Guest Column | July 19, 2023

Why Do So Many Alzheimer's Clinical Trials Fail?

By RJ Tesi, MD, CEO and chief medical officer, INmune Bio

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Since 2003, 98% of Alzheimer’s disease (AD) treatment clinical trials have failed, showing a disappointing 2% success rate (aducanumab included). While clinical trials are difficult in and of themselves, AD is a complicated disease, and there are common issues across these particular trials that have caused so many failed attempts.

There are also ways to manage the issues with AD clinical trials and move forward with successful ones. Understanding why AD clinical trials fail and how to best mitigate those failures is vital to the future of AD clinical success. Here are three primary reasons why so many AD clinical trials fail, as well as ways to improve the chance of success.

1. Recruiting the right participants is difficult.

Enrollment of elderly patients with dementia is challenging because it involves the patient’s whole family. Because the evaluation period to determine eligibility for participation in the trial is long and complicated, a patient cannot simply walk in and sign up. They must undergo 30 to 60 days of testing before eligibility is determined. This testing includes cognitive testing and neuroimaging tests such as positron emission tomography (PET) scans and Magnetic resonance imaging (MRI). These tests often happen at different locations over the course of several days. This requires a commitment by the patient, the caregiver, and often the extended family.

Another barrier to recruitment is that while placebo groups are essential for trials, they are off-putting to patients and their families. A patient may undergo one or two months of evaluation to determine eligibility for the clinical trial only to end up in the placebo arm. Even more daunting is that many trials last 18 months or longer. If a patient is assigned to the placebo group, their disease worsens for a year and a half and, at the end, the patient may be too sick to participate in another trial. The sheer possibility of being on placebo makes patients and their families hesitant to enroll. However, it is important to note that the placebo group is necessary in these clinical trials as they ensure accuracy.

Almost all clinical trials in patients with AD are looking for patients with early AD. Yet, in general, patients are diagnosed late in their disease state and are often too far along to participate in a clinical trial. A 2019 study found “diagnostic and care pathways hindered identifying patients with mild-moderate AD, with a lack of up-to-date patient records and data access problems affecting screening.” Early diagnosis starts with the patient inquiry of concern but requires the patient’s medical team to act on that concern. In the past, due to lack of effective therapies, there was little reason for the patient to ask and even less for the physician to act. This is a slowly changing issue, as people learn more about managing the disease and some treatments are becoming available, but more education around the importance of an early diagnosis is needed.

Everyone from the patient to the payer needs to understand the problem can only be solved with their help. A clinical trial is only possible with the right participants in the right stage of their disease with a supportive family or caretakers to help the patient through the process. Providing proper screenings that are rapid, easy and convenient, and diagnoses early is an important first step to solving this issue.

2. Typical trial design is plagued with shortcomings.

There are many issues with how Alzheimer’s clinical trials were designed, including poorly chosen primary clinical outcome measures, insufficient accounting for potential AD subtypes, and the too-late administration of therapeutic interventions.

AD is defined as cognitive decline in patients with amyloid in their brain. This inclusion criteria assumes amyloid is causing a person’s cognitive decline. The standard assumption is that decreasing amyloid will then change the course of the disease. Thus, the 30-year quest to eliminate amyloid has been successful — the current therapies remove amyloid. Unfortunately, the success in removing amyloid did not result in dramatic improvements in cognition.

Preclinical data and human experience now confirm amyloid plays only a small part of the cognitive decline in patients with AD. This focus on decreasing amyloid as the primary clinical outcome measure has been proven to be misplaced, and clinical trial leaders now need to look for other outcome measures that will have a larger impact on stopping cognitive decline.

Another issue has been the old-fashioned trial design used in AD clinical trials. Most AD trials are “all comer” trials. That is, if you carry the diagnosis of AD, you are eligible. Oncology gave up “all comer” trial design two decades ago because it was proven not to work. For example, in breast cancer, if you have a drug that is meant for HER2 positive breast cancer but include all patients with breast cancer, your results will have limited success due to the population not being the right fit. If you only enroll patients with HER2 positive breast cancer, the results will be stronger, even with a smaller trial because you are targeting the correct patient population. The need for personalized and precision treatments has been recognized. In cancer, enrichment criteria are used to match the patient’s disease with the drug’s mechanism of action. As a result, trials are smaller and more successful so that many drugs get approved in oncology faster at lower cost.

The old-fashioned trial design assumed that AD is just one disease. AD is complicated; it is more than a single disease, and the role of amyloid is minimal. The same can be said for tau, which is a protein that is released by dying neurons in the brain. Some believe that tau must be a cause of AD because it is present in the brains of those with AD. However, tau appears when cells die, they do not cause cell death. Clinical trials need to match the patient's specific disease with a therapy, a precision medicine approach that is already standard in oncology. Why is it not done with AD?

Finally, the cognitive scales used in most AD clinical trials have been designed for testing patients with moderate and severe AD, even though clinical trials enroll patients with mild cognitive impairment (MCI) or mild AD. Therefore, the cognitive scales are not “fit for purpose” in determining cognition in patients with early AD. For instance, many trials use ADAS-Cog13, a cognitive test designed for patients with moderate-severe disease. The “13” stands for the number of tests in the scale. For patients with early AD (MCI and mild AD), nine of the 13 elements of the ADAS-Cog evaluation are at “ceiling effect.” A ceiling effect happens when too large a percentage of participants achieve the highest score on a test, this results in the measurement losing its value. Since these tests are meant for patients with a more advanced disease, they are not useful for testing patients with early AD. Thus, the ADAS-Cog13 is really an ADAS-Cog4 (13 tests minus nine tests at ceiling effect equals four valid tests). This is not good enough.

The second issue with cognitive testing is subtle but easy to understand. None of the standard cognitive measurement scales can demonstrate cognitive improvement. That is, they only show stable or worsening cognition. This is a major statistical disadvantage if a therapy actually makes patients better. As researchers are striving to make patients better, not just slow their decline, we need better measures.

3. Scientific approaches for treating AD are outdated.

One of the biggest issues that AD clinical trials have faced is the overreliance on treatments targeting amyloid protein that has given, at best, modest success. At least five other causes of neurodegeneration — neuroinflammation, mitochondrial dysfunction, lysosomal dysfunction, insulin resistance, and lipid abnormalities — drive the disease. Each may work alone, but they most likely work in concert with amyloid. Amyloid is only part of the problem.

Traditionally, researchers viewed nerve cell dysfunction and death (neurodegeneration) as the cause of AD. Now, we understand synaptic function is a key part of the disease. While you cannot “fix” a dead nerve cell, you can repair synaptic dysfunction. Repairing synaptic dysfunction is now a target for the treatment of AD.

More recently, demyelination has been identified as a critical pathology in patients with AD. Myelin pathology is no longer under the exclusive purview of multiple sclerosis. Surprisingly, demyelination may be one of the earliest pathologies in AD. Finally, the number of cells involved in the disease is increasing beyond nerve cells. Microglia and astroglia, the immune cells of the brain, and oligodendrocytes that produce myelin are recognized as major players in the disease and are “drug targets.” This rapidly changing landscape converts simple AD, once thought of as a disease of amyloid, into a complicated disease. There will be no silver bullet.

Given the complexity of AD, researchers must realize monotherapy may not be good enough; complex diseases need complex therapies. The remarkable advances in cancer therapy come from using new drugs in innovative combinations. Combination therapy for treatment of cancer, cardiovascular disease, pulmonary disease, autoimmune diseases, and other complex diseases is the rule. AD will be no exception.

We at INmune Bio believe neuroinflammation is the future target of Alzheimer’s treatment. Cognitive decline is the sum of synaptic dysfunction and nerve cell death, and neuroinflammation is what causes both synaptic dysfunction and nerve cell death. Stopping neuroinflammation solves both problems. Repairing synaptic dysfunction is the most important and fastest strategy to “fix” cognitive decline. Targeting neuroinflammation also will help other strategies work better.

The Real Failure Is When You Stop Trying

Even though so many AD clinical trials have failed, much of the failure has been caused by the industry itself. We must design better and smarter clinical trials in AD. The need is great and the aging population is growing. AD patients and their caregivers and families deserve the best we can give.

By exploring other causes of neurodegeneration and synaptic dysfunction, we can design modern trials utilizing all the best practices that have been successful in the development of drugs for other deadly diseases. Oncology drug development should be our model — the system works. As this new trial implementation begins, there is new hope for ending this devastating disease.

About The Author:

RJ TesiRJ Tesi, MD, is the cofounder and CEO of INmune Bio, a publicly traded clinical-stage biotechnology company developing therapies that target the innate immune system to fight disease. INmune Bio has two product platforms that are both in clinical trials, the DN-TNF product platform and the Natural Killer Cell Priming Platform, which includes INKmune™. From November 2011 to May 2015, Dr. Tesi was CEO, president, and acting chief medical officer of FPRT Bio Inc., a development-stage biotech company formed to develop XPro1595 for the treatment of neurodegenerative disease and other inflammatory diseases.