By the end of last Tuesday’s midday press briefing at the Alzheimer’s Association’s International Conference on Alzheimer’s Disease, it was clear that the next news cycle would be chock full of stories around mid-Phase trial results of Singapore-based TauRx’s drug rember, a formulation of methylthionium chloride (MTC—the well-known reagent methylene blue), which has been used to treat urinary tract infections and some hemoglobin disorders since before there was a US Food & Drug Administration.
For one thing, it was an otherwise slow news day, at least to that point: the full Phase II results of Elan-Wyeth’s bapineuzumab wouldn’t be until later in the afternoon, and in any event nothing about that drug had been included in the advance press briefing. TauRx had also put out an unusually aggressive press release, claiming among other things “a new treatment that appears to slow the progress of the disorder by 81% over a year…an unprecedented result in the treatment of Alzheimer's disease” and that the Phase II results “strongly suggest that it is possible to halt progression in mild and moderate Alzheimer's.”
So there was the expected headline grabbing: London’s The Independent ran with “Alzheimer’s drug hailed as a ‘major’ development.” The Daily Mail heralded the "biggest breakthrough against disease in 100 years." News of the rember data even reached Kandahar, Afghanistan, TauRx chairman Claude Wischik told me the next day. But gladly, responsible news outlets seemed mostly to grasp that the work was early, and framed it as such.
What may not be apparent, however, is just how early, at least in terms of a US regulatory timeline. Although Wischik said he expects a Phase III trial to begin in the US, EU, Asia, and the Middle East within a year, there’s been no US IND filing yet. (The Phase II was conducted in the UK and Singapore.) Nor have any large species toxicology studies been completed. Wischik expressed some hope that these could be done in parallel with an IND review, and if not, he said, almost as an aside, it’s likely that the US trials will start with a different formulation than the one in the reported Phase II. Presumably, that means at least a bridging study.
In fact, the extent to which rember's safety profile has been vetted is unclear. Plus, treatment at the highest dosage form showed minimal efficacy in the Phase II due to cross-linking of the gelatin capsule shell by the MTC, leading to impaired dissolution/absorption of active drug. Those data were excluded altogether from the results presented at the meeting.
That said, the data are tantalizing because of the approach. In addition to plaques, the presence in the brain of tangles—abnormal fibers of aggregated tau protein--appears to correlate with dementia. Rember is a tau aggregation inhibitor; it appears to work by breaking up the bonds between tau molecules in tangles, allowing them to be cleared by normal cell pathways. The drug produced significant improvement relative to placebo at 24 weeks in moderate AD patients, and stabilized the progression of AD over 50 weeks in both mild and moderate patients. Plus, the effects were supported by SPECT and PET imaging showing evidence of efficacy in brain regions strongly affected by tau pathology.
As a proof of concept of the mechanism of tau inhibition, the TauRx study is significant. Showing that breaking up tangles has an effect on cognition adds credence to the belief that targeting them is a useful approach to treating AD. It also provides an alternative to drug strategies based on the amyloid beta (Abeta) hypothesis--trying to stop synthesis of amyloid beta or dissolving Abeta once plaques form, the basis for passive immunotherapies using antibodies, such as bapineuzumab. Indeed, Abeta immunotherapy appears to also lead to tau clearance in the brain.
Check this space and the upcoming September IN VIVO for more from the ICAD meeting, including putting what happened with Elan-Wyeth’s bapineuzumab in context now that the dust has settled, as well as a look at Baxter’s IVIg and the anti-histamine dimebon, both set to enter Phase III.