The results of a moderate sized trial on a new Alzheimer’s drug have just been announced and the results, if reliable, may suggest that the treatment is one of the most important medical breakthroughs of the century.

Alzheimer’s disease is a type of dementia, a degenerative disorder of where the brain starts to degrade more quickly than would be expected through normal ageing.

One of the common features of Alzheimer’s disease is the accumulation of neurofibrillary tangles in the brain. These are clumps of tau protein that accumulate inside dying neurons. There have been debates about whether these cause the problems or are just the result, but most researchers are now coming round to the idea that tau protein tangles are the main problem.

The drug has been given the tradename ‘remben’ and was initially thought to be useful as it dissolved tangles in the test tube. It has just been tested in a Phase II trial which have been announced at an Alzheimer’s research conference.

The results of the first announced trial has not been published but there are details on the conference press release which I’ve included below the fold.

What’s most impressive from the preliminary details, is that the drug seemed to both slow or even stop cognitive decline in some cases, as well as eliminating the decline in blood flow in the areas usually most affected by the disease suggesting that it is halting the spread of tangles.

Interestingly, the company behind the drug, TauRx, have just launched their website today to catch the wave of publicity.

However, I’m wondering whether there’s more to it than meets the eye because, if I’ve got it right, the drug isn’t actually new.

Its chemical name is methylthioninium chloride but it’s also known as methylene blue and was synthesised way back in 1876. It was shown to be active against malaria by Paul Ehrlich in 1891 and later as a useful antibacterial drug (have a look at this fascinating NYT article from 1910).

In the late 1980s it was tried as a treatment for manic-depressive disorder and found to be useful.

Is this seems surprising, you may be interested to know that methylene blue was the basic compound from which the first antipsychotic drug chlorpromazine or Thorazine was made (in case you’re wondering, this family of antipsychotics can also work as anti-bacterial drugs, but have not been used due to other drugs having less side-effects).

If this is really just methylene blue, what this means in financial terms is that the drug can’t be patented.

In other words, anyone can make the drug which means its much harder to make money on it as pricing becomes competitive. In contrast, a patent gives you a time-limited monopoly – albeit one that can earn billions.

A widely available cheap generic drug that treats a major disease is actually a fantastic thing for society, but developing them is not typical behaviour for pharmaceutical companies who tend to shun unpatentable drugs.

Also, it’s probably true to say that the history of drug development shows a typical three stage process:

1. We’ve found a miracle cure!

2. We’ve found a miracle cure, but it can kill people.

3. It’s not a miracle cure, it can kill people, but it’s worth the risk in many cases.

So, time will tell how useful it is in the real world, but pretty much everyone has their fingers crossed that it will work out as a useful treatment.

Link to write-up from The Telegraph.

A Phase IIb Trial of a Tau Aggregation Inhibitor Therapy

[ Press Release from Alzheimer’s Association International Conference on Alzheimer’s Disease 2008. Original here ]

As an alternative to anti-amyloid therapies for Alzheimer’s, researchers continue to examine a variety of treatments and targets with the potential to curb the disease. This includes presenting data supporting the viability of therapies targeting tau protein and its aggregation into the “tangles” originally discovered by Alois Alzheimer.

Previous research has shown that the buildup of brain lesions known as neurofibrillary tangles, which are composed of a short fragment of a protein called tau, is correlated with increasing levels of dementia symptoms. And, these tangles first appear in the brain long before symptoms of the disease become clinically apparent. Methylthioninium chloride (MTC, or brand name remberTM) has been shown in the test tube to dissolve tau tangle filaments and prevent aggregation of tau into tangles. MTC has also been shown to block the toxic effects of aggregated tau in cells. In animal models, MTC has demonstrated cognitive and behavioral benefits in line with reduced tau pathology.

In research reported at ICAD 2008, Claude M. Wischik, Professor in Mental Health, University of Aberdeen, United Kingdom and Chairman, TauRx Therapeutics, Singapore, and colleagues conducted a 24-week, double-blind, randomized, dose-ranging, parallel design trial of MTC monotherapy in 321 people with Alzheimer’s at 17 centers in the United Kingdom and Singapore, followed by a 60-week, blinded, active treatment extension. The control group received placebo for the initial 24 weeks and then a minimal efficacy dose subsequently. The primary objective was to investigate the effects of oral MTC at 30, 60 and 100 mg doses three times per day, compared with placebo, over 24 weeks on cognitive function as measured by the ADAS-cog in patients with mild or moderate Alzheimer’s, stratified by stage of the disease. Another objective was to determine MTC’s potential to modify the course of Alzheimer’s over 19 months. Imaging results from SPECT and PET scans were collected at baseline and after 24 weeks of treatment.

The researchers found that, at 24 weeks, MTC produced a significant improvement relative to placebo of -5.5 ADAS-cog units in moderate subjects at the 60 mg dose (p = 0.0208). There was no placebo decline in people with mild Alzheimer’s in the control group over the first 24 weeks preventing initial efficacy analysis, although efficacy was demonstrated in mild Alzheimer’s by SPECT-scan outcomes over the same period. MTC stabilized the progression of Alzheimer’s over 50 weeks in both mild and moderate Alzheimer’s. The overall effect size was -6.8 ADAS-cog units vs. decline of 7.8 units in the control arm (p < 0.0001), with significant efficacy demonstrated separately in mild and moderate subgroups.

According to the researchers, as a first approximation to supporting disease modifying efficacy, treatment with MTC at the 60mg dose produced a significantly larger effect size at 50 weeks than at 24 weeks implying an effect on the rate of cognitive decline (p = 0.0014). This was confirmed in a mixed effects slope analysis, showing an 81 percent reduction of long run rate of progression of decline over 50 weeks (p < 0.0001). The final 84-week analysis confirmed the long term effect of the 60mg dose in subjects remaining on treatment, with apparent decline still not significantly different from baseline at the final assessment, whereas there was significant decline in the other study arms.

The researchers added that brain imaging using SPECT and PET confirmed the clinical trial results. SPECT measures regional cerebral blood flow (rCBF) which is closely related to brain cell activity. The study showed that treatment with MTC at the 60mg dose eliminated the rCBF decline that was seen in control subjects. The effect was greatest in brain regions that had the most severe tau aggregation pathology, namely the hippocampus and the entorhinal cortex, which are regions affected early and most severely in Alzheimer’s.

“This is the first instance of a disease-modifying Alzheimer’s therapy that has attained its primary, pre-specified cognitive efficacy target in a clinical trial,” said Wischik. “This trial therefore provides the first clinical trial evidence that an Alzheimer’s therapy aimed at blocking tau aggregation may be a viable disease-modifying treatment. We now need to confirm this in a larger Phase III trial.”

“Our results appear to meet the draft EMEA clinical guidelines for disease-modifying therapy, supported by SPECT and PET evidence of efficacy in brain regions heavily affected by tau pathology,” Wischik added.