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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: Twitter: Dereklowe

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March 25, 2013

The FDA's New Alzheimer's Guidance: Wonder or Blunder?

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Posted by Derek

You can get either answer, depending on whom you ask. Last month, the agency unveiled new guidelines for developing Alzheimer's therapies. They're trying to deal with the difficulty of showing actual cognitive improvement in more advanced patients, while at the same time figuring out how to evaluate therapies in early-stage patients who really aren't cognitively impaired yet. It's a worthy problem, for sure, and a good thing to be thinking about. Two of the agency's scientists laid out the thinking in a NEJM editorial:

The current landscape of research and drug development in Alzheimer's disease offers a study in contrasts. On the positive side, numerous discoveries over the past decade have begun to unmask complex pathophysiological processes that underlie disease progression. Such advances have, in part, resulted from large, well-organized observational studies, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), that have elucidated various disease biomarkers that reflect, or even predict, the progression of disease. On the negative side, drug discovery has been disappointing. Despite all best efforts to translate mechanistic insights concerning Alzheimer's disease into new drug products, several candidate agents have failed to demonstrate efficacy in large, well-designed, phase 3 clinical trials of late-stage disease.

That they have, and how. Avoiding these, or at least finding out ways to fail more cheaply, is very much on the minds of everyone working in the field. The New York Times, though, had a rather unexpected fit about the whole idea, culminating in this editorial:

. . .The goal is commendable — to find ways to prevent or slow the progression of this terrible disease before it can rob people of their mental capacities. But the proposal raises troubling questions as to whether the agency would end up approving drugs that provide little or no clinical benefit yet cause harmful side effects in people who take the medications for extended periods. . .

. . .F.D.A. officials say they would never approve drugs based on cognitive effects alone unless absolutely convinced that patients with very early-stage Alzheimer’s that is likely to progress to full-blown dementia could be reliably identified. It will be up to the drug companies or other sponsors of clinical trials to do the convincing.

The F.D.A.’s proposal is open for comment for 60 days. Independent analysts need to look hard at whether the F.D.A. should lower the bar for these drugs — or should demand a very high level of proof of safety and effectiveness before exposing still-healthy people to possible harm. Even if drugs are eventually approved under this new approach, it will be imperative to force manufacturers to conduct follow-up studies, as required by law, to see if patients benefit in the long run. . .

That's not a crazy point of view at all, though - I've worried about something similar myself. But I think that the Times is a bit too worked up over the current FDA guidance. On the other hand, as BioCentury has it in their latest issue (March 25), there are people in the biotech industry who have been talking up the new guidelines as some sort of regulatory breakthrough. "Not So Fast", is the response:

. . .The only reasonable conclusion to be drawn from a careful reading of both the guidance and the commentary is that while FDA would be willing to accelerate approval of AD drugs, the science isn’t there to allow it to do so. . .

The guidance states FDA would grant accelerated approval to a treatment for AD “based on the use of a biomarker as a single primary surrogate efficacy measure” — if a biomarker that reliably predicted clinical benefit existed.

As the guidance notes — and as anyone who follows the field knows — “no reliable evidence exists at the present time that any observed treatment effect on such a measure is reasonably likely to predict ultimate clinical benefit (the standard for accelerated approval), despite a great deal of research interest in understanding the role of biomarkers in AD.”

. . .The process of reaching scientific consensus on an appropriate assessment tool will take years. And no one knows how much longer it will take for regulators to generate sufficient confidence in the tool to use it as the sole basis for approving an AD drug.

I think that's the key part of all this. It's fine that the FDA is open to the idea of biomarkers for Alzheimer's; we're probably going to have to do it that way. But no one knows how to do that yet, and it's not like the agency is just going to pick one of the current measures and tell everyone that that's fine. What I would expect this latest initiative to do, actually, is to end up pushing more money into the hunt for such biomarkers, with perhaps less going to direct shots-on-goal. That's disappointing, from one perspective, but the shots on goal will bankrupt us all at the current rate.

Comments (8) + TrackBacks (0) | Category: Alzheimer's Disease | Regulatory Affairs


1. emjeff on March 25, 2013 11:52 AM writes...

The NY Times need not worry, we are about as close to a good treatment for Alzheimer's as we are to making gold from discarded Diet Coke cans.

Biocentury has it right; this guidance makes it appear that FDA is open to new ideas, but the devil is in the details. Sure they're open to biomarkers - IF they predict outcome and safety. The fact that none currently exist is not mentioned, nor is the amount of evidence that would be required of a sponsor to qualify a biomarker discussed. However, it surely would be easier to just do the clinical trials.

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2. David Borhani on March 25, 2013 11:58 AM writes...

The FDA's new guidance seems, to me, to be an unneeded free rein given to Pharma (i.e., I largely agree with the Times editorial). The devil is in the details.

Current drugs to ameliorate the decline due to (probable) Alzheimer's Disease are not particularly effective. Lowering the bar further would seem to invite more ineffective drugs that, somehow, manage to demonstrate short-term cognitive benefit, while not significantly altering the course of the disease.

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3. David M. on March 25, 2013 2:34 PM writes...

If one look at the definition of dementia, it is cognitive deficits that are necessary and sufficient to explain the decline from a pre-morbid level in social or occupational function.

Dementia was defined CLINICALLY based on observable changes in memory, along with aphasia, apraxia, agnosia, and executive dysfunction. Nothing was known of the pathology, and its progression. The FDA, relying on the clinical definition of Alzheimer's, mandated a co-primary endpoint schema, where benefits in cognition, function, and/or overall clinical effect were required. Cholinergic enhancement was symptomatic in nature, but enhanced cognition enough to make changes in patient function reliably observable in large RCTs. This effectively set the current bar where it is based on the FDA bean counters artificial classification of Mild to Moderate AD based on the MMSE range of 10-20. We now know that AD is a continually progressive disease, where artificial definitions cause you to lose out on the whole picture of the disease.

The main question is: what then happens when you go earlier in the disease, when function is not impaired? We now know that if we control for encoding, a decline in episodic memory that does not normalize to cueing is highly correlated with the presence of Alzheimer's. Add in the presence of a biomarker, and the specificity for AD is very high (International Working Group Criteria, 2010). We also know these patients will progress onward eventually, but early on their function is not impaired.

Forget PRECLINICAL AD (i.e. NIA/AA Criteria, 2011) for now. The FDA has said in EARLY AD, such as MCI/Prodromal described above, or very mild AD, it is dropping the requirement of a co-primary endpoint schema in favor of a single composite endpoint like the CDR-sum-of-boxes. The CDR-SB detects clinically meaningful changes, where changes in cognition are highly correlated to changes in patient function.

These are totally reasonable positions to take, given the ADCS-ADL, CIBIC+, and even IADL scales are not sensitive enough to detect any benefits in patient function that early in the disease. But when function is not impaired, why do you need an improvement in function?

Preclinical AD is a whole another bag of worms, and like everyone else has said, the devil is in the details, and Rusty Katz knew exactly what he was doing.

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4. braintheoryguy on March 26, 2013 10:30 AM writes...

#3: good points. With preclinical AD, a decline in episodic memory function might be a useful marker. For instance, changes in speed, accuracy, or capacity of episodic recall could be measured. Significant decline in these measures would indicate hippocampus and memory problems, primarily. It then becomes just a matter of knowing the right memory components to target, and the best way to measure them.

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5. Lane Simonian on March 26, 2013 3:35 PM writes...

I chalked my last post full of links, so it may still be in the queue. If so, sorry for being repetitive.

The FDA's change of course seems to be a move to accomodate drugs such as Eli Lily's solanezumab which had no effect on patients with moderate Alzheimer's disease and only a slight effect on patients with mild Alzheimer's disease. Solanezumab is now being studied as a possible preventive drug for Alzheimer's disease. The hypothesis is this: amyloid plaques are the cause of Alzheimer's disease and the problem is that too much damage has been done to the brain once amyloid-reducing drugs are given.

The hypothesis is flawed on several levels. For one thing, amyloid plaques contribute to the cause of Alzheimer's disease through increasing the production of peroxynitrites, but anti-amyloid drugs do not reverse the damage already done by peroxynitrites nor do they inhibit the principal pathway to peroxynitrite formation (phospholipase C--protein kinase C--p38 MAPK). It is not that the drugs were given too late; the problem is that they are not the right drugs to either prevent or treat Alzheimer's disease.

Currently the best biomarker for Alzheimer's disease is not amyloid plaques, but myo-inositol. About 20 percent of all cases of Mild Cognitive Impairment adavance to Alzheimer's disease. Myo-inositol is found in high levels in 70 percent of the people who advance to Alzheimer's disease.

Myo-Inositol, N-Acetylaspartate Are Sensitive Biomarkers for Conversion From MCI to Alzheimer's Disease
: Presented at ECR

High glucose levels, high blood pressure (due to high sodium levels) and Down syndrome all increase myo-inositol levels and all are risk factors for Alzheimer's disease. Myo-inositol also inhibits the neuroprotective phosphatidylinositol 3 kinase/AKT pathway (as do presenilin gene mutations, the APOE4 gene, and bisphosphonate osteoporosis drugs such as Fosamax). Myo-inosito thus increases the substrate (phosphatidylinositol 4,5 biphosphate)for phospholipase C. Phospholipase C results in the release of intracellular calcium which stimulates enzymes that result in the formation of amyloid plaques. Plaques alone do not create the levels of peroxynitrites needed to trigger Alzheimer's disease.

Very importantly, the damage done by peroxynitrites in Alzheimer's disease is partially reversible. Methoxyphenols such as eugenol, curcumin, ferulic acid, vanillic acid, syringic acid, sinapic acid, and myricinol are not only effective peroxynitrite scavengers, they also partially reverse the oxidation to receptors involved in short-term memory, sleep, alertness, social recognition, smell, and brain growth. They also partially reverse the nitration of tau proteins allowing for better neurotransmission and the nitration of NMDA receptors limiting inflammation and the death of neurons. With the right natural products or synthetic versions of natural product which increase their absorption, one can delay the onset of Alzheimer's disease and treat it in its early, middle, and even in its latest stages.

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6. Christian Kleineidam on March 29, 2013 9:34 AM writes...

Short time cognitive effects aren't nothing. A person may very well profit from something that produces those short term effects even when the will still get full blown Alzheimers at the same time.

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7. mumtaz elia on April 8, 2013 8:29 PM writes...

from where ican buy this new drug rember for alzheimers

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8. mumtaz elia on April 8, 2013 8:29 PM writes...

from where ican buy this new drug rember for alzheimers

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