Therapeutic focus - Hopes for Alzheimer's placed firmly on A-beta

In what could be a defining period in the development of potential disease-modifying treatments for Alzheimer’s disease, the next two months should reveal pivotal trial results for Elan and Wyeth’s much vaunted bapineuzumab and Myriad Genetics’ Flurizan.

Detailed results from these trials and other candidates will be presented at the Alzheimer's Association International Conference on Alzheimer's Disease (ICAD), starting on July 26th. With astronomical potential sales assigned to these products in recent months, some attracting $8-11bn values, the pressure is clearly on the companies developing these products to deliver positive and conclusive results. EP Vantage assesses their chances.

Symptomatic therapy so far

For a disease classified about 100 years ago, the development of truly disease-modifying therapies has been a long time coming. Current drugs approved for use in Alzheimer’s patients are only capable of treating the symptoms by improving cognition, dominated by acetylcholinesterase inhibitors such as Eisai’s and Pfizer’s Aricept and Novartis’ Exelon.

Sales of acetylcholinesterase inhibitors last year amounted to $4.06bn, representing a 68% share of the overall Alzheimer’s market worth $5.98bn. Critically, all these products are expected to go off-patent within the next five years, the main reason there are no similar symptomatic treatments in development.

Amyloid beta the culprit

Almost all current research and development efforts are therefore focused on agents that may have the ability to delay disease progression. Current scientific consensus strongly suggests that excess levels in the brain of a peptide called amyloid beta (A-beta), especially the version that consists of 42 amino acids (A-beta-42), is the underlying cause of Alzheimer’s.

A-beta, which is thought to be a regulator of synaptic strength, is normally shuttled from the brain into the bloodstream for degradation. The balance between A-beta production in the brain and subsequent clearance therefore determines how much A-beta accumulates in the brain. If production is too high and/or clearance too low, A-beta can accumulate to abnormally high levels, which tend to then aggregate into clusters called “oligomers”. These oligomers precede the creation of senile plaques, or A-beta deposits, which affect communication between nerve cells and can lead to neuronal degeneration and nerve cell death.

It is now accepted that A-beta oligomers are the neurotoxic entities in Alzheimer’s disease and this process is often referred to as the “A-beta hypothesis of AD”.

Dr Sangram Sisodia, a leading expert on Alzheimer’s disease pathology at the University of Chicago, is convinced this hypothesis is sound and that A-beta is a valid target. “Whilst the exact nature of these oligomers is still to be fully defined, A-beta is clearly the toxic species, no question about that.” Confirming that early targeting of A-beta is the key, Dr Sisodia added, “I’m not so enthusiastic about any of the other theories out there, such as Tau pathology or mitochondrial oxidation, mainly because it’s already too late by then.”

Two-pronged attack

Based on this accepted hypothesis, there are therefore two ways to reduce the accumulation of A-beta-42 in the brain: either promote the clearance of A-beta-42 from the brain, or reduce the production of A-beta-42 in the first place.

These two approaches form the backbone of current research into Alzheimer’s, with 30% of pipeline candidates based on the A-beta hypothesis, according to pipeline data from EvaluatePharma. Interestingly, almost half of all pre-clinical projects are focused on A-beta.

Count of products in development for Alzheimer's disease
Phase (current)  A-beta based products  Total Alzheimer's pipeline % of pipeline on focused on A-beta
 Phase III 4 14 29%
 Phase II 4 32 13%
 Phase I 14 50 28%
 Pre-clinical 24 57 42%
 Research project 12 41 29%
Total 58 194 30%

As this analysis is drawn from company-disclosed information about the targets for their Alzheimer’s research, often quite vague in the early stages, the percentage devoted to A-beta is likely to be higher still.

A-beta clearance

Most of these products are based on an immunisation approach to clearing A-beta from the brain. There are two approaches adopted: active vaccination and passive immunisation.

Elan and Wyeth lead the way with active immunisation, stimulating the production of antibodies to A-beta, but they had to stop development of their lead vaccine, AN-1792, in 2002 as some patients developed encephalitis, swelling of the brain, in phase II trials.

The companies therefore switched to the passive immunisation approach, developing antibodies against A-beta, which can then be injected into the bloodstream, to bind to A-beta once it has left the brain, so A-beta cannot re-enter the brain, thus gradually reducing the levels of A-beta in the brain.

Elan and Wyeth’s lead antibody candidate is bapineuzumab, being held up so far as the great white hope for Alzheimer’s, attracting huge peak sales forecasts of $8-11bn if the product demonstrates disease-modifying activity in clinical trials.

Alzheimer's products in clinical development to enable clearance of A-beta WW annual sales ($m)  
Phase (Current)  Product Company Pharmacological Class 2010 2011 2012 Launch WW
Phase III Bapineuzumab (AAB-001) Wyeth Anti-beta amyloid MAb 54 225 488 31/12/2010
  Bapineuzumab (AAB-001) Elan Anti-beta amyloid MAb - - - 31/12/2010
Phase II Gammagard S/D IGIV/KIOVIG Baxter International Immunoglobulin        
  AZD-103 Elan Beta amyloid aggregation inhibitor - - - -
  A beta Antibody Eli Lilly Anti-beta amyloid MAb - - - -
  ACC-001 Elan Beta amyloid vaccine - - - -
  ELND005/AZD-103 Transition Therapeutics Beta amyloid aggregation inhibitor - - - -
Phase I CAD106 Cytos Biotechnology Beta amyloid vaccine - - - -
  R1450 MorphoSys Anti-beta amyloid MAb - - - -
  V950 Merck & Co Alzheimer's disease vaccine - - - -
  CAD106 Novartis Beta amyloid vaccine - - - -
  R1450 Roche Anti-beta amyloid MAb - - - -
  933776 GlaxoSmithKline Alzheimer's disease MAb - - - -
  RN1219/PF-4,360,365 Pfizer Anti-beta amyloid MAb - - - -
  V950 Pfizer Alzheimer's disease vaccine - - - -
* excludes Alzhemed, beta amyloid aggregation inhibitor, developed by Neurochem, but failed phase III trials

These valuations are mightily impressive considering the companies have yet to present any efficacy data on the product, despite already initiating phase III trials in December.

There is some expectation within the market that top-line phase II data will be revealed ahead of the ICAD conference at the end of July, which will be a critical event for both companies, especially Elan, with the drug representing half of its total NPV of $8.96bn. This is still some way short of its current enterprise value of $13.3bn, suggesting the market is expecting a great deal from bapineuzumab.

The lack of data so far means there is still a reasonable level of scepticism from analysts, and the weight of expectation for the drug could be starting to bear on Elan. (See EP Vantage article: Elan nervous ahead of bapineuzumab data?, May 16)

So far, bapineuzumab is the only candidate with this mechanism of action to have been assigned any tangible value from analysts. Consensus forecasts have been gradually upgraded over the last year, now sitting at $488m by 2012, but still significantly risk-adjusted if the massive peak sales numbers are to be realised.

Baxter International is taking a slightly different approach to immunisation. Instead of developing highly-specific antibodies to A-beta, Gammagard is derived from donor plasma, containing lots of antibodies, some of which are expected to be naturally targeted at A-beta.

Baxter announced positive final phase II data in April, the six-month trial demonstrating improved cognition and significantly reduced A-beta levels compared to placebo. Phase III trials are expected later this year.

Another approach to A-beta clearance is Transition Therapeutics’ AZD-103, designed to break down A-beta aggregates. Encouraging phase I data led to Elan licensing the product, who is now conducting phase II trials.

Reducing A-beta production

The compounds in this category are designed to inhibit the enzymes that are required to produce A-beta in the first place, namely gamma-secretase and beta-secretase.

Whilst these enzymes are certainly valid targets, safety concerns remain high as both enzymes are also crucial to process a number of other important proteins, such as notch, the inhibition of which can cause skin cancer.

Leading the way within the gamma-secretase inhibitor class is Myriad Genetics’ Flurizan, which can selectively block the production of the toxic A-beta-42, whilst allowing the generation of A-beta-40, so A-beta can still perform its synaptic strength role.

Alzheimer's products in clinical development to regulate production of A-beta WW annual sales ($m)
Phase (Current) Product Company  Pharmacological Class 2009 2010 2011 2012 Launch WW
Phase III Flurizan (Alzheimer's disease) Myriad Genetics Gamma secretase inhibitor 89 188 310 432 30/06/2009
  LY450139 Eli Lilly Gamma secretase inhibitor - - - 34 31/12/2011
Phase I GSI-953 Wyeth Gamma secretase inhibitor - - - - -
  SRA-444 Wyeth Gamma secretase inhibitor - - - - -
  Gamma secretase inhibitor Bristol-Myers Squibb Gamma secretase inhibitor - - - - -
  E2012 Eisai Gamma secretase inhibitor - - - - -
  CTS-21166 Astellas Pharma Beta secretase (BACE) inhibitor - - - - -
  CTS-21166 CoMentis Beta secretase (BACE) inhibitor - - - - -

Crucial top-line phase III data is due to be released this month, with full details presented at ICAD. As with Elan, these results will provide a crucial event in assessing the product and therefore the biotech’s potential value. Flurizan currently has an NPV of $1.01bn, 63% of the company’s total NPV of $1.73bn, according to EvaluatePharma’s NPV Analyzer. This total NPV is still below Myriad’s current enterprise value of $1.87bn, again suggesting the market is placing a lot of faith in this product delivering positive data and becoming an approvable product.

Dr Rudy Tanzi, a leading expert on Alzheimer's disease genetics at the Massachusetts General Hospital, believes that “given the size of Myriad's phase III trial, there is a good chance that it will reach statistical significance for improvement of cognition on the same scale as Aricept, in which case it could make it to market”. However, Dr Tanzi considers Flurizan to be one of the weaker candidates in its class and its success “would likely only serve to open the door for other more potent gamma secretase modulators in the pipeline at Eisai, TorreyPines Therapeutics, Lilly and others”.

Of the beta-secretase inhibitors, CoMentis’s CTS-21166 is furthest in development in phase I trials. The potential for this drug was highlighted when Astellas Pharma agreed to fork out up to $760m for worldwide rights in April.

Gold-plated eggs

Whilst some candidates might show greater disease-modifying properties than others, most experts believe an integrated approach, using drugs that both clear and reduce A-beta levels in the brain and bloodstream, will provide the smartest strategy in attempting to treat this critical disease.

One thing is clear; the scientific community and biotech companies are placing all their eggs in one basket by focusing so heavily on the A-beta hypothesis. Investors in the companies developing products based around this theory will be hoping this path proves to be the correct one.

If the bapineuzumab and Flurizan data fails to demonstrate suitable efficacy, it will not mean the A-beta hypothesis is dead, but will certainly make investors more nervous and question their chances of success.

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