Donanemab Demonstrates Significant Slowing of Cognitive Decline in Phase 3 TRAILBLAZER-ALZ 2 Study

Anne White

Months after the FDA handed Eli Lilly a complete response letter (CRL) for its investigational antiamyloid agent donanemab, the company has announced positive results from its phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511), showing significant slowing of cognitive decline and functional decline in patients with early symptomatic Alzheimer disease (AD) over an 18-month period. Based on these results, Eli Lilly will proceed with global regulatory submissions as soon as possible and anticipates making a submission to the FDA this quarter.¹

In the double-blind, placebo-controlled trial, a total of 1182 individuals with an intermediate level of tau and clinical symptoms of AD comprised the primary analysis population. Over 18 months of treatment, investigators observed a significant 35% slowing of decline (P <.001) on the integrated Alzheimer’s Disease Rating Scale (iADRS), the primary end point, as well as a 36% slowing of decline on Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, a key secondary end point.

"These Phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer's disease, and allow them to continue to participate in activities that are meaningful to them,” Anne White, executive vice president, Eli Lilly, and president of Lilly Neuroscience, said in a statement.¹ "We believe our data meets the 'high level of evidence' the Centers for Medicare & Medicaid Services (CMS) has described as the trigger for reconsideration of its National Coverage Determination. People with early Alzheimer's disease need and deserve full coverage and access for approved therapies."

In January, when the FDA issued its CRL for donanemab, the agency felt as though there was not enough sufficient, longer-term evidence to approve the agent, considering its application was supported by the phase 2, 12-month TRAILBLAZER-ALZ study (NCT03367403). Because patients met the goal and subsequently stopped dosing as early as 6 months in, less than 100 patients ended up receiving at least 12 months of the therapy. The FDA indicated that the data to meet the exposure expectation would likely need to include the unblinded controlled safety data from TRAILBLAZER-ALZ 2 upon completion.²

TRAILBLAZER-ALZ 2 initially started as a phase 2 study of 500 individuals, but was enlarged to a phase 3 trial with a final total of 1736 participants, with the primary efficacy determined in those whose tau burden is below the cutoff of 1.46 standardized uptake value ratio. In addition to showing promising results on primary and secondary end points, 47% of patients on study drug showed no decline on CDR-SB, compared with 29% of those on placebo (P <.001). Furthermore, 52% of participants completed their course of treatment by 1 year and 72% completed by 18 months as a result of achieving plaque clearance.¹

"We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening," Mark Mintun, MD, group vice president, Neuroscience Research & Development, Eli Lilly, and president, Avid Radiopharmaceuticals, said in a statement.¹ "We note that these results suggest that people in the early pathological stage of disease could be the most responsive to therapeutics targeting amyloid."

Using the Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), patients on donanemab showed a 40% less decline in ability to perform daily activities at 18 months (P <.0001). In comparison with placebo, the donanemab-treated group had a 39% lower risk of progressing to the next stage of the disease (HR, 0.61; P <.001).

When including patients with high (n = 552) and low tau (n = 1182) at baseline, results continued to be significant, with 29% and 22% slowing of decline on CDR-SB and iADRS, respectively (P <.001). Using PET scans, 34% of participants in the intermediate tau population achieved amyloid clearance at 6 months and 71% achieved clearance at 12 months.

In terms of safety, the incidence of amyloid-related imaging abnormalities (ARIA) were consistent to the phase 2 study, occurring in 24% of treated participants, with 6.1% experiencing symptomatic ARIA microhemorrhages. ARIA occurring as superficial siderosis (ARIA-H) occurred in 31.4% of donanemab-treated patients and 13.6% of those on placebo, although the majority of ARIA cases were mild to moderate and resolved or stabilized with appropriate management. Serious ARIAs occurred in 1.6% of the study population, including 2 participants whose death was attributed to ARIA and a third participant who died after an incident of serious ARIA.

In the original phase 2 study, patients treated with donanemab declined 32% slower on the iADRS in comparison with placebo. Additionally, donanemab reduced amyloid plaque by an average of 78%, or an 84-centiloid reduction at 76 weeks compared with a baseline of 108 centiloids. ARIA occurred in 27% of the patients treated with donanemab, 6% of which were symptomatic cases.³

Last year, at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, findings from TRAILBLAZER-ALZ 4 (NCT05108922), a phase 3 head-to-head trial between donanemab and aducanumab (Aduhelm; Biogen), the first approved antiamyloid therapy for AD, showed that donanemab outperformed aducanumab in terms of amyloid clearance. Using flortaucipir F18 PET scans, 37.9% of donanemab-treated participants achieved amyloid clearance at 6 months compared with 1.6% of those on aducanumab (P <.001).⁴

The trial included 148 participants with early AD, randomly assigned 1:1 to either donanemab or aducanumab for an 18-month treatment period, with end points assessed at 6 months. For patients on donanemab, the percent change and mean change in brain amyloid levels were –65.2% and –3.9%, respectively, compared with changes of –17.0% and –4.0% for those on aducanumab (P <.001). In the intermediate tau subpopulation, percent and mean change in brain amyloid levels were –63.9% and –7.4% on donanemab vs changes of -25.4% and –7.8% for those on aducanumab (P ≤.001).

REFERENCES
1. Lilly’s donanemab significantly slowed cognitive and functional decline in phase 3 study of early Alzheimer’s disease. News release. May 3, 2023. Accessed May 3, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional
2. US Food and Drug Administration Issues Complete Response Letter for Acceleterated APproval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed May 3, 2023. prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html
3. Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N J Med. Published online March 13, 2021. doi: 10.1056/NEJMoa2100708.
4. Lee E, Papka M, Pain A, et al. TRAILBLAZER-ALZ 4: topline study results directly comparing donanemab to aducanumab on amyloid lowering in early symptomatic Alzheimer’s disease. Presented at: 2022 CTAD Conference; November 29-December 2; San Francisco, CA. LB3.