Trontinemab

Third time may be the charm for Roche’s efforts to develop an anti-amyloid beta monoclonal antibody (mAb) to treat Alzheimer’s disease (AD). After shuttering two high-profile programmes in as many years, the Swiss drugmaker shared mid-stage data for a third candidate that suggest this time, it may have cracked the blood-brain-barrier code.At a neurology-focused investor event on Monday, Roche unveiled early Phase II data for trontinemab, a beta-amyloid-targeting antibody, which demonstrated a rapid rate of plaque clearance that could rival Eisai and Biogen’s approved mAb Leqembi (lecanemab), as well as donanemab from Eli Lilly, which is under FDA review. “Alzheimer’s has traditionally been a difficult area,” SVP Paulo Fontoura said during the event. “I think we possibly have turned a corner in the past couple of years with these first approvals, and that also sets us up with trontinemab to really develop something better than what exists right now. So in some ways the door is opening and it’s an opportunity for us.” Fontoura serves as global head of neuroscience, immunology, ophthalmology, cardiometabolic, infectious and rare diseases clinical development at Roche.AD setbacksThe positive data are a refreshing change of pace for Roche, which has seen several recent amyloid antibody failures.In January, Roche’s Genentech unit returned a pair of mAbs to AC Immune after neither candidate showed a functional benefit in early AD across a series of mid- and late-stage studies. Genentech had in-licensed anti-amyloid beta mAb crenezumab in 2006, and the tau-targeting candidate semorinemab in 2012. And in 2022, Roche halted development of its internally developed amyloid programme gantenerumab after it failed a pair of Phase III studies. Brain-penetrating boostTrontinemab, the compound highlighted by Roche on Monday, is a reformulation of gantenerumab. Thanks to the pharma’s Brainshuttle technology, trontinemab can bind to transferrin receptors on endothelial cells to smoothly cross the blood-brain-barrier and then home in on amyloid-beta plaques in the brain. Roche has been working on the Brainshuttle platform for over 15 years, according to AzadBonni, global head of neuroscience & rare diseases in the company's Pharma Research and Early Development (pRED) division. While standard mAbs have to cross the blood-brain-barrier where it’s thinnest, trontinemab can pass through at any affected region by utilising the brain’s dense capillary network.“From a pharmacological approach, this technology allows us to get higher exposure, superior targeting, engagement and a broader distribution in the brain,” Bonni said. Quick plaque clearance So far, the Brainshuttle technology does seem to have boosted the antibody’s plaque-attacking abilities. Roche shared data from a dose escalation Phase II trial that enrolled people who are amyloid-positive, and have either mild cognitive impairment due to AD or were in the early stages of the disease, to receive a trontinemab injection every four weeks. The pharma had previously disclosed that the 1.8 mg/kg dose cohort saw a mean amyloid reduction of 84 centiloid units (CLs) at week 28.On Monday, Roche revealed data from the 3.6 mg/kg dose cohort, which experienced a mean reduction of 91 CLs by week 12 – a greater reduction in less than half the time of the smaller dose. Of eight evaluable patients, five were amyloid-negative.The rapid, three-month clearance of brain amyloid plaques – defined as achieving plaque levels of <24.1 CLs – contrasts sharply with comparator data Roche shared during its presentation. According to the company, Leqembi requires about 18 months to reach clearance, and donanemab takes roughly a year.“The take-home message from these data, from these results, is that trontinemab is moving a lot of amyloid in a short period of time, which is really quite remarkable,” Bonni said.The speed of clearance may be related to the impact an anti-amyloid antibody has on functional endpoints. “What we have learned is that the faster and the deeper that you bring down amyloid, the more likely there’s a correlation in all of these studies in terms of an effect on the clinical point,” he added. A safety edgeFurthermore, the 3.6 mg/kg-dose arm saw no cases of amyloid-related imaging abnormalities (ARIA), which Bonni called “remarkable.” In comparison, Leqembi’s label includes a boxed warning of ARIA. For donanemab, ARIA was the most common treatment-emergent adverse event, with modestly higher incidence rates than Leqembi, which may be one of the reasons behind the FDA’s recent about-face to require an advisory committee meeting for the mAb. For more, see Spotlight On: Last minute AdCom for Eli Lilly’s donanemab raises eyebrows.Bonni acknowledged, however, that the trontinemab trial still has a ways to go to confirm the data. Roche plans to expand the dose cohorts with the most promising results and enrol around a couple hundred patients in each.

Pictured: Roche Diagnostics building in California/iStock, JHVEPhoto Roche in a virtual investor event on Monday unveiled promising Phase Ib/IIa data for an investigational Alzheimer’s therapy that could define the pharma group’s neurology franchise in the coming years. The event spotlighted mid-stage results for trontinemab, an investigational monoclonal antibody targeting amyloid-beta being assessed in Alzheimer’s. Data were presented by Azad Bonni, senior vice president and global head of neuroscience and rare diseases at Roche, which “demonstrated rapid and robust amyloid plaque reduction.” Developed using Roche’s proprietary Brainshuttle platform, trontinemab can cross the blood-brain barrier and achieve higher levels of brain exposure and broader distribution across the central nervous system, according to the company. The antibody was assessed in a Phase Ib/IIa dose-escalation trial with a staggered, parallel-group and adaptive study design, with four sequential cohorts receiving increasing doses of trontinemab or placebo. At 28 weeks, patients who received the lowest 0.2-mg/kg dose of trontinemab saw a mean amyloid reduction of 20 centiloid units, compared to only five centiloid units in the placebo group. The second-highest dose of 1.8-mg/kg elicited a mean amyloid drop of 84 centiloid units. The highest dose of trontinemab—3.6-mg/kg—did not have 28-week data available for analysis, but at 12 weeks, it demonstrated further acceleration of clearance of amyloid plaques. Majority of patients who were treated at this dose level fell below the threshold of amyloid positivity at 12 weeks. Trontinemab was also safe and well-tolerated overall, with only one documented case of amyloid-related imaging abnormality (ARIA) indicative of edema, and another such abnormality suggestive of microhemorrhages. Both ARIA cases occurred in the second-highest dose cohort. These promising Alzheimer’s data follow Roche’s previous failures in the field, which had far-reaching implications for the industry. In June 2022, crenezumab failed a Phase III trial, unable to slow or prevent Alzheimer’s disease in people with healthy mutation who were harboring a specific gene mutation associated with early-onset Alzheimer’s disease. The monoclonal antibody in 2019 had previously failed two other late-stage trials in early Alzheimer’s, forcing Roche to discontinue both studies. A few months after crenezumab’s third flop, Roche again stumbled. In November 2022, another investigational Alzheimer’s therapy—ganenterumab—fell short of its primary efficacy endpoints in the GRADUATE I and GRADUATE II studies, which demonstrated that the candidate could not significantly slow clinical decline versus placebo. During Monday’s investor event, Roche also unveiled long-term data for its investigational antibody prasinezumab showing that the candidate could slow motor progression in Parkinson’s disease. However, Roche was quick to caution that the current data supporting prasinzeumab are still exploratory and need to be verified in independent trials. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.