Antiamyloid Drugs Could Transform Alzheimer's : In the future, these agents may 'catch' disease presymptomatically in patients who screen positive.

Both phase III trials are testing two, twice-daily doses (100 mg and 150 mg) against placebo, and will be followed by an 18-month open-label extension. About 350 patients have already completed the North American trial, and 85% of them have signed onto the extension study.

Some of the phase III study patients will have pre- and posttherapy MRI to help evaluate the drug's effect on brain atrophy.

R-Flurbiprofen: SALA

Myriad Genetics Inc. is just revving up its phase III trials for this drug (Flurizan). The U.S. trial is in its last stage of recruitment, looking for 1,600 Alzheimer's patients with mild disease. A global study will enroll 800 patients. Both are 18-month trials that pit R-flurbiprofen (800 mg twice a day) against placebo.

R-flurbiprofen rode an efficacy seesaw during its phase II trials. Preliminary results showed no significant effects in any of the three end points (activities of daily living, dementia score, and cognitive function) for the overall group of 207 patients with mild to moderate disease. However, patients with mild AD who were taking the 1,600-mg/day dosage showed a statistically significant benefit at 12 months in activities of daily living and global function, with a positive trend in the Alzheimer's Disease Assessment Scale with the cognitive function subscale (ADAS-cog) (Neurology 2006;66 [Suppl 2]:A347).

The 12-month follow-up study showed that patients with mild disease who stayed on the drug continued to improve, actually regaining up to 2 points on the ADAS-cog. “Although not statistically significant, we saw that the less advanced the patients' disease, the bigger the response they get from the drug,” said Adrian Hobden, Ph.D., president of Myriad.

An additional benefit of R-flurbiprofen may be its ability to delay the onset of psychiatric symptoms in Alzheimer's patients, according to data presented in a poster at the 10th International Conference on Alzheimer's Disease and Related Disorders, held in Madrid. In a secondary analysis of the phase II trial, Dr. Jacobo Mintzer, of the Medical University of South Carolina in Charleston, showed that by 1 year, about 90% of patients on the 1,600-mg/day dosage were free of psychiatric symptoms, compared with about 70% of those on placebo.

The European trial will collect cerebrospinal fluid at baseline and at 18 months for exploratory biomarker studies, once reliable markers have been identified.

Myriad also is contemplating separate imaging studies to examine hippocampal and whole-brain volume changes associated with the drug. An exploration of the drug's effect on amyloid plaque deposition with PET imaging using Pittsburgh Compound B is also a possibility. Such studies may be key to showing whether the drug has any effect on existing brain plaques in humans.

LY450139 Dihydrate: γ-Secretase Inhibitor

Eli Lilly & Co. will get its first glimpse of this drug's effect in cognitive and functional domains from a 29-week phase IIB study, launched at six U.S. sites earlier in 2006. The trial will include 45 patients with mild to moderate Alzheimer's randomized to placebo or LY450139.

Two previous human trials demonstrated the compound's ability to significantly lower total Aβ levels in plasma, but were unable to show a significant decrease in cerebrospinal fluid levels.

Both studies provoked concern among the research community for adverse events that could be tied to Notch signaling toxicity. In the 2004 dose-ranging trial (Clin. Neuropharmacol. 2005;28:126–32), two of seven healthy volunteers who took the 50-mg/day dosage for 2 weeks withdrew: one for an increase in serum amylase and lipase concentrations and exacerbation of previous gallbladder and biliary disease, and the other for nausea, vomiting, weakness, and diarrhea accompanied by elevation in white blood cell count.

A single death occurred during the 2005 trial (Neurology 2006;66:602–4). In this study, 70 patients with mild to moderate Alzheimer's took placebo or a titrated lower dose of the drug (1 week of drug at 30 mg/day followed by 5 weeks at 40 mg/day). One patient in the active group died from endocarditis 5 months after withdrawing from the trial as a result of gastrointestinal bleeding from Barrett's esophagus. Neither the endocarditis nor the Barrett's was associated with the drug, according to the study.

Other patients may have shown mild Notch toxicity. Diarrhea was more common among the active group (six subjects vs. none taking placebo), but reports of “loose stool” were more common among placebo-treated subjects (in one subject vs. six taking placebo). Active patients also had small but significant increases in T lymphocyte and eosinophil counts.

The short half-life of LY450139–only 2.5 hours–may be its saving grace in this area, Dr. Eric Siemers, medical advisor for Lilly, said in an interview. “Based on our data thus far, in adults you can apparently inhibit Notch signaling for up to 12 hours a day and not really see any Notch-related toxicity.”