Clinical Worsening Shown in AD Patients Taking Semagacestat

Pauline Anderson

July 26, 2013

Treatment with the γ-secretase inhibitor semagacestat (Eli Lilly and Company) is associated with dose-related clinical worsening on numerous measures, including activities of daily living, global functioning, and quality of life, according to results of a multinational phase 3 study.

The study was stopped early following a futility analysis that was conducted earlier than planned, when clinical worsening and safety concerns were identified. Development was halted by the company in 2010.

"These disappointing results call for careful further analysis of the data in order to learn as much as possible about the reasons for the clinical worsening," write the authors, led by Rachelle S. Doody, MD, PhD, Alzheimer's Disease and Memory Disorders Center, Department of Neurology, Baylor College of Medicine, Houston, Texas.

The study is published in the July 25 issue of the New England Journal of Medicine.

The study included 1537 otherwise healthy patients aged 55 years or older with mild to moderate Alzheimer's disease (AD). They were randomly assigned to 100 mg (n = 507) or 140 mg (n = 529) of semagacestat or to placebo (n = 501) daily for 76 weeks.

Semagacestat is a small molecule inhibitor of γ-secretase, which has been identified as a potential therapeutic target for AD. The sequential action of γ-secretase (as well as β-secretase) results in amyloid β (Aβ) protein plaques that are the hallmark of AD.

The study found that cognitive status worsened in all 3 groups. The mean change in the Alzheimer's Disease Assessment Scale–Cognitive score at week 76 was 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of semagacestat, and 7.8 points in the group receiving 14 mg of the drug (P = .15 for 100 mg vs placebo; P = .07 for 140 mg vs placebo).

Functional status also worsened in all groups. The mean change in the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory score was -9.0 points with placebo, -10.5 points with 100 mg of semagacestat, and -12.6 points with 140 mg (P = .14 for 100 mg vs placebo; P < .001 for 140 mg vs placebo).

As for secondary outcomes, scores on the global functioning Clinical Dementia Rating–Sum of Boxes showed worsening severity of dementia in all 3 groups with greater deterioration in both groups receiving active treatment than in the placebo group. The Mini-Mental State Examination and the Neuropsychiatric Inventory scores showed significant worsening in the 140-mg treatment group compared with placebo in the modified intention-to-treat population.

Adverse Events

Adverse events were more common in the 2 semagacestat groups than in the placebo group (P < .001 for each dose vs placebo). There were more cancers, especially nonmelanoma skin cancer, and more infections in the 2 active treatment groups.

The rate of serious adverse events was higher in the semagacestat groups than in the placebo group: 24% in the 100-mg group and 25% in the 140-mg group compared with 14% in the placebo group (P < .001). There were also more deaths among patients receiving the active drug (9, 14, and 6 deaths for 100 mg, 140 mg, and placebo, respectively; P = .25 for both comparisons).

A possible reason for the clinical worsening in the active treatment groups is that inhibiting γ-secretase could interfere with the receptor-related nuclear signaling of Notch, a transmembrane protein and γ-secretase substrate, and with the function of cell-surface receptors and proteins involved in embryonic development and other cell-cell contracts.

Or, the worsening could be related to the effects of semagacestat on its target — amyloid precursor protein metabolism. The study did show biological marker evidence that this target was engaged (eg, levels of both A β40 and Aβ 42 were reduced in the 2 active treatment groups). However, lack of significant change in cerebrospinal fluid levels of these Aβ proteins in any of the groups suggests that the target was engaged peripherally rather than in the brain, said the authors.

"The question of whether this worsening represents an on-target effect of central γ-secretase inhibition and central Aβ reduction or an unintended effect related to the known engagement of other inhibitory substances remains unanswered," the authors conclude.

Eli Lilly has indicated that the decision to halt further development of semagacestat does not affect its ongoing clinical trials of solanezumab, the company's other experimental treatment for AD.

Although both compounds focus on amyloid-β proteins, they have different mechanisms of action. Last year, the company reported that a phase 3 study of solanezumab showed modest benefit in slowing the progression of cognitive decline in patients with mild to moderate AD.

The study was supported by Eli Lilly and the University of California at San Diego (the latter is a fiduciary for the Alzheimer's Disease Cooperative Study), a clinical trials consortium established by the National Institute on Aging.

N Engl J Med. 2013;369:341-350. Abstract

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