A novel experimental anti-amyloid therapy lowered brain amyloid levels below the threshold of positivity in 92% of patients with early asymptomatic Alzheimer’s disease (AD) treated at the highest test dose after just 28 weeks, interim results of a phase 1b/2a study suggest.

Trontinemab, which is under development by Roche, is an engineered antibody derived from gantenerumab’s binding regions and equipped with a Brainshuttle delivery module. The module enables therapeutic molecules to cross the blood-brain barrier, leading to rapid uptake, substantially increased monoclonal antibody (mAb) concentrations at lower doses, and improved target engagement throughout brain tissue.

Although this mid-stage study was not designed to adequately assess clinical efficacy, trontinemab treatment was associated with numerically less decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) relative to placebo, with a low incidence of amyloid-related imaging abnormalities (ARIA).

“We believe Brainshuttle technology holds immense potential to fundamentally change how we deliver therapeutics for neurological disorders, including Alzheimer’s disease,” said lead author Luka Kulic, MD, PhD, vice president and head of early development in neuroscience and rare diseases at F. Hoffmann-La Roche Ltd in Basel, Switzerland.

The findings were presented on December 1 at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference.

The Blood-Brain Barrier Challenge

Crossing of the blood-brain barrier is a major challenge faced by large molecules such as amyloid-beta-lowering mAbs, with only 0.03%-0.2% penetration into brain tissue, investigators noted.

The Brainshuttle AD trial is a multipart, randomized, placebo-controlled phase 1b/2a proof-of-concept study assessing safety and tolerability, pharmacokinetics, and pharmacodynamics, including PET amyloid imaging and cerebrospinal fluid biomarkers.

Kulic presented 28-week results from study cohort 3 (testing 1.8 mg/kg) and cohort 4 (testing 3.6 mg/kg) in a total of 151 participants with early symptomatic AD.

There was “rapid and robust” amyloid plaque clearance, especially at the higher 3.6 mg/kg dose, Kulic said.

At this dose, the adjusted mean change from baseline to week 28 was -99 centiloids; 92% of participants fell below the amyloid-positivity threshold (< 24 centiloids) and 71% were “deeply cleared,” reaching levels at or below 11 centiloids, Kulic reported.

“These effects were associated with early and pronounced effects across a range of downstream markers of AD pathophysiology, including pTau217, where we saw a remarkable more than 50% median reduction vs baseline at the 3.6 mg/kg within 6 months,” he said.

Although the study was not powered to detect clinical benefit, exploratory clinical efficacy outcomes at 28 weeks favored trontinemab, with less decline of the CDR-SB and MMSE scores, relative to placebo.

No New Safety Concerns

The overall safety profile was consistent with prior readouts with no new safety signals, Kulic said. The higher-dose cohort actually had fewer adverse events and fewer withdrawals than the lower-dose cohort.

Anemia was uncommon and mostly mild and transient. Infusion-related reactions were the most common side effect but were mild to moderate in severity and were significantly reduced with steroid premedication — “supporting a clear and effective mitigation strategy,” Kulic said.

There was a low incidence of ARIA with edema (< 5%), consistent with prior data.

Two large, identical global phase 3 trials (TRONTIER 1 and 2) have been initiated to evaluate clinical efficacy and safety in adults with early AD.

Shuttling Past ARIA Risk 

Reached for comment, Aaron Burstein, PharmD, head of search and evaluation at the Alzheimer’s Drug Discovery Foundation in New York City, told Medscape Medical News that the “excitement” around trontinemab and Brainshuttle technology is “understandable” and reflects “the continued evolution of how we administer and deliver anti-amyloid monoclonal antibodies to optimize the efficacy while minimizing some of the risks of side effects, including ARIA.”

The data on trontinemab to date demonstrate that the drug is getting into the central nervous system “much better than the original gantenerumab formulation,” Burstein said.

Encouragingly, said Burstein, the rate of ARIA with trontinemab “is low — quite a bit lower than what we’re seeing with the other anti-amyloid therapies. So the safety looks really good, and we’re seeing effects on relevant biomarkers.”

Burstein added that this shuttle approach could have broad applications.

“One could envision that any molecule that is restricted in its ability to get across the blood-brain barrier could potentially be considered for this type of approach,” he said.

This study was funded by F. Hoffmann-La Roche Ltd. Several authors have disclosed having relationships with the company. Burstein had no relevant disclosures.