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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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« Sanofi's Feeling Just Wonderful | Main | Hosed-Up X-Ray Structures: A Big Problem »

June 9, 2014

Good News! Our Alzheimer's Drug Didn't Work!

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Posted by Derek

Alzheimer's disease is one of the notorious rocks of drug development. Around it are piles of debris, shipwrecks of clinical research programs large and small. But late last week, as yet another company sailed in close, something new happened.

Unfortunately, that may not mean "new" an in "good". A small company called AFFiRiS (that's really how they spell it) was testing a vaccine against beta-amyloid (an idea that has been tried numerous times before, although with the immune system you never know what'll happen next). Here's what happened next:

On June 4, AFFiRiS AG offered a smattering of results from its Phase 2 clinical trial of AD02, an active vaccine for Alzheimer’s disease derived from the company’s proprietary method of making synthetic antigens based on the Aβ peptide. At a press conference in Vienna, company scientists reported that among older people with early Alzheimer’s, a placebo group fared better than any other. Patients in this group reportedly had less cognitive decline over the course of 18 months, correlating with less hippocampal shrinkage. This group had been injected not with any Aβ-based antigen, but only with what the company calls an immunomodulator that was part of the AD02 formulation. Company scientists then named this placebo formulation AD04, and said they planned to explore options for clinical development.

Now, not every story about this actually picks up on this switcheroo. Try this one: you'd think that the company marched into the clinic with several vaccine ideas and got one of them to work. But that's not what happened.

I'm having a lot of trouble with this idea. Serendipitous discoveries there are, and this may be one of them. But I very much doubt it. The company provided no real data in their announcement - no error bars, no actual numbers. The "immunomodulator" was present in the actual vaccine formulation, but those patients (apparently) showed no effect. That Alzforum story linked above also notes that the company took two clinical rating scales, usually used separately and combined them into their own composite score. It is generally a safe bet that no one does that unless that was the only way that their results look promising.

So no, I have to disagree with the company that these results represent some sort of breakthrough. Breakthroughs in the clinic have clearly stated sample sizes, and error bars, and don't require any mixing and stirring of the numbers. Odds are excellent that this is noise. AFFiRiS (can't say I enjoy typing that) can move ahead with its mysterious immunomodulator if they like, and for the sake of Alzheimer's patients everywhere we can hope that it does something. But when a small company tries to say "Oh look, turns out our control group is actually a new Alzheimer's therapy! Isn't that great!", well, I think some skepticism is appropriate.

Comments (25) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. anonymous on June 9, 2014 9:16 AM writes...

Sounds like they're giving up on plan A, and plan B is the pump-and-dump.

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2. alig on June 9, 2014 10:51 AM writes...

Doesn't this just indicate that AD02 accelerates cognitive decline?

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3. Anonymous on June 9, 2014 10:54 AM writes...

Does this mean that beta amyloid is protective?

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4. johnnyboy on June 9, 2014 11:36 AM writes...

LOL - and by that I mean that I actually laughed out loud. Talk about gilding a turd !

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5. Teddy Z on June 9, 2014 12:04 PM writes...

What's the chance that the immunomodulator is good Aluminum phosphate adjuvant? And seriously wouldn't that bring us full circle?

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6. Anonymous on June 9, 2014 12:18 PM writes...

Pump and dump? No, worse, this is outright fraud, they know full well that they have nothing, and are effectively lying to investors by calling placebo anything other than what it is, and making out that it's some kind of proprietary breakthrough.

Send them to prison!

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7. bluefoot on June 9, 2014 12:30 PM writes...

@alig That's certainly how I read it. The treatment group AD02 + mystery immunomodulator performed worse than mystery immunomodulator alone. I'd certainly be scrutinizing the data with a seriously skeptical eye. I'd also love to know why (and how) they combined ADAS-Cog and ADCS-ADL. One would think such a move would need to be validated first...

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8. Esteban on June 9, 2014 12:51 PM writes...

Or what if the immunomodulator is a peroxynitrite scavenger?

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9. Barry on June 9, 2014 12:54 PM writes...

it's not dissimilar to the story of naked DNA vaccines. In doing proper controls, some animals were given saline, some were given the full vaccine, some were given just one of the components. The surprise (which stood up on replication) was that the adjuvants and the liposomes weren't needed.
Up to that point, it's just doing good science. The rest is spin.

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10. Cellbio on June 9, 2014 2:13 PM writes...

..and johnnyboy you passed the laugh along, as I had a chuckle remembering a failed drug's side effect, diarrhea, became the new cure for constipation. And don't ask if it came out well.... it didn't.

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11. Derek Lowe on June 9, 2014 2:36 PM writes...

#8 Esteban - Don't call up anything that you don't know how to send down again (!)

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12. sgcox on June 9, 2014 3:20 PM writes...

Indeed.
Esteban summons the wrath..

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13. Esteban on June 9, 2014 4:11 PM writes...

@11,12: Good point...now where is that counter-curse?...ah, here it is...

Commentus Amendus!

Hmm, didn't work. Derek: As was always your prerogative, delete if you see fit.

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14. Lane Simonian on June 10, 2014 12:01 AM writes...

#8 Wouldn't that be funny?

But just for old time sake, let's run it down again (with a new early feedback mechanism thrown in for good measure).

H2O2 and peroxynitrite...are known to upregulate BACE1 and activate the enzyme...

The amyloid precursor protein in turn upregulates peroxynitrite production via activation of g proteins (isoleucine which is the most common substitute in amyloid precursor mutations provides an example as does presenilin 1 gene mutations).


The growth rate of rodent embryonic neuroblasts and human neuroblastoma cell lines is regulated in part by autocrine or paracrine actions of neuropeptides of the family that includes vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), and pituitary adenylate cyclase-activating peptide (PACAP). These peptides act via seven transmembrane G-protein-linked receptors coupled to cAMP elevation, phospholipase C activation, intracellular Ca2+ release [necessary for the gamma secretase}, and/or of mitogen-activated protein (MAP) kinase activation [beta secretase activation via p38 MAPK and then peroxynitrites].


The Presenilin 1 ΔE9 Mutation Gives Enhanced Basal Phospholipase C Activity and a Resultant Increase in Intracellular Calcium Concentrations.


All of these problems are partially ameliorated with peroxynitrite scavengers.


Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.

Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

J Med Food. 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.

Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.
Kang KS1, Tanaka T, Cho EJ, Yokozawa T.
Author information

Abstract
To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]
Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.

Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.

RESULTS: The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:
These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

Of course no one other than the people who ran the trial know what was in the placebo and it may very well be another dead end. But peroxynitrite scavengers are the only compounds that have partially reversed Alzheimer's disease in human clinical trials, and that does not happen by chance.


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15. a. nonymaus on June 10, 2014 10:41 AM writes...

Perhaps they hope to attract investment from potential patients who can't remember what they read about the company, only that it was in the news recently.

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16. Lane Simonian on June 10, 2014 11:49 AM writes...

Here is one of the patents by AffiRis:

Complement component c5a- based vaccine
WO 2013174920 A1

ABSTRACT
The present invention relates to a vaccine comprising at least one peptide consisting of 7 to 19 amino acid residues consisting of the amino acid sequence (X3)mKDX2QLGX1 (SEQ ID No. 99), wherein X1 is an amino acid residue selected from the group consisting of alanine, asparagine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, serine, threonine, tyrosine and valine, X2 is an amino acid residue selected from the group consisting of alanine, arginine, histidine, isoleucine, leucine, lysine, methionine, threonine, tyrosine and valine. X3 is (X4)nANISX5 (SEQ ID No. 100) or an N-terminal truncated fragment thereof consisting of 1 to 4 amino acid residues, X4 is VVASQLR (SEQ ID No. 101) or an N-terminal truncated fragment thereof consisting of 1 to 6 amino acid residues, X5 is an amino acid residue selected from the group consisting of alanine, asparagine, glutamine, glutamic acid, histidine, arginine, isoleucine, lysine, methionine, serine and threonine, m is 0 or 1, and n is 0 or 1, wherein said at least one peptide is coupled or fused to a carrier comprising at least one T-cell epitope.


This is a mix of amino acids--some positive; some negative for the treatment of Alzheimer's disease.
That may explain the lack of significant results for ADO2.


Now I will go in a direction that I don't want to go in: the immunomodulator may have been aluminum
hydroxide.

(Mimotopes discovered by Affiris GmbH have been termed Affitopes)...The trial is designed as a patient-blinded, single-center, randomized, controlled, parallel group, phase I clinical study of repeated once every 4 weeks administration by subcutaneous injection of Affitope AD01 alone or adsorbed to aluminum hydroxide in 24 patients with mild to moderate Alzheimer's Disease.

In some instances, aluminum hydroxide increases uric acid levels and uric acid is a peroxynitrite scavenger.

If (and it is a big if) this is the case, one can do much better than this. Slowing down the progression of the disease in about half the patients for at least 18 months is not as good as partially reversing it.

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17. Esteban on June 10, 2014 1:07 PM writes...

I am become Esteban, the destroyer of worlds

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18. Lyle Langley on June 10, 2014 2:05 PM writes...

You just had to poke the bear, didn't you?

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19. bank on June 10, 2014 4:11 PM writes...

Esteban: Bad boy!

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20. Lane Simonian on June 10, 2014 6:05 PM writes...

Esteban: Good boy!

This is more lovely yet (from Motley Fool):

According to Table 54-1 in the book Vaccines by Stanley E Plotkin et al, the formulation contains the "AFFITOPE peptide" linked to KLH [Keyhole limpet hemocyanin]. This can also be inferred from the Clincial Trial Register at https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-.... So the two adjuvant groups could be KLH and KLH + Alum. That Alum has been used in their vaccine formulation can be read about in Scheeberger et al (2009) JNHA 13(3):264-267.

Nitrated keyhole limpet hemocyanin is an antibody against tyrosine nitration which is one of the main toxic effects of peroxynitrites in Alzheimer's disease.

Free Radic Biol Med. 1998 Nov 15;25(8):953-63.
Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA.
ter Steege JC1, Koster-Kamphuis L, van Straaten EA, Forget PP, Buurman WA.

In context of the development of an ELISA for detection of nitrotyrosine in plasma, monoclonal anti-nitrotyrosine antibodies were developed by injecting mice with nitrated keyhole limpet hemocyanin.


Whether you want to put it together or you don't want to put it together does not matter to me. What matters to me is that someone puts it together.

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21. bank on June 10, 2014 6:23 PM writes...

Lane,

Frankly, you are someone clearly dedicated to the topic of Alzheimer's disease (though probably not a currently working scientist).

I hope that you are involved in the wider field, for example in raising awareness in the general population or raising funds for research. You could even put such funds towards funding your peroxynitrite theory, if you raise enough. You need about $100K per year per scientist to fund salaries and overheads in a typical academic institute.

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22. Anonymous on June 11, 2014 6:50 AM writes...

Lane, I hope you realize that pushing forward the same speculative idea over and over, without ever doing any real work to test your ideas, is merely raising antibodies and alienating both you and your ideas from ever being considered seriously. Frankly you sound like a religious fanatic, only able to see your own faith, and cherry picking only the papers that fit your own beliefs. With this attitude you are doing more harm than good, and have no place in a scientific community.

Please go away.

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23. Anonymous on June 11, 2014 7:50 AM writes...

...and allow real scientists to do their job of testing ideas in an objective, unbiased manner.

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24. Lane Simonian on June 11, 2014 11:23 AM writes...

First of all it is not my idea. I have no financial or intellectual stake in it. It was developed by scientists not by me.

As far as all scientists (I am an environmental historian with a substantial background in biology) being objective--I don't buy it. The amyloidists (nice religious touch) are no less fanatical than I am. You might have excused them when the data was limited as making an educated guess. But when an educated guess becomes hardened orthodoxy, then your chances of effectively treating a disease diminishes. The amyloidists made the oldest mistake in the book: they mixed up correlation with causation (and then only partial correlation). Neurons die in the presence of the amyloid precursor protein alone and some people with Alzheimer's disease have neither the oligomers nor the plaques in their brains. The oligomers through their enhanced production of hydrogen peroxide may contribute to the progression of the disease, but they are not the cause.

But people who are finacially and egoistically involved in the amyloid hypothesis keep advancing it. When trial after trial fails, they keep seeking answers--did not reduce amyloid enough or at all, reduced the wrong form of amyloid, was not given early enough, etc. The idea that it could be largely the wrong target is anathema to them (as I am guessing it is to several people on this site).

I have seen plenty of scientist state that past a certain point Alzheimer's disease cannot be reversed. Where is the evidence for that? It has actually been partially reversed several times in human clinical trials. Not all of the human clinical trials using peroxynitrite scavengers were rigorously conducted. But if you read several studies in which peroxynitrite scavengers have partially reversed Alzheimer's disease, then the cumulative evidence points you into what is likely the right direction. You can find plenty of reasons for negative results but it is hard to find explanations for why multiple sustained positive results are not real.

The fact that many of the results were attained with natural products involving plants or their components is neither pseudoscience nor second-rate science and that attitude only reflects the bias of some U.S.(and European)scientists. You find it less often reflected in other countries and that is why some of the best studies on Alzheimer's disease come from outside the United States.

So when ten years of accumulating the scientific evidence for the causes and treatments of Alzheimer's disease is chalked up to pseudoscience it does strike a nerve.

The following anonymous quote sums it up.

[Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer's disease. Similarly most drugs used to treat Alzheimer's disease do little to slow the deterioration, but instead offer a mild temporary
symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite,which may mediate both amyloid and tau accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer's disease in human clinical trials being repeatedly demonstrated. IMHO, the only thing which may be preventing the abolition of
Alzheimer's disease is the mental inertia of scientists, as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful
ones. Common sense is anything but...]

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25. Despairer of Estaban on June 11, 2014 1:16 PM writes...

Estaban... *shakes head*

Lane...*removes own head*

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