Draft Guidance Issued on Early Alzheimer's Treatment

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FDA published the draft guidance to support sponsors in developing treatments for the states of sporadic Alzheimer’s disease.

Editor's Note: This article was previously published on PharmTech.com on March 15, 2024.

On March 12, 2024, FDA issued a draft guidance for the development of treatments for early Alzheimer’s disease (AD). The guidance document will assist sponsors who are in the clinical phases of development of drugs for treating the stages of sporadic Alzheimer’s disease that occur before dementia becomes overt.

In the document, FDA refers to these stages as “early AD” but stresses that the disease occurs on a “continuum and patients in the last stage of early AD (i.e., late Stage 3) and patients with AD in the earliest stages of overt dementia (i.e., early Stage 4) may not differ significantly in clinical presentation.” The agency expects the document to create discussions between the Office of Neuroscience in the Center for Drug Evaluation and Research, the Office of Therapeutic Products in the Center for Biologics Evaluation and Research, sponsors, the scientific community, and the public, where appropriate. The draft guidance is a revision of the February 2018 guidance and is open for comments until June 10, 2024.

According to the guidance document, in the past, enrollment in clinical trials for AD treatments were based on clinical criteria that defined the later stages of AD. Because of this, the study subjects “exhibited both the cognitive changes typical of clinically evident AD and the degree of functional impairment associated with overt dementia,” according to the FDA guidance document. Approved treatments were, therefore, based on that context.

FDA states in the document that there has been an effort to use biomarkers that reflect underlying AD pathophysiological changes and to include study subjects with early AD. “These efforts are particularly important because there may be an opportunity to intervene very early in the disease process of AD, given the slowly progressive course of AD and the development of characteristic pathophysiological changes that greatly precede the development of clinically evident findings,” the document states. “Delaying or, preferably, halting or reversing the pathophysiological process that will lead to the initial clinical deficits of AD is the ultimate goal of presymptomatic or very early symptomatic intervention, and treatment directed at this goal must begin before there are overt clinical symptoms. This opportunity carries with it the need to understand ways to assess treatment benefit in these earlier stages of disease.”

The document details diagnostic criterial and clinical staging of AD for the selection of endpoints for the disease stages and enrollment in clinical trials. The document does not cover clinical trials designed to focus on patients with AD that have developed overt dementia or any of the autosomal dominant forms of AD. It also does not apply to treatment of other forms of dementia.


Treatment options for AD have been a focus for industry. In September 2023, Roche entered into an agreement with Ionis Pharmaceuticals for early stage programs for a RNA-targeting investigational therapeutic for treating AD (1). Roche gained exclusive worldwide rights and is responsible for clinical development, manufacturing, and commercialization of the candidate worldwide. The agreement built upon a 10-year-long partnership between the companies, which started in 2013. In 2018, the companies entered another collaboration to develop an Ionis therapeutic candidate for immunoglobulin A nephropathy and geographic atrophy treatment.

"We are excited to expand our partnership with Roche … ," said Brett P. Monia, CEO, Ionis, in a company press release, at the time (1). "With this new collaboration, we are joining forces to accelerate the discovery and development of novel therapies for people living with Alzheimer's disease and Huntington's disease globally. Collaborating on these two programs enables Ionis to advance our wholly owned programs, including those in neurology, aligned with our strategic priorities."

"Our lasting partnership with Ionis … is a great example of two collaborators mutually benefiting from their relationship by complementing and learning from each other," said James Sabry, global head of Roche Pharma partnering, in the press release (1). "By expanding our alliance, we bring together the companies' combined knowledge of the science in Alzheimer's disease and Huntington's disease with Roche's proven capabilities in the development and commercialization of innovative treatments in neuroscience."


1. Ionis Pharmaceuticals. Ionis Enters Agreement with Roche for Two Novel RNA-targeted Programs for Alzheimer’s Disease and Huntington’s Disease. Press Release. Sept. 27, 2023.

Source: FDA