Gantenerumab Fails to Slow Decline of Early Alzheimer’s in Phase 3 Trials

Top-line data for GRADUATE 1 and 2 studies 'disappointing,' Roche says

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by Steve Bryson, PhD |

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The experimental therapy gantenerumab did not significantly slow clinical decline in people with early Alzheimer’s disease, failing to meet a primary trial goal, data from the Phase 3 GRADUATE 1 and 2 studies showed.

Gantenerumab’s ability to remove beta-amyloid — the protein that forms plaques in patients’ brains — was lower than expected.

“So many of our families have been directly affected by Alzheimer’s, so this news is very disappointing to deliver,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, the therapy’s developer, said in a press release. “We are profoundly grateful to the study participants, their care partners and study sites for their contributions to this research.”

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Top-line data from the two GRADUATE studies will be presented at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) Conference on Nov. 30, the company stated.

“While the GRADUATE results are not what we hoped,” added Garraway, “we are proud to have delivered a high quality, clear and comprehensive Alzheimer’s dataset to the field, and we look forward to sharing our learnings with the community as we continue to search for new treatments for this complex disease.”

In a separate statement, the Alzheimer’s Association also expressed its disappointment while noting the results will contribute to disease understanding.

“Although the drug did not meet its primary endpoint, the trials further illustrate the relationship between removal of beta-amyloid and reduction of clinical decline,” the associated stated. “Each anti-amyloid treatment is being tested in a different way and may act differently on the protein that is one of the hallmarks of Alzheimer’s. Research into their effectiveness and safety must continue.”

GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973) evaluated the safety and efficacy of the anti-amyloid, antibody-based therapy in people with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia over 27 months (2.3 years).

A total of 1,965 patients across 30 countries were randomly assigned to gantenerumab or placebo given by subcutaneous (under-the-skin) injection. The therapeutic dose was slowly increased to reach a target dose of 510 mg every two weeks.

Both studies’ main goal was a change at 116 weeks (about two years) on the clinical dementia rating-sum of boxes (CDR-SB). This test measures cognitive and functional change across six areas: memory, orientation, problem solving and judgment, community affairs, home and hobbies, and personal care.

Trial data showed gantenerumab’s use slowed clinical decline in GRADUATE 1 by –0.31 CDR-SB points and in GRADUATE 2 by –0.19 CDR-SB points. However, neither change was deemed statistically significant, meaning chance could have a role. Compared with placebo, these findings represent an 8% relative slowing in cognitive decline in GRADUATE 1 and a 6% relative slowing in GRADUATE 2.

Data on 17 secondary outcome measures that evaluated disease severity, gantenerumab’s therapeutic levels, treatment side effects and adverse events, disease biomarkers, and patients’ scans have not been released.

The incidence of amyloid-related imaging abnormalities (ARIA-E), a common radiological finding associated with amyloid-targeting therapies, was 25% across those treated with gantenerumab. The vast majority of cases were asymptomatic and resulted in very few treatment discontinuations, Roche reported.

“If you’ve seen one anti-amyloid therapy, then you’ve seen one anti-amyloid therapy. The results we’ve seen from drugs in this class points to the urgent need to bring a range of amyloid and non-amyloid therapies to market to slow the course of Alzheimer’s disease,” Howard Fillit, co-founder and chief science officer for the Alzheimer’s Drug Discovery Foundation, said in a statement by the group.

“Successes and disappointments are an expected part of the scientific process, but we are unmistakably in a modern era of Alzheimer’s research, on the cusp of a new generation of therapies that will take a more holistic approach to treating the disease by targeting all of its underlying causes,” Fillit added.

Gantenerumab, a monoclonal antibody, is designed to target aggregated forms of beta-amyloid to clear disease-causing amyloid plaques and prevent further buildup and tissue damage.