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Why did Roche kill off its Alzheimer's program for the BACE inhibitor RG7129?

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When Roche reviewed its big drug pipeline last fall, the pharma giant ($RHHBY) started its review of an ambitious and wide-ranging set of programs for Alzheimer's disease with a mention of RG7129, an early-stage BACE inhibitor that held the promise of preventing the production of amyloid beta, the toxic protein that figures prominently among the likely causes of Alzheimer's.

RG7129 was one of just a handful of BACE drugs--which inhibit beta secretase, a key player in the production of toxic amyloid beta clusters in the brain--to make it to the clinic. But while Eli Lilly ($LLY) attracted broad attention for the failure of its BACE inhibitor, LY2886721, after evidence of liver toxicity in patients, Roche quietly axed its program for RG7129 recently without stirring much attention.

"A BACE1 inhibitor (RG7129) was indeed being investigated in a Phase I trial for Alzheimer's disease," a spokesperson for Roche told FierceBiotech in an email. "Whilst we have decided to terminate the clinical development of this particular compound, we remain committed to the target."

Asked why the program was scuttled, and what safety and efficacy issues may have been involved, Roche's spokesperson declined to answer.

It's not unusual for a company the size of Roche to kill off early-stage programs, but this case could have much broader ramifications. Eli Lilly's failure earlier this year highlighted a real fear that Alzheimer's investigators are putting patients at significant risk when they experiment with these new drugs. Lilly experienced that twice, first when semagacestat--a gamma secretase inhibitor--proved to be harmful to cognition and the ability to handle routine functions and the second time with its BACE inhibitor. Lilly noted at the time that it appeared that the problem was more with the drug than the target, which has excited considerable interest as a blockbuster approach against a disease that afflicts millions. But BACE inhibitors could affect much more than the production of amyloid, including myelination and the thickness of myelin that forms around nerves.

Investigators keep coming back to BACE because it's been repeatedly highlighted as a very promising approach to interrupting the disease pathology, a point that was underscored just yesterday by Yong Shen, an investigator at the Roskamp Institute, who concluded that "there is more and more evidence that BACE1 is intricately involved in the development of AD."

AstraZeneca ($AZN) also has an early-stage BACE inhibitor in the clinic, hoping that AZD3293 could help reverse the company's woeful R&D track record over the past 5 years.

Safety fears prompted Merck to put its own BACE inhibitor through a preliminary safety review before hitting the green light on two late-stage studies which will enroll thousands of patients. One of those will be in mild to moderate Alzheimer's--a field that has vexed a range of programs for drugs, most prominently solanezumab and bapineuzumab.

"Now we can get an answer on the amyloid hypothesis," Darryle Schoepp, Merck's ($MRK) vice president of neuroscience, told Bloomberg this week. "We will have the data that will tell one way or the other" if reducing levels of amyloid can slow down the disease's projectory.

Of course, that's also what Lilly was shooting for with the failed solanezumab, which is back in a new late-stage study targeting early-stage prevention.

Roche's decision to dump RG7129 raises some important questions for the field. But Roche isn't offering any answers--at least not yet. -- John Carroll, Editor-in-Chief. Follow me on Twitter and LinkedIn.