Positive Biomarker Data for AD Drug, but No Clinical Benefit

Megan Brooks

July 24, 2015

WASHINGTON ― A biomarker-only analysis of the discontinued phase 3 clinical trial of the antiamyloid agent gantenerumab (Roche) in prodromal Alzheimer's disease (AD) shows that the drug engaged its target in the brain and generated positive biological changes, despite not producing a clinical benefit.

This may suggest that the gantenerumab dose used in SCarlet RoAD trial was "likely too low to be clinically efficient and effective," said Philip Scheltens, MD, PhD, director of the Alzheimer’s Center at the VU University Medical Center in Amsterdam, the Netherlands.

Dr Scheltens presented the biomarker analysis of the SCarlet RoAD study at a press briefing July 22 at the Alzheimer's Association International Conference (AAIC) 2015.

To recap, the study randomly allocated 799 patients with prodromal AD (mild cognitive impairment and evidence of amyloid pathology) to gantenerumab 105 mg or 225 mg once monthly or placebo. The study was halted last year on the basis of results of a preplanned futility analysis and a recommendation by the independent data monitoring committee.

After 2 years of treatment, there were no differences between placebo and gantenerumab groups in the primary efficacy endpoint ― change in Clinical Dementia Rating–Sum of Boxes scores.

There were also no differences between placebo and gantenerumab at 2 years on the Alzheimer's Disease Assessment Scale–cognitive subscale 13, the Mini-Mental Health State Examination, and the Functional Activities Questionnaire.

However, in a subgroup analysis, there was evidence of efficacy in patients with fast-progressing disease who had higher exposure to the drug. And the biomarker data reported at the AAIC show the drug is biologically active.

Results of amyloid PET scanning indicated a dose-dependent effect of gantenerumab on lowering amyloid burden, mainly at the higher dose of 225 mg. "The numbers are small, but the results are statistically significant, showing target engagement of gantenerumab," Dr Scheltens said during the briefing.

Gantenerumab also led to a significant reduction in CSF levels of total tau and phosphorylated tau, markers of neurodegeneration, and the effects were dose- and time-dependent.

Table. Mean Percent Change From baseline to Week 104 in CSF T-tau and P-tau

Biomarker Placebo Gantenerumab 105 mg Gantenerumab 225 mg
T-tau +2.62 -4.85 -7.52
P-tau +3.11 -1.45 -2.94

 

There was no change in CSF amyloid beta-42 during the course of the study, "as expected based on the mode of action of gantenerumab," Dr Scheltens said.

"This is the first study showing clear changes on both standard biomarkers in people with very early Alzheimer's," Dr Scheltens said. "These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration."

Gantenerumab was "safe and well tolerated by patients with prodromal AD [with] no unexpected safety signals," Dr Scheltens said.

Amyloid-related imaging abnormalities (ARIA) and injection-site redness were the most common adverse events. "The ARIA-related side effects are what we expected from phase 1 and are in line with what you see with other compounds as well," Dr Scheltens said. No notable changes across groups were seen in vital signs, ECG results, and laboratory measures.

Given the safety and positive biomarker data, future studies should test higher doses of gantenerumab, said Dr Scheltens.

"Genuine Progress"

David Knopman, MD, medical and scientific advisor to the Alzheimer's Association, moderated the press briefing in which the gantenerumab biomarker data were presented along with data on two other antiamyloid therapies ― solanezumab, from Eli Lilly, and aducanumab, from Biogen Idec.

These are "exciting and promising early results" with several drugs from one class attacking amyloid accumulation in the brain, he commented in an AAIC video highlight interview. Although these results are not "definitive at this point and aren't going to lead to a therapy being marketed tomorrow, they [are] very encouraging. We had some evidence of genuine, albeit small, benefit from these drugs in these early studies."

As reported by Medscape Medical News, using a novel delayed-start study design, solanezumab showed potential disease-modifying effects, with some benefit in cognition and function, when started earlier rather than later in the course of disease.

As for aducanumab, Jeff Sevigny, MD, from Biogen, presented mixed results of a prespecified interim analysis that looked at the 6-mg dose given to patients with prodromal or mild AD for whom results on florbetapir PET scanning were positive in the phase 1b PRIME study.

At 54 weeks, the 6-mg dose was associated with reduced beta-amyloid levels in the brain, as has been previously reported with the 3-mg and 10-mg doses.

However, the 6-mg had no significant effect on measures of cognitive function, which goes against findings previously reported with the 3-mg and 10-mg doses, which did show some benefit on cognition.

Amyloid remains "an important target, but it's not the only target," Dr Knopman commented, "and the field is already turning to nonamyloid approaches and novel approaches that use different mechanisms of action."

Overall, this was an "exciting meeting, and we saw some interesting and hopeful preliminary results, and I think there was some genuine progress made. I think within a few years we are going to have a drug that has some genuine effects on slowing down the biology of the disease itself," he said.

The study was funded by Roche. Dr Scheltens is a consultant for Roche.

Alzheimer's Association International Conference (AAIC) 2015. Abstracts DT-01-02, O4-04-05, and F4-03-02. Presented July 22, 2015.

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