CTAD – Over and out for sola, while Biogen takes the spotlight

Down for Lilly is up for Biogen. The Indiana-based big pharma drew a line under its discontinuation of solanezumab at the year’s final Alzheimer’s disease conference, while its slightly smaller biotech rival continues to titillate investors with data from aducanumab.

Overshadowing both of the presentations is, of course, the debate over whether reducing the burden of amyloid beta can change the course of Alzheimer’s disease. New data, albeit early, suggest that Biogen has some answers by binding to amyloid in brain tissue rather than the blood, although it comes with signs of neurotoxicity that could hinder its regulatory and commercial outlook.

Lilly wants to believe

Surprisingly, even though Lilly has given up the solanezumab ghost, there were those clinging onto its carcass, as well as to the amyloid beta hypothesis. A numerical benefit on two secondary endpoints – the cognitive measure mini-mental state examination (MMSE) and the cognitive and functional clinical dementia rating sum of boxes (CDR-SB) – had some suggesting that the antibody, which binds with soluble forms of a-beta, could yet have promise.

If this line of enquiry is to be pursued, Lilly has not indicated whether it will be a part of it, although it gave a strong signal this morning when it announced that it was partnering with Astrazeneca to co-develop MEDI1814, an antibody selective for amyloid beta 42.

As for sola, Lilly has already announced that the costs of Expedition 3 resulted in a pre-tax fourth-quarter charge of $150m. Spinning the asset off or licensing it out could be options – and not necessarily so implausible since Roche found a willing partner for the failed cholesterol drug dalcetrapib in the startup Dalcor Pharmaceuticals, which is looking at a specific genetically defined subgroup.

With the Lilly-Astra partnership announced today, the message is that faith in the amyloid beta hypothesis is as strong as ever in spite of the evidence, a point that the sellside stressed as they looked for readthrough to Biogen – in short, the message is that all the things wrong with solanezumab are all the things right with aducanumab.

Investors appear to be receptive to that message: Biogen shares are up 5% in early trading today.

Encouraging signs, for some

Biogen presented updated results from the phase I Prime trial in prodromal and mildly ill patients that included 24-month data from fixed-dose arms and 12-month data from a dose-titration arm of aducanumab, which binds to more insoluble forms of amyloid beta. That latter arm has been included to reduce the occurrence, at higher doses, of imaging abnormalities suggestive of vasogenic oedema – a safety measure called ARIA-E – that have created concerns around aducanumab.

The highest fixed dose, 10mg/kg, showed that aducanumab slowed the progress of the disease as measured by the exploratory endpoints MMSE and CDR-SB. But this was at a cost of a 55% incidence of ARIA-E in patients carrying the apolipoprotein E4 (ApoE4) gene that has been associated with a higher risk of Alzheimer’s.

The titration arm got this incidence down to 35%. Importantly, aducanumab also improved the CDR-SB at a p value of <0.05, although it should again be stressed this was an exploratory endpoint. However, this is the endpoint Biogen chose for phase III, so the takeaway for investors has clearly been that what is positive in small numbers will naturally be duplicated in a bigger population.

The incidence of ARIA-E in the dose-titration arm should not provide comfort, as this is the approach being taken in the phase III Engage and Emerge trials in patients positive for ApoE4.

The 24-month data from a long-term extension found no new cases of ARIA-E in patients who continued on treatment, although placebo patients who crossed over into active treatment had an incidence consistent with the 12 month data, according to the company; full data will not be revealed until later today.

Aducanuamb bulls and bears have found evidence to point to that can support their side, so this will be one of the sector’s most talked-about late-stage projects until phase III readout. It remains the main vehicle to carry the hopes of the amyloid beta hypothesis for now, however, so it is no surprise to see a rush from investors who still believe.

Project Trial ID
Solanezumab Expedition 3 NCT01900665
Aducanumab Prime NCT01677572
Engage NCT02477800
Emerge NCT02484547

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

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