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US: Stakeholders provide feedback on FDA draft guidance on drug development for early Alzheimer's disease

2024/05/21  RAPS

Guidance for developing drugs to treat early Alzheimer’s disease should focus on factors such as cognitive changes and brain atrophy, according to comments submitted to the US Food and Drug Administration (FDA) on draft guidance addressing the subject.

In March, the FDA proposed an update to its 2018 draft guidance on developing drugs for early AD. It includes biomarkers and outcome measures that can be used to select clinical trial participants. Another major change in the guidance is that the agency said it will allow the use of endpoints based on cognitive assessments or surrogate endpoints.

The public comment period for the updated guidance closed on 13 May, but before it did, Johnson and Johnson wrote to FDA with further recommendations. The company said it supports the changes to the guidance but wants clarification on the cognitive measures that can be used to diagnose early AD and the use of modeling approaches.

Johnson and Johnson noted that the guidance states that in certain cases, a “pattern of putative meaningful changes” could be more persuasive than a single measure to determine if a patient has early AD. The company said the guidance should recognize that changes may take time to present themselves. In the early stages of the disease, they may present as single or limited cognitive deficits.

The company also asked that FDA clarify in the guidance that understanding of mild cognitive impairment (MCI) is evolving and should be based on the latest research and agreement with regulators.

“We appreciate the Agency’s position that marked cognitive changes alone may represent an opportunity to provide adequate support for marketing approval,” said the company. “The field has no consistent, clear definition of early MCI. However, as research in this field progresses, further discussions with the Agency will be necessary to better define guidance for transition within the early stages of disease.”

Johnson and Johnson also asked FDA to clarify its thinking on using modeling approaches, such as quantitative systems pharmacology (QSP) models and disease progression modeling, to develop endpoints depending on the disease stage.

“It would be helpful if the guidance added some considerations for the use of modeling to support approval, for example, for combination therapy and validation of a surrogate endpoint,” the company added.

The Spirit of the Coast Analytics (SOTC), a publication covering neurodegenerative and neurodevelopmental disorders, also commented on the updated guidance. It said that FDA’s decision to separate activities of daily living (ADL) requirements from stage one through early third state when assessing patients with AD in the updated guidance was appreciated and would ensure more clinical reliability.

“Very early stage patients are unlikely to have enough variance in ADL to warrant a statistically meaningful outcome,” said SOTC. “In fact, requiring ADL in early stages likely only adds clutter to the end outcome of a clinical trial and may result in the clinical failure of a compound that otherwise would not.”

SOTC asked FDA to focus on pathophysiological changes instead, specifically brain atrophy when assessing early AD. It noted that data discrepancies in trials assessing monoclonal antibodies, such as Aduhelm (aducanumab), Leqembi (lecanemab), and donanemab, prove the difficulty of assessing AD based on Amyloid levels.

“Atrophy of the brain is the most obvious, most testable, and likely most meaningful alterable symptom of Alzheimer’s disease,” said the organization. “In our studies, researchers have found that annual whole brain atrophy levels increase in MCI by 140% over baseline, and in clinical Alzheimer’s by over 280%.”

SOTC argued that MCI and Alzheimer’s patients have proven to have significantly higher brain atrophy, and an AD drug is likely not doing its job if it can’t show meaningful improvement or stabilization of brain atrophy.

“We are certain the draft guidance omitted specific pathophysiological factors as to welcome a myriad of targets and outcomes addressing multiple disease-states; however, we feel that without further guidance on a hierarchy of targets, industry and key sponsors (e.g. Alzheimer’s Association) will continue applying ineffective focus on the Amyloid hypothesis,” the organization added. “To conclude, we hope regulators will consider adding specific pathophysiological targets to guidance and in best case, include a hierarchy to these targets - ideally in a manner that have the most meaningful correlation to patient quality of life, and lifespan.”

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