One in five cancer drug gets through a clinical trial successfully. With Alzheimer’s drugs, one can say the same for only one in 250. And this poor success rate matters because Alzheimer’s, a form of dementia, is a rapidly growing problem.
In the US, for example, it is becoming proportionally more deadly, even as other diseases become less so:
Now, a company says that it has developed “the first drug to halt Alzheimer’s” (paywall). This claim has caused controversy. Only 15% of 900 patients in TauRx pharmaceuticals’ clinical trial seem to have shown any positive effect, and the company’s spin on those results have been been widely criticized by scientists. Others say that even some positive effect is a big sign of progress.
To understand the hype around TauRx’s “breakthrough” drug we must understand just why Alzheimer’s is such a hard disease to treat.
Dementia is an umbrella term for diseases that cause decline in cognitive skills: poor memory, slurred speech, difficulty to think, and so on. Alzheimer’s disease accounts for nearly three out of four dementia cases.
Alzheimer’s is thought to be caused by the excess formation of protein clumps that damage and can even kill brain cells. These clumps come in two forms: plaques created by the clumping of beta-amyloid proteins, and tangles of tau proteins.
The drugs that exist to treat Alzheimer’s only relieve symptoms temporarily and they don’t work in all patients. Among the 244 Alzheimer’s drugs tested in clinical trials between 2002 and 2012, only one succeeded. In short, despite intensive research, we still don’t have an effective drug.
There are many reasons for our lack of success. First, we’ve only really understood what Alzheimer’s is in the last 20 years, after we developed the technology to probe inside the brain. But, despite this progress, we still don’t have a test to determine whether someone has dementia. Diagnosis involves taking into consideration many factors, before expensive tests that can determine the presence of Alzheimer’s can be considered worth doing.
People only seek doctors when there are signs of mental decline, but often it’s too late by then. This late diagnosis makes it difficult to recruit patients with early Alzheimer’s, which is where most drugs being developed are meant to act.
Additionally, the brain is protected by the blood-brain barrier, which is normally beneficial, such as when it stops a nasty bacteria from entering the brain. But it also makes getting drugs into the brain very hard.
The most promising route pursued by major US pharma companies is to attack the formation of plaques. Aging causes beta-amyloid clumps in everyone, but it occurs much more rapidly in Alzheimer’s patients. The theory behind this group of drugs is that if we reduce plaque formation early enough, then we can halt the progression of Alzheimer’s. But no drug following the beta-amyloid strategy has succeeded yet.
The other route pursued by a smaller number of pharma companies is to attack the formation of tangles. The theory is the same as stopping the clumping of beta-amyloid proteins, but instead the focus is on tau proteins. This is where TauRx, as the names makes it clear, comes in.
The company has a drug called LMTX. Its chemical structure is similar to that of a dye called methylene blue, a compound with many uses, including as a stain and medication. Because of the similarity to a stain, LMTX colors the patient’s urine bluish green.
The researchers recruited 891 patients from 16 countries with a mild or moderate form of Alzheimer’s. The patients were randomly split into three groups. One group received a lower dose of LMTX, one a higher dose, and one a placebo. (The placebo group was given a tiny amount of LMTX, which colored their urine so that they wouldn’t suspect that they were part of the placebo group.)
Mostly the drug failed. Some 85% of patients who took LMTX or a placebo, along with their regular Alzheimer’s drug, showed no improvement in symptoms. But TauRx says that the remaining 15% of patients, who got LMTX doses (low or high) and didn’t consume any other Alzheimer’s drug, showed no decline in cognitive skills. For that sub-group, Alzheimer’s stopped progressing for the 15 months that the trial lasted.
If there is any hope to derive from this trial, it comes with a lot of caveats. The limited success in the trial has led to both positive and negative media coverage. “Unprecedented Alzheimer’s drug slows disease by 80 per cent,” says New Scientist. “Promising Alzheimer’s treatment flops in new trial, crushing hopes,” says STAT News.
The sub-group that TauRx claims showed positive results is tiny. This kind of reporting, some scientists say, is cherry-picking of data. TauRx explains this odd result by suggesting that other Alzheimer’s drugs interfered with how LMTX acts. One hypothesis put forth by Claude Wischik, founder and chief executive of TauRx, is that other drugs “set off a mechanism that cells use to expel drugs.” But, for now, it is just a hypothesis. If there is indeed any real effect from LMTX, then TauRx will need to run a trial that specifically tests patients using only LMTX as an Alzheimer’s therapy.
Moreover, TauRx’s positive results are a comparison between those who received LMTX alone and the entire placebo group—whether or not patients in the placebo group were taking a different Alzheimer’s drug. But a better comparison would be to a placebo group not on any other Alzheimer’s drug.
TauRx only announced the results at a conference and in a press release. They have promised to release the full results later this year. So there may still be a chance to bring the controversy to a firm conclusion.
Regardless of whether LMTX works, it is clear that pharma companies will keep trying. By one estimate, Alzheimer’s cost the US economy more than $200 billion annually. An effective treatment would save and improve many lives, while making someone a lot of money.