12 June 2007. To borrow a Twainism, news about the death of γ-secretase inhibitors proves to have been exaggerated. At the second Alzheimer’s Association International Conference on Prevention, held from June 9 to today in Washington, D.C., scientists presented results from a phase 2 trial of a compound called LY450139 (a more mellifluous name is to follow soon, promised Eric Siemers of Eli Lilly, the drug’s sponsor.) Developed by Eli Lilly and Company, the compound is hoped to prove itself as a mechanism-based AD drug because it inhibits the γ-secretase enzyme complex that generates the Aβ peptide. The Alzforum has covered this compound as an example of how drug companies use biomarkers in their preclinical research to plan their human trials (see ARF related news story). Here is a summary of the phase 2 human data.

To conduct this trial, Eli Lilly collaborated with the Alzheimer Disease Cooperative Study (ADCS), a consortium of some 90 U.S. and Canadian academic centers for the clinical testing of candidate AD drugs. The ADCS Data Core analyzed the phase 2 data independently of Lilly. Elaine Peskind of the University of Washington School of Medicine in Seattle presented the data in the scientific session, and Siemers presented the same data to reporters at a press briefing yesterday.

This trial was unusual in that it was a biomarker trial. It used as its endpoint reduction of Aβ concentration in plasma and cerebrospinal fluid, not improvement in cognitive or clinical measures. The reason for this design is, basically, that the power calculations for measuring the cognitive/clinical effect of a disease-modifying drug call for trials so large and long that they essentially turn into phase 3 efforts like the one for Alzhemed/tramiprosate (see ARF related story from this conference). (Symptomatic drugs tend to show their effect faster so are easier to test in phase 2.) To conduct a trial within the scope of phase 2, Lilly scientists decided to place their bet on a biomarker readout that has scientific support but has not been definitively shown to improve the disease. That makes this strategy faster, if risky.

The study enrolled 51 patients with mild to moderate AD, randomized 15 to placebo and 36 to treatment. Of those, 22 received the lower dose throughout the trial, and 14 were titrated up to the higher dose after 8 weeks. Treatment lasted for 14 weeks, and follow-up for 26. Three placebo patients discontinued, as did five of the treated patients.

Because this class of drug has caused toxicity primarily in the immune and gastrointestinal systems before, the scientists laid out all side effects in detail. Five people had a skin rash, and three people saw their hair turn lighter. Seven people on the lower drug dose and three people on the higher dose, but also two people on placebo, reported diarrhea, nausea, and vomiting. Eight people on the lower dose, six on the higher dose, and two on placebo reported sleepiness, lethargy, and weakness. These side effects are quite possibly related to the drug, Siemers said, and warrant close monitoring. He also said that they were mild, lasted for a week or two, and then disappeared on their own. He noted that when a drug is overtly toxic, typically the sponsor hears of this during the trial because the local investigators see something is amiss and report back informally. This did not happen in this case, Siemers said. One patient withdrew from the trial because of diarrhea. This at first rings alarm bells because prior γ-secretase inhibitors cause serious side effects in the gut of mice (Wong et al., 2004). But Peskind told scientists that this man, who was enrolled at her site, had been at a potluck with his wife the night before and the couple both got diarrhea. The man did not want to discontinue, but the study rules required that he do, Peskind said.

Chemistry lab data indicated a marked drop in uric acid, which led Peskind to quip that the drug might work for gout, if nothing else. It also caused a small but statistically significant reduction in CD 19 white blood cells. This was not accompanied by increased infection rates or other clinical signs in this study but needs close monitoring, Siemers said. Likewise, there was a slight elongation of the QT interval on electrocardiograms that requires monitoring, but no clinical cardiovascular events.

On efficacy, Siemers and Peskind reported a decrease of plasma Aβ 40 concentrations, 58 percent at the lower 100 mg dose and 65 percent at the higher 140 mg dose. “That is the most robust plasma effect of any drug in development that I have seen,” Siemers said. Dose ranging studies showed that plasma effects become detectable starting at 40 mg of inhibitor. CSF Aβ40 levels showed a smaller decrease. Plasma Aβ42 were low to begin with and dropped below the level of detectability in treated patients, Siemers said. Changes in CSF were not statistically significant. One open question is whether the drug might have a marked effect in the body but less so in the brain.

In response to a question about what Aβ lowering means anyway when it is already low in AD, Siemers said that they cannot know for sure at this point. The working hypothesis is that CSF Aβ levels drop in advance of AD as amyloid deposits in the brain and less Aβ comes out of the brain. A further CSF reduction in response to a γ-secretase inhibitor would be due to a different biological reason, i.e., less Aβ production, but there is no data to show this in humans at this point.

The company has decided to launch a phase 3 trial, which is expected to start enrolling this fall and winter, quite possibly at some of the same sites that will also enroll patients into the phase 3 trial of Elan/Wyeth’s bapineuzumab (see ARF related news story). At least at some clinics, then, patients will have a choice of taking a pill once a day or getting an antibody infusion. Like Lilly, Elan/Wyeth made an unconventional decision in phase II. In their case, the sponsor decided to start a phase III even before the phase II trials were completed. This illustrate how pressing the need is, but also just how much of a race it is to get to the market first with a disease-modifying treatment and try to become the standard of care. —Gabrielle Strobel.