Lundbeck’s non-amyloid Alzheimer’s move could embolden others

Yesterday’s start of a phase III Alzheimer’s programme that will eventually enrol 3,000 patients confirms Lundbeck and Otsuka’s seriousness about Lu AE58054, and will have had the handful of other developers of 5-HT6 antagonists sitting up and taking note.

Alzheimer’s disease remains a hot area despite a lamentable success record in trials, and an approach that avoids the amyloid and tau hypotheses should naturally generate interest. EvaluatePharma reveals a couple of imminent competitor study readouts, as well as deal opportunities at the small biotechs Avineuro and Biotie Therapies (see table).

The logic of targeting the 5-HT6 receptor is based around its expression in brain regions involved in cognition, and its role in modulating the activity of neurotransmitter systems. Most 5-HT6 inhibitors have also been studied in schizophrenia, but this has now taken a firm backseat to Alzheimer’s.

Pack leader

The start by Lundbeck and Otsuka of the first of four phase III studies confirms Lu AE58054 as the leader of the pack. Behind it are two big pharma projects at phase II: Pfizer’s PF-05212377 and GlaxoSmithKline’s GSK742457.

Pfizer’s started a phase II trial last November in 342 Alzheimer’s patients, as an add-on to Aricept – the same design as the phase II study whose positive readout spurred Lundbeck’s deal with Otsuka over Lu AE58054 and its move into phase III (Lundbeck Alzheimer’s data justify Otsuka’s exuberance, July 17, 2013).

Things seem to be going less well at Glaxo; GSK742457 has completed four phase II studies in an impressive total of 1,840 patients, but results can at best be described as mixed, and since the last ended two years ago no further work appears to have been done. But Glaxo still lists the compound as a phase II project in dementia, and is no doubt paying close attention to the progress of Lu AE58054.

Another important data point is readout of the 20-patient phase II study of AbbVie’s ABT-354 against background acetylcholinesterase therapy; the trial, also in mild to moderate disease, ends next month.

5-HT6 antagonists in clinical trials in Alzheimer's disease
Project Company Status Trial IDs Details
Lu AE58054 Lundbeck/Otsuka Phase III NCT01955161 First of four trials
PF-05212377 Pfizer Phase II NCT01712074 Trial started Nov 2012
GSK742457 GlaxoSmithKline Phase II NCT00710684
Mixed data in four trials
AVN 101 Avineuro Phase II Trial started in Feb 2010
ABT-354 AbbVie Phase I NCT01908010 Trial ends Nov 2013
SYN-120 Biotie (Roche declined opt-in) Phase I Seeking partner
SUVN-502 Suven Life Sciences Phase I

Still, as far as deal-making goes, perhaps the greatest interest that Lu AE58054 will generate could be in a private US start-up, Avineuro, and in Finland’s Biotie.

Avineuro has focused on 5-HT6 inhibitors since being founded in 2008, but its progress has been sporadic. After showing promise in phase I, AVN 101 entered phase II three years ago, but there has been no word on data generated, and the group now looks like it might be turning back towards schizophrenia with its 5-HT6 inhibitor series.

Still, bankers should keep a close eye on Avineuro given the current enthusiasm for funding US biotechs and the hot IPO market.

Meanwhile, Biotie’s SYN-120 is slightly different in that it has dual activity at 5-HT6 and 5-HT2a, but despite having completed phase I studies it was not licensed by Roche, its originator, which had an option that expired last year. The Finnish company is seeking a partner for further development.

Lu AE58054’s first pivotal study, Starshine, is set to enrol 930 mild to moderate Alzheimer’s patients and test two doses against background Aricept. The primary endpoint is change in cognition – the one hit in phase II – while the tougher functional endpoint is secondary.

It is interesting that none of the 5-HT6 inhibitors seem to be targeted solely at mild Alzheimer’s – the disease thought least difficult to treat and the one in which the amyloid beta hypothesis might still have some relevance.

Pfizer, Glaxo and AbbVie, as well as any companies pondering the merits of AVN 101 and SYN-120, will have noted this and will keenly await news of the design of Lundbeck’s three remaining pivotal studies.

To contact the writer of this story email Jacob Plieth in London at or follow @JacobEPVantage on Twitter

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