Gantenerumab Lowers Key Protein Levels in Early-onset Disease Trial

The investigational therapy gantenerumab significantly lowered levels of established biomarkers in a rare, inherited form of early-onset Alzheimer’s disease, despite failing to slow cognitive decline or memory loss in symptomatic and asymptomatic patients, according to data from a Phase 2/3 clinical trial.

Based on these results, enrolled patients may choose to continue, or start, on gantenerumab as part of an open-label extension study.

Another possible treatment evaluated in the trial, solanezumab, failed to either prevent cognitive decline or show an improvement in these biomarkers.

“Gantenerumab had a major impact on Alzheimer’s biomarkers,” Randall Bateman, MD, a neurology professor at Washington University and the study’s principal investigator, said in a press release. “The drug’s ability to shift multiple Alzheimer’s biomarkers toward normal indicates that it is positively affecting the disease process.”

“The effect was strong enough that we launched an open-label extension of the trial, so participants have the opportunity to stay on the drug as we continue to study it,” he added.

The study, “A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease,” was published in the journal Nature Medicine.

A rare and inherited form of early onset Alzheimer’s, also known as dominantly inherited Alzheimer’s, is caused by a mutation in the PSEN1, PSEN2, or APP genes. People with these mutations experience a decline in thinking and memory starting in their 30s or 40s.

Similar to the more common late-onset Alzheimer’s, changes occur in the brain up to 20 years before symptoms are noticeable, beginning with the buildup of amyloid-beta, the protein responsible for plaque formation in the brain.

Later, levels of the proteins tau and neurofilament light chain (a marker of neurodegeneration) rise in the cerebrospinal fluid (CSF) that surrounds the spinal cord and brain, and the brain begins to shrink. Tangles of tau protein next form — and only then do people start showing signs of cognitive decline, memory loss, and confusion.

Gantenerumab (developed by Roche and its U.S. affiliate Genentech) and solanezumab (developed by Eli Lilly) are two investigational therapies that aim to reduce amyloid-beta buildup in the brain to slow, stop or prevent cognitive decline and memory loss.

The DIAN-TU-001 Phase 2/3 clinical trial (NCT01760005), sponsored by the Washington University School of Medicine, was designed to evaluate the safety and effectiveness of these two medicines in people with this early-onset Alzheimer’s form, whether symptomatic or asymptomatic. The study was led by scientists at the St. Louis university, as part of its Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU).

Gantenerumab (given subcutaneously or as an under the skin injection) was randomly assigned to 52 patients with a mean age of 46, of which 40% were female. Of this group, 60% were asymptomatic or cognitively normal, as defined by a Clinical Dementia Rating (CDR) score of 0.

Solanezumab (given via intravenous infusion or into the vein) was assigned to 52 patients (60% asymptomatic), with a mean age of 42.5, of which 58% were female.

A placebo (given subcutaneously or intravenously) was given to 40 participants (55% asymptomatic) of similar age.

Patients were treated every four weeks at escalating doses to improve the chances of a beneficial effect. The mean treatment duration was about four years, ranging from a little less than a year to up to seven years. The study’s main goal was a change in cognition as measured by the DIAN Multivariate Cognitive End Point (DIAN–MCE).

Data showed that this main objective — to slow cognitive decline and prevent memory problems — was not achieved with gantenerumab or solanezumab.

“Overall, the analyses indicate that there was no difference in cognitive decline between the gantenerumab and control groups and suggest a faster cognitive decline in the solanezumab group versus the control groups,” the team wrote.

Notably, patients who did not have symptoms before treatment (baseline) did not demonstrate cognitive decline over the trial period. “Because cognitive decline was not observed in the asymptomatic subgroup, the results were not con­clusive regarding treatment effects in this population,” the researchers wrote.

In contrast, patients who entered the trial with symptoms showed a substantial cognitive decline by the time doses were increased.

“The first dose escalation for both drugs occurred relatively late, which limited exposure to higher doses,” they added.

However, as a secondary outcome, the study also examined the therapies’ effect on molecular and cellular signs of Alzheimer’s disease. Gantenerumab showed potential benefits in these measures.

Gantenerumab significantly reduced amyloid plaque formation in the brain at two years and four years compared with placebo, as assessed by positron emission tomography (PET) scans. This represented a relative change from baseline of 9% at year two (4% reduction with gantenerumab vs. 5% increase with placebo).

This benefit was more pronounced by year four, when a larger number of patients were exposed for a longer time to gantenerumab at a higher dose, with a change from baseline of 24.3% over placebo. These biomarker effects were seen in both symptomatic and asymptomatic groups.

Gantenerumab also significantly reduced total tau in the CSF at year four (20.6% reduction vs. placebo) as well as a disease-associated version of tau known as phospho-tau181 (32.8% reduction vs. placebo).

Neurofilament light chain — a marker of inflammation — rose after treatment with gantenerumab by 1.7% compared with 3.9% in the placebo group. Differences in tau and neuronal injury markers between gantenerumab and placebo were more prominent in the asymptomatic patients than symptomatic ones, but the difference was not statistically significant.

“These biomarker results suggest that gantenerumab had a favorable impact on the target and downstream markers of Dominantly Inherited Alzheimer’s Disease,” said Rachelle Doody, MD, PhD,  global head of neurodegeneration at Roche and Genentech.

The safety profiles of gantenerumab and solanezumab were consistent with trials in people with sporadic Alzheimer’s, with no new safety issues observed.

Amyloid-related brain swelling (cerebral edema) was seen in 19.2% of the gantenerumab group, 0% in the solanezumab group, and 2.5% in the placebo group.

This adverse event was mostly asymptomatic (8 out of 11), and those with symptoms experienced mild headache, dizziness, and balance problems with ear pain. All were resolved.

Participants were invited to continue gantenerumab treatment as part of an open-label extension study, given the significant biomarker benefits.

“We support the continued scientific investigation of gantenerumab in Washington University’s exploratory, open-label extension study to build on learnings from DIAN-TU-001, and are grateful to be a part of this close collaboration … as we continue to tackle the complex challenge of Alzheimer’s disease,” Doody added. “We are encouraged by the advancements being made and look forward to continued progress.”

Despite the lack of cognitive benefit in this study, improvements in biomarkers following gantenerumab treatment may support preventing or slowing disease progression via amyloid lowering. This may benefit patients in earlier stages of the disease, in  inherited forms and in those who develop late-onset Alzheimer’s after age 65.

“Although the trial focuses on people with rare mutations, drugs that are successful in this population would be promising candidates for preventing or treating the forms of Alzheimer’s that occur more commonly in older adults,” Bateman said. “The destructive molecular and cellular processes in the brain are similar in both types of the disease.”