Rember: "Breakthrough" Alzheimer's Drug?

Summary: results of Phase 2 clinical trials of a new Alzheimer's drug called rember look promising. The drug is thought to reduce tau, the protein that makes up Alzheimer's tangles. Drugs that look effective in Phase 2 trials have a low chance of proving effective in Phase 3, so we'll have to wait for the results of the Phase 3 trials before calling rember a "breakthrough."

The positive results of this Phase 2 trials lend credibility to those who would like to broaden Alzheimer's research beyond the amyloid hypothesis.

I estimate there were 5400 minutes of presentations at ICAD, last month's Alzheimer's research conference in Chicago. There were also around 2000 poster presentations.

One twenty minute presentation on a potential Alzheimer's drug called rember, along with six related posters, generated more excitement than all the other presentations put together.

First, some background. In mice genetically altered to have Alzheimer's pathology, rember appears to prevent tau (the protein in Alzheimer's tangles) from clumping together. At least in humans, this clumping or aggregation is thought to form tangles. What's more, rember may actually reduce the amount of abnormal tau and have other beneficial effects in the brain.

These apparent properties have led to speculation that rember could be the "holy grail" of Alzheimer's - a drug that could both treat and prevent the disease.

Claude Wischik, Professor and Chair in Mental Health at the University of Aberdeen in Scotland, presented the results of a Phase 2 clinical trial of the drug to an overflow crowd during the Tuesday afternoon Drug Discovery: Clinical Trials session. According to his biography, he also chairs two companies:

TauRx, the company he co-founded to bring rember and related drugs to market
WisTa Laboratories, which conducts initial research and holds patents on these drugs.

Professor Wischik, who, along with colleagues, discovered tau in Alzheimer's tangles, started the presentation by saying that, contrary to what many researchers think, tau is present in the early stages of Alzheimer's, and so makes an attractive drug "target."

The Phase 2 trial was designed as a 24 week trial of three different doses of rember (30 mg., 60 mg. or 100 mg.), three times per day for mild or moderate Alzheimer's. More than 300 people in the UK and Singapore who participated in the trial were given one of these doses or a placebo. Participants were not taking other Alzheimer's drugs. At the end of 24 weeks, the participants with moderate Alzheimer's in the 60 mg. group declined 5.4 points [out of 70] less on the ADAS-Cog test than those with moderate Alzheimer's taking the placebo.

Here's where it gets a bit complicated, at least for a layperson. Professor Wischik said that in those taking the 100 mg. dose, there was no effect. He believes this is due to an interaction between the drug at that concentration and the capsule preventing the drug from being absorbed. Results from the 100 mg. group were then lumped with the placebo group. And at 24 weeks, for the group with mild Alzheimer's, there was no difference in the ADAS-Cog test scores between those treated with rember and those given the placebo. Professor Wischik said this was due to the fact that the test scores of the placebo group did not decline in 24 weeks.

The study was extended to 50 weeks, at which point results were significant in both the mild and the moderate groups at the 60 mg. dose, he said. Looking at the mild and moderate groups together, those taking the treatment didn't show a significant decline in their performance on the ADAS-Cog, while those on placebo declined 6.8 points. A follow-up of those on the 60 mg. dose at 84 weeks showed no significant decline in their ADAS-Cog performance, Professor Wischik said. Because there was no placebo group after 50 weeks, it's unclear how that would compare to no treatment.

Some of the trial participants underwent brain imaging (SPECT) during and/or after the trial, and Professor Wischik said these tests showed the reduced blood flow in certain brain regions associated with Alzheimer's in patients on placebo, but not in those receiving treatment. He said these SPECT tests were confirmed by PET tests [that would measure reduced glucose use in the brain].

The safety of rember "appears OK," according to Professor Wischik, but some participants experienced side effects he thought were comparable to those of cholinesterase inhibitors, except a larger percentage reported diarrhea.

The results of this Phase 2 trial suggest that 60 mg. is the minimum effective dose of rember, he said, and that the drug can halt Alzheimer's disease in early stages. TauRx plans to start Phase 3 trials of the drug in 2009, and it could be on the market by 2012.

After this presentation, I had a lot of questions. If the study participants had been taking other Alzheimer's drugs, would rember still have had a significant effect? Would the results have been different if the 100 mg. group hadn't been lumped with the placebo group for analysis? Which participants underwent imaging, and what were the results by group? Would analysis of the amount of tau in spinal fluid or in the brain indicate that those in treatment groups actually had reduced amounts of tau in the brain?

Rather than get lost in the details of the Phase 2 trial, though, I think it's more useful to put the tantalizingly positive results of these lab tests and clinical trials in perspective. From my layperson's point of view, that means we should keep in mind:

what works in genetically altered mice doesn't always work in humans (just because scientists can reduce tau in the brains of genetically altered mice doesn't mean they can reduce tau in the brains of humans)
a drug that looks effective in Phase 2 trials has a low chance of proving effective in Phase 3 trials (see Dr. Paul Aisen's comments from ICAD's Thursday plenary session)
Phase 3 trials are expensive and difficult to conduct. TauRx will need to raise money for this phase of research, negotiate with regulators on trial methodology, recruit investigators and participants and analyze data. All this takes time, so having a drug on the market by 2012 may be optimistic.
we still don't know exactly what role tau plays in contributing to cognitive problems
these results come at a time when there's a lot of publicity about "disease-modifying" drugs under development. Those of us who have memory loss or whose family members have memory loss are hungry for a "cure." This may cause us to have unrealistic hopes about each new "breakthrough" announced.

Whether or not rember makes it through Phase 3 trials, though, these positive Phase 2 results lend credibility to those who would like to broaden Alzheimer's research beyond the amyloid hypothesis. From my layperson's point of view, research on multiple hypotheses and multiple types of drugs would seem to increase the chances of success.

Comments

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For once I have nothing to add to your perceptive analysis, Mona...oops! Except for one observation: My guess is that the "hungry for a 'cure'" aspect now pervading Alzheimer's speculation and research, if the Phase 3 trials are even minutely optimistic, will, indeed, bring this drug to market by 2012, whether or not it's particularly effective; wherein lies some danger.
As my mother would say, "I'll bet you a million."
As I would respond, "Ah, what the hell, let's make it two million."

Posted by: Gail Rae Hudson | August 20, 2008 at 02:44 PM