Crenezumab Fails in Alzheimer's but Is There a Silver Lining?

Nancy A. Melville

July 25, 2014

COPENHAGEN, Denmark ― In 2 phase 2 clinical trials on the investigational drug crenezumab (Genentech), the drug failed to slow cognitive decline or improve global functioning in patients with mild to moderate Alzheimer's disease (AD) ― findings that are in keeping with results from other antiamyloid agents.

However, the results from both studies did show an effect of high-dose crenezumab in patients with mild forms of AD, adding further evidence to the theory that the key to success in tackling Alzheimer's may be to begin treatment very early in the disease course.

"We saw a drug-placebo difference that was consistent with a treatment effect in patients who received a higher dose and who had mild impairment, and the effect was reproduced in the second study," lead author Jeffrey L. Cummings, MD, director of the Cleveland Clinic Lou Ruvo Center for Brain Health, in Las Vegas, Nevada, told Medscape Medical News.

"I think that this, like [other studies], suggests that if the antiamyloid therapies are going to have benefits, they will have to be initiated very early in the disease course."

Dr. Cummings presented the findings on the 2 crenezumab studies here at the Alzheimer's Association International Conference (AAIC) 2014.

Reason for Hope

The larger of the studies, the ABBY trial, involved 431 patients with mild to moderate AD who had a baseline Mini–Mental State Examination (MMSE) score of 18 to 26.

Patients were randomly assigned to receive either low-dose subcutaneous crenezumab (300 mg) every other week or matching placebo, or high-dose intravenous (IV) crenezumab (15 mg/kg) every 4 weeks or matching placebo, for 68 weeks.

The results showed that in the high-dose group of patients with mild to moderate disease, the reduction in cognitive decline, measured by the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12), was, at 16.8%, described as a trend (P = .19), and reduction in global functional decline, measured by Clinical Dementia Rating–Sum of Boxes (CDR- SOB), was not significant at 3.1% (P = .85).

Similar results were seen in the second study, the BLAZE trial, which involved 91 patients with mild to moderate disease who also had baseline MMSE scores of 18 to 26. These patients received the same treatment doses for 68 weeks.

In that study, there was a 10.3% reduction in cognitive decline and a 7.4% reduction in global functional decline in the high-dose group (both, P = .84).

The primary endpoint of the BLAZE trial was change in brain amyloid load, as determined by florbetapir–positron emission tomography. Those much-anticipated results are due to be presented at a conference later this year.

Analyses of patients with milder symptoms (MMSE, 22-26) in the ABBY trial, however, showed a 35.4% reduction in cognitive decline that was statistically significant (P = .036). Those patients had a 19.6 reduction in global functional decline (P = .42).

And patients in the BLAZE trial with mild AD (MMSE, 20-26) who were treated with high-dose IV crenezumab also showed a trend in reduction of cognitive decline of 52.0% (P = .29). Reduction in global functional decline, at 41.5%, did not reach statistical significance (P = .44).

"The important observations in the trial were the consistency of the observations across both trials and across several different outcome measures. These are the things that give me increased confidence that this is a real biological insight and not just a spurious outcome," said Dr. Cummings.

Need for Combination Therapies

In terms of safety measures, crenezumab was well tolerated, and adverse events were similar to those of other antiamyloid drugs. However, the incidence of pneumonia was higher in patients treated with the drug, at 3.2%, compared with 0.6% for those receiving placebo.

Five deaths occurred during the 2 trials; however, the rate is consistent with that of the elderly AD population, and the causes were determined to be unrelated to treatment with crenezumab.

Although trials on fellow antiamyloid drugs bapineuzumab (Pfizer Inc and Johnson & Johnson) and solanezumab (Eli Lilly and Company) have shown similar lackluster results in patients with moderate disease, solanezumab also showed a similar trend for improvement in people with mild AD.

Efforts to better understand the potential effects of treatment with crenezumab in early-stage disease or even before symptoms begin are already under way and include a study of the drug on a group of patients at high genetic risk for early onset of the disease in Medellin, Colombia.

In the meantime, however, greater effort is needed to pursue another likely essential treatment approach that has proven successful in other diseases such as HIV ― combination therapies, said Dr. Cummings.

"Advances in HIV and cancer have focused a lot on combination therapies, yet there is almost nothing being done in that arena in terms of Alzheimer's disease," he added.

Still Worth Pursuing

Dean Hartley, PhD, director of the Alzheimer's Association's Science Initiatives, agreed, and he called for continued funding to support diversified approaches to tackle the disease.

"There may be multiple drugs that will be needed, as we've learned there are multiple issues going on in brain," he told Medscape Medical News.

"We may have to do some kind of combination in order for therapy to be effective, based on the initiation of the disease."

He also agreed that research into antiamyloid drugs should continue, despite the lack of efficacy seen in mild to moderate forms of disease.

"Clearly, the majority of the data have suggested the importance of amyloid deposits in the cascade of events leading to Alzheimer's disease, so we can't necessarily abandon that line of research, particularly with new data suggesting amyloid deposits may start as much as 10 to 20 years prior to the clinical outset," Dr. Hartley said.

As has largely been the case throughout pharmacologic history, the process is likely to be one of trial and error.

"These are clinical trials in which hypotheses are being tested, and they could be wrong, but we need to continue to have that pipeline of research funding for many different drugs," Dr. Hartley said.

"If you look at the history, for instance, of statins ― there were many failures along the way before they found a true benefit, so we certainly shouldn't abandon this."

The study was funded by Genentech. Dr. Cummings has served as an advisor or consultant for Acadia; Adamas Pharmaceuticals, Inc; Anavex Life Sciences Corp; Avanir Pharmaceuticals; Baxter; Bristol-Myers Squibb Company; Eisai Inc; EnVivo Pharmaceuticals; GE Healthcare; Genentech, Inc; GlaxoSmithKline; Lilly USA, LLC; Lundbeck, Inc; MedAvante, Inc; Merck & Co, Inc; Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical Co, Ltd; Pfizer Inc; Prana Biotechnology Limited; QR Pharma; Resverlogix; Sonexa Therapeutics, Inc; Suven Life Sciences Limited; Takeda Pharmaceuticals North America, Inc; and Toyama Chemical Co, Ltd. He owns stock, stock options, or bonds from Adamas Pharmaceuticals, Inc; Prana Biotechnology Limited; Sonexa Therapeutics, Inc; MedAvante, Inc; NeuroTrax Corporation; and Neurokos, Inc. Dr. Hartley has disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2014. Abstract O4-11-06. Presented July 16, 2014.

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