More Good News for Solanezumab in Alzheimer's

MONTE CARLO, Monaco — Results of an independent biomarker analysis of phase 3 trial data on solanezumab (Eli Lilly and Company), a monoclonal antibody that binds to soluble forms of beta amyloid, suggest that this compound has a positive effect on levels of amyloid in the brain and spinal fluid of patients with Alzheimer's disease (AD).

An early composite analysis of several regions of the brain in patients taking the drug showed that levels of amyloid beta 40 (Aβ40) declined significantly. Other tests revealed that levels of both Aβ40 and Aβ42 increased significantly in the spinal fluid. Plasma levels of amyloid increased severalfold; for example, Aβ increased from an average of approximately 300 pg/mL to over 150,000 pg/mL.

"We're talking about pretty substantial fluxes of amyloid," said Rachelle Doody, MD, PhD, Baylor School of Medicine's Effie Marie Cain Chair in Alzheimer's Disease (AD) Research, who presented the results here at Clinical Trials in Alzheimer's Disease (CTAD) 2012.

"What the biomarkers show us is that the drug had a pharmacodynamic effect in the brain and in the periphery; so it took some of the amyloid out of the brain and put it in the blood," Dr. Doody told Medscape Medical News. "The overall cognitive effect is small, but the likelihood is that it's related to moving the amyloid around."

Other markers that Dr. Doody and her research team looked at for this analysis, including cerebrospinal fluid (CSF) tau, CSF phospho-tau, magnetic resonance imaging (MRI) hippocampal volume, and whole-brain volume, were negative for a drug effect, she said.

Second Wave

The release of these biomarker results represents the second wave of the independent analysis of pooled raw data from the Eli Lilly Expedition clinical trials.

The analysis was carried out by the Alzheimer's Disease Cooperative Study, part of the National Institute on Aging (NIA) Division of Neuroscience that aims to facilitate the testing of new drugs in the field of AD. Dr. Doody presented data related to cognition and function last month at the American Neurological Association (ANA) annual meeting in Boston, Massachusetts, that were reported by Medscape Medical News at that time.

For EXPEDITION 1 (n = 1012), the Alzheimer's Disease Assessment Scale 11-item cognitive subscale (ADAS-cog11) was used to assess cognition, and the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) was used to assess function.

The EXPEDITION 2 (n = 1040) study used a modified statistical analysis and had a single cognitive endpoint using the ADAS-cog14, which has 3 additional items considered relevant for patients with mild AD.

Patients aged 55 to 94 years with mild to moderate AD were eligible for these trials. They received 400 mg of solanezumab or placebo infused intravenously every 4 weeks for 18 months. They could stay on their stable standard-of-care medications during the trials. Most were taking an acetylcholinesterase inhibitor or memantine.

Original Analysis

Lilly's original analysis of EXPEDITION 1 showed that neither primary endpoints of cognition or function were met in the 2 trials of patients with mild to moderate AD.

However, a prespecified secondary analysis showed a 42% reduction in cognitive decline at 18 months among patients with mild AD taking solanezumab compared with those taking placebo (P = .008). There was no statistically significant difference in activities of daily living as reflected by the ADCS-ADL scores.

In EXPEDITION 2, Lilly found a non–statistically significant 20% reduction (P = .12) in cognitive decline and a 19% reduction in functional decline (P = .076) in the prespecified secondary endpoint of the ADCS-ADL among patients with mild disease who were taking solanezumab.

At the ANA meeting, Dr. Doody reported that the EXPEDITION trial data showed positive results in slowing the progression of cognitive decline in the prespecified subanalyses of mild patients that was more pronounced in the pooled analyses when the 2 mild to moderate studies were combined. She also reported that there was some evidence of functional benefit in the subgroups of patients with mild disease.

Cognitive Signal

"What we see here is a cognitive signal when we combine both studies in mild to moderate patients," said Dr. Doody in an interview. "In either study, it looks like it's there in the mild [patients]. When we combine the 2 mild populations, it's there for both cognition and activities of daily living."

She added that solanezumab is the only AD agent proven to have such a "cognitive signal."

Solanezumab is not the only anti-AD drug with emerging biomarker data. Medscape Medical News reported recently that results of substudies of bapineuzumab, another amyloid-targeting agent, showed significant differences in the amount of amyloid in the brain and phospho-tau in cerebrospinal fluid between patients with AD carrying the apolipoprotein E ε4 (APOE4) genotype who received bapineuzumab and those taking placebo.

However, as pointed out by William H. Thies, PhD, chief medical and scientific officer, Alzheimer's Association, bapineuzumab did not meet any of the original study's endpoints, and its development has been stopped. If analyzing carriers of the APOE4 genotype had been part of the original design of trial, "it would have been more interesting than just pulling those people out," he said.

A consensus among researchers seems to be that the new solaneuzumab findings will help set the course for AD secondary prevention trials that are due to start in 2013. Those trials will focus on people who have biomarker evidence of AD but have yet to show any symptoms, the idea being that targeting these patients early may result in more effective treatments.

Prevention Trial

Solanezumab is 1 of the 3 agents targeting beta amyloid that will be evaluated in an AD prevention trial to be conducted by the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN TU) at Washington University School of Medicine in St. Louis, Missouri.

The other 2 agents are gantenerumab (Roche), a monocolonal antibody that binds to all forms of aggregated beta amyloid and is currently being tested in an international phase II/III trial in prodromal AD, and the BACE inhibitor (also from Eli Lilly), which targets beta amyloid, theoretically reducing the production of beta amyloid and slowing the accumulation of plaques in the brain.

Researchers selected these agents from more than a dozen nominations submitted by the DIAN Pharma Consortium, which is composed of 10 pharmaceutical companies.

Funded by the National Institutes of Health, the DIAN trial, which is expected to start by early next year, will include individuals who are mutation carriers (MCs) for autosomal-dominant AD and therefore genetically destined to develop the rare and aggressive form of the disease at a young age, typically in their 30s, 40s, or 50s.

The trial will involve 160 individuals, 80 MCs and 80 individuals who are DIAN participants but not MCs.

For Dr. Thies at the Alzheimer's Association, which is providing major funding for DIAN, it's "certainly possible" that this prevention trial could supply the "confirming data" needed by the US Food and Drug Administration to move solanezumab into the marketplace.

Cautious Optimism

His cautious optimism was boosted by the newly released biomarker results for this drug.

"I would endorse the idea that we should be cautiously enthusiastic about this kind of data," Dr. Thies said. "It's telling us an awful lot about the science of Alzheimer's disease treatment and certainly fits with an emerging picture that lowering amyloid concentrations in the brain early results in some benefit to people who are at risk for dementia."

However, he noted that the results were "mixed," inasmuch as the analysis did not show much change in things such as MRI volume, tau, and phospho-tau, which are indicators of cell damage.

Dr. Thies did think it was significant that Lilly was willing to give its raw data to an independent group for analysis. The AD Cooperative Study, which is essentially the clinical trials arm of the NIA, is made up of academic scientists interested in carrying out clinical trials and who have no vested interest in their outcome other than to see better treatments, he said.

Also approached by Medscape Medical News to comment on the new solanezumab biomarker results, Ron Petersen MD, PhD, director of the Mayo Alzheimer's Disease Research Center, in Rochester, Minnesota, agreed that the new information "supplies some additional evidence that the compound is engaging its intended target."

But he cautioned that "we will have to wait to see if that is clinically meaningful."

Dr. Doody is a speaker for and has received honoraria from AC Immune, Allon, Biote, Cardeus, Chiese, Elan, Genzyme, GlaxoSmithKline, Hoffman-LaRoche, Medivation, Merck, Nautricia, Pfizer, QR Pharma, Shire.

Clinical Trials on Alzheimer's Disease (CTAD) 2012. Presented October 30, 2012. Symposium 5.