The safety and efficacy of Roche’s gantenerumab, a treatment candidate for Alzheimer’s, will be tested in two global Phase 3 clinical trials in patients with early to mild forms of the disease. The studies follow a long research process that defined the therapy’s optimal dose.
The GRADUATE1 (NCT03444870) and GRADUATE2 (NCT03443973) trials will both run for two years (104 weeks) and are set to start in July 2018. They will measure treatment effectiveness against placebo by looking changes in dementia severity at the trials’ end. The company plans to enroll 750 patients, ages 50-90, in each trial at sites across the U.S, Europe, South America, Australia and Asia.
Both will transition into open-label extension studies. Patients not wishing to continue in them will be followed for up to 50 weeks after the last gantenerumab dose.
Gantenerumab is a fully human antibody that targets beta-amyloid, a protein that accumulates in neurons and is the main component of amyloid plaques found in the brains of Alzheimer’s patients.
Potential benefits of treatment — given as under-the-skin injections — will be compared with placebo. Both studies will analyze effectiveness using the Clinical Dementia Rating Sum of Boxes (CDR-SB) scores, a global assessment tool that determines dementia severity.
Scientists will also assess gantenerumab’s effects using other Alzheimer’s-related scales, and in terms of adverse events, the development of anti-gantenerumab antibodies, and for changes in brain amyloid levels, among other markers. Roche anticipates that the two trials, both very similar, will finish in 2023.
The therapy’s background, latest results, and plans for these Phase 3 studies were presented by Rachelle Doody, MD, Roche’s global head of Neurodegeneration, and by Gregory Klein with Roche Research Pharma and Early Development at the 10th international conference on Clinical Trials in Alzheimer’s Disease (CtAD) 2017, held in November 2017.
Clinical studies with gantenerumab started in 2008, and showed that increasing intravenous doses of the investigational therapy led to reduced brain amyloid levels in Alzheimer’s patients.
This research was part of gantenerumab’s early clinical program, which involved Phase 1 trials in a total of 308 people. Overall, these studies evaluated the safety, tolerability, and pharmacological profile of multiple doses of the therapy.
Despite positive safety data, researchers were concerned with amyloid-related imaging abnormalities (ARIA-E) in patients’ brain, such as inflammation in areas with the greatest amyloid decrease.
In 2010, the company began the SCarlet RoAD Phase 2 trial testing gantenerumab in prodromal (early, presymptomatic) Alzheimer’s patients versus placebo. Roche changed the therapy’s delivery route to subcutaneous (under-the-skin) administration and the study assessed efficacy and safety of lower doses (105 or 225 mg) of the treament, given monthly to 360 participants.
In 2012, Roche moved SCarlet RoAD into a multi-national Phase 3 trial (NCT01224106) involving a planned 799 people with prodromal Alzheimer’s. The research evaluated the effects of two-year treatment with gantenerumab on patients’ cognition and function.
All patients had evidence of beta-amyloid in their cerebrospinal fluid — the liquid that fills and surrounds the brain and spinal cord. The study’s primary goal was to assess changes in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores, much like the new Phase 3 trials.
Roche also launched the Marguerite RoAD Phase 3 trial (NCT02051608) in mild Alzheimer’s patients in 2012, intending to enroll 1,000 patients. Subcutaneous gantenerumab was also given monthly.
Patients began receiving a 105 mg dose of gantenerumab over six months, followed by a higher dose of 225 mg. The trial’s primary goal was to measure changes in two clinical scales of dementia called ADAS-Cog 13 and ADCS-ADL.
However, in 2014, the company decided to discontinue the Scarlet RoAD study based on the recommendation of an independent analysis. The recommendation suggested it would be futile to continue the study as designed, since no improvements in cognition or function were found comparing to placebo. As a result, dosing was suspended.
Despite this drawback, in 2015, Roche reported that a subsequent analysis — using positron emission tomography (PET) scans — demonstrated that higher exposure to gantenerumab (225 mg) was associated with lower brain amyloid at one year of treatment in both the SCarlet RoAD and Marguerite RoAD studies.
Results also indicated that higher doses of gantenerumab slowed cognitive decline in patients with the fastest disease progression.
These data led to the development of a model to predict pharmacodynamic results, which refer to the relationship between the concentration of a medication at a specific site and its effects.
Researchers predicted that they would need to target a minimum of 20% reduction in aggregated amyloid levels. This could only be achieved by increasing the dose of a gantenerumab injection to 1,200 mg.
With this increase in dosing, researchers wanted to guard against brain ARIA-E — brain imaging abnormalities suggestive of inflammation in areas with amyloid decrease[contact-form-7 404 "Not Found"]
. Evidence of ARIA-E is typically evident in the first months of treatment.
To explore different titration (dosing) schemes while keeping ARIA-E low, Roche decided to convert the double-blinded SCarlet RoAD and Marguerite RoAD studies to open-label extensions, or studies in which all patients receive gantenerumab treatment.
The studies, intended to inform the design of the soon-to-begin Phase 3 trials, revealed gantenerumab at higher doses significantly reduced brain amyloid without worrisome scans. The company anticipates completing both SCarlet RoAD and Marguerite RoAD trials in 2020.
“About one third of patients fell below amyloid positivity threshold after six months exposure to higher dose gantenerumabm,” Doody said in her presentation. A total of 81 patients received PET scans in the open-label studies to measure brain amyloid, Klein added.
Findings also indicated great similarity between predicted and observed ARIA-E incidence across all Alzheimer’s genotypes.
Of note, the investigators were able to develop a single titration scheme for all patients, which reduces the risk of ARIA-E.
Further results will be presented at AAT-AD/PD 2018, to be held March 15-18th in Torino, Italy, Roche added.
Gantenerumab and Eli Lilly‘s solanezumab are being investigated by the Dominantly Inherited Alzheimer Network (DIAN) in a Phase 2/3 trial of familial Alzheimer’s (NCT01760005), which is also currently recruiting participants.