Roche Holding AG has established itself as a leader in areas like oncology, infectious disease, liver disease and inflammatory disease. Now, the company is eyeing the central nervous system as a new frontier for its R&D, stealthily building a considerable clinical-stage pipeline in the process.

Roche’s interest comes at a time when historical industry leaders in the space – GlaxoSmithKline PLC for example – have opted out because of increasing development and commercial challenges. The endpoints for clinical trial design are far from clear and the availability of generic drugs in traditional blockbuster categories like depression and schizophrenia have resulted in increased payer pressures.

CNS Strategy: Science And Biomarkers

Those challenges haven't scared Roche, which has the first drugs emerging from its CNS efforts moving into mid- to late-stage development. Roche’s emphasis on fundamental science differentiates it from the historical leaders in the field, said Luca Santarelli, head of early CNS research at the Swiss pharma.

"We are drifting away from the random serendipitous drug discovery that has characterized psychiatry over the past 60 years," he said in a recent interview. "We have a requirement, which is that we need to understand the mechanism of the disease, before we approach it."

Indeed, CNS offers enormous unmet medical needs and lucrative commercial opportunities, particularly in neurodegenerative diseases like Alzheimer's and Parkinson's. Roche is investing in those areas, though the company also sees opportunities for new drugs in competitive commercial markets like schizophrenia and multiple sclerosis, which also still need improvements in treatment. The company has amassed a pipeline of some 10 drugs in clinical development (see chart).

Coming into the CNS space as a relative newcomer has given Roche the freedom to pursue drug development with a fresh perspective and without commercial hang-ups, Santarelli said. CNS is one of six core research areas at Roche; others include inflammation, metabolic disease, oncology, ophthalmology and virology.

"We had the benefit of not having to protect anything," he said. "We could come from left field with whatever we thought was appropriate scientifically."

Roche is also playing up its CNS efforts at a time when its backbone oncology franchise, which accounted for 57% of Roche's pharmaceutical sales in 2010, is taking hits. Most notably, the blockbuster Avastin (bevacizumab) has come under fire over cost and efficacy, and FDA is in the process of pulling the drug's breast cancer indication, though Roche is appealing the decision (Also see "Avastin Breast Cancer Dispute Centers On “Magnitude Of Benefit” Questions" - Pink Sheet, 30 May, 2011.).

At Roche's R&D review in December, management highlighted the CNS portfolio, mainly a Phase III glycine reuptake inhibitor (GlyT-1) RG1678 for schizophrenia, while some other late-stage drugs like trastuzumab-DM1 (T-DM1) for breast cancer and the glucagen-like peptide-1 receptor agonist taspoglutide for type 2 diabetes faced setbacks (Also see "Roche Plays Up Potential First-In-Class Schizophrenia Drug In R&D Review" - Pink Sheet, 9 December, 2010.).

The company's CNS focus falls into three core areas, according to Santarelli: neuro-degeneration including Alzheimer's and Parkinson's disease; development disorders like autism and Fragile X Syndrome; and classical psychiatric diseases like schizophrenia and treatment-resistant depression.

Most of the research is internal, some 80%, Santarelli estimated. Even in cases where a compound or technology is in-licensed – like the Alzheimer's disease candidate gantenerumab, which came out of an antibody engineering pact with Morphosys AG – the partnerships are very early-stage, with most of the work done within the Roche group, he said. Another example of Roche's partnering strategy in CNS is the collaboration the company signed with the Belgian protein folding specialist Remynd last year to develop treatments for Alzheimer's and Parkinson's. That deal focused on two preclinical-stage compounds.

"We tend to establish our alliances very early as opposed to buying products," Santarelli said. The CNS unit is very much interested in academic collaborations, consortiums and other pre-competitive partnerships like those it is forging with patient advocacy groups. For example, the company is supporting the Michael J. Fox Foundation's Parkinson's Progression Markers Initiative (PPMI) – a five-year clinical trial focused on identifying and validating biomarkers for Parkinson's disease. "The majority of the innovation that is out there is not in our company," Santarelli acknowledged.

Forging A New Path In Alzheimer's Research

Santarelli is most excited about Roche's research in Alzheimer's disease. Roche hasn't been front and center with its Alzheimer's research, although the company has several drugs in mid-stage development for the disease.

Most recently, Roche initiated a Phase II study of an amyloid-beta peptide antibody gantenerumab in patients with prodromal Alzheimer's disease, the phase when patients have only mild cognitive impairments and have not yet been diagnosed with Alzheimer's. The trial is a complex one involving an investigational companion diagnostic to identify early Alzheimer's patients and novel trial endpoints. Companies have typically not aimed therapies at early-stage disease because scientists haven't had the tools for diagnosing the disease when it is asymptomatic (Also see "The Alzheimer's Divide" - In Vivo, 1 September, 2008.). Roche is relying on a cerebral spinal fluid biomarker identified by the Alzheimer's Disease Neuroimaging Initiative (ADMI) as being a predictor of Alzheimer's risk.

The recent high-profile Phase III drug failures have targeted patients with late-stage disease. Gantenerumab is the first antibody to be studied in a clinical trial in such early patients, though Bristol-Myers Squibb Co. already launched a Phase II trial of a small molecule gamma secretase inhibitor in early patients. If gantenerumab should show benefits in early patients it could give Roche a lead in a space that others have dominated (Also see "Roche Is Sudden Pioneer In Alzheimer's Research With New Trial In Early Patients" - Pink Sheet, 12 May, 2011.).

Genentech's Early Antibody Breakthrough

Some of Roche's research initiatives in Alzheimer's disease are coming out of its Genentech unit, which also fired up the CNS R&D engines about four years ago (Also see "Next For Genentech: Tackling Neuroscience And Infectious Disease" - Pink Sheet, 24 March, 2008.).

Genentech is separately developing an anti-amyloid beta antibody that it licensed from AC Immune SA in 2006. A Phase II clinical trial investigating that antibody, now called RG7412, in patients with mild to moderate Alzheimer's disease just kicked off.

Genentech has also been conducting pioneering research on getting antibodies into the brain. In two papers, published in the May 25 issue of Science Translational Medicine, Genentech scientists laid out their discovery of a route to get large antibodies across the blood brain barrier at therapeutic levels, potentially opening the door to new treatments in Alzheimer's and other neuro-degenerative diseases.

The first pass at antibody therapeutics for Alzheimer's disease – if successful at all – will likely result in modestly efficacious therapeutics due to the limited level of antibodies that reach the brain. The hope is that the published research, which was demonstrated in animal studies and still needs to be shown to work in humans, could pave the way for drugs that will have substantially better outcomes.

"We think this is a good first attempt," said Genentech scientist Ryan Watts of the antibodies currently in the clinic. "But increasing the antibody uptake in the brain will certainly give a better chance for targeting a-beta."

Watts led the team that made the breakthrough discovery. Ultimately, the team found a way to get antibodies that bind to a-beta across the blood brain barrier at therapeutic doses by attaching them to the transferrin receptor, a pathway that naturally brings iron to cells across the blood brain barrier. Getting the antibodies to detach and release in the brain required further engineering.

"We were able to generate antibodies that get taken up to the brain five- to 10-fold greater than control antibodies and significantly reduce a-beta production with a single dose," Watts said.

Roche's Alzheimer's research is years away from yielding returns for investors or patients, however, and the track record in the space has left many justifiably wary. Data from the gantenerumab trial isn't expected until 2015, and the timeline for the RG7412 trial is similar.

The potential first-in-class GlyT-1 inhibitor for schizophrenia and a next-generation anti-CD20 molecule ocrelizumab in development for multiple sclerosis with Biogen Idec Inc. are the two lead CNS candidates, both in Phase III testing. Those drugs, if the Phase III data are positive, will face competitive commercial markets.

Roche has launched a massive Phase III program for RG1678, including six studies, three on the negative symptoms of the disease and three as an add-on to current therapy in patients with suboptimally controlled positive symptoms. Roche is hoping to develop the drug for both indications and thinks the GlyT-1 inhibitor could be the first drug to treat the negative symptoms of schizophrenia, which include social withdrawal and neglect. Data from the trials is expected in 2013.

By Jessica Merrill

Roche's CNS Drug Pipeline Matures: More Investment, More Promise

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