Eli Lilly’s donanemab for early symptomatic Alzheimer’s disease (AD) has most experts dubious of the drug’s clinical benefit due to marginal and mixed Phase II results, despite the primary endpoint meeting statistical significance. Although the ongoing Phase III trial will likely produce similar results with greater statistical precision, the study is not designed to address these critical concerns, they said.

Still, because the Phase II TRAILBLAZER-ALZ trial its primary endpoint, the delay in disease progression could provide a significant benefit if it is replicated in the Phase III TRAILBLAZER-ALZ 2, two experts said.

However, four other experts were more sceptical of the primary endpoint of Integrated Alzheimer’s Disease Rating Scale (iADRS), as the two subscales within iADRS, while well-established, did not reach statistical significance on their own. Additionally, iADRS has not traditionally been used in AD trials, making it difficult for clinicians to interpret the meaning of the combined results of two subscales, one expert explained. The overall benefit shown was not clinically meaningful, and it was unlikely to show a significantly greater magnitude of effect in TRAILBLAZER-ALZ-2, which uses the same iADRS primary endpoint, the four experts said.

Furthermore, the Phase III is the same duration as the Phase II, which experts noted is too short to assess durability and fully understand the possible long-term consequences of the common adverse event (AE) of amyloid-related imaging abnormalities (ARIA). Since the disease progressed in both the placebo and treatment groups, and because the difference in progression between the two groups did not necessarily increase with time in each endpoint, experts’ concerns have increased.

While the two more optimistic experts pointed to the pending approval of Biogen’s amyloid-targeting aducanumab as evidence this target has promise, others agreed the controversial aducanumab data, whose efficacy was rebuked by a panel of experts in a November 2020 FDA AdCom, was more evidence of the target’s failure. In response to request for comment, a Lilly spokesperson said the TRAILBLAZER-ALZ findings suggest a role for amyloid and tau imaging in AD research and the potential for long-term disease modification following fixed duration treatment.

TRAILBLAZER-ALZ data were published on 13 March (Saturday), and Lilly’s stock dropped 9% by end of day on 15 March (Monday). Lilly’s market cap is $179.79bn. TRAILBLAZER-ALZ 2 was originally recruiting as a 500-patient Phase II but was updated to a Phase III on ClinicalTrials.gov on 25 March. The primary completion date is February 2023.

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The spokesperson said the company believes replicating the Phase II results is important, and the company aims to do so in TRAILBLAZER-ALZ 2.

Scepticism over primary endpoint, benefit shown

Although donanemab showed a statistically significant change in its primary endpoint, most experts were dubious about whether the measure was designed to detect a meaningful change or just any change at all. Lilly developed iADRS, which combines traditional cognitive and functional scales, Alzheimer’s Disease Assessment Scale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), respectively. Because iADRS has not traditionally been used in AD trials, it is harder for clinicians to determine what this data actually means for clinical use, noted Robert Howard, Professor of Old Age Psychiatry, University College London, UK.

A difference of 3.20 points on the 144-point iADRS, particularly for an intensive 72-week treatment with no signs of stopping disease progression, holds little clinical value, said Jorge Barrio, PhD, professor, Institute for Neurodegenerative Diseases, University of California, Los Angeles. The treatment and placebo groups, which each had a baseline of 106 on the iADRS, showed a -6.86 and -10.06 change, respectively (Mintun, M, et al. New England Journal of Medicine, 13 March 2021).

The two scales comprising iADRS also did not reach statistical significance separately, Howard noted. Combining the statistically insignificant data from the cognitive and functional scales should not be considered clinically meaningful even though the composite score narrowly reached statistical significance (p=0.04), he added.

Typically, clinicians consider a 3-point ADAS-Cog13 improvement to be a noticeable, albeit small, effect, Howard explained. The 85-point ADAS- Cog13 scale showed a 1.86-point difference (95% CI, −3.63 to −0.09) and the 59-point ADCS-iADL scale a 1.21-point difference (95% CI, −0.77 to 3.20). The Lilly spokesperson told this publication the ADAS- Cog13 component, which was not corrected for multiple comparisons, was nominally statistically significant (p=0.04) with a 39% slowing of disease progression, and the ADCS-iADL component was nominally significant in three of the four last time points, with a 23% slowing of disease progression.

Because TRAILBLAZER-ALZ was the first Phase II AD trial to meet its primary endpoint, its demonstrated slowing of disease progression represents a breakthrough, noted Dr Christopher Rowe, neurologist, University of Melbourne, Australia. The iADRS has not historically been used, but its subcomponents ADCS-iADL and ADAS-Cog13 are well established.

Even a small delay in disease progression could provide a sizable benefit to families of AD patients, agreed Rowe and Dr Peter Nelson, Sanders-Brown Centre on Aging, University of Kentucky, Lexington. By rejecting any form of small progress, the AD field risks missing out on a treatment with the potential to provide value to a subset of patients or provide an initial steppingstone to research with the potential to improve survival curves over time, Nelson added.

Phase III design unlikely to address concerns

While Rowe and Nelson said donanemab should be made available, provided it demonstrates similar results in TRAILBLAZER-ALZ 2, other interviewed experts noted the Phase III is not designed to answer the lingering questions left in the wake of Phase II data.

Although Barrio and Howard agreed the 1,500-patient TRAILBLAZER-ALZ 2 could find a greater degree of statistical significance in its iADRS primary endpoint due to its larger size compared to the 257-patient TRAILBLAZER-ALZ, they do not expect a substantial change in the magnitude. As a result, donanemab likely “will never hold a place in the clinic,” Howard said.

Lilly announced a change for the TRAILBLAZER ALZ-2 primary measure from the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) to iADRS during an investor call on 15 March. The 18-point CDR-SB score showed a 0.36-point difference in the Phase II, which was not statistically significant (95% CI, −3.63 to −0.09).

Adding to the scepticism are mixed trends in the ADAS-Cog13, ADCS-iADL and CDR-SB scales, which raise questions over donanemab’s durability, said Erin Abner, associate professor, Department of Epidemiology, University of Kentucky, Lexington. While ADAS- Cog13 showed the greatest difference between placebo and treatment at the end of the study, both ADCS-iADL and CDR-SB demonstrated the biggest separation at week 52, which lessened through to the study end, she explained.

Without running a longer study, there is considerable uncertainty over whether the treatment effect will persist for even one or two years after the 76-week study period, Barrio and Abner agreed. The Phase III replicates the Phase II 76-week trial duration and dosing once every four weeks for 72 weeks or until patients tested amyloid negative, according to ClinicalTrials.gov.

In a disease characterised by slow disease progression over decades, follow up of least two years after treatment is necessary, Howard explained. Furthermore, because the primary endpoint includes patient- and physician-based assessments, an open-label continuation would not be sufficient, he continued. Barrio added he would not be surprised if donanemab’s effect lessened with a longer study.

Moreover, donanemab is not a benign AD treatment, as ARIA, could be damaging to patients in the long term, agreed Barrio and George Perry, PhD, Semmes Foundation Distinguished University chair in Neurobiology, University of Texas, San Antonio. Rowe noted stopping treatment reversed damage from ARIA, but Barrio said the potential long-term effects of ARIA would require a minimum of two to four years of additional study.

ARIA events occurred in 51 of the 131 donanemab-treated patients and eight of the 125 placebo-treated patients, with symptomatic ARIA-E reported in 6.1% o and 0.8% of patients, respectively. All ARIA-E symptoms were resolved by a mean of 18 weeks. One placebo patient was not included in the modified intent to treatment population.

Because patients and physicians are aware of the risk of ARIA, its presence could add some bias to the study, Rowe said. However, there is no evidence of this. Patients with signs of ARIA had a different dosing schedule, which could have given patients a signal they were most likely in the donanemab arm and in turn subconsciously influenced their assessments, he explained.

Biomarker data has experts mixed on amyloid hypothesis

Despite only finding a marginal benefit in slowing disease progression, donanemab was successful in removing amyloid plaque, casting doubt as to whether this target could have a disease-changing impact, agreed Barrio and Howard. At the end of the study 67.8% of donanemab patients were amyloid-negative, defined as amyloid plaque of less than 24.10 centiloids. They had an 85.06-centiloid greater amyloid-plaque reduction than placebo patients. The similarly marginal results seen in aducanumab studies, which also successfully reduced amyloid levels, and the long history of failed drugs targeting the amyloid pathway, demonstrate this target is unlikely to produce more than a small, nondisease-altering effect, Perry said.

Additionally, despite the trial selecting patients based on their tau levels, there was no measured effect on tau to go along with the decrease in amyloid measured. Amyloid cascade hypothesis states stopping or clearing the accumulation of misfolded amyloid plaque in the brain could have downstream effects on cognition and accumulating tau levels, explained Abner.

Without longer-term data, it cannot be determined if tau levels will eventually decrease as a result of removing amyloid, Abner explained. Still, because tau accumulation occurs slowly over years, donanemab could affect tau over a longer period, Rowe added.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.