Conference Coverage

Two Antiamyloid Antibodies Will Undergo Further Study

Investigators hypothesize that solanezumab and gantenerumab will show benefits with earlier administration and higher doses.


BOSTON—Solanezumab and gantenerumab, both of which failed in phase III studies, will be examined in further trials at much higher doses, according to lectures presented at the 10th Edition of Clinical Trials on Alzheimer’s Disease.

Reisa Sperling, MD

Based on a reassessment of the failed EXPEDITION series of trials, researchers will quadruple the dose of solanezumab in the ongoing Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) prevention study. Patients who already have been enrolled will have their infusions titrated from 400 mg/month to 1,600 mg/month, said Reisa Sperling, MD, Director of Clinical Research in the Memory Disorders Unit at Brigham and Women’s Hospital in Boston.

Gantenerumab will be tested in two new phase III studies at a much higher dose than was used in the Scarlet Road and Marguerite Road studies, according to Gregory Klein, PhD, Principal Scientist and Biomarker Experimental Medicine Leader at Roche in Basel, Switzerland.

The Challenges of Antiamyloid Therapies

Solanezumab and gantenerumab are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild to moderate disease. Other studies of antiamyloid therapies have had similar results. Although these drugs stimulate several mechanisms of plaque removal, none has significantly improved thinking or memory.

Some investigators have questioned whether the drugs’ doses were high enough. Doses had been chosen with caution, partly because antiamyloid antibodies can cause amyloid-related imaging abnormalities (ARIA), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has decreased with the accumulation of more adverse-event data. Most cases of ARIA have been asymptomatic and resolved spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model, have increased confidence that patients will tolerate the antibody at subcutaneous doses as high as 1,200 mg.

Researchers also have examined the question of therapeutic timing. It is increasingly apparent that plaque eradication does not rescue cognition. It is possible that Alzheimer’s disease must be treated before amyloid and tau damage the hippocampus and neocortex.

After evaluating the failures of solanezumab and gantenerumab, researchers hypothesized that higher doses delivered earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline.

“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s [disease],” said Dr. Sperling. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”

Other investigators hold that tau is the prime concern and the main cause of declines in memory and cognition. Tau is present in the brains of most people experiencing cognitively normal aging, but amyloid deposition may spur tau to spread into the neocortex. Preventing amyloid accumulation may prevent dementia not only by controlling amyloid levels, but also by removing a stimulus for the spread of tau.

Dr. Sperling cited unpublished data showing subtle cognitive decline in cognitively normal patients who have amyloid and tau in the brain. Although the cognitive scores were within the normal range, subjects with both proteins declined over two years on specific measures of memory and were more likely to progress to MCI.

“This [result] is striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again, we have this suggestion that amyloid is associated with tau, and tau is associated with poor memory, even in normal people.”

A New Study of Solanezumab

Solanezumab’s failure in the series of EXPEDITION studies has prompted the modification of the A4 protocol. “We think solanezumab has an increased chance of success here [compared with the EXPEDITION trial] because we are employing it 10 to 15 years earlier in the disease. But we also want to maximize its chances.”

Thus, she said, investigators have decided to quadruple the dose administered in A4. Subjects will undergo titration from 600 mg to 800 mg for two months and then to 1,600 mg every four weeks. A safety cohort of 200 patients will be monitored for adverse events, especially hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” said Dr. Sperling.

So far, 1,151 patients have been recruited into the study. Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.

Gantenerumab May Reduce Amyloid Burden

Gantenerumab will be examined in further trials, following investigators’ analyses of open-label extension data from the Scarlet Road and Marguerite Road studies, said Dr. Klein. Patients in these studies were randomized to either 105 mg or 225 mg of the antibody. Researchers observed no significant cognitive benefits of therapy, but noted trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. These results encouraged researchers to examine higher doses in 52-week open-label extensions of each study.

Dr. Klein presented new imaging data for these studies. In both studies combined, 40 patients were maintained for six to nine months on the highest doses (ie, from 900 mg to 1,200 mg). Of these participants, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, appear to show traces of amyloid or to be amyloid-negative. The effect was consistent, regardless of the amount of amyloid at baseline. “These are encouraging biomarker data,” he said. “We are going into our new phase III studies, Graduate I and II, optimistic.”

According to a Roche press release, these studies will target patients with prodromal to mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. Dr. Klein’s comments suggest that studies of gantenerumab will continue.

—Michele G. Sullivan

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