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12:00 AM
Oct 24, 2011
 |  BioCentury  |  Product Development

Alzheimer's rewind

Gamma secretase woes in Alzheimer's prompt search for alternative targetsNext Phase III data in AD will come from beta amyloid mAbs in 2012

A string of Phase II and III failures in Alzheimer's disease has prompted companies to look for new targets beyond the well-known players in the core mechanism of AD - the production and accumulation of beta amyloid deposits in the brain. The next wave of candidates includes more than 20 clinical stage small molecules for targets that indirectly affect beta amyloid production and/or toxicity, or aim for solutions that might be disease-modifying even as they ameliorate symptoms.

Among the latest casualties are gamma secretase inhibitors, which first entered the clinic more than a decade ago. The two most advanced molecules, one in Phase III and one in Phase II, have shown safety signals that suggest the basic approach to the target will need to be refined. A handful of clinical and preclinical programs aiming to create a second generation of molecules are already underway.

Meanwhile, the AD field is awaiting the results of the remaining Phase III candidates, a trio of immunotherapeutics against beta amyloid. Behind them are at least 11 more clinical stage immunotherapies(see "Awaiting mAb Data," A13).

Gamma ghost town

Gamma secretase, the proteolytic complex that processes amyloid precursor protein (APP) into the neurotoxic beta amyloid form, was first proposed as a target in the 1990s and at least a dozen candidates have reached the clinic in AD.

Data presented at the Alzheimer's Association International Conference (AAIC) in July highlighted the difficulty of finding a therapeutic window for hitting the target.

Eli Lilly and Co. presented the results of a follow-up to the Phase III IDENTITY and IDENTITY-2 trials of its semagacestat (LY450139) gamma secretase inhibitor.

Those trials were suspended last year when a safety monitoring committee uncovered evidence of cognitive worsening in treated patients compared with placebo (see BioCentury, Aug. 23, 2010).

New data from a follow-up of 1,534 patients showed that seven months after dosing was stopped, patients who had received once-daily 100 and 140 mg oral semagacestat, respectively, had ADAS-Cog11 scores that were 7.29 and 7.68 points lower than baseline. Patients who got placebo showed a 6.19 point decline compared with baseline.

These data mean the harmful effect was not reversed after treatment was suspended. The rate of cognitive decline after termination of dosing was the same as placebo.

"Semagacestat produced an effect on cognition," said Eric Siemers, the senior medical director at Lilly who presented the findings. "Unfortunately it wasn't the effect we wanted."

Doubts about the target were compounded by results from a Phase II trial of Bristol-Myers Squibb Co.'s BMS-708163, a gamma secretase inhibitor that was intended to be more selective for APP processing.

The rationale for greater APP selectivity was to not interfere with the processing of other gamma secretase substrates such as Notch 1 (NOTCH1), which is involved in normal tissue regeneration in the gastrointestinal tract and skin.

Bart de Strooper, professor of human genetics at the Catholic University Leuven, said his own studies using improved gamma secretase assays suggest that BMS-708163 in fact blocks NOTCH1 processing at least as potently as semagacestat.

de Strooper led a team that discovered the key enzymatic components of gamma secretase in the 1990s.

Although BMS's Phase II trial met its primary endpoint of establishing a well-tolerated dose, it did not improve cognition endpoints or have the expected effect on biomarkers of efficacy.

Data from the double-blind, placebo-controlled, international Phase II CN156-013 trial in 209 patients with mild to moderate AD showed doses below 100 mg/day had acceptable tolerability and were associated with discontinuation rates similar to placebo. Patients given 100 mg/day or more had higher discontinuation rates than placebo patients, mostly due to GI or dermatological side effects.

However, doses below 100 mg/day showed no effects on the secondary efficacy endpoints of improving ADAS-Cog and ADCS-ADL scores vs. placebo. Indeed, the 100 and 125 mg cohorts showed "trends for cognitive worsening," according to Howard Feldman, VP of global clinical research in neuroscience at BMS.

It's not yet known whether patients who received high-dose BMS-708163 developed the same sort of irreversible cognitive decline seen with semagacestat or whether the harmful effects will wear off.

Furthermore, lower 25 and 50 mg doses of BMS-708163 showed no significant difference in beta amyloid in the cerebrospinal fluid (CSF) at the trough level of drug concentration vs. placebo, although the 100 mg dose led to a 40% reduction.

The pharma said the trial was not powered to determine efficacy but that measurements of CSF beta amyloid at post-dosing peak suggested the compound could inhibit gamma secretase at well-tolerated doses.

Bristol-Myers said BMS-708163 at doses below 100 mg/day thus provides a "potential therapeutic window" for evaluation in Phase III studies.

The company is awaiting the result of a second Phase II trial in early stage or predementia AD patients before deciding how to proceed. In that study, patients were started at 125 mg BMS-708163 daily but were shifted to a 50 mg dose after the tolerability problems in the first trial came to light.

Interim results of the second trial, whose primary endpoints are safety and tolerability, are expected this fall.

Probing deeper

Trying to avoid neurological toxicity with next-generation compounds will require guesswork, because the mechanism through which it occurs with gamma secretase inhibitors is not fully understood.

In his presentation on semagacestat at AAIC, Siemers discussed several hypotheses. He concluded the most probable was that inhibiting the enzyme outright prevented the...

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