As a lifelong follower of the so-called ‘tau hypothesis,' TauRx Therapeutics chief executive Claude Wischik ploughed a lonely furrow for many years.
After the dramatic Phase III failure of Eli Lilly’s (NYSE: LLY) solanezumab late last year, followed by Merck & Co’s (NYSE: MRK) verubecestat in February, his Aberdeen, UK-based research team might have more company.
"I think the evidence was always there,” he told The Pharma Letter. “It's just taken time for the Americans to catch up.”
The most recent trial upsets are not the first to impact the rival ‘amyloid hypothesis’ side of Alzheimer’s research. Back in 2012, the failure of bapineuzumab wiped large amounts from the market caps of American drugs behemoths Pfizer (NYSE: PFE) and Johnson & Johnson (NYSE: JNJ).
But some commentators have started to ask whether the leading scientific theory in Alzheimer’s needs to be reconsidered.
"We chose to invest in tau a long long time ago, and we're now way, way ahead."
Dr Wischik puts it this way. “There have been now 25 failed amyloid trials at Phase II or Phase III. The juggernaut has started to change course, and companies are now starting to invest in tau. We chose that path a long long time ago, and we're now way, way ahead.”
In May, America’s Merck & Co teamed up with Teijin Group (TSE: 3401) to develop an antibody in this area. Other major companies including J&J, AbbVie (NYSE:ABBV) and Roche (ROG: SIX) have tau programs as well.
Time for tau?
While Lilly’s loss could have been TauRx’s gain, the company has been struggling with its own Phase III disappointment, which Dr Wischik attributes to: “some things I screwed up in the design of the trials.”
At last year’s AAIC, the Alzheimer’s Association International Conference, the company presented data from a key trial into anti-tau candidate LMTX which showed the drug did not meet its primary endpoint.
Despite this, the company presented an upbeat interpretation of the data, which some media outlets picked up on, based on a secondary analysis that excluded those patients who were receiving other Alzheimer’s medicines concurrent with TauRx’s candidate.
Enrolling these patients in the trial was a mistake, Dr Wischik says, because: “For reasons that we are now busily getting to the bottom of, the action of our drug is blocked by having these other drugs on board.”
“We're just starting to unpack that phenomenon and it turns out to be quite complicated. It depends on which other drugs are being taken, for example. We'll be publishing that in due course.”
The results of the trial, he says: “don’t invalidate the fundamental tau premise.”
The origin of TauRx Therapeutics
That premise has been explored by a minority of Alzheimer’s researchers who argue that a buildup of tau protein tangles in the brain is the main factor in the disease, not amyloid plaques, as the leading hypothesis has it.
Discussing his earlier work at Cambridge University, Dr Wischik says: “My boss at the time, Sir Martin Roth, showed that tangles were the main driver of dementia. So we already knew that, in the 1980s. The field has just discovered it in the last couple of years.”
“We solved a low resolution structure of the filament that made up the tangle that Alzheimer discovered. The next step was to discover that those were made of tau protein, and in that process I discovered, quite by accident, that it's possible to dissolve the tangle filament in the test tube with compounds that are potential pharmaceuticals.”
Dr Wischik says that, when measuring levels of amyloid in the brain: “There’s hardly any difference between normal elderly controls, and people with advanced terminal dementia.”
“Amyloid really does not distinguish normal aging from people with terminal dementia."
“Amyloid really does not distinguish normal aging from people with terminal dementia. Whereas, if you look at the levels of aggravated tau it’s night and day - a yes/no phenomenon.”
TauRx was born in collaboration with Tay Siew Choon, the former COO of Singapore Technologies, who Dr Wischik describes as “the business brains of the company.”
Perhaps unusually in a world where biotech startups seem to go from zero to IPO very quickly, particularly in the Alzheimer’s space, TauRx has remained a privately-held company since it was founded 15 years ago.
Dr Wischik is critical of what he regards as an asymmetry in the level of financial investment available to researchers targeting amyloid, saying: “The key opinion leaders influence pharmaceutical investment, so every company that wanted to get into the Alzheimer’s space, which is very, very, very, valuable, backed a variation of the amyloid hypothesis. It's been completely one-sided. About $20 billion has been sunk into amyloid, we estimate.”
However, it’s clear his company too has been able to secure funding for a costly clinical development program.
He says: “As it happens, most of our financing has come from the far east, through Siew Choon, from Singapore, Hong Kong, China, Malaysia. We've raised about $500 million to date, which is really extraordinary for a little company.”
Asked about the company’s decision to remain private for many years, chief operating officer Timothy Earle adds that: "We need to provide an exit route for our investors. We have a substantial number of private investors. They've been very patient for a very long time, and at some stage we need to provide the exit."
However, he says that: "At the moment, as private capital remains available to us, we continue to use that route."
The future for LMTX
Asked about the weight of scientific evidence motivating research into amyloid, Dr Wischik says: "There has been a tremendous amount of amyloid hype. In the 90s it was essentially impossible to get research funding for anything other than amyloid.”
Dr Wischik believes that, despite the recent trial failure of his anti-tau candidate, the science is pointing in the right direction. The company plans to launch a new Phase III trial this year, chasing the signal their secondary analysis picked up in the LMTX-only cohort.
"LMTX...could be four times better than what Lilly are hoping for."
Of his self-described trial design failure, he says: “It's painful to have discovered it in a mega, global Phase III trial. The trouble is that you can only discover these things clinically.”
“The drug, if it can be confirmed to work as we've seen it as monotherapy in the Phase III trials, is still four times better than what Lilly are hoping for. It retards the rate of progression of brain atrophy.”
Critics say that the path of pharmaceutical research is littered with failed secondary analyses that offered heavily vested researchers hope they could snatch victory from the jaws of defeat.
While TauRx has a lot riding on the pathological significance of its namesake, Dr Wischik is clear he’s just following the science, saying: “You put forward your best hypothesis, most consistent with current data, and you do that damn experiment.”
“I've reached an age where it would be perfectly acceptable for me to just stop. The only reason I keep going is that I believe in this, and I believe we can really do good for people. Having been a clinician in this space I really understand the depth of desperation and suffering out there.”