Friday, August 01, 2008

TauRx’s Alzheimer’s Drug: A Web of Tangles

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.


Anonymous said...

From The Times
August 4, 2008
Alzheimer drug puts TauRx on biotech map
Leo Lewis, Asia Business Correspondent
TauRx Therapeutics, an almost unknown drugs company, has found itself at the centre of worldwide attention after details of its Rember drug for Alzheimer's disease were released last week.
Global drugs giants are beating a path to TauRx's door and, if the Rember drug fulfils its early promise, it could help to catapult Singapore on to the global biotechnology map.
TauRx, which operates from an industrial estate in Singapore, was founded in 2002 by scientists from Aberdeen University, who shunned their domestic venture capital market and looked east for financing.
Stephen Logan, senior vice-principal of Aberdeen University, a neurologist and a member of the TauRx board, told The Times that, while there was plenty of venture capital money in Britain, the cost of taking it was high in terms of equity.
"We found that Singapore and the Singaporeans were much more accommodating investors than they are in the UK,” he said.
The Aberdeen-based scientists - led by Claude Wischik, the driving force behind the Alzheimer's research - initially raised about £15 million.
The academics and other researchers who founded the company own 34.8 per cent, with the rest owned by external investors, including Temasek, one of two Singapore sovereign wealth funds.
TauRx has been structured so that while it is technically a Singaporean business, its principal contract is to carry out research led by Professor Wischik and his colleagues at Aberdeen.
The board holds regular meetings in Singapore and the company has research operations in Berlin and Warsaw.
Even before TauRx unveiled its progress on the Rember drug, its investors had been actively pursuing business partnerships and other potential exit strategies.
Professor Logan hinted that discussions may take place over the next few months. The intellectual property of the drug is wholly owned by TauRx.
The Singaporean Government has only recently begun touting itself as a biotech hub, but it has made rapid progress in attracting foreign researchers and international firms to its seven-year-old Biopolis complex.
Tharman Shanmugaratnam, Singapore's Minister of Finance, told The Times that the Government was bidding for international talent.
“We reckon that basically if you don't get the best, you're not going to get traction,” he said. “We are not the leading player, but we are now in the senior league.”

Anonymous said...

The Daily Mail blowing a story out of proportion... well I never...

Anonymous said...

another Entremed?