Roche’s Alzheimer’s strategy matures as key readouts approach

The next test of the tarnished amyloid beta hypothesis in Alzheimer’s disease is approaching with the readout of phase II data for Roche’s crenezumab. The antibody is the understudy in the Swiss group’s Alzheimer’s programme, but it no less significant than gantenerumab as it is believed that the earlier-stage agent could be used as a preventative.

Although like most projects in the space crenezumab is viewed as a low-percentage shot, the mid-stage data to be disclosed, if positive, could help break Roche out of the share price doldrums that have affected it for the past year. Its mighty oncology engine has been overshadowed by competitors’ advances in immunotherapy, and it needs to show some positive clinical news this year to reverse its fortune.

Hard targets

Roche is set to disclose details on two trials, Abby and Blaze, at the Alzheimer’s Association International Conference (AAIC) in Copenhangen on July 12-17. Both trials completed enrolment in 2013.

The 450-patient Abby trial, a cognition study, should be revealing as to crenezumab’s promise. Hard clinical endpoints – clinical dementia rating and ADAS-Cog – will be applied over the course of the 18-month trial, a departure from what was used in phase II for Elan’s failed amyloid-beta antibody bapineuzumab and Lilly’s solanezumab, which is undergoing another phase III programme to tease out its somewhat modest benefit.

A second trial, the 91-patient Blaze study, will assess the change in amyloid burden over a similar time period.

All of these antibodies work under the same principle and assumption – that amyloid beta plaques in the brain are the primary cause of Alzheimer’s disease. The plaques are the result of a failure to break down the protein, as happens in healthy brains. By binding with amyloid beta, the hope is that further plaque accumulation can be prevented and that patients will stabilise.

Crenezumab is a product of the private Swiss Alzheimer’s specialist AC Immune, and has a high specificity for the protein; it has been shown to have the highest binding affinity for all three “species” of amyloid beta – monomers, oligomers and plaque.

In theory, this should give it the best chance for success, but that is of course why clinical trials need to be conducted. In a recent note on Lilly’s pipeline, Bernstein Research analyst Tim Anderson said he believed that the crenezumab data would be positive. If they are, a decision on starting phase III will be made by the end of 2014.

As a sign of how much hope is being put in its amyloid-clearing power, crenezumab has been advanced into the first ever Alzheimer’s prevention trial, in an extended family in Colombia with a genetic defect that causes symptoms to appear around the age of 45.

How this work will interact with development of Roche’s other Alzheimer’s antibody, gantenerumab, is also an open question. That agent is in phase III development now, with the possibility of an interim analysis to be announced in coming weeks. However, the programme might not deliver a final verdict until 2018.

Gantenerumab binds primarily to plaque, much like bapineuzumab, and given the Elan project’s failure the odds on success must appear rather long.

Growing promise

Central nervous system drugs are likely to figure more prominently for Roche in the coming years, with annual growth in the space forecast at 19% between 2013 and 2020, according to EvaluatePharma’s consensus.

Nearly $3bn in group sales will be derived from the CNS, making this the second biggest disease area Roche works in – although it should be noted that it will be a distant second to oncology, which should earn the group nearly $36bn in revenue that year.

Forecasts for crenezumab remain modest. Bank of America-Merrill Lynch is one of the few that has pencilled in an estimate, suggesting $400m in 2023 on a risk-adjusted basis and $4bn unadjusted. The bank has forecast exactly the same amount for the more-advanced gantenerumab, a sign that more promise is seen in the earlier-stage antibody.

With the chances of either one succeeding being put at 10%, any positive signs would generate heightened interest in the Roche Alzheimer’s pipeline and, perhaps, begin to turn market sentiment positive once again.

Alzheimer’s disease has continued to perplex clinical researchers and business development executives alike. The fact that big pharma continues to plug away at antibodies to inhibit amyloid beta, an approach that has yielded repeated failure, is a sign of the potential reward for an agent that can succeed in slowing or reversing progression.

Trial Setting ID
Abby Measuring cognition in 450 patients NCT01343966
Blaze Measuring biomarkers in 91 patients NCT01397578

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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