I-SPY 2 Breast Cancer Trial as a Model for Innovation in Alzheimer Disease Therapies

Abstract

Alzheimer disease (AD) causes significant economic and social burdens for patients, families, and the health care system. To date, the US Food and Drug Administration (FDA) has approved few treatments for AD, and these temporarily ameliorate symptoms but do not slow, stop, or reverse disease progression. 1 Meanwhile, 99.6% of AD trials conducted between 2002 and 2012 have encountered safety problems or failed to demonstrate benefit. 1 In the face of these challenges, there is global interest to innovate clinical trials that enable more effective outcomes. Adaptive clinical trials for AD treatment could advance understanding of biological mechanisms and clinical progression and access regulatory review avenues such as accelerated approval. Trial innovation could also reinvigorate investment in drug development.Clinical trial failures result from many factors: inadequate understanding of actionable targets and pathways (molecular or biological), inappropriate dosage or treatment duration, and variance owing to heterogeneity of the research population. A major cause of many AD trial failures has been the inability to meet FDArecommended functional and cognitive clinical end points. 1 At a recent FDA patient-centered drugdevelopment meeting, patients and families stressed the need to alleviate cognitive impairment and its disabling consequences. 2 The FDA has indicated that delaying cognitive impairment before the onset of overt dementia may provide sufficient evidence of efficacy for clinical trials in AD. 3 Innovative clinical trial designs have proved successful for other diseases, such as breast cancer, and have enhanced research by identifying relevant outcomes and encouraging financial investment. Since 2008, financing of breast cancer trials has increased while investment in AD trials has declined (Figure ) 4 ; total investment for breast cancer trials far exceeds that for AD. In addition, 34% of breast cancer trials are in later stages of development compared with 13% of AD trials. The decline in investment in AD trials has resulted in a narrow portfolio of drugs currently in development.Alzheimer disease research might emulate the I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) clinical trial, an adaptive clinical trial platform structured to expedite drug development. I-SPY 2 recruits women with triple-negative breast cancer who are at increased risk for tumor recurrence and death despite standard adjuvant treatment. The trial uses a hybrid umbrella/basket design 5 with the "umbrella" consisting of concurrent testing of up to 12 experimental therapies in patient subgroup "baskets" defined by genetic markers and tumor type. Numerous parties col-VIEWPOINT

Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options

“…The Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis (I-SPY) model used in breast cancer clinical trials offers an adaptive trial design that could also be used in AD [76]. I-SPY combines two types of trial designs: an “umbrella” trial in which many therapeutic agents are tested in parallel (with treatment groups sharing a protocol and a placebo group) and a “basket” trial in which patients are grouped by genotype or other disease features.…”

Disease modification and biomarker development in Parkinson disease

“…The scientific efficiencies of this type of adaptive design include a shared placebo group, sample size savings, the study of multiple drugs and multiple markers, and the flexibility to add/remove agents. Successful examples in which a platform trial has been implemented include the Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2 (I-SPY 2) to screen drugs in neoadjuvant breast cancer 55 and Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) in at-risk or early-onset genetic AD. 56 The first Platform Trial Initiative for amyotrophic lateral sclerosis was recently established at the Healey Center for ALS at Massachusetts General, with 5 promising drugs entering evaluation as of September 2019 (massgeneral.…”