Rember

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CHICAGO, July 29 -- An old drug for urinary-tract infections,

methylene blue (Urolene Blue), may hold the key to a therapy that can

slow the progress of Alzheimer's disease for as long as 19 months,

researchers here reported.

After 24 months of treatment with 60 mg three times a day of

methylthioninum chloride (rember), patients with moderate Alzheimer's

disease achieved a treatment effect that " was twice the effect seen

with donepezil (Aricept), " said Claude Wischik, Ph.D., of the

University of Aberdeen in Scotland.

The drug called rember is a formulation of methylene blue made by

TauRx Therapeutics, and Dr. Wischik is founder and chairman of TauRx

Therapeutics. The drug attacks tau, which promotes tangles, as

opposed to amyloid plaques.

After 50 weeks, pooled data from mild and moderate Alzheimer's

disease patients indicated an 81% reduction in the rate of cognitive

decline versus controls, which was a difference of 6.8 units on the

Alzheimer's Disease Assessment Scale, that was highly significant

(P<0.0001).

Moreover, there was a significantly greater effect size at 50 weeks

than at 24 weeks (P=0.0091), he said at the International Conference

on Alzheimer's Disease. At 24 weeks, patients with moderate disease

had a 5.5 unit difference on the Alzheimer's Disease Assessment Scale

compared with controls (P=0.021).

Methylene blue, used to treat urinary tract infections, was developed

from a common dye that is used in products ranging from ink to jeans,

Dr. Wischik said.

Although the drug is available, Dr. Wischik said he could not

recommend widespread use of methylene blue to treat Alzheimer's

disease, because proof of efficacy requires a phase III trial.

He added that the drug used in his trial was " much purer " than the

formulation currently available.

In the trial reported here, 321 patients were randomized to 30 mg, 50

mg, 100 mg or placebo.

The drug, Dr. Wischik said, was effective when it dissolved in the

stomach, but was not effective when the drug was absorbed through the

intestines.

This was an issue for the 100-mg dose, which had " absolutely no

activity because it didn't dissolve in the stomach. "

Moreover, because the 100-mg dose dissolved in the intestines, it was

more likely to cause diarrhea, which was reported by about 30% of

patients and was the most common adverse event.

Patients were assessed at six week-intervals through 50 weeks and

then followed for an additional 34 weeks.

The dropout rate in each arm of the trial was about 25%, which Dr.

Wischik said was about the same as the dropout rate for trials of

cholesterase inhibitors.

Dr. Wischik's trial gathered data over 84 weeks, which made it the

largest and longest phase II trial of an Alzheimer's disease-

modifying agent.

But limitations include the fact that the study was conducted and

presented by Dr. Wischik, who is co-founder and chair of TauRx

Therapeutics. Another, difficulty -- and one mentioned by other

Alzheimer's researchers -- is that Dr. Wischik has not published any

data on the drug.

During an interview, Dr. Wischik said he planned to publish three

major papers -- preclinical, imaging, and clinical data -- but he

would not do so until after his company had secured an okay from the

FDA for a phase III trial.

Another potential problem is Dr. Wischik's assertion that amyloid

hypothesis, which contends that the buildup of amyloid plaque in the

brain was the main mechanism of Alzheimer's disease, was flat out

wrong.

Alzheimer's disease, he said, " is all about tangles. " Attacking tau,

which promotes tangles, can dissolve tangles and thereby stop the

disease process. Amyloid, he said, may exacerbate the disease

process, but it is not the primary mechanism.

Sam Gandy, M.D., Ph.D., of Mount Sinai School of Medicine in New

York, said that while the data were impressive, they were hardly

enough to discount years of amyloid research.

The more likely explanation, Dr. Gandy said in an interview, was that

both amyloid and tau were important factors. The ideal treatment, he

said, might include a cocktail that targeted both.

Moreover, Dr. Gandy said that " it is dangerous to make statements

about efficacy based on phase II data, since these trials are really

designed to address toxicity and dosing, not efficacy. "

Dr. Wischik's findings need to be reproduced and efficacy requires a

phase III trial, Dr. Gandy said.

In an interview, Dr. Wischik said that a phase III trial with 1,000

to 1,200 patients is being planned, but details await talks with the

FDA. He said " my agents have contacted the FDA, and we hope to meet

by the end of the year. "

At issue, he said, was whether the FDA would require toxicity trials

in primates to be conducted prior to a phase III trial or

concurrently with phase III. " Because this is an old drug, that has

been around for years, we hope that the toxicity study could be done

concurrently, " he said.

Primary source: International Conference on Alzheimer's Disease

Source reference:

Wischik CM, et al " Tau aggregation inhibitor (TAI) therapy with

rember arrests disease progression in mild and moderate Alzheimer's

disease over 50 weeks " ICAD 2008; Abstract O3-04-07.