Neuroscience Experts Insight

Lessons Learned From the Recent Approval of Donanemab for Treatment of Early Alzheimer’s

What accounts for this recent pattern of approvals and what lessons can developers of Alzheimer’s disease therapies and imaging agents take from this history? The trajectory reflects three things:  The FDA’s support of biologically based diagnostic criteria (described in detail in the revised March 2024 Guidance:  Early Alzheimer’s Disease Developing Drugs for treatment), improvements in the use of these biologically based criteria to guide patient selection for clinical trials, and utilization of these criteria as surrogate endpoints supporting accelerated approval.

Consider the recent donanemab approval described above. Donanemab is an amyloid-targeting treatment designed for patients with mild cognitive impairment (MCI) and those in the mild dementia stage of early symptomatic Alzheimer’s disease, with confirmed amyloid pathology. Following receipt of a complete response letter (rejecting a potential accelerated approval due to a smaller than expected 12 month safety population in the Phase 2 TRAILBLAZER-ALZ study), Lilly sought full approval for donanemab based primarily on results from the Phase 3 TRAILBLAZER-ALZ 2 study, a multicenter, randomized, double-blind, placebo-controlled, parallel group study in subjects with early symptomatic Alzheimer’s disease.

Notably enrolment criteria in TRAILBLAZER-ALZ 2 required patients to have evidence of both brain amyloid and tau pathology on PET scans—an enrichment strategy using biologically based diagnostic criteria associated with different rates of decline—generally slower in the case of amyloid and more rapid for tau.  With this framework in mind, TRAILBLAZER-ALZ 2 defined two populations for evaluation:  all enrolled subjects, and a low/medium tau population.  The hypothesis was that the total group, with its sub-population of higher tau patients, might reflect a more advanced disease state overall and therefore show a weaker overall response compared to the low/medium tau population.

The primary endpoint was the change from baseline in integrated Alzheimer’s Disease Rating Scale (iADRS), a scale that combines a measure of cognition (ADAS-Cog 13) with measure of activities of daily living (ADCS-iADL).  The endpoint was a somewhat controversial choice, with the Agency expressing the need for demonstration of statistically significant effects on each component individually.  At Week 76, donanemab demonstrated a statistically significant effect on combined cognitive and functional decline in the donanemab treatment arm compared to placebo in both the low/medium tau population (3.3; 95% CI 1.9, 4.6; p<0.001) and the overall population (2.9; 95% CI 1.5, 4.3; p<0.001).  Notably, statistical significance was also demonstrated for the individual cognitive and functional components in both the overall population and low/medium tau groups, but with stronger effects seen in the low/medium group.  Based on these results, an FDA advisory panel unanimously gave a green light on June 11^th, 2024 to the donanemab and the FDA subsequently approved on July 2^nd, 2024.

Returning to the question of what we can learn from these approvals, we see a number of lessons:

1. Improvements in the technology of tau PET tracers could in principle lead to appreciable advances in the diagnosis and treatment of Alzheimer’s disease.  This is an area of active discovery with several sponsors of tau PET tracers currently poised to seek approval.
2. Accelerated approval as a pathway to innovation is working, and arguably working particularly well in the case of AD where there is a mutually reenforcing need to develop better PET technologies to push the therapeutic window earlier and defend the cost of available therapy.
3. Three years and just about 3 months after the controversial approval of Aducanumab, it’s safe to say the field has advanced.  The door is not exactly wide open, but incremental progress is infinitely better than no progress. It begs the question of whether other challenging treatment modalities and indications might benefit from a similar approach.

While the approvals summarized above represent progress in the fight against Alzheimer’s disease, major challenges remain, including:

• Enrolment of more diverse patient populations in both PET tracer and therapy studies
• Development of drugs targeting mechanisms of action beyond amyloid
• Development of therapies targeting more severe stages of the disease

At MMS our extensive experience in Alzheimer’s disease is focused on these challenges, with forward thinking approaches to diversity planning, data management, clinical development planning, and regulatory interactions.

As our primary therapeutic area, CNS accounts nearly a third of our current project load and we’ve completed more than 500 projects related projects in the past 5 years. A sample of our CNS experience is summarized below.

Extensive knowledge of US and EU regulatory authority requirements 

• Neurology-specific experience in leveraging Fast Track, Breakthrough, PRIME, and ILAP throughout development
• Strategy support for rare neurological conditions
• Recent interaction with FDA review divisions under the Office of Neuroscience
• Knowledge of current guidelines for development of diagnostic radiopharmaceuticals

Comprehensive understanding of CNS topics related to development and safety

• Considerations for when seamless/adaptive designs may provide accelerated approval timelines
• Design elements to reduce placebo response and increase power
• Considerations for interim analysis
• Options for establishing durability of effect
• Simulation approaches to establish overall probability of success
• Considerations for when a relapse preventions study are optimal
• Amyloid related imaging abnormalities
• Suicidality, Weight gain, and Nerve conduction velocity
• Assessment for abuse potential