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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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July 31, 2008

Rember for Alzheimer's: Methylene Blue's Comeback

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Posted by Derek

Today we take up the extremely interesting story of Rember, hailed in this week’s press as a potential wonder drug for Alzheimer’s. There are a lot of unusual features to this one.

To take the most obvious first, the Phase II data seem to have been impressive. It’s hard to show decent efficacy in an Alzheimer’s trial – you can ask Wyeth and Elan about that, although it’s a sore subject with them. But Rember, according to reports (this is the best I've seen), was significantly more effective than the current standard of care (Aricept/donezepil, a cholinesterase inhibitor). In light of some of the more breathless news stories, though, it’s worth keeping in mind that this was efficacy in slowing the rate of decline – not stopping it, and certainly not reversing it. Especially in the later stages of the disease, it’s extremely hard to imagine reversing the sort of damage that Alzheimer’s does to the brain (and yes, I know about the TNF-alpha reports – that subject is coming in a post next week). If Rember is twice as effective as Aricept, that's great - except Aricept's efficacy has never been all that impressive.

But that's still something, considering how the drug is supposed to work. Its target is different than the usual Alzheimer’s therapy. Accumulation of amyloid protein has long been suspected as the cause of the disease, but there have always been partisans for another pathology, the neurofibrillary tangles associated with tau protein. Arguments have been going on for years – decades – about which of these has more to do with the underlying cause(s) of Alzheimer’s. Rember is the first clinical shot (that I’m aware of) at targeting tau. If the first attempt manages to show such interesting results, it’s a strong argument that tau must be important. (Other people are working in this area, too, of course, but my impression is that it's nowhere near as many as work on amyloid).

That’s food for thought, considering the amount of time and effort that’s been expending on amyloid. It may be that both pathologies are worth targeting, or it may even be that these results with Rember are a fluke. But it’s also possible that tau is really the place to be, in which case the amyloid hypothesis will take its place in the medical histories as a gigantic dead end. I’m not quite ready to bet that way myself, but it’s definitely not something that can be ruled out. I wouldn’t put all my money on amyloid either, at this point. (Boy, am I glad I'm not still working in Alzheimer's: this sort of stuff is wonderful to watch from the outside, but from the inside it's hard to deal with).

Now, what about the drug itself? It’s coming from a small company called TauRx, whose unimpressive web site just went up recently. The underlying science (and the clinical data) all come from Dr. Claude Wischik of the University of Aberdeen, who has so far not published anything on the drug. The presentation this week has, by far, been the most that anyone’s seen of it (papers are said to be in the works).

And Rember itself is. . .well, it’s methylene blue. Now there’s an interesting development. Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it’s turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer’s urine greenish/blue, generally to their great alarm: a storied med school prank from the old days). What on earth is it doing for tau protein?

According to TauRx, the problem is that the aggregation of tau protein is autocatalytic: once it gets going, it's a cascade. They believe that methylene blue disrupts the aggregation, and even helps to dissociate existing aggregates. Once they're out in their monomeric forms, the helical tau fragments are degraded normally again, and the whole tau backup starts to clear out.

Now for another issue: there's been some commentary to the effect that Rember can't possibly make anyone any money, because it's a known compound. Au contraire. While we evil pharmaceutical folks would much rather have proprietary chemical matter, there are plenty of other inventive steps worth a patent. For one thing, I suspect that formulation will be a challenge here (and that Medpage story seems to bear this out). I doubt if methylene blue crosses the blood-brain barrier so wonderfully, and I also believe that it's cleared pretty well (thus that green urine). So TauRx had to dose three times a day, and their highest dose didn't seem to work, probably because of absorption issues. (That's also going to lead to gastrointestinal trouble). So formulating this ancient stuff so it'll actually work well could be a real challenge: t.i.d with diarrhea is not the ideal dosing profile for an Alzheimer's therapy, to put it mildly.

And for another, there's always mechanism of action. I deeply dislike patent claims that try to grab hold of an entire area, but there's so much prior art in tau that no one could try it. But use of a specific compound (or group of compounds) for a specific therapy: oh, yes indeed. It's a complicated area, and the law varies between Europe and the US, but it definitely can be done. The people who say that this can't be patented should check out the issued patents US7335505 or US6953794. Or patent applications US20070191352, WO2007110627, WO2007110629, and WO2007110630. There you go; that wasn't hard. Mind you, there might be some prior art for using such compounds as cognition-improving agents: I'd start here if I were in the business of looking into that sort of thing.

Finally, is methylene blue (or some derivative thereof) actually going to be a reasonable drug? There's that dosing problem, for one thing, but the long history in humans is encouraging (and is a key part of TauRx's hopes not to spend so much money on toxicity testing in the clinic - talks with the FDA should be starting soon). There have been contradictory reports (plus, minus) on the effects of the compound on the brain in general, though, so they may have to do more work than they're planning on. All in all, a fascinating story.

Comments (116) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Patents and IP | Regulatory Affairs


COMMENTS

1. Fred Cohen on July 31, 2008 8:49 AM writes...

Out of curiousity, I took a look at the granted US patent covering the method and compositions for treating Alzheimer's via tau aggregation disruption (the 695 patent).

What I found interesting is that Methylene Blue wasn't the best tau aggregation disruptor in vitro. The patent doesn't make it clear why Methylene Blue was preferred as a lead by TauRx, but it does imply that there was at least as strong a rationale for selecting carbemazepine, pyridoxine (B6), or cobalamine (B12), among other comnpounds tested.

As you might know, there has been a single RCT looking at supplementation that included 5 mg daily of pyridoxine and 500 mg of oral B12 (mecobalamin) plus 1 mg folate in mild/mod AD (Sun et al 2007, PMID: 18042476). The vitamins were studied under a different hypothesis of action: the homocysteine hypothesis. There was no benefit of the vitamins on top of ACHase inhibition. Observational data have been mixed, but there's little evidence of a correlation between AD progression and intake or serum levels of pyridoxine or B12 (see for example Luchsinger 2007, PMID: 17210813).

I couldn't find any studies with carbemazepine specifically looking at cognition in AD.

Although the results of the TauRx Phase 2 study appear promising at face value, I'd want to understand why MB was chosen over these other tau aggregation disruptors (just commercial considerations?) and why other compunds with the same tau MOA, namely pyridoxine and B12, appear to offer little or no benefit clinically before loosening the reins on my enthusiasm.

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2. from_sgc on July 31, 2008 9:27 AM writes...

But apparently methylene blue also inhibits the aggregation of amyloid with the same IC50 ~2uM:
http://www.ncbi.nlm.nih.gov/pubmed/15611092?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

There might be no contradiction with amyloid hypothesis.

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3. pcr on July 31, 2008 9:39 AM writes...

Assuming they generate sufficient efficacy and safety data to warrant approval, would FDA accept Rember as the brand name? Isn't it too similar to "Remember"?

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4. satan on July 31, 2008 9:55 AM writes...

One of the problems with companies based outside N. America is that those environments have no accountability (legal or otherwise).

For all the problems with pharma companies here, reality ultimately triumphs. Asian cultures are often driven by names, personalities and "legends" as opposed to reality. Even japan is still stuck in modes of thinking that would not have been acceptable here in the 1950s.

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5. seth on July 31, 2008 10:22 AM writes...

Best description I've seen is here..

http://www.alz.org/icad/_release_icad_072908_130pm_trials.asp

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6. john.spevacek@aspenresearch.com on July 31, 2008 10:53 AM writes...

Just the fact that you can buy methylene blue off the shelf will make it difficult to maximize profits, even with US and EPO patents. I can easily imagine clinics in third world countries running the treatment themselves, even with the modifications that you suggest are needed.

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7. from_sgc on July 31, 2008 11:08 AM writes...

The trial is claimed to be double-blinded.
BUT the obvious sign of methylene blue in the body is a blue urine. It should immediately become obvious to doctor/patient who is on placebo and who is treated. Unless of course there is a blue-urine placebo pill.

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8. processchemist on July 31, 2008 11:13 AM writes...

#6

But if they patent a formulation for parenteral use and this one has the best effect, things should be different, I suppose

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9. Still Scared of Dinosaurs on July 31, 2008 12:10 PM writes...

#7 is a good point. It's hard to imagine a way to measure cognition that wouldn't be susceptible to bias.

Maybe they need to test the drug in patients with porphyria.

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10. natas on July 31, 2008 5:16 PM writes...

#4 that's an... interesting view. Perhaps you could back it up with something more than anecdote and spittle?

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11. anon on July 31, 2008 5:42 PM writes...

#7, #9 - Nahh, one of the conditions of the trial was that you can only go to the bathroom blindfolded...with a nurse to make sure there's no peeking!

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12. CMC guy on July 31, 2008 6:11 PM writes...

I thought there were some drugs that caused "blue urine" and heard story of one drug development was halted becasue of this side effect. Google search hit two and suggested some foods. (I assume there is no Methylene Blue in the formulations).

Triamterene – a mild diuretic and can cause a blue urine color.
Rinsapin ...antibiotic sometimes used to treat a staph infection and can cause you to see a blue or green urine color

http://www.urinecolors.com/blue_urine_color.php

Don't know how could use as Placebo but in addition to #11 anon suggestion could always make them wiz in the dark...

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13. Jose on July 31, 2008 6:25 PM writes...

A web site for "urinecolors.com?" I think I see the horsemen of the Apocalypse headed this way....

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14. Retread on July 31, 2008 9:15 PM writes...

"It’s hard to show decent efficacy in an Alzheimer’s trial" -- not so at all -- if the drug reversed the disability, we'd know in a flash. This just shows how low our expectations of this class of drugs has become.

In 9/70 two great things happened: I finished my two years as a doc in the Air Force, and L-DOPA was released in the USA (having been used in Europe for years). The chief assigned me to run the L-DOPA clinic (set up because we had zero experience with the drug) in our residency program and I watched people get out of wheelchairs. Interestingly, just like the anti-depressants (which we thought and probably still think muck around with catecholamine neurotransmitters and serotonin) L-DOPA doesn't work right away, the effects build over several weeks.

While Aricept may be the standard of care -- it is a lousy drug. I never saw significant improvement (this was how this class of drugs was initially touted), nor did any clinical neurologist I knew. We clearly need something better.

Assuming Rember does help, the next thing would be to combine it with a drug in the Aricept class. Few, if any, cancers are beaten with a single drug.

#9 -- amusing idea, but porphyrics when not in an attack have normal looking urine. When they're in an attack, they are very, very sick.

As a clinician, I was exposed to some nasty bugs and once had to take prophylactic rifampicin for a while -- which turns the urine orange. Unfortunately I went to a college football game while taking it and got some very strange looks in the john -- which consisted of several 40 foot long urinals.

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15. Morten on August 1, 2008 3:33 AM writes...

@#4 Um... wow. "One of the problems with companies based outside N. America is that those environments have no accountability (legal or otherwise)."

@#7&9 I'm assuming that the placebo was just straight-up methylene blue since TauRX wanted to show efficacy for their formulation... or is that dumb?

@Derek It's called a Swiss-type claim when you use a known substance for new indications. Rather than those patent links you might want to just link here: http://en.wikipedia.org/wiki/Claim_(patent)#Swiss-type_claim

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16. Alan Hochberg on August 1, 2008 9:57 AM writes...

The efficacy might be modest rather than stellar, but still it's nice to see a drug on which there is decades of safety data, and that is benign enough for college students to slip into to their friends' drinks as a joke without getting arrested. Let the formulation and derivatization begin.

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17. Still Scared of Dinosaurs on August 1, 2008 10:48 AM writes...

"which turns the urine orange. Unfortunately I went to a college football game while taking it and got some very strange looks in the john -- which consisted of several 40 foot long urinals."

Lemme guess - the 'bama fans thought there was something seriously wrong with you and the Clemson fans wanted to know where they could get some.

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18. retread on August 1, 2008 12:56 PM writes...

Nope -- it was a Syracuse game. They are known as the Orangemen, whence I gave new meaning to their cheer "Go Orange"

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19. Still Scared of Dinosaurs on August 1, 2008 1:41 PM writes...

I almost, ALMOST went with 'cuse, but the last game I attended was Clemson at BC so I went with that. Dohhh!

I guess people taking Rember can go to Giants games and shout "Go Big Blue!" Just trying to return the thread to the original topic.

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20. John Bosnitch on August 2, 2008 2:38 AM writes...

The author and many posters on this topic seem to be professionals in this field.

So here's my question #1: With a family history of Alzheimer's, an aged (89) father who is starting to become noticeably forgetful, and 'rember' promising to slow but NOT reverse the disease... why should I wait for further trials before getting my father on this apparently non-threatening drug by simply buying Methylene Blue.

And the inevitable question #2: Where can I buy it and how should I administer the 60mg "effective" dose?

I would appreciate any advice you have... either here in these postings or directly to me: john.b@imcnews.com

Thanks!

John Bosnitch

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21. Spottymaldoon on August 2, 2008 8:15 AM writes...

In terms of general import to humanity, this announcement is reminiscent of 1989 claim to have produced 'cold fusion' of deuterium using a palladium electrode! Quite on the same scale if it proves to be valid and, of course, it's inevitable that many people are going to jump the gun and start dosing themselves well ahead of any clinical trials.

I understand that methylene blue prices have already shot up - as did palladium in 1989.

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22. sharon on August 2, 2008 9:52 AM writes...

Hi Satan,

I'll have you know that Singapore is near the very top of the world's economic league and have zero debt as opposed to Mr. Bush's sorry economic legacy so make you criticism of Asian countries carefully in the future. And by the way, the science of the rember™drug could well have been formulated in a world class university in Singapore but, as it is, the research was done mainly out of the University of Aberdeen in Scotland where Prof. Wischik is based.

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23. bobtaylor8@hotmail.co.uk on August 2, 2008 11:54 AM writes...

As an apprentice pharmacist in 1954 I dispensed many a bottle of 'magic' medicine for one of our local doctors in Durban South Africa. Apart form a 'mess' of ingredients, he used to include metylene blue and liquor sact (burnt sugar or dark caramel) so that the patient would swallow black medicine and pee blue. This was the magic, which probably did the patient as much good as the other ingredients!!

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24. bobtaylor8@hotmail.co.uk on August 2, 2008 11:55 AM writes...

As an apprentice pharmacist in 1954 I dispensed many a bottle of 'magic' medicine for one of our local doctors in Durban South Africa. Apart form a 'mess' of ingredients, he used to include metylene blue and liquor sact (burnt sugar or dark caramel) so that the patient would swallow black medicine and pee blue. This was the magic, which probably did the patient as much good as the other ingredients!!

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25. losingit2 on August 2, 2008 6:00 PM writes...

All,

Interesting discussion as I am a 58 year old early onset patient. I was diagnosed about 2 years ago and am currently on Aricept and Namemda.

I appreciate the gallows humor, but I think this is a hoax.

Based on what I see, I am amazed that he was allowed to present at ICAD

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26. EISERMANNS on August 3, 2008 8:53 PM writes...

INDIGO CARMINE WOULD BE A PERFECT PLACEBO - URINE DISCOLORING AGENT !

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27. EISERMANNS on August 3, 2008 8:53 PM writes...

INDIGO CARMINE WOULD BE A PERFECT PLACEBO - URINE DISCOLORING AGENT !

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28. Petros on August 4, 2008 5:25 AM writes...

The patent position of Rember is discussed in this wek's Current Patents GAzette. The author suggests that the filings published to date, assigned to WISTA LABORATORIES (now TauRx), offer little, if any, effective protection to Rember.

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29. bets on August 5, 2008 12:42 PM writes...

Like a previous contributor I notice there are a few folks of a scientific 'bent' posting on this site. I wish to God this disease was only of academic interest to me. My father is 77 and was diagnosed a year ago ( there were some delays in getting specialist help) . To be honest I would give him dynamite if I thought it would blow this 'worm' out of his brain. ( I exaggerate but I really wouldn't care what colour his pee was if this helped him.) He is on Arricept which helped initially but the effect has tailed off and the worm continues eating ... Any advice gratefully received. Four years is too long to wait and watch a person revert to toddlerhood.

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30. eugene on August 5, 2008 2:57 PM writes...

Even though most of us are of a scientific bent, most of us are chemists and not physicians, so we can't give you any useful advice. Our choice on what to do by reading the info would be just as good as yours (with the difference that if I decided to dose myself, I'd read up on the formulation details used in the study or ask an insider if that was unavailable).

And even if we were physicians, no physician who is not involved in this study would urge you to take a drug that hasn't been fully tested or that at the end of the day could prove to offer no benefit. There is just no possible value to possibly misleading strangers over the internet no matter how bad their circumstances are. And I sympathize of course.

Now if you put up an online poll of this blog's readership asking: "If you had early Alzheimer's yourself and knew the formulation details of Rember, would you dose yourself based on these perliminary results?", the percentages who vote 'yes' or 'no' would serve as guidance for you. But giving advice from a single scientist (not a physician) to a single person with a devastating problem concerning an experimental drug over the internet? That is going to be very difficult here.

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