The trial will use PACC-5 score as its primary end point and expects to enroll 1200 participants who have confirmed amyloid pathology without signs of cognitive impairment.
Roche has announced that it will be conducting a new phase 3 clinical trial, called SKYLINE (NCT05256134), which will evaluate its subcutaneous investigational antiamyloid antibody, gantenerumab, as a preventive treatment for patients with early signs of Alzheimer disease (AD).1
The trial will include an estimated 1200 participants aged 60-80 years who have amyloid positivity confirmed by cerebrospinal fluid (CSF) or PET, without signs of cognitive impairment. Its primary end point will be the change from baseline to year 4 in Preclinical Alzheimer’s Cognitive Composite-5 (PACC-5) score—a composite of total recall score from the Free and Cued Selective Reminding Test (FCSRT), delayed recall score on the Logical Memory IIa subtest from the Wechsler Memory Scale, the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, and Mini-Mental State Examination (MMSE) total score.
Roche intends to present the SKYLINE trial design at the 2022 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD), on March 18, 2022, in Barcelona, Spain.
“My colleagues, collaborators, and I are pleased about the chance to continue working with Roche, helping to inform the study design, endpoints, recruitment options, and promising blood-based biomarker tests used in this important prevention trial,” said study principal investigator Eric M. Reiman, MD, Executive Director, Banner Alzheimer's Institute, in a statement.1 “We are eager to help find and support the widespread, appropriate, and affordable use of prevention therapies for people facing Alzheimer’s disease as soon as possible.”
According to Roche, there are several strategies in place to address the challenges associated with running clinical trials in an AD prevention setting, including an optional blood-based biomarker prescreening, dosing flexibility for study participants—either every week or every 2 weeks—and an at-home administration option. The trial is part of a collaboration agreement with Banner Alzheimer’s Institute’s Alzheimer’s Prevention Initiative (API), which Reiman helps to lead, as well as Massachusetts General Hospital and the University of Southern California Alzheimer’s Therapeutic Research Institute to further exchange scientific insights and advance the trial goals.
“As populations continue to age, Alzheimer’s is a looming global health crisis. The possibility to detect this disease at scale more effectively and to intervene even earlier could potentially improve the lives of millions of people and those who care for them,” Levi Garraway, MD, PhD, Chief Medical Officer and Head of Global Product Development, Roche, said in a statement.1 “We are proud to collaborate with key experts in the field and the broader Alzheimer’s community on this study, and we look forward to sharing our learnings in the future.”
Gantenerumab was awarded a breakthrough therapy designation by the FDA in October 2021, after findings from the ongoing SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) open-label extension trials, which showed that the therapy significantly reduced brain amyloid plaques.2 It is additionally being assessed in a pair of phase 3 studies, GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973), which are expected to read out data in Q4 2022. The trials include a combined 2000 participants who are being treated with a monthly target dose of 1020 mg. Participants will also have the option to have an optimized titration, which is aimed at maximizing exposure and minimizing dose interruption throughout the study period for better detection of a potential clinical benefit.
The subcutaneous antiamyloid agent has experienced a bumpy ride to this point. Previously, in 2014, Roche had stopped dosing in SCarlet RoAD based on interim futility analysis, after it started the Marguerite RoAD trial earlier that year.3 Then, in 2016, an update to the clinicaltrials.gov page showed that enrollment had stopped at 389 participants, well short of the anticipated 1000, and like SCarlet RoAD, Marguerite RoAD failed its interim futility analysis. At that time, the trials were switched to open-label extension studies, where participants with clinical diagnoses of mild AD were titrated up to 1200-mg gantenerumab. Additionally, Open RoAD, a rollover open-label study of the open-label extensions of SCarlet RoAD and Marguerite RoAD, is currently ongoing.
The therapy was also assessed in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU-001) study (NCT01760005)—the design of which informed GRADUATE 1 and 2—that measured cognitive outcomes of gantenerumab and solanezumab, Eli Lilly’s investigational agent, over a maximum 7-year follow-up period. Using the unique DIAN Multivariate Cognitive Endpoint to measure cognitive performance, both agents failed to reach the primary end point in patients with early-onset inherited form of AD in a 2020 data readout.4 There is currently an exploratory open-label extension of DIAN-TU-001, aiming to build on learnings from the original trial, as well as further understand the relationship between biomarker changes with cognitive and clinical findings.
Notably, at the 2018 Alzheimer’s Association International Conference (AAIC), data from those trials showed that treatment with the high-dose agent lowered brain amyloid by an average of 59 centiloids on florbetapir PET. At years 1 and 2, 37% and 51% of patients, respectively, had Aß plaque levels below the Aß positivity threshold. Amyloid-related imaging abnormalities, which were a concern in the phase 1 trials, were found in about one-third of participants in the extension studies, most of which were asymptomatic.5