Silver lining for first anti-tau Alzheimer’s treatment in phase III?

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By Dr Laura Phipps | Wednesday 27 July 2016

Findings were reported today from the first phase III anti-tau drug in people with mild-to-moderate Alzheimer’s. The drug, called LMTM, was being tested in a 15-month double-blind, controlled trial in 891 people.

Sadly, the drug failed to meet the aims it set out to, but there may be a silver lining for the small number who were treated with the drug alone i.e. not in combination with their existing Alzheimer’s drugs. Here is everything you need to know about the announcement.

What is the drug?

The drug is called leuco-methylthioninium-bis(hydromethanesulfonate) or LMTM. It is based on the structure of a chemical called methylene blue, a blue dye that has been used for many years in research laboratories across the world. As early as 1891 it was explored for its medicinal properties and it’s currently used as a stain in surgical procedures.

The drug has been developed by TauRx Therapeutics, a company led by Aberdeen-based scientist Prof Claude Wischik – a founding member of the Alzheimer’s Research UK Scotland Research Network Centre. Initially called Rember, scientists have been modifying and improving drugs based on methylene blue to create LMTM (also known as TRx-0237) – the version used in this current trial.

How does LMTM work?

The exact mechanism by which LMTM works is still unclear, but it’s thought to block the tau protein from clumping together in the brain in Alzheimer’s. This process causes toxic ‘tau tangles’ to form inside nerve cells, which are a hallmark of both Alzheimer’s disease and frontotemporal dementia.

There has been lots of excitement in recent years about potential of new drugs to block the other hallmark Alzheimer’s protein, amyloid, but this is the first result of a phase III clinical trial with a drug aimed at blocking tau.

Is it effective?

Disappointingly, today’s overall phase III trial results did not meet their primary goal. The drug was not able to slow memory and thinking decline or day-to-day function any more than the placebo.

While 85% of those on the trial were still taking their normal prescription Alzheimer’s drugs like donepezil and memantine, 15% (136 people) were not taking other drugs and so LMTM was being given in isolation – as a ‘monotherapy’. Of these 136 people, 26 received a 150mg dose and 25 had a higher dose of 250mg LMTM, and 54 were on placebo or ‘control treatment’ made up of a low dose of 8mg of the drug.

In this small group, those being treated with LMTM monotherapy had little decline in memory and thinking and day-to-day ability compared to those treated with placebo.

In addition, those receiving LMTM showed around a third less brain shrinkage in a particular area of the brain, suggesting the drug may have slowed a loss of nerve cells in the disease. This backs up data from their earlier exploratory phase II clinical trial, which was carried out only in those not taking other medicines for their disease.

How excited should we be?

It’s disappointing that the main trial did not meet its primary goals, but the data from the small number of people who took LMTM as a monotherapy is encouraging. It’s unusual that LMTM would work only in people not on other Alzheimer’s drugs and this observation definitely needs exploring further to understand what it may mean. Researchers at the conference, who attended the presentation of the results, also voiced methodological concerns about how the differences between the groups had been calculated, raising questions about whether the observed benefits were real. The full picture will not become clearer until the detailed results from the trial have been published or the results have been validated in further, more statistically robust studies.

You can read our full comment on the findings.

“While today’s announcement marks an important step in the evolution of Alzheimer’s clinical trials, we must be cautious in our interpretation until questions raised by the trial have been explored further.”

Dr David Reynolds

What were the side effects?

Some of the side effects of LMTM, reported in today’s trial, were diarrhoea and pain when going to the toilet. One of the most unusual side-effects of the drug is that it turns urine blue, and you can even see a blue tinge in the whites of some patient’s eyes. As well as making it very hard to do well-controlled clinical trials without giving away who is and isn’t on placebo, this also poses practical challenges for people with dementia who are prone to urinary incontinence. People must not try to self-medicate with this compound, as it may have serious side-effects if misused.

How long until LMTM might become available?

Phase III clinical trials are the final stages of clinical testing required before a company can approach a regulator to seek approval (or a ‘licence’) to market that drug for use in patients. Regulators must look at the trial data and be satisfied that the treatment is safe and effective, and they usually need data from two large phase III clinical trials before this can happen.

Today’s promising results are only in a subset of participants and only represent the first phase III trial. A second phase III trial is underway, which will need to confirm today’s findings. Based on those results (due later in the year), a regulator may consider a licence or may ask for further trials to be done. While a definite step in the right direction, this is not a fast process.

If a drug is given a licence, The National Institute for Health and Care Excellence (NICE), and its counterparts in Scotland and Northern Ireland, must then judge whether the treatment is cost-effective before it could be given on the NHS.

The process from the end of phase III trials to having a treatment on the NHS can take around five years.

What can I do in the meantime?

We believe that the ongoing trials for this drug are not currently recruiting new patients, however several new drug trials for Alzheimer’s are just opening on Join Dementia Research. If you want to find out more about studies you may be eligible for, you can visit or call our Dementia Research Infoline on 0300 111 5 111.

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Dr Laura Phipps