Roche scuttles PhIII Alzheimer's study in yet another setback for the field

Yet another big Phase III test of an experimental Alzheimer's drug has flopped. And this time it's Roche's turn to admit defeat.

The pharma giant ($RHHBY) has opted to discontinue a late-stage study of gantenerumab, another drug that targeted amyloid beta--toxic protein clusters in the brain which have been associated with the disease. Like solanezumab and bapineuzumab--two other big Phase III flops in the field--the antibody failed to register significant signs of efficacy.

Luca Santarelli, Roche's head of neuroscience

But this study was one of the first to move upstream in the patient population, recruiting presymptomatic, or prodromal, patients. Failures at Eli Lilly ($LLY) and Johnson & Johnson ($JNJ) in mild to moderate patients persuaded scientists that they needed to move at an earlier stage of the disease, before it had done irreparable damage to the brain. The early termination of the study will once again trigger renewed debate over the amyloid beta theory and the likely cause of a disease that afflicts millions.

Despite the decision to terminate the study, Roche says it will continue studying patients in a separate Phase III trial for mild cases of Alzheimer's, even though any positive indications that could come of it would be heavily clouded by the sudden halt to the SCARLET-ROAD study.

The failure also marks a setback for MorphoSys, which partnered with Roche on the program.

Roche neuroscience chief Luca Santarelli was excited about gantenerumab's chances after researchers saw signs in 2011 that the antibody was clearing amyloid beta in a small group of patients. "The playing field has changed dramatically and gantenerumab is now the most advanced monoclonal antibody in early Alzheimer's and the next big news to read out in this space," Santarelli told Reuters in late 2012.

Roche also has another Alzheimer's program in play for crenezumab.

"In July, crenezumab showed some signs of efficacy when results from a Phase II trial were cut a certain way to look at "mild" patient specifically," notes Bernstein's Tim Anderson this morning. "While similar to gantenerumab, there are enough differences with this product that we suspect it will likely advance into Phase III development, primarily because of the encouraging July results." 

In a follow-up note, Anderson went on to highlight some key differences between gantenerumab and two other drugs he follows. Gantenerumab is targeted against deposited amyloid beta (where damage may have already occurred) while Lilly's solanezumab goes after soluble monomeric AB and Biogen Idec's ($BIIB) BIIB037 appears to have an effect on soluble oligomeric AB. Just how significant that is, though, is uncertain.

All the analysts tend to view this field with considerable caution. A winner in Phase III would ignite a blockbuster market for any company that gets over the finish line. But the failure rate for these drugs over the last decade has run at about 99%, making the risk involved daunting. Lilly, though, mounted a new Phase III program for solanezumab, while Merck ($MRK), AstraZeneca ($AZN) and others have been focused on a BACE approach to amyloid beta by preventing the formation of the protein.

"We are disappointed with these study results because people with early stage Alzheimer's need new medicines that delay disease progression," said Sandra Horning, the head of global product development at Roche. "This is the first Phase III trial to evaluate a potential disease-modifying medicine in this early prodromal stage of Alzheimer's disease. We remain committed to investigating new medicines for this devastating illness."

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