Donanemab BLAZEs through Alzheimer’s treatment TRAIL in first active comparator trial

The first study to directly compare two disease-modifying agents for Alzheimer’s disease (AD), the phase III TRAILBLAZER-ALZ 4 study shows promising efficacy and safety data on donanemab vs aducanumab for the treatment of early symptomatic AD.

“This study met all primary and secondary endpoints at the 6-month timepoint,” shared Dr Stephen Salloway from Brown University, Providence, Rhode Island, US, at AAN 2023. “This study provides the first active comparator data on amyloid plaque clearance in [this patient setting].”

In the full analysis (FA) set, donanemab demonstrated superiority over aducanumab at 24 weeks in terms of the fraction of participants who had substantial lowering of amyloid plaques (37.9 percent vs 1.6 percent; p<0.001). The same was true for the intermediate tau (IT) subgroup (38.5 percent vs 3.8 percent; p=0.008).

To put it into context quantitatively, only one patient from the aducanumab FA set (n=64) and one from the IT subset (n=26) achieved amyloid plaque clearance (<24.1 Centiloids [CL]). In the donanemab arm, the numbers for these respective subgroups were 25/66 and 10/26. [AAN 2023, abstract 3126]

“If you look at the actual reduction of the amyloid load, you can again see this quantitatively, with a substantial reduction of about 62 CL for donanemab and 16 CL for aducanumab,” said Salloway. These correspond to a 65-percent reduction from baseline with donanemab as opposed to only 17 percent with aducanumab (p<0.001). Again, this was seen in the IT subset (-64.1 vs -23.8 CL), with corresponding percent reductions from baseline of 64 percent and 25 percent (p<0.001).

Donanemab continued to prevail over aducanumab in reducing plasma log10 P-tau217, both in the FA set (least squares mean [LSM] change from baseline, -25 percent vs +2.8 percent; p<0.001) and IT subgroup (LSM change from baseline, -26 percent vs -2.9 percent; p=0.061).

“It is encouraging to see that donanemab produced significant reduction of amyloid build-up in the brain and P-tau in the blood after 6 months. This suggests that this treatment modified the biology of AD early on in treatment,” noted Salloway in a press release. [investor.lilly.com/news-releases/news-release-details/lilly-shares-positive-donanemab-data-first-active-comparator, accessed April 30, 2023]

“It is also notable … that the higher amyloid clearance by donanemab vs aducanumab at 6 months was not associated with a higher rate of ARIA,” he continued.

 

Safety profile

“ARIA-E* is the most common treatment-emergent adverse event (TEAE) … The rates were very similar between arms in the low 20-percent range … Therefore, even though the amyloid lowering is greater with donanemab, there was no difference in ARIA rates between arms,” Salloway noted.

Sixty percent of aducanumab recipients with ARIA-E had Ɛ4/Ɛ4, as opposed to 33 percent in the donanemab arm. “This is very important because [these data support that] APOE carrier status does affect risk, especially for those who carry two copies of the Ɛ4 allele,” underscored Salloway. Hence, if this drug moves forward into clinical practice, APOE testing is strongly recommended for patients being considered for this treatment, he stressed.

There were more ARIA-E earlier on with donanemab than with aducanumab, but by week 24, the rates have become similar. “[This might be due to] exposure to higher doses with donanemab earlier … There was a difference in [drug] titration, which has a big impact,” Salloway said.

 

Nondefinitive, but informative

Donanemab was initially given at a dose of 700 mg (first three doses), followed by 1,400 mg (subsequent doses). For aducanumab, the initial dose was 1 mg/kg (first two doses), followed by 3 mg/kg (next two doses), 6 mg/kg (next two doses), and 10 mg/kg (all subsequent doses). Both drugs were administered intravenously Q4W for up to 18 months.

A total of 148 participants were randomized 1:1 to each arm.  Of these, 55 comprised the IT subset. About two-thirds of the cohort were APOE Ɛ4 carriers. Average MMSE** was around 24 points. All were amyloid-positive with a CL value of around 100.

Salloway noted that while their study was not definitive, it “certainly is informative [as to] how much amyloid lowering is needed to produce a clinical benefit.”

“Donanemab’s rapid and deep plaque clearance [was] associated with improvements in plasma P-tau, a key biomarker in AD … [Our data also show that] speed and depth of amyloid removal is not driving ARIA,” said Salloway. “We would have to further validate [these data], but this would certainly be extremely helpful in clinical practice.”

The study is ongoing and will have 12- and 18-month readouts, said Salloway.

The FDA has granted Breakthrough Therapy designation for donanemab in June 2021 based on data from the phase II TRAILBLAZER-ALZ trial. In August 2022, the FDA accepted the application for review (with Priority Review designation) of donanemab for AD under the accelerated approval pathway.