12:00 AM
 | 
Oct 08, 2012
 |  BioCentury  |  Product Development

Contrarian thinking

Why Genentech, Roche say neuroscience R&D is ripe for investment

While many pharma companies are exiting or externalizing neurology R&D, a few have decided to double down, seeing the glimmer of a new understanding of CNS diseases where others see biological black boxes leading to late-stage clinical failures.

Among these contrarians, Roche and its Genentech Inc. unit say neuroscience is breaking open because of advances in genetics, imaging and an improved understanding of pathways and targets.

Based on the foundation provided by those advances, the pair is investing in internal R&D and deals to build a pipeline of potentially disease-modifying treatments for neurodegenerative diseases, pain and psychiatric indications.

"What we do is focus on mechanism in choosing what to work on - what we understand and now can make tractable," said Luca Santarelli, head of neuroscience research in Roche's Pharma Research & Early Development (pRED) group.

Roche and Genentech also say they are learning from first-generation failures to design better molecules against known targets such as beta amyloid in Alzheimer's disease.

"In Alzheimer's, I think we have learned a lot about the disease mechanism and are now learning about the course - it's as long as 20 years, which we did not think [was the case] before," said Santarelli.

These changes are leading the companies to new patient populations and clinical trial designs.

Sean Bohen, SVP of early development at Genentech, said this approach required challenging the conventional wisdom for how to test its candidates.

According to Bohen, the company asked itself whether a classical development plan in patients diagnosed with dementia could lead to a negative result, but not because the target was wrong.

"What about treating people who are cognitively normal - redefine the patient population, test the therapeutic and test new endpoints?" he said. "That's what we're doing."

Roche and Genentech, which have separate R&D organizations for discovery through Phase II development, each have an antibody against beta amyloid in clinical trials for AD.

Roche is testing gantenerumab in a Phase II/III trial in patients with prodromal AD, who have memory loss but do not yet have dementia.

Genentech is testing crenezumab to prevent AD in cognitively normal patients with a mutation that causes early onset AD, and in two Phase II trials to treat mild to moderate AD.

While the groups are taking similar approaches to prioritizing programs in neurodegenerative diseases, they have arrived at different conclusions about psychiatric indications.

Roche has moved three compounds targeting glutamatergic dysfunction into clinical testing. Meanwhile, Genentech is conducting research seeking a greater understanding of what cell types and circuits are affected in neuropsychiatric diseases.

Roche also is working on neurodevelopmental disorders, including autism and fragile X syndrome, while Genentech is working on pain (see "Roche/Genentech CNS Pipeline," A3).

Ripe for investment

Roche has been working in neuroscience since the late 1950s, and reiterated CNS as one of its focus areas in a 2007 R&D reorganization. The company has intensified its research in neuroscience over the last decade and ramped up its development activity over the last five years.

Relative to its parent, Genentech is a newcomer, having announced its re-entry into neuroscience in 2006 when it licensed rights to antibodies against beta amyloid from AC Immune S.A. (see BioCentury, Dec. 11, 2006).

Five years earlier, then-independent Genentech out-licensed much of its neurology IP, mostly covering pain and neuropathy, to Rinat Neuroscience Corp., now part of Pfizer Inc. (see BioCentury, Nov. 12, 2001).

Both groups say neuroscience is more attractive than it has ever been, despite high-profile clinical failures of gamma secretase inhibitors last year and anti-beta amyloid antibodies to treat AD this summer.

Morgan Sheng, VP of neuroscience at Genentech Research & Early Development (gRED), pointed to advances in the science of the brain, particularly in human genetics and imaging.

"Human genetics is the lynchpin of our strategy," Sheng said, noting it is much more advanced in neurodegenerative diseases than in neuropsychiatric diseases.

In the latter, he said, "there are very few examples of a smoking gun; more like warm cigarettes in an ashtray. It is lagging years behind."

Like Bohen, Sheng said Genentech decided to eschew the conventional paradigm.

"We are not interested in traditional neuropharmacology approaches - showing a molecule alters neurotransmitters, and it works in animals," he said. "Rather, we want to understand which cell types are affected, and what circuits are affected."

Sheng added: "Traditional CNS drug discovery treats the brain as...

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