Since Alzhemed is a disease modifyer, the use of biomarkers by quantification of Abeta in CSF and/or plasma to assess its efficacy in this trial may be a real asset.

View all comments by Luc Buee

The Alzhemed study was disappointing for the actual treatment arm. But it does suggest – unexpectedly - that a substantial fraction of patients with the current Alzheimer medications (i.e. anticholinesterases and memantine) alone (the control arm) performs quite well over a period of 18 months, at least in cognitive performance. Except for a small number of open-label studies (some going out to 4 years), this hypothesis hasn’t been tested to such an extent. In addition, the freedom to change medications allowed for many patients to settle on the most optimal treatment in terms of benefit and side-effect. Unfortunately we don’t know how much brain amyloid load was changed in the treatment arm, as the study was started well before the amyloid imaging probes became available. Such information would have given us some idea of how much of the cognitive benefits could be linked to a reduction of brain amyloid for patients in this stage of the disease.

The major lesson from this trial is that the currently marketed medications provide an unexpected high overall cognitive benefit,...  Read more

The Alzhemed study was disappointing for the actual treatment arm. But it does suggest – unexpectedly - that a substantial fraction of patients with the current Alzheimer medications (i.e. anticholinesterases and memantine) alone (the control arm) performs quite well over a period of 18 months, at least in cognitive performance. Except for a small number of open-label studies (some going out to 4 years), this hypothesis hasn’t been tested to such an extent. In addition, the freedom to change medications allowed for many patients to settle on the most optimal treatment in terms of benefit and side-effect. Unfortunately we don’t know how much brain amyloid load was changed in the treatment arm, as the study was started well before the amyloid imaging probes became available. Such information would have given us some idea of how much of the cognitive benefits could be linked to a reduction of brain amyloid for patients in this stage of the disease.

The major lesson from this trial is that the currently marketed medications provide an unexpected high overall cognitive benefit, which raises the hurdle for any future ‘disease modifying’ trial.

View all comments by Hugo Geerts

This news story is a bit too optimistic and accepting of the company line. In truth, Neurochem managers knew in early April that their trial was negative and gave away as much in their April 19 press release by discussing the need for post hoc statistical models. Since then, they have issued carefully parsed public statements, press conferences, investor teleconferences, and a meeting presentation. In my opinion, close observers and certainly statisticians recognize the spin. The company’s statements sound like a distraction to avoid the outright admission that tramiprosate showed no effect compared to placebo. Even the company’s most recent news release does not quite get to this fact, nor does the ARF news story. Wall Street analysts and some investors finally got it, as the stock price tanked.

The company spent over 4 months dredging, sifting, slicing, dicing, and remodeling their database, positing one, another, or several potential “confounding” variables that might have influenced outcomes. All the while, they issued periodic press releases stating that their “external...  Read more

This news story is a bit too optimistic and accepting of the company line. In truth, Neurochem managers knew in early April that their trial was negative and gave away as much in their April 19 press release by discussing the need for post hoc statistical models. Since then, they have issued carefully parsed public statements, press conferences, investor teleconferences, and a meeting presentation. In my opinion, close observers and certainly statisticians recognize the spin. The company’s statements sound like a distraction to avoid the outright admission that tramiprosate showed no effect compared to placebo. Even the company’s most recent news release does not quite get to this fact, nor does the ARF news story. Wall Street analysts and some investors finally got it, as the stock price tanked.

The company spent over 4 months dredging, sifting, slicing, dicing, and remodeling their database, positing one, another, or several potential “confounding” variables that might have influenced outcomes. All the while, they issued periodic press releases stating that their “external team of statisticians” was hard at work making adjustments to the statistical models “as set out in the statistical plan”; making this sound about as formidable and intellectually challenging an endeavor as decoding the human genome.

At the Alzheimer’s Association’s prevention meeting in June, Neurochem held a press conference and scientific presentation and issued a news release where it spoke about “potential confounding factors,” “numerical differences in favor of tramiprosate,” and “differences between groups on the primary disease modification endpoint as measured by magnetic resonance imaging,” all without providing any data. At the meeting, they presented a slide listing about 19 such factors from which they included from four to six (the slide is ambiguous) in their “adjusted statistical model(s).” Each factor involves an aspect of antidepressant, vitamin E, memantine, or cholinesterase inhibitor use, disuse, and/or dose change. They stated again, “no statistical comparisons can be conducted yet on the preliminary data as the primary statistical model is not reliable…. No conclusions can be drawn presently,” yet they obviously did such statistics.

This level of vagueness has no place in scientific presentations, and arguably no place in drug company communiqués, especially when the presentations can be interpreted as federally required disclosures of information on material changes in the company. It strains the company’s credibility and is virtually impossible to interpret. By withholding data and analysis results while talking around the results, there is really nothing of substance to learn.

The company presentations speak as though some sites may be at fault for site-to-site variability. The significance of this is not apparent, since we expect site variability; it is one reason why we do multicenter trials. They suggest that there was something about the discontinuation of cholinesterase inhibitors (after an average of nearly 2 years’ use) or memantine (average of nearly 1 year’s use), or that antidepressant and vitamin E use suppressed favorable outcomes. The latter is odd because antidepressant use is frequent in AD trials, and vitamin E is not cognitively effective. In the absence of data from the company, one must wonder how strong the potential effect of tramiprosate can be if drugs that have very modest to no cognitive effects are confounders.

Moreover, Neurochem further obfuscates their outcomes by seeming to blame the placebo group for not worsening as expected. ARF quotes that “30 percent of the control group did not decline in cognition,” but this is probably close to what is expected. For example, the ADASc worsens by about 6 to 7 points in other 18-month trials with a standard deviation of about 8 or more. Therefore, about a third of a placebo sample would score the same or better than at baseline.

If any of these “potential confounding factors” really influenced outcomes or suppressed an otherwise significant tramiprosate outcome, then Neurochem would have said as much. No, they would have shouted it, as would their sell-side financial analysts.

The difficulty, of course, is that the company makes assertions without showing supporting data. They imply variously that the trial may have significant outcome elements to it, would have been significant if there had not been “confounders,” or that the trial failed because there was something wrong with the placebo group. Trust us, they seem to say. Better yet, believe our external statisticians, our advisors, or what we say the FDA said in a confidential meeting: “FDA deems…results inconclusive,” or “FDA is encouraging Neurochem to continue working on the U.S. trial data set post hoc.” In effect, they cloak themselves in perceived external authority such that it appears that Neurochem, FDA, and consultants make these statements together.

I doubt that a commission of academics—however capable and well-intentioned—can provide anything additional beyond more breathing space and cover for the company. What can they do with the trial that the company hasn’t already attempted for more than 4 months? Even so, the company has stated that they will hold back outcomes of this trial until July 2008 at ICAD, the next Alzheimer’s Association science meeting.

The company knows well their limited options with regard to both their trials and their business. Neurochem’s development program (and possibly its survival) rests on the European trial that finished enrolling in August and whose last patient would complete about February 2009. The company can increase sample size, tweak the statistical plan, shorten the treatment period, or end the trial and move on. Yet it has only $80 million cash, $45 million in debt, a burn rate of $3 million per month, two other iffy drug programs, and probably some angry investors with leverage. In this context, using an advisory board that won’t produce a report until Christmas strikes me as a play for time while the company does other things and hopes for good luck. Maybe they will get positive opinions from FDA or EMEA about their other, similar drug, eprodisate (branded Kiacta) for amyloid A amyloidosis, or maybe they will reveal phase 2 results from their trial of tramiprosate (here brand named Cerebril) to prevent hemorrhagic stroke in patients with cerebral amyloid angiopathy. I hope so, because good news there would increase the likelihood that the European AD trial is completed.

Neurochem could have made this easier on everyone if they had presented their results in a straightforward manner when they knew them. Then they could have shown any unusual site-to-site variability, confounds, and discussed threats to the trial’s validity. Such forthrightness would have most directly benefited patients in the trials, physicians, other consumers, and stockholders. A straightforward presentation of their results might even gain them new investors. It is not too late for this.

The evolving Neurochem story and its relationship with the Alzheimer’s Association is as much an example of the big business of how little companies finesse research results that have a material impact on their futures, as it is a story of scientific reporting when there are no facts to report. These may be the lessons yet to learn from this trial.

Relevant disclosures: During the last year, I have consulted with the manufacturers of one marketed drug for AD, Forest, Lundbeck, and Merz; consulted with companies developing drugs for AD but without marketed drugs for AD, including AstraZeneca, Elan, GSK, Roche, Sanofi-Aventis, Takeda, Wyeth, Voyager, Myriad, and others. I serve as co-PI of Myriad North American AD trial. I have received a grant from the Alzheimer’s Association and am a member of the NIA ADCS steering committee.

References:
Neurochem news releases and financial statements.

View all comments by Lon Schneider

Wow!

View all comments by Larry Nault

Unfortunately I couldn't make this conference but the reports are fascinating. We have argued for some time that certain plaque types are particularly dense (e.g. fibrillar and dense-core plaques) and act as microscopic 'space-forming' lesions. Double-labelling immunohistochemical experiments have shown that the denser plaques effectively displace normal axons and dendrites, with the aberrant regenerative axonal pathology likely to follow from squeezing and constriction of axons (eg Dickson et al., 1999; Vickers et al., 2000; Adlard et al., 2002). Removing the plaques may be effective at reducing the aberrant regenerative response, but won't alleviate damage already done to the neurons of origin of these axons. Thus, it is unlikely that there will be significant therapeutic benefit for established AD cases (i.e., damage is already done).

In light of the data regarding increased atrophy in A-beta immunized individuals, it may not be due to the absolute loss in weight of the deposit, rather the reduction in space that follows clearance of thousands (if not millions) of...  Read more

Unfortunately I couldn't make this conference but the reports are fascinating. We have argued for some time that certain plaque types are particularly dense (e.g. fibrillar and dense-core plaques) and act as microscopic 'space-forming' lesions. Double-labelling immunohistochemical experiments have shown that the denser plaques effectively displace normal axons and dendrites, with the aberrant regenerative axonal pathology likely to follow from squeezing and constriction of axons (eg Dickson et al., 1999; Vickers et al., 2000; Adlard et al., 2002). Removing the plaques may be effective at reducing the aberrant regenerative response, but won't alleviate damage already done to the neurons of origin of these axons. Thus, it is unlikely that there will be significant therapeutic benefit for established AD cases (i.e., damage is already done).

In light of the data regarding increased atrophy in A-beta immunized individuals, it may not be due to the absolute loss in weight of the deposit, rather the reduction in space that follows clearance of thousands (if not millions) of space-forming lesions, perhaps also accompanied by a reduced inflammatory reaction associated with the damage done by the space-forming lesion. It would be fascinating to examine the morphology of nerve cells following removal of the dense plaques.

References:
Dickson, T.C., King, C.E., McCormack, G.H. and Vickers, J.C. (1999) Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer’s disease. Experimental Neurology 156, 100-110. Abstract

Vickers, J.C., Dickson, T.C., Adlard, P.A., Saunders, H.L., King, C.E. and McCormack, G. (2000) The cause of neuronal degeneration in Alzheimer’s disease. Progress in Neurobiology 60, 139-165. Abstract

Adlard, P.A., King, C.E. and Vickers, J.C. (2000) The effects of taxol on the central nervous system response to physical injury. Acta Neuropathologica 100, 183-188. Abstract

View all comments by James Vickers

I believe it is the time to finally admit that Elan’s AN-1792 trial is a failure! There is no clear evidence on cognitive benefits, neither on global measures nor on neuropsychological tests; moreover, in a subset of subjects a potentially fatal complication emerged (encephalitis) and, now, after Nick Fox's report we became aware that vaccination seems to accelerate the rate of brain atrophy... The major unsolved problem is the mechanism and, hopefully, it will be vigorously looked for before anybody starts a new trial. Maybe cases of encephalitis might give us a hint on the mechanism of the vaccine toxicity. Isn't it possible that in fact an inflammatory response (of one sort or another) occurs invariably in all vaccinated subjects but only in some leads to clinically significant symptoms? By the way, very interesting and mostly ignored results were shown on Tuesday the 20th with oral vaccination by the Japanese group (Takeshi Tabira, Hideo Hara; oral session 03-06). What is really impressive about this particular research group is that they're NOT planning an immediate...  Read more

I believe it is the time to finally admit that Elan’s AN-1792 trial is a failure! There is no clear evidence on cognitive benefits, neither on global measures nor on neuropsychological tests; moreover, in a subset of subjects a potentially fatal complication emerged (encephalitis) and, now, after Nick Fox's report we became aware that vaccination seems to accelerate the rate of brain atrophy... The major unsolved problem is the mechanism and, hopefully, it will be vigorously looked for before anybody starts a new trial. Maybe cases of encephalitis might give us a hint on the mechanism of the vaccine toxicity. Isn't it possible that in fact an inflammatory response (of one sort or another) occurs invariably in all vaccinated subjects but only in some leads to clinically significant symptoms? By the way, very interesting and mostly ignored results were shown on Tuesday the 20th with oral vaccination by the Japanese group (Takeshi Tabira, Hideo Hara; oral session 03-06). What is really impressive about this particular research group is that they're NOT planning an immediate trial in humans once highly promising results in mice have been achieved (notably, no signs of an inflammatory response whatsoever..). They have decided to go to primates first, a very reasonable and cautious approach.

View all comments by Tomasz Sobow

The summary by Gabrielle Strobel was nicely done. One further aspect from Sid Gilman's talk was that although a Z score for all cognitive tests showed the treatment group better than placebo as summarized, the ADAS-Cog score for the responder immunized group was -3.8, compared to -2.7 for placebo. Thus, a widely accepted test more focused on cognitive decline in Alzheimer disease correlates with the loss of brain volume. Immunization against a protein that has a natural function seems inadvisable with 3 strikes: greater cognitive decline, even more brain loss and risk of encephalitis. In baseball, wiser managers try new talent. Perhaps it's time for better funding for competitors of the amyloid hypothesis.

View all comments by Gregory J Brewer

The brain volume changes in patients who were immunized and developed antibodies is interesting, but perhaps not so surprising in retrospect when the information available from the neuropathology is taken into account. You might predict (1) an initial transient phase (days to weeks) of brain swelling due to activation of microglia and edema (fluid retention), followed by (2) a reduction in brain volume due partly to resolution of this inital reaction and partly due to removal of plaques (Aβ and all the other plaque-associated proteins), and shrinkage and/or removal of the microglia and plaque-associated astrocytes, followed by (3) stabilization or even increased volume if regeneration occurs. This sequence of events would seem to fit with what we know so far from the imaging and the neuropathology.

View all comments by James Nicoll

Lest this become the "Jurgen Gotz solo" stage, I'd like to sound my three notes:

First, to thank Lon Schneider for his most enlightening dissection of the problems surrounding the Alzhemed trial. To be honest, while I had hoped for the best, I am not really surprised by the outcome of the Phase III because Alzhemed could not be labeled a "disease-modifying" compound - at the most pathology-modifying.

Second, to recommend the study by Santa-Maria and the group of Jesus Avila, for indicating another problem with the compound, totally overlooked - or rather invisible - in amyloid model mice! Actually, we do not understand tau dynamics well enough yet to predict if the tramiprosate effect on tau will be a problem or not, but it needs to be studied. The study stresses once again the importance of realizing that AD is invariably amyloid and tau pathology combined and the pre-clinical models must reflect that fact.

Third, to congratulate AlzForum for bringing this story and showing us all sides of it.

View all comments by Fred Van Leuven

Unacknowledged in the public dialog surrounding Alzhemed's failure is the virtual certainty that trials of other anti-amyloid strategies that remain hopeful will exclude Alzhemed users.

The desperation of the disease can drive families and carers to make irrational choices. But, Alzhemed "nutraceutical" users, Caveat Emptor: You may unintentionally deny yourselves access to trials of immunotherapies and/or secretase modulators that, unlike Alzhemed/tramiprosate, continue to hold promise for slowing cognitive decline.

View all comments by Samuel Gandy

The decision to market tramiprosate as a supplement is surprising news. It does not speak well of nutraceuticals as a refuge for drugs that fail in clinical trials. From my perspective, it would be okay to fail in a clinical trial if they had compelling biomarker data from humans showing that the drug can really move a target, and established the dosing required to do it. The hippocampal volume data looks promising, but needs its own supplement, perhaps with a CSF biomarker cocktail that includes tau given the report from Avila (see ARF related news story) that the compound can promote tau aggregation. One problem with people self-dosing a nutraceutical is the typical lack of information about the dose required to move an endpoint. And at least they have a dose response on the hippocampal volume, and apparently at least some patients clamoring for more because they thought that it helped them.

The great value with nutraceuticals would be for prevention. There, the clinical endpoint is hard to come by, especially in...  Read more

The decision to market tramiprosate as a supplement is surprising news. It does not speak well of nutraceuticals as a refuge for drugs that fail in clinical trials. From my perspective, it would be okay to fail in a clinical trial if they had compelling biomarker data from humans showing that the drug can really move a target, and established the dosing required to do it. The hippocampal volume data looks promising, but needs its own supplement, perhaps with a CSF biomarker cocktail that includes tau given the report from Avila (see ARF related news story) that the compound can promote tau aggregation. One problem with people self-dosing a nutraceutical is the typical lack of information about the dose required to move an endpoint. And at least they have a dose response on the hippocampal volume, and apparently at least some patients clamoring for more because they thought that it helped them.

The great value with nutraceuticals would be for prevention. There, the clinical endpoint is hard to come by, especially in diseases with long and very expensive trials. Also, insurance may not pay without a diagnosis. So I think you could argue that tramiprosate might work for prevention but not with established AD. In the absence of a convincing clinical trial, tramiprosate needs solid data to show that it moves a panel of biomarkers relevant to pathogenesis. I have been unable to understand how tramiprosate could get into the brain as a charged compound, and not understanding makes me suspicious.

My Alzheimer Center colleagues pointed out that tramiprosate is a modification of taurine. Taurine is a major component of the "energy drink" Red Bull, which is also loaded with caffeine. At SfN, Gary Arendash talked at a news conference about how caffeine is treating his transgenics and is blocking both β- and γ-secretase. So it is beginning to sound like we'll be seeing something like a cross between Red Bull and Rock Star (another energy drink containing ginkgo extract and caffeine) for seniors, Perhaps we should have a naming contest? Combining the last too initials in the cross would tempting, but so far I like Senior Bull.

View all comments by Gregory Cole

Reader advisory: These comments may appeal only to readers of a certain age, who remember black-and-white TV and Richard Nixon.

Sean Silcoff, a reporter for Neurochem’s hometown paper, The Toronto Financial Post, describes the Alzhemed story as playing out like the Monty Python dead parrot sketch, a discussion between a pet store owner and a customer over whether a dead parrot is dead or just resting or stunned.

Neurochem had been going around and around about the vital status of its North American trial, and landed its most recent stunner on November 8, 2007, the essence of which is that since there is no evidence for tramiprosate’s efficacy by any conventional scientific standard, Neurochem will market homotaurine—the amino acid formerly known as the drug tramiprosate—as a food...  Read more

Reader advisory: These comments may appeal only to readers of a certain age, who remember black-and-white TV and Richard Nixon.

Sean Silcoff, a reporter for Neurochem’s hometown paper, The Toronto Financial Post, describes the Alzhemed story as playing out like the Monty Python dead parrot sketch, a discussion between a pet store owner and a customer over whether a dead parrot is dead or just resting or stunned.

Neurochem had been going around and around about the vital status of its North American trial, and landed its most recent stunner on November 8, 2007, the essence of which is that since there is no evidence for tramiprosate’s efficacy by any conventional scientific standard, Neurochem will market homotaurine—the amino acid formerly known as the drug tramiprosate—as a food supplement or nutraceutical so that people with Alzheimer disease can buy it over-the-counter and not be deprived of the drug’s perceived potential benefits that the company touted in prior news releases and presentations.

This may be great news to some, “but wait, there’s more!” as Ron Popeil, the consummate TV purveyor of Veg-O-Matics, might say. According to the Financial Post, Neurochem expects to “scare up US $1 billion-plus sales” selling this nutraceutical and will use the proceeds to develop an effective AD drug, presumably one minimally effective enough that the FDA could actually approve it. In the meantime, people with or without AD can soon take tramiprosate thinking that it will both help them directly and also help fund Neurochem to develop effective future drugs.

One such Neurochem gleam-in-the-eye is the previously unheard-of NRM-8499, said to be a pro-drug of the very “food supplement” they will be selling—inevitably—on their TV infomercials. Neurochem states that NRM-8499 is five times more potent than their “Alzhemed” brand of homotaurine. (This of course begs the question why consumers shouldn’t just buy five times more of the nutraceutical than they would have bought of the prescription drug had it been demonstrated effective). The sales message—to be voiced probably by Hollywood and medical celebrities—could be, “Help Neurochem fight AD as you help yourself.” A Beverly Hills celebrity statistician could make an appearance here, too, because statistical modeling is so much a part of the Alzhemed story.

While they are at it, Neurochem could go further and tithe a portion of their proceeds to the Alzheimer’s Association, gaining a hefty tax credit and stating on each bottle of the Alzhemed brand of homotaurine, “all proceeds to Alzheimer’s charity.”

Even as the company announces that tramiprosate is not worth pursuing as an ethical pharmaceutical product, it continues to imply that there is efficacy to be found somewhere deep within the North American trial data. Seven months after they knew their results, they still speak of “promising results from preliminary post-hoc analysis,” “descriptive data” showing “numerical differences in favor of tramiprosate on the primary clinical endpoints,” “descriptive data also shows…differences between groups on the primary disease modification endpoint of change in the volume of the hippocampus,” or, to further obfuscate, “preliminary post-hoc analysis…that allowed adjustment for potential confounding factors showed a dose-dependent reduction in hippocampal atrophy in patients treated with tramiprosate.” Never mind inferential statistics; facts about efficacy matter less now than they had before for the marketers of a food supplement.

And now for something completely different…(as I am trying to “always look on the bright side....”): Having acknowledged—not by its press spin but by its business actions—that the North American trial did not show efficacy and that the company could not withstand the risks of its European trial, Neurochem might now just put their bird to rest. It should post the North American trials database, statistical analyses, data files, and clinical study report on their website for others to review and analyze. They cannot get FDA approval and by law cannot make specific AD health claims for a food supplement. Any manufacturer can make homotaurine or conceivably extract it from one or another species of algae, so they no longer have a proprietary need to hide the data. Posting the data would provide the best and most transparent support for their press releases. Consumers will be able to examine directly the efficacy evidence and judge for themselves.

Open access to the database and statistical models would allow clarification of the alleged methodological problems that Neurochem enumerates but doesn’t document (e.g., site variability, diagnostic uncertainty, confounding, and metrical issues). It may even allow other methodologists—using other Veg-O-Matics—to find things that may have eluded the Neurochem experts. Academics and advisors to companies and the NIH would learn more about AD clinical trials methods, avoid the repetition of mistakes that might be dooming otherwise effective drugs, and improve future trials methods. This, in turn, might help us to find effective drugs for AD sooner by improving the designs of trials and serve the common good. Of course, other companies and the NIA ADCS should post their clinical trials data, as well, and may do so if Neurochem sets the example. Finally, posting these data and reports would not undermine the publication of a primary paper in any major journal.

I leave it to others to explain why such a modest proposal for companies to share their data from negative trials so that others can benefit would be dead on arrival.

Disclosure: See 14 September 2007 comment.

View all comments by Lon Schneider

These types of press releases and hyped reviews only give false hope to the public. The AD community should be more aware of the impact that such company-driven statements have on the families of those suffering from the disease.

View all comments by Elliott Mufson