The SKYLINE Trial: Gregory A. Rippon, MD, MS, on Roche’s New Study of Gantenerumab

Greg Rippon, MD, MS

Last week, Roche, announced that it was initiating a new trial of its investigational antiamyloid antibody, gantenerumab, a phase 3 clinical trial in those with early signs of Alzheimer disease (AD) dubbed SKYLINE (NCT05256134).1 The trial design is expected to be presented on March 18, 2022, at the 2022 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD), in Barcelona, Spain.

SKYLINE’s initiation follows another pair of ongoing phase 3 trials of the therapy, GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973), which are expected to read out data in Q4 2022. Gantenerumab was also previously granted a breakthrough therapy designation in fall 2021 by the FDA. The therapy is an IgG1 antibody that binds to ß-amyloid aggregates to remove amyloid plaques, delivered subcutaneously.

To find out more about the SKYLINE trial and gantenerumab to this point, NeurologyLive^® inquired with Gregory A. Rippon, MD, MS, neurodegeneration program lead, Genentech (a member of the Roche Group), who offered his perspective on the trial’s goals and design and context on what is known to this point about Roche’s investigational therapy.

NeurologyLive^®: What should the clinical/physician community know about SKYLINE? Are there any aspects of the design that are unique or of note?

Gregory A. Rippon, MD, MS: SKYLINE aims to evaluate the potential of gantenerumab to slow the progression of Alzheimer in people with the earliest biological signs of the disease.

The trial has been uniquely designed to address some of the perceived barriers to participation in clinical research for the clinically asymptomatic Alzheimer population. This includes optional blood-based biomarker (BBBM) prescreening for participants and providing the choice to participants of dosing every 1 or every 2 weeks, with the flexibility of administration at home following a titration period. Also, for participants who are randomized to placebo and progress to mild cognitive impairment or dementia due to Alzheimer within the 4-year study period, we will offer gantenerumab investigational treatment, unless the ongoing phase 3 studies of gantenerumab in early AD (GRADUATE 1 and 2) do not demonstrate efficacy.

How would you describe gantenerumab’s performance in its clinical development thus far? Have there been any particularly notable data points for its safety/efficacy?

We have been studying and developing gantenerumab for 2 decades. Over the years, we have faced setbacks in this program and in Alzheimer disease therapy development more broadly, but we have gleaned significant scientific insights on ß-amyloid lowering—as well as on biomarkers, dosing approaches and clinical trial design—that have contributed to the body of science and understanding of AD.

For example:

• Although the SCarlet RoAD and Marguerite RoAD studies of gantenerumab in patients with sporadic Alzheimer’s were stopped early, both showed significant reductions in markers of brain degeneration. We converted both into open-label extension studies—in which all patients receive the study drug instead of a placebo—to learn more about the effect of gantenerumab in people with early Alzheimer.
• Gantenerumab significantly reduced amyloid-ß plaque levels in the brain in patients with sporadic Alzheimer in the SCarlet RoAD and Marguerite RoAD open-label extension studies and in patients with an inherited form of the disease caused by a genetic mutation in the DIAN-TU-001 study. Other biomarkers associated with brain degeneration also were significantly reduced in the DIAN-TU-001 study.

Notably, we have built on our experience and these learnings from our clinical development program to inform the design of our ongoing phase 3 GRADUATE clinical trials, for which data is expected in the fourth quarter of 2022. Regardless of the outcome, we expect this to be one of the most important datasets to emerge from the AD field. And if positive, the findings will enable us to seek full regulatory approval for gantenerumab from the FDA.

When should the community expect trial data to be available?

Screening of potential participants was initiated in late January 2022. The study will enroll 1200 participants, who will be randomized to receive gantenerumab or placebo for 4 years.

Transcript edited for clarity.

REFERENCE
1. Roche and three leading research institutions combine expertise on new Alzheimer’s prevention trial. News release. Roche. March 3, 2022. Accessed March 7, 2022. https://www.roche.com/investors/updates/inv-update-2022-03-03