Daniel M. Keller, PhD

October 11, 2012

October 11, 2012 (Boston, Massachusetts) — Solanezumab, a drug in phase 3 development for the treatment of Alzheimer's disease (AD), showed modest benefit in slowing the progression of cognitive decline in mild to moderate disease.

There was also some evidence of functional benefit in the subgroups of patients with mild disease, Rachelle Doody, MD, PhD, professor of neurology and the Effie Marie Cain Chair in Alzheimer's Disease Research at Baylor College of Medicine in Houston, Texas, reported for the Alzheimer's Disease Cooperative Study (ADCS), an academic research consortium.

The new analysis was presented here at the American Neurological Association (ANA) 137th Annual Meeting.

Benefit on Cognitive but Not Functional Decline

Solanezumab is a humanized monoclonal antibody that binds to the central region of ?-amyloid. Eli Lilly and Company, the drug's sponsor, made the raw data from 2 double-blind, placebo-controlled trials available to the ADCS, which did an independent analysis.

EXPEDITION 1 (n = 1012) had co-primary endpoints. A cognitive endpoint was evaluated by using the Alzheimer's Disease Assessment Scale 11-item cognitive subscale (ADAS-cog11). The Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) was used to assess function in patients with mild to moderate AD.

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

Patients aged 55 to 94 years were eligible for the 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.

There were no significant differences in either trial between the groups taking solanezumab or placebo at baseline in terms of age, sex distribution, education, proportion APOE4-positive, or mental test scores.

Lilly's original analysis of EXPEDITION 1 showed that neither the primary endpoints of cognition nor function was 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 taking solanezumab.

Pooled data from these trials with similar protocols showed that in patients with mild AD, taking solanezumab was associated with a significant 34% reduction in cognitive decline vs placebo as measured by the ADAS-cog14 (P = .001). Their 17% reduction in functional decline as measured by the ADCS-ADL was not significant compared with placebo (P = .057).

The ADCS analysis produced generally similar results. At 80 weeks, there was no difference between groups in the EXPEDITION 1 co-primary outcomes of the ADAS-cog11 score (P = .12) or the ADCS-ADL (P = .84). Nor was there a difference in the EXPEDITION 2 primary outcome of ADAS-cog14 in patients with mild AD (P = .08) or the additional outcome of ADCS-ADL in patients with mild or moderate AD (P = .12).

However, when the mild and moderate patients were considered as a group by using the pooled data from both trials, solanezumab recipients benefited significantly, showing a 1.41-point lower ADAS-cog14 score (95% confidence interval, 0.35 - 2.47; P = .009). A lower ADAS score denotes better cognition. One panelist in a news conference raised the question of whether a difference of less than 2 points is clinically meaningful.

In both EXPEDITION 2 and in the analysis of pooled data, solanezumab did show an advantage over placebo for mildly affected patients on the functional measure of ADCS-ADL (both P = .04).

In the news conference, Dr. Doody summarized what she reported. "It's saying that for the overall studies you're not seeing an effect on ADLs, but in some of the mild subpopulations in the overall combined data, you're seeing that," she said.

She explained that many factors go into an analysis, including how data are handled and modeled and what statistical tests and even software to use, so it is not unusual for findings to differ slightly even on the basis of the same raw data.

From her analysis, she could say that solanezumab slowed the rate of cognitive decline over time by about 30%.

"That's why we do the slopes analysis as a sensitivity analysis, and you could describe that slopes analysis as showing that you're slowing decline by about 30%," she said. "I treat my patients an average of 7 years, and if you could slow decline by about 30% for 7 years, I think that's impactful."

Solanezumab was generally well tolerated. There were no adverse events in at least 2% of the patients, and the rate of these events was at least 2-fold higher in the solanezumab group than in the placebo group.

'Whiff' of a Signal

Edward Koo, MD, professor of neurosciences and co-director of the Shiley-Marcos Alzheimer's Disease Research Center at the University of California, San Diego, School of Medicine, who was not involved in the trials, told Medscape Medical News that "without any accompanying biomarker data to suggest whether the clinical signal is perhaps real, I think it's a little too early, at least for just recently disclosed data, to be confident whether the signal is real or not. From my perspective, I think this is what I would qualify as a 'whiff' of a signal and perhaps enough to say that we need to look deeper."

He said even if biomarker data were available, the big question in the field is whether any early change in biomarker is early enough or too late to effectively treat the disease. In addition, he said, "Our clinical measurements are still relatively crude and insensitive," so they may miss some people in the earliest stages of the disease.

Maria Carillo, PhD, vice president for medical and scientific relations at the Alzheimer's Association in Chicago, Illinois, said that biomarker data will be presented at the Clinical Trials Conference on Alzheimer's Disease in late October.

In an interview with Medscape Medical News, she emphasized 2 critical points. One is the need to continue to diversify the portfolio of therapeutic targets, "not only the ones we currently know about but really [to] have a robust basic science program that understands the full nature of the pathology of this disease," she said.

"The second thing...is the idea of any therapy today being approved on top of current standard of care is important to note," Dr. Carillo added. "The results that were presented today...had to show an improvement above what's already being boosted by current therapy."

In the case of these trials, most of the patients were already taking drugs for the disease.

Both trials were supported by Eli Lilly and Company. 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 Sonexa, Targacept, Transition, Talceda, and Zinfandel. Dr. Koo has been on scientific advisory boards for Pfizer, GSK, and some biotechnology companies. He is currently on a scientific advisory board for Pfizer. Dr. Carillo, who was not involved in the studies, has disclosed no relevant financial relationships.

American Neurological Association (ANA) 137th Annual Meeting, in partnership with the Association of British Neurologists. No abstract. Presented October 8, 2012.

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