‘Basket’ Trials for Dementia Aim to Bring Precision Medicine to Neurogenerative Diseases

A new type of clinical trial for dementia that aims to accelerate treatments for neurodegenerative disease by adapting one of the precision medicine approaches that have defined 21^st century cancer therapy has been developed by clinician–scientists at the UCSF Memory and Aging Center (MAC).

Cancer researchers, realizing that seemingly different cancer types such as ovarian or breast cancer often share common underlying biology, have begun to conduct so-called “basket trials,” which group together patients with different forms of cancer based on shared genetics or other biological mechanisms. These trials have successfully shown that drugs developed for melanoma, for instance, also work in patients whose lung cancers are caused by the same genetic defects, dramatically expanding the number of patients who stand to benefit.

Similarly, despite the stark differences in symptoms between Alzheimer’s, with its profound memory impairments, and frontotemporal dementia, with its crumbling of personality and decision-making, these and most other forms of neurodegenerative disease share a common feature: the buildup of one or more types of misfolded protein in different areas of the brain, leading to the death of brain cells and gradual loss of brain function.

In the Nov. 11, 2019, issue of JAMA Neurology, UCSF MAC researchers will publish results of the first basket trial in neurodegenerative disease, which combines patients with multiple different forms of dementia thought to be caused by a common underlying pathology: the toxic buildup of a protein called tau. The study included 94 patients diagnosed with Alzheimer's disease, progressive supranuclear palsy, and corticobasal syndrome, and tested the efficacy of a drug that researchers hoped would make up for cellular problems caused by mutated tau.

We spoke with Adam L. Boxer, MD, PhD, the Endowed Professor in Memory and Aging in the UCSF Department of Neurology and director of UCSF’s Neurosciences Clinical Research Unit and the Alzheimer’s Disease and Frontotemporal Degeneration (FTD) Clinical Trials Program at the UCSF MAC, about the new study and the potential of basket trials to accelerate drug development for dementia and neurodegenerative disease. 

Why the optimism for the “basket trial” approach? 

Tau protein is a high-priority therapeutic target because it accumulates in Alzheimer’s disease as well as other disorders such as frontotemporal dementia, progressive supranuclear palsy, or PSP, and chronic traumatic encephalopathy, or CTE, which has been increasingly linked to high-impact sports. However, while tau is a clearly key player in these disorders, we have limited knowledge of how exactly it contributes to disease progression.

There are concerns that animal and other laboratory models don’t precisely correspond to any of these diseases, so a basic question is, which of our patients are most likely to benefit from a drug that seemed promising in laboratory tests? 

One possibility would be to run multiple large clinical trials in succession until we find evidence that one of these diseases responds to a particular drug, but that isn’t feasible. Instead, in cancer, basket trials have applied the same drug to multiple cancers with related biology and have found unexpected responses in cancers for which a drug wasn’t originally intended. In this way, cancer researchers, using precision medicine, have quickly and efficiently identified people who will respond to a drug. We are attempting to bring the same precision medicine approach to patients with neurodegenerative disease.

How has the UCSF Memory and Aging Center adapted oncology-style basket trials for dementia patients?

In oncology, basket trials have identified the same cancer-causing protein in multiple different types of cancer (such as melanoma, colon and breast cancer) and treated patients with these different types of cancer with a drug that targets this shared underlying tumor biology. We are taking the same approach with the tau protein by combining patients with multiple different forms of neurodegeneration thought to be caused by toxic buildup of tau into a single study so that we can test drugs directed at tau in all these patients at once. 

So far we have completed one study in which we tested a drug called TPI-287 for three different diseases where tau is believed to play a key role: Alzheimer’s, PSP and corticobasal syndrome. 

With the recent launch of our ALLFTD project, funded by a $63 million multi-site grant from the NIH, we aim to further develop methods and tools to make newer and more efficient basket trials possible with different groups of tau-driven neurodegenerative disorders and other types of potential therapies.

Your new JAMA Neurology study is the first basket trial approach to tackle different forms of dementia caused by a common type of biological brain degeneration. What did you learn from this first study?

We learned that the drug TPI-287, which was hypothesized to fix a specific problem caused by abnormal tau in nerve cells, was better tolerated in patients with CBD and PSP than patients with Alzheimer’s Disease. Patients with Alzheimer’s had severe allergic reactions to the drug that were not seen in the other patients. These allergic reactions might be related to the genetic risk factors for Alzheimer’s, most of which involve immune system function and differ from the genetic risk factors for corticobasal syndrome and PSP. 

Ultimately, the drug was not found to be promising for any of these diseases, but the basket approach taught us something very important: some tau-directed therapies might be safer in one tau-related disease than another. If we can learn this kind of lesson early on in the course of developing a drug, it can potentially save us time and effort in deciding which tau disease might best respond to a given therapy.

What other dementia basket trials are you running, and what are your hopes for those studies? 

In one newer basket trial, we are testing the safety of a different tau drug, called gosuranemab, and evaluating how well it actually interacts with the misfolded tau protein it’s supposed to eliminate, in four different tau-related diseases: corticobasal syndrome, nonfluent variant primary progressive aphasia, tau mutation carriers and patients with clinical symptoms of CTE. 

We hope to learn how the drug’s safety profile and ability to bind to and potentially neutralize tau compares between these different disorders, potentially revealing clinically relevant differences in the structure of the tau protein that causes disease. 

Our precision medicine approach to clinical trials will hopefully allow us to more quickly and efficiently identify which of our patients are most likely to benefit from these new therapies.

Are you hopeful about the ability of this precision medicine approach to lead to effective treatments for dementia in the near future?

We’re probably a decade or two behind our oncology colleagues in developing treatments for dementia, but we can learn from their experience to accelerate our progress. 

Over the next few years, we expect to see some very exciting new high-tech therapies to treat tau-related diseases. Some are antibodies like the drug gosuranemab, others have the potential to genetically alter the amount of tau that is produced by the brain, while others may be able to target toxic forms of tau protein to cellular garbage disposals. 

Our precision medicine approach to clinical trials will hopefully allow us to more quickly and efficiently identify which of our patients are most likely to benefit from these new therapies.