24 Jul 2026
Part 2 of 2
No, they are not Optimus Jr, Megatron’s clones, or any other new, amyloid-shattering members of the Tron family franchise of transformer robots, though perhaps Roche does not mind if you think so for a moment. Rather, the TRONTIER twins are currently enrolling Phase 3 trials for early AD, and PrevenTRON is a Phase 3 secondary prevention trial gearing up on the heels of trontinemab’s Phase 2 and OLE data (see Part 5 of this series). At the Alzheimer’s Association International Conference, held July 12-15 in London, Roche’s Janice Smith sketched out the design of this much-anticipated preclinical AD trial, which will use plasma p-tau217 and a simple cognitive test to select its participants. Reisa Sperling from Brigham and Women’s Hospital in Boston brought together data from past treatment and prevention trials to strengthen the case that going earlier is better, and that plasma p-tau217 can pick out people with preclinical AD who are most likely to benefit.
Trontinemab’s rapid amyloid-clearing power combined with its safety profile make it an attractive therapeutic for use in the very early or preclinical stages of AD, Sperling and other scientists noted at the meeting.
“For my patients and their families, the key thing is about maintaining independence, and going earlier, we have the greatest chance,” said Nick Fox of University College London, who co-chaired the session with Sperling.
Underway since September 2025, TRONTIER 1 and 2 are identical Phase 3 trials that evaluate trontinemab versus placebo in 800 participants with MCI or mild AD each. These trials will run for a total of 18 months. In London, Roche’s Janice Smith showed the outlines of the design of the upcoming secondary prevention trial, a global Phase 3 study. PrevenTRON will enroll 1,600 cognitively normal participants with biomarker evidence of amyloid, who will be randomized to receive placebo or 3.6 mg/kg trontinemab. After a six-month induction phase of monthly dosing, participants will switch to a maintenance regimen with quarterly dosing, in other words, four infusions per year. The primary endpoint is time to progression to a CDR global score above zero. Like in Lilly’s TRAILBLAZER-Alz3 trial, PrevenTRON’s placebo-controlled portion will conclude once a preset number of people have progressed; after that, participants can opt into an OLE.
Roche is using its master prescreening program, called TRAVELLER, to recruit participants for all of its Phase 3 trials. Designed to reduce the burden on potential enrollees, TRAVELLER uses a combination of plasma p-tau217 and the international shopping list cognitive test to prescreen enrollees. For recommendation into TRONTIER, plasma p-tau217 is already being used to rule out participants who are highly unlikely to have amyloid. In contrast, for PrevenTRON, a higher threshold of p-tau217 will be used to rule in people with a high likelihood of brain amyloid. Potential TRONTIER participants must exhibit cognitive impairment on the ISLT, while PrevenTRON potentials must perform normally on it.
Smith said that some participants who “failed” screening for the TRONTIER trials might now be eligible for PrevenTRON. This echoes the design of A4, which enrolled biomarker-positive people for treatment with solanezumab (Jan 2013 news). People who fell just below the screening cutoffs for entry were gathered into an earlier-stage cohort called LEARN, which proved informative for biomarker observation while simultaneously forming a wellspring of phenotyped participants for subsequent drug trials (Mar 2023 news). Smith noted that A4 had been informative for the design of PrevenTRON.
In addition to using convenient prescreening protocol, TRAVELLER also accelerated recruitment by working with the Global Alzheimer’s Platform Foundation and deploying mobile research units to reach a broader community (Aug 2025 conference news). This decentralized approach has previously proven successful in speeding recruitment in other secondary prevention trials, such as Lilly’s TRAILBLAZER-ALZ3 (Nov 2024 conference news).
With apologies for yet another TRANSFORMERS quip, TRAVELLER has been a smashing success. After decades of painfully slow AD trial enrollment, this prescreening program enrolled 10,000 participants within its first six months, nearly 30 percent of whom were recommended for further screening in one of the TRONTIER studies. On average, TRAVELLER enrollees received a recommendation to move forward with screening, or not, within a week of prescreening. The ease of its protocol has also increased the percentage of groups who were traditionally under-represented in clinical trials, Smith said. In the U.S., the proportion of black and Hispanic enrollees in TRAVELLER slightly exceeded their respective proportions in the general population. To what extent this will persist among the eventual Phase 3 trial enrollees is not yet known, Smith said.
When it kicks off later this year, PrevenTRON will be the third ongoing secondary prevention trial. AHEAD3-45, which is testing lecanemab in cognitively normal people with different levels of amyloid, is expected to read out in 2028. TRAILBLAZER-ALZ3 is testing donanemab in people with high p-tau217; because it uses an event-based primary endpoint, it’s unknown when it will finish, but it may be sooner.
In London, Sperling showed data from previous trials to make the case for starting treatment in preclinical AD. For example, subgroup analyses from the Phase 3 lecanemab and donanemab trials hinted that participants with the least amyloid and tau pathology at baseline, respectively, benefitted most from the drugs.
Baseline data from the A4 secondary prevention trial, which tested solanezumab in cognitively normal people with a positive amyloid-PET scan, showed that people with more amyloid were more likely to decline within the next four years. Plasma p-tau217, measured retrospectively with Roche’s Elecsys assay in A4 baseline blood samples, predicted impending decline even more strongly, Sperling reported. Those in the highest tertile of baseline p-tau217, who had an average of 84CL of amyloid, were at substantially greater risk of cognitive impairment than those who started the trial with less p-tau217 in their blood (see upcoming AAIC story).
Sperling noted that baseline plasma p-tau217 correlated not only with the degree of brain amyloid and impending decline, but also with the spread of tangles from the medial temporal lobe to the neocortex, as measured by tau-PET. Among A4 participants in the highest tertile of baseline p-tau217, 52 percent had tau pathology in the mTL, and 31 percent had tangles in the neocortex, Sperling reported. People in the middle and lowest tertiles were less likely to have tangles in both of these regions, especially the neocortex.
What does all this mean for secondary prevention? To Sperling’s mind, collective evidence from past trials strongly supports early intervention, and suggests p-tau217 can help identify people in a Goldilocks stage—i.e., enough amyloid to be at high risk for progression, but still prior to the so-called “ca-tau-strophe,” when tangles inundate the neocortex and the disease becomes less responsive to anti-amyloid therapy.
Where does the p-tau217 cutoff used to select participants for PrevenTRON land on this Goldilocks scale? Sperling told Alzforum that the PrevenTRON selection cutoff corresponds with roughly 70CL amyloid, compared to the 84CL amyloid among A4 participants in the highest tertile of p-tau217, 30 percent of whom had neocortical tau pathology. Therefore, a majority of PrevenTRON enrollees likely won’t have experienced ca-tau-strophe yet, she speculated.
Attendees wanted to know if starting treatment even earlier might benefit people even more. Sperling said that while secondary prevention trials need to start a bit later to see an effect within a four-year time frame, ideally treatment should start even earlier, when amyloid is accumulating but p-tau217 is low. If the three ongoing secondary prevention trials return positive results, Sperling envisions using biomarker outcomes to run trials that test amyloid therapies even earlier. DIAN-TU is conducting a primary prevention trial in autosomal-dominant mutation carriers.
Circling back to trontinemab, Sperling said that the drug’s rapid amyloid clearance, combined with its low ARIA risk, makes it well-suited for use in asymptomatic people with preclinical AD, where the risk-benefit ratio must be extremely low.—Jessica Shugart