FirstWord List: Taking stock of next wave of late-stage Alzheimer’s disease readouts as it heads for shore

Alzheimer’s disease (AD) has proven to be an exceedingly tough nut to crack, but the untold riches that await any company that successfully develops a therapeutic for the devastating yet increasingly prevalent condition means that there is no shortage of drugmakers willing to take their best shot – and sometimes shots.

Eli Lilly and Roche are among those that have rolled the dice by moving two products into expensive pivotal studies, though Biogen is on the verge of unveiling Phase II data for two different agents that could put the bellwether biotech on a path towards joining the club of companies with multiple products in Phase III testing.

In the coming weeks Biogen and partner Eisai are expected to provide the Street with the first look at efficacy results for BAN2401, a mAb that targets soluble protofibrillar beta-amyloid. As seems always to be the case just before a big AD readout, analysts have begun sounding increasingly bullish about the programme’s prospects, pointing to potential advantages in both the agent’s selectivity profile and an innovative adaptive study design as reasons for optimism.

However, there have historically been plenty of impressive Phase II readouts in the AD setting – it has been recreating this success in Phase III that has proven exceedingly difficult. For that reason, and because Biogen already has one mAb targeting beta-amyloid in Phase III testing (aducanumab), the bar is going to be high in terms of what the company will want to see in order to launch a pivotal study with BAN2401.

George Scangos, Biogen’s CEO, confided in investors at the JP Morgan Healthcare Conference in January that the company is unlikely to be willing to dedicate the resources needed to conduct simultaneous Phase III programmes with mAbs against beta-amyloid. “If BAN2401 has better risk/benefit profile then we might have to move forward with that instead of aducanumab, but it’s a very high hurdle,” he said. (See ViewPoints: Beauty of Biogen’s aducanumab data depends on the eye of the beholder.)

A second milestone looming on the horizon for Biogen (and Eisai) is a safety and pharmacokinetic/pharmacodynamics readout from a Phase II trial of E2609, an oral small molecule inhibitor of beta-secretase (BACE) that blocks what is believed to be a key step in the generation of beta-amyloid peptides that form amyloid plaques.

Unlike with BAN2401, E2609 will not have to out-compete a more advanced, similarly-targeted programme in Biogen’s pipeline. The programme will still face plenty of competitive pressures though as it appears to be third in the race to market behind verubecestat from Merck & Co. and AZD3293 from Eli Lilly and partner AstraZeneca, the latter of which has a Phase II/III readout slated for next quarter. (See ViewPoints: Second Phase III study in earlier-stage patients likely to be key for Merck & Co.'s Alzheimer's disease hopes.)

As a result, the next couple of months are shaping up to be big for not only the companies that will be reporting results, but for the controversial amyloid hypothesis – that amyloid plaques play a central role in the pathophysiology of AD – upon which many of them are based. (See ViewPoints: Alzheimer's disease - Beta-amyloid theory down but not out and ViewPoints: BIIB037 could be a big win for Biogen Idec – and the amyloid hypothesis.)

Perhaps the most watched of this year’s data announcements will be a Phase III readout for Eli Lilly’s solanezumab, which failed an earlier study but is now being tested in an earlier-stage patient population based on the premise that this is a more amenable setting for a mAb against soluble beta-amyloid. (See ViewPoints: Eli Lilly’s solanezumab data ‘okay’ enough to avoid Biogen’s downdraft.)

The next few months will also witness important inflection points for programmes addressing AD from non-amyloid-related angles. Among these is TauRx’s LMTX, a tau aggregation inhibitor that was designed based on the theory that reducing neurofibrillary tangles will result in a therapeutic benefit. Results from a Phase III trial are slated to read out next quarter. What's more, the leading 5-HT6 receptor modulator, Lundbeck and Otsuka’s idalopirdine, will produce its first Phase III results early next year, with the hope being that it can offer symptomatic relief for AD patients. (See ViewPoints: Axovant can take the hype, but Lundbeck and Otsuka retain the lead.)

Below is a list of selected products in late-stage clinical testing for the treatment of AD, including estimated timeframes for when the studies are expected to finish up.

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