Eli Lilly and Company announced yesterday that it is halting development of semagacestat, a gamma-secretase inhibitor being studied as a potential treatment for Alzheimer’s disease. The decision was made after preliminary results from two separate phase 3 studies showed that the drug did not slow disease progression and worsened cognition and the ability to perform activities of daily living.
In the 2 trials, called IDENTITY (Interrupting Alzheimer’s Dementia by EvaluatiNg Treatment of AmyloId PaThologY) and IDENTITY-2, semagacestat was compared with placebo in more than 2600 patients with mild-to-moderate Alzheimer’s disease. Endpoints for the trials were the Alzheimer’s Disease Assessment Scale–Cognitive subscore and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory.
Analysis showed that cognition and the ability to complete activities of daily living worsened in placebo-treated patients, as expected. However, by these same measures, patients treated with semagacestat worsened to a statistically significantly greater degree than those treated with placebo. In addition, semagacestat was associated with an increased risk of skin cancer compared with placebo.
What does this mean for the Amyloid Hypothesis? And what does it mean for clinical trials of AD drugs?
I think the amyloid theory is still valid, but this clearly tells us that our current views may be too simple— clearing amyloid at the stage of mild-to-moderate AD may have little, if any impact on cognition. It must be kept in mind that amyloid deposition in the brain occurs over decades. By the time synapses are lost, administering a drug that decreases beta-amyloid may be too little, too late. In fact, if hippocampal atrophy is present, then there is clearly loss of brain tissue and amyloid had already done its damage.
I think a good analogy for AD is that of heart disease. If a patient presents with a heart attack, starting them on a cholesterol-lowering drug will have little impact on their symptoms from the heart attack. But, if the cholesterol levels are checked five or even 10 years prior, then a cholesterol-lowering drug would certainly reduce the risk of having a heart attack in the first place. By measuring beta-amyloid levels in the brain and cerebrospinal fluid, measuring hippocampal atrophy and trying to identify AD in its earliest stages, we will allow these drugs to have their greatest impact.
In fact, Bristol Myers Squibb is conducting such a trial. It is a phase II study of their gamma-secretase inhibitor in “prodromal” AD. Subjects must not have a diagnosis of dementia, and entry into the trial requires direct measurement of CSF amyloid. Their compound is even more selective for Amyloid Precursor Protein and may, therefore, be more likely to have a beneficial effect.