A recent drug trial by the UCSF Memory and Aging Center is the first of its kind for neurodegenerative disorders and represents an exciting new method for evaluating the effectiveness of a single drug on participants with the same underlying biology, but different diagnoses. First used in cancer research, basket trials lump together patients by disease pathology, not by diagnosis or symptoms. The UCSF trial evaluated the effectiveness of a drug, TPI-287, in treating toxic buildup of tau protein in the brains of patients with Alzheimer’s disease (AZ), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). While the drug ultimately did not show promise, scientists still drew useful takeaways from the study, and future studies of neurodegenerative disease may benefit from utilizing a basket trial design.

What is a basket trial? 

A fairly recent innovation in cancer research, basket trials evaluate the effect of a drug on one underlying mutation that can cause a variety of different cancers [1]. For instance, treatment developed for melanoma has also been shown to treat some forms of lung cancer [2]. Basket trials are an offshoot of precision medicine that helps scientists and clinicians identify which patients are likely to be helped by specific treatments. By lumping patients together into the same “basket,” scientists can evaluate a drug’s effects among a broader group to see if benefits are observed. This is distinct from an “umbrella” trial that contains different arms of study, with patients assigned to separate arms depending on their cancer type [1].

An added benefit of the basket study is that it has the potential to open up future treatment eligibility to a larger patient population.

Why is this important for research in neurodegenerative disorders? 

Most patients with a neurologic disease have had the frustrating and time-consuming experience of trying multiple medications before (hopefully) finding one that is helpful for their symptoms. Precision medicine aims to eliminate some of that guesswork, by allowing clinicians to more accurately predict which patients will respond to which medications. 

In the neurologic world, basket trials could translate to studying the effect of a drug on a specific brain pathology—rather than on a cancer mutation—among patients with a variety of neurologic diagnoses and symptoms, who nonetheless share the same underlying biology.  

The UCSF Memory and Aging Center has adapted this approach to look at different types of dementia which share a common pathology. A type of mis-folded protein called tau is known to accumulate in the brains of people with Alzheimer’s disease (AZ), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD), among other diseases [3]. Although the symptoms of tau pathology may manifest differently among individuals, the underlying toxic action of the tau protein is thought to be the same.

What did the UCSF study find? 

In November 2019, UCSF researchers published results of the first-ever basket trial in neurodegenerative disease, which included 95 participants with AZ, PSP, and CBS, and evaluated their response to the drug TPI-287 [3]. This was a safety and feasibility study, to make sure the drug did not harm participants; if well tolerated, it was hoped that TPI-287 would repair some of the damage caused by abnormal tau in the brain. 

While results showed that the drug was ultimately not helpful to treat any of these diseases, the researchers did learn some important takeaways [4]:

• TPI-287 caused significant allergic reactions in participants with AZ, but not in those with CBS or PSP. This may be due to the difference in risk factors between these diseases: AZ involves the immune system and carries different genetic risk factors than either CBS or PSP.
• Some medications that aim to treat tau pathology may not affect all patients with tau disease the same. Further research will help to identify these differences and make such treatments more useful.

What comes next?

The basket approach proved useful in this study, and the UCSF Memory and Aging Center is continuing to deploy it in further research. Another basket trial is currently underway to evaluate the effects of drug BIIB092 (Gosuranemab) on patients with tauopathies including CBS, primary progressive aphasia (nonfluent variant), tau mutation carriers, and chronic traumatic encephalopathy [5].

Researchers are optimistic that continued use of basket trials will help to speed the progress of research into other exciting therapies for neurodegenerative disorders.

Reference List:

1. Clinical trial design and methodology. American Society of Clinical Oncology. https://www.asco.org/research-progress/clinical-trials/clinical-trial-resources/clinical-trial-design-and-methodology Accessed on December 3, 2019.
2. Weiler N. ‘Basket’ trials for dementia aim to bring precision medicine to neurodegenerative diseases. UCSF press release. https://www.ucsf.edu/news/2019/11/415901/basket-trials-dementia-aim-bring-precision-medicine-neurogenerative-diseases Published on November 11, 2019. Accessed on December 3, 2019.
3. Medina M. An Overview on the clinical development of tau-based therapeutics. Int J Mol Sci. 2018 Apr; 19(4): 1160. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979300/  Accessed on December 3, 2019.
4. Tsai RM, Miller Z, Koestler M, et al. Reactions to multiple ascending doses of the microtubule stabilizer TPI-287 in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome. JAMA Neurol. 2019 Nov. https://jamanetwork.com/journals/jamaneurology/article-abstract/2753779 Accessed on December 3, 2019.
5. Boxer A. BIIB092 in primary tauopathies: CBS, nfvPPA, sMAPT, and TES (TauBasket). ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03658135 Accessed on December 3, 2019.