Last week Eli Lilly announced that later this year it would start another late-stage (Phase 3) study of its monoclonal antibody, solanezumab, to test whether it can slow the advance of Alzheimer's disease.  A pair of solanezumab Phase 3 trials last year failed to show efficacy in patients with mild-to-moderate stages of the disease.  After much analysis and deliberation, Lilly decided to design this latest study using higher doses of the compound, while enrolling only those patients with mild, early-stage Alzheimer's.

The thinking among Lilly's scientists and a sizeable segment of neurologists is that the buildup of beta-amyloid plaque in the brain is the principal factor in the onset and progression of Alzheimer's.  Lilly's failed studies with solanezumab last year, as well as the failure of an earlier monoclonal antibody belonging to Elan and its two partners, have convinced researchers that they must intervene earlier in the disease process to prevent these beta-amyloid tangles from forming.

Given the enormous sales potential of a truly effective drug for Alzheimer's, it should come as no surprise that other compounds besides Lilly's solanezumab are working their way through the pipeline.  Roche has two monoclonal antibodies while Merck, AstraZeneca, Roche and Takeda have compounds known as BACE inhibitors in clinical development.  BACE is an acronym for beta-amyloid converting enzyme.  It represents another approach based on the hypothesis that beta amyloid is the key to Alzheimer's.

To this point all approaches based on the beta-amyloid hypothesis have the problem that while reducing the buildup of amyloid plaque may slow the progression of Alzheimer's, none of the compounds relying on this approach has demonstrated a dramatic halt, much less a reversal to clinical deterioration.

When pharma companies show payer representatives the response curves for beta-amyloid drugs, the results basically show that the functional and cognitive declines continue even with those therapies, albeit at a slower pace and for longer periods.  The payers, for their part, appear somewhat cool about covering therapies that will slow the deterioration of Alzheimer's only marginally.  A business analyst at one of the pharmas paraphrased the response of payers who told him, "Well, if the beta-amyloid hypothesis is true, then why isn't the response more robust?"

Increasingly payers demand that pharmas pair a biomarker test with their drug before agreeing to cover an expensive new therapy.  Such diagnostic tests can assess which patients stand the greatest likelihood of benefitting from those drugs.  According to another company analyst, "With high-priced drugs like the ones pharmas are developing for Alzheimer's, payers are used to more black and white results, not some esoteric, reduced degradation concept."

The challenge of getting private insurers to pay for a beta-amyloid drug is especially difficult because treatment would need to start on the basis of a PET scan or some other diagnostic well before any loss of memory or other functional capacity becomes noticeable.  Pharma company analysts acknowledge this fact raises the cost exposure of payers by virtue of tripling the potentially treatable population and lengthening the period for which patients will be required to take the medication.  All the pharmas developing beta-amyloid drugs prefer this sort of wide-use, long-term scenario, where a substantial proportion of the entire population would need to start therapy at roughly the age of 60 or 65 and continue on it indefinitely.

Other factors come into play by suggesting that these beta-amyloid drugs may only affect a small piece of the Alzheimer's puzzle.  For example, it seems that while beta-amyloid is usually involved in Alzheimer's disease, that is not always the case.  Moreover, other factors such as tau-type pathologies also seem to play a role in the disease, while behavioral issues such as education and exercise also affect the rate and extent of clinical decline.  Finally, while the BACE inhibitors may be able to suppress amyloid formation without adverse effects in the short term, it remains questionable -- if not doubtful -- whether patients could tolerate the long-term therapy on these drugs that would be required to prevent the disease from progressing.

Although Alzheimer's is a disease that develops over decades, payers take a much shorter view toward the lives they cover.  Consumers move to different private payers on a fairly frequent basis, usually coinciding with employment changes.  That makes payers hesitant to cover therapy costs for people with only preclinical indicators because they figure the coverage will benefit a subsequent payer such as Medicare.  For this reason payers have strongly hinted they would be likely to put step therapy controls in place as a means of discouraging widespread preventive use.  Other payers even raised the prospect of differential copays for people with family histories of Alzheimer's.

The beta-amyloid hypothesis is the subject of enormous controversy within the neuroscience research community.  That means while a company can develop an accurate test for the early buildup of amyloid plaque, if payers consider the test to be expensive, they may not be willing to pay for it.  Without positive results from a diagnostic test, their likelihood of paying for the medication remains even smaller.

Despite these obstacles, if the beta-amyloid products are able to gain regulatory approval, the public clamor to make them accessible would be enormous.  Payers reimburse for current Alzheimer's products such as Aricept and Nimenda, even though most neurologists admit they prescribe them mainly to appease the patient's family rather than to benefit the patient herself.

The reluctance to pay for warding off a condition or reducing risk for a subsequent payer represents one of the key limitations of making health care subject to the profit-seeking requirements of corporations in three separate sectors: manufacturing, insurance and health care practice.

There are many other limitations besides those relating to drug development.  One of them involves what policy analysts call the problem of "unaligned redundancy."  A prime example of that concerns the difficulty of developing a national patient database.  The hundreds of payers and providers in this country use database systems that are incompatible with one another.  IT experts claim they may be able to resolve those differences by the end of this decade but, meanwhile, Canada already has a national patient database because its provincial governments that pay for health care have agreed on a common technology system.

In Alzheimer's it appears that researchers must complete substantially more work in basic science to understand the fundamental disease process.  That means the question facing Merck, Lilly and the other pharmas with beta-amyloid compounds in their pipelines is whether they want to spend another four to seven years and billions of dollars developing products that can be obsolesced shortly after approval.

If the past offers a guide, these pharmas probably figure they can get their products to market before basic science research uncovers the definitive pathway.  Even at that point, any clinical development based on a thorough understanding of the Alzheimer's process would require many more years to develop a truly effective drug.  In the meantime the marginally effective BACEs and MAb's can still make a ton of money in their role as pacifiers for patients' families.

Such are the vagaries of developing and distributing effective therapies in a profit-seeking health care system.  The profit objectives of drug developers and distributors must mesh with those of insurers and medical providers.  Even when they're working in synch with one another, that usually means we'll pay more for what we get than other countries.  The quality of our care and its accessibility often leave much to be desired.

Of course, private enterprise needn't be the adversary of good health care.  For example, France's health care system relies on profit-making corporations and, by most accounts, they enjoy the finest health care in the world.  Yet when the government there recently announced that it would reduce some medical benefits because the country's 11 percent unemployment rate is straining the national budget, few Europeans seriously doubted that France will still have the world's best health care system after those cuts take effect.

By starting from a premise that health care constitutes a national right for its citizens which is more important than corporate profit, they can get to a cost-effective system a lot more easily than the US.

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