitor treatment class, but combination therapy research cannot be explored until a drug is approved.

Additionally, there is a growing consensus among scientists that treatment needs to begin in the early stages of the disease, and as there are no symptoms yet, biomarkers will be required. Measuring levels of Aβ protein deposits in the brain is the best diagnostic tool for detecting the progression of the disease, and the current way to definitively diagnose AD is through brain scans and tests of cerebrospinal fluid (CSF) that must be collected via lumbar puncture. These procedures are invasive and expensive. The lumbar puncture procedure requires local anesthetic before a doctor inserts a needle between two vertebrae in the lower back, while a positron emission tomography (PET scan), which is highly expensive, can only detect amyloid-beta peptides in the brain with 20% to 30% accuracy.

That said, there is a great unmet need for simple, inexpensive and non-invasive tests that could be applied on a large scale to screen for AD. This could be addressed by blood tests that are more sensitive in detecting the amyloid deposition in the brain compared to the gold standard, PET brain scan. Blood tests can also be used as a widespread population screening test and replace CSF testing and brain imaging if they keep proving to be more accurate than tests that are currently used.

At the end of 2020, one product was commercialized, the C2N test, called the PrecivityAD. It uses an analytic technique known as mass spectrometry to detect specific types of Aβ. The test costs $1,250 and is not currently covered by insurance, though a financial assistance program can bring out-of-pocket costs down to between $25 and $400 for eligible patients. They can also possibly help to accelerate the screening of patients for participation in clinical trials and enroll people with early signs of disease, evaluating whether drugs can prevent AD.

Finally, patient enrollment takes years, which is time-consuming and very expensive. This is currently one of the biggest challenges for the development of new DMTs for this disease. Having patients with early signs of the disease in clinical trials will help scientists develop a new treatment for AD and significantly impact the lives of patients.