Optimism About New Alzheimer's Drugs

Contributed by: Dennis Fortier, President, Medical Care Corporation

A few weeks ago, we wrote about the glimmering ray of hope that had emanated from bad news about potential new Alzheimer's treatments.

Both Bapineuzumab and Solanezumab, the two most progressed new drugs in the development pipeline, had both failed the final stage of their respective clinical trials, and would not be approved by the FDA. However, there was some evidence, and much speculation, that both drugs had shown signs of efficacy in secondary data analyses.

Now, as presented at the American Neurological Association's 2012 annual meeting earlier this week, those secondary analyses have been verified and a newfound optimism has swept the field.

Of course, drug approvals require a massive investment of time and money, and drug companies must always weigh the costs of completing that high risk process, against the benefits they might capture during the few remaining years of the drug's patent life, once the process is completed and the drug is commercialized.

Readers might be surprised to learn that drug companies sometimes abandon effective drugs, if the approval process takes too long and the viable (patent protected) period for recouping their investment is too short. This is the decision that Eli Lilly (Solanezumab) and Pfizer (Bapineuzumab) must now face as they consider the time and cost of next steps to bring these drugs to market.

At this point, there are two encouraging signs that each company might push forward and lobby the FDA for an efficient path to near-term approval.  One is that the Federal government, under the National Alzheimer's Prevention Act, is committed to identifying new treatments for this disease.  The other, is that the Wall Street analysts, ever pessimistic about success of new AD drugs, have pushed Lilly's stock price upwards in the wake of this new information.

New Generation Alzheimer's Drugs: Do They Work?

Contributed by: Dennis Fortier, President, Medical Care Corporation

We've all been hopeful that a new class of Alzheimer's drugs (monoclonal antibodies) would soon bring effective treatment to the growing number of Alzheimer's patients.

The latest approach is based on using antibodies that bind with harmful amyloid protein.  The idea is that the antibodies will be naturally flushed from the body by the immune system, and take the harmful amyloid away as well.

Major trials have now concluded on two such drugs: Bapineuzumab and Solanezumab.  The primary outcome measures of these trials were "improved cognition" and/or "improved function" versus a placebo group.  That is to say, if subjects who took these drugs had either better cognition or better physical ability to perform daily activities, compared to subjects who did not, then the drugs were probably effective enough to be approved by the FDA. On these measures, all trials have failed.

But that is not necessarily the end of the story for either drug.

A secondary analysis, performed on a combination of the data from the multiple Solanezumab trials, shows a small improvement in cognition among treated subjects.  It is a weak signal, but it provides some hope on which to build.  Especially noteworthy is that the positive effect was most evident in the earlier stage patients with healthier brains.

A stronger signal has come from a look at the targeted biomarkers (amyloid and tau proteins) that these drugs target.

Researchers have speculated (and common sense has suggested), that using such drugs to remove amyloid from the brains of subjects who have already suffered a fair amount of brain damage, may not be helpful.  The obvious experiment would be to remove the amyloid at an earlier stage, before brain damage occurs, which is before symptoms of memory loss and other cognitive decline are noted. This makes intuitive sense and is well-aligned with the possible effect detected in the Solanezumab trial on early stage subjects.

As such, a key indictor of the true potential for each drug may be actual measures of amyloid reduction in those subjects who were treated.  Researchers involved in the Bapineuzumab trial announced yesterday that the drug did in fact dramatically reduce amyloid in the brain and spinal fluid of trial subjects.  Similar biomarker data from the Solanezumab trial is expected in the coming weeks.

Overall, we wish that the drugs had produced great improvements in cognition and function.  While those goals were not met, it is encouraging to note that some, small measure of cognitive improvement may have been realized in the Solanezumab trials, and a clear reduction in amyloid protein was seen in the Bapineuzumab trials.

This leaves us with a hopeful hypothesis that, if used on subjects at an earlier stage of Alzheimer's disease, before extensive brain damage has occurred,  either or both drugs may yield more effective treatment than what is currently available.

Alzheimer's Drugs in the Pipeline

Contributed by: Dennis Fortier, President, Medical Care Corporation

Recent history has not been kind to R&D efforts aimed at developing new Alzheimer's drugs.  While four approved drugs can help manage symptoms of the disease, and perhaps slow its progression to a small degree, the field has aggressively pursued new treatments that can significantly slow or stop progression.

These efforts have been hampered by the complexity of the disease and by, what most experts consider, a fairly rudimentary understanding of its pathology.  We understand that Alzheimer's disease manifests as a decline in cognitive function, and that the decline is caused by a loss of brain cells and the connections between them.  We also understand that an accumulation of amyloid proteins in the brain, and a chemical change in Tau proteins (phosphorylation) in the brain, are major factor contributing to that loss of brain cells.

However, the picture becomes less clear when we try to identify the many possible processes that start the pathology.  The answer may be related to cell metabolism, to brain chemistry, to inflammation, or trauma, just to name a few of the leading areas of scientific inquiry.  Probably, a host of these processes interact and lead to a cascade of biological responses along the way.

The questions to which we do not yet have solid answers are: which processes matter most, are they inter-related, and why do they lead to this disruptive outcome?  Without those answers, it is difficult to develop drugs that will target the right process, at an early stage.  It is a very complex problem involving the most complex of organs.

Nonetheless, research persists and scientific efforts are ongoing.  At this point, several promising agents are moving along the pathway in FDA clinical trials.  A good overview of the Alzheimer's pipeline was recently published by Fierce Biotech.  It is slightly technical, and geared toward financial analysts, but it is comprehensive and gives a good foundation of the theory behind each approach.

Intriguing New Insight into Cause of Alzheimer's

Contributed by: Dennis Fortier, President, Medical Care Corporation

As the experts in the field readily acknowledge, they really don't understand Alzheimer's disease very well.  A new hypothesis, based on a recent publication in the Journal of Neuroscience, suggests that previous views and treatment approaches might be aiming at the wrong target.

The dominant theory (the amyloid hypothesis) is that excess accumulation of beta-amyloid, a naturally occurring protein in the brain, aggregates into toxic plaques that disrupt cell function and leads to cognitive decline.  Based on the new research, it is plausible that beta-amyloid is in fact the main culprit, but that it does its damage inside the brain cells, prior to breaking free and accumulating into plaques.

Some of the general press on these findings have described the science as a complete contradiction of the amyloid-hypothesis.  In reality however, it is fairly consistent with one important difference.

The new insight is that beta-amyloid might be causing harm earlier in the biological process than previously believed.  This study suggests that once the beta-amyloid has been dispensed from brain cells and clumps together into a plaque, the damage has already been done. Previously, it has been theorized that the formation of the plaque is the beginning of a toxic biological process.

The implications for treatment are that we should be looking to reduce the presence of beta-amyloid inside the cells, as opposed to clearing it away later, once it has aggregated into a plaque. Fortunately, two of the most promising agents in the FDA pipeline, Bapineuzumab and Solanezumab, are both antibodies that bind to beta-amyloid and clear it away through the natural immune function. It is hoped that one or both of these agents might function at the early, biological stage suggested by this new insight.

Promising Alzheimer's Drugs on the Horizon

Contributed by: Dennis Fortier, President, Medical Care Corporation
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While we often emphasize the importance of non-pharmacologic therapies for treating Alzheimer's disease, more effective drugs could have an enormous, positive impact on our ability to combat its looming threat. A such, here is a brief summary of three of the most promising treatments in the FDA pipeline.

All three of these agents operate on the amyloid hypothesis which holds that, an accumulation of beta-amyloid, a naturally occurring protein in the brain, is the cause of Alzheimer's disease. While two recent trials on agents developed to reduce the production of beta-amyloid have failed, these three are intended to remove beta-amyloid from the brain.

Two similar drugs are Solanezumab and Bapineuzumab. Both are anti-bodies that attach to amyloid and then carry it away when they are flushed out of the body by the immune system. Solanezumab most likely operates outside of the brain which may lead to better tolerance than Bapineuzumab, which had more evidence of efficacy in its earlier stage studies. Each trial is well underway and the first published data should be forthcoming in late 2011 or early 2012.

Gammagard is Baxter's intraveneous immunoglobulin or IVIG, which also relies on removing amyloid through immune system mechanisms. IVIG is already on the market but with no approved claims for treating Alzheimer's disease.

There are certainly other approaches in the pipeline, some of which may bring better results in a shorter time frame than the three highlighted here. But these seem to have the strongest theoretical underpinnings and have bred the most optimism in the scientific community.
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Alzheimer's Drug Development by Eli Lilly

Contributed by: Dennis Fortier, President, Medical Care Corporation
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There seems to be a bit of confusion about the various drug trials currently underway by Eli Lilly. Here is a brief summary of their activity:

The IDENTITY trials are enrolling patients aged 55+ in over 30 countries including the USA. The compound in these studies is a gamma-secretase inhibitor that is hypothesized to reduce the accumulation of amyloid plaques in the brain.

The more recently announced EXPEDITION trials are enrolling patients aged 55+ in 16 countries including the USA. These studies are measuring the potential effects of an anti-amyloid monoclonal antibody (Solanezumab) delivered via intravenous infusion.

More details about each trial including how to inquire about enrolling can be found in this announcement from Eli Lilly.

Solanezumab: Information on the Clinical Trial

Contributed by: Dennis Fortier, President, Medical Care Corporation
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The phase III clinical trial (EXPEDITION2) for Solanezumab is now open and enrolling patients.

Participants must be over the age of 55, be diagnosed with mild to moderate AD, and have an MMSE score of 16 through 26 in addition to a few other criteria (here) related to other health conditions and medications.

This is the third of three interesting drugs in phase III right now (Dimebon and Bapineuzumab) that could take us much closer to effective treatment for Alzheimer's disease.

Solanezumab – Another monoclonal antibody reaches Phase III

Contributed by: David Geldmacher, M.D., Medical Director of the Memory Disorders Clinic at the University of Virginia.
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On May 21, Eli Lilly and Co. announced that a Phase III Trial of their agent solanezumab, also known as LY2062430, would begin enrollment.

In Lilly’s Phase III program, a total of 2000 patients with mild to moderate AD are expected to receive either a 400 mg infusion of solanezumab or a placebo once every four weeks. Each research volunteer will participate over about 19 months. The overall trial is anticipated to be completed in mid 2012.

On first pass, this agent would appear to be similar to bapineuzumab which is already in Phase III trials being carried out by Elan and Wyeth. There are molecular differences between the two monoclonal antibody lines, which suggest that solanezumab acts primarily outside the brain to sequester soluble amyloid beta peptide in the peripheral circulation. If true, this would predict a lower risk for toxic events in the brain, like the vasogenic edema (brain swelling) reported in Elan’s Phase II trials.

On the other hand, a site of action outside the central nervous system might mean lower overall potency. Given the small absolute effects seen with bapineuzumab in its Phase II trial, lower potency would not bode well for solanezumab’s effectiveness. Of course, all anti-amyloid immnunotherapies depend a great deal on the validity of the amyloid hypothesis.

At a practical level, participants in the solanezumab trial will receive infusions every four weeks instead of the quarterly regimen for bapineuzumab. This will triple the risk for infusion related complications, and places a higher burden on patients. If approved under their current regimens, costs of drug administration would also likely favor the agent requiring the fewest number of infusions. However, a dramatically greater effectiveness would go a long way to off-setting increased treatment costs.