All Eyes are on Medicare

  

            When the FDA approved Biogen’s new Alzheimer’s drug, aducanumab (brand name Aduhelm) on June 7, the reaction was surprise, dismay and, in some quarters, enthusiasm. But everyone was shocked by the drug company’s audacity in setting the price for the medication at $56,000 per year. As one STAT article put it, the only question about the consequences for Medicare, the insurer for close to 97 percent of Alzheimer’s sufferers, was whether the impact would be big, huge, or catastrophic. 

Pharmaceutical manufacturers figured out some time ago that they could bring out “specialty drugs,” typically targeted against a single relatively rare disease, if they charged ten or even a hundred times more than for an average medication. The list price of crizotinib (brand name Xalkori), for example, used against a relatively uncommon type of lung cancer found in non-smokers, is just under $20,000 for a one-month supply—and patients usually take the drug until they die or develop resistance to it. But aducanumab is intended for all people with Alzheimer’s disease, and according to recent Alzheimer Association estimates, that means 6.2 million people over age 65.

            The high price is especially disturbing because it’s not even clear that the drug works. A number of studies have been carried out with similar drugs, other monoclonal antibodies that, like aducanumab, were designed to mop up abnormal brain amyloid deposits, which are the hallmark of Alzheimer’s disease—but none of those drugs proved helpful in practice. The trials of aducanumab were likewise discontinued because interim analysis showed the drug was ineffective. Then, in a surprise move, the manufacturer nonetheless applied to the FDA for approval after a reanalysis of the data showed some evidence of benefit when the drug is given in high doses. The independent scientific review panel convened by the FDA to evaluate the data was not convinced, however, with 10 out of 11 members rejecting approval and one abstaining—but the FDA nonetheless approved the drug.

            Even if aducanumab does work, “work” means slowing the rate of decline slightly, not stopping or reversing the disease process. And the potential side effects of the drug are considerable: 40 percent of patients experienced brain swelling, in some cases of sufficient magnitude to cause nausea, vomiting, confusion, or visual changes. 

            Patients and their families, who are desperate for an effective drug against this progressive, ultimately fatal disease, are eager to try something with promise, anything. But they are worried about the side effects of aducanamab, about the need for regular MRI scans to monitor for those effects, and about its high cost.

            Most critiques of the new drug—and there are many, the NY Times alone has published eight articles on the subject between June 7, when the FDA announced approval of the drug, and July 9 , and STAT has published at least 16—assume that since it has been approved by the FDA it will necessarily be paid for by health insurers. In the case of aducanumab, that will principally be Medicare. In fact, CMS is not obligated to provide coverage for the drug just because the FDA approved it.

            Medicare, like all other health insurance companies, can decide what tests, procedures, and treatments it will cover. The relevant part of Medicare that will be responsible for paying for aducanamab, if Medicare covers the drug, will be Part B: oral medications fall within the jurisdiction of Medicare Part D plans (prescription drug plans), but medications administered intravenously in a physician’s office, such as aducanumab, fall under Medicare Part B. Most determinations of whether to provide coverage for this kind of treatment are made locally, by the private carriers that process Medicare claims. But the decision about coverage can be made nationally if requested by CMS, by the manufacturer, or by members of the medical profession, in which case the decision becomes binding on all the private carriers. Such “National Coverage Decisions” are reviewed by an internal arm of CMS, the Special Coverage and Analysis Group. For particularly controversial decisions, especially if they have social or ethical implications, CMS may request the guidance of the quasi-independent committee, MEDCAC, the Medical Evidence Development and Coverage Advisory Committee. This is a group of 100 experts including economists, ethicists, physicians, scientists and others, from whom a subgroup of 15 is selected to provide in-depth analysis on the particular test or treatment under consideration. 

            Since its inception, MEDCAC (or its predecessor, the Medicare Coverage Advisory Committee), has issued 348 National Coverage Decisions. These comprehensive analyses have addressed topics as diverse as cardiac pacemakers, Pap smears, and lipid testing. On rare occasions, they have dealt with drugs, for example, an intravenous medicine used in the treatment of heart failure, Nesitiride. When MEDCAC deliberates Medicare coverage for a particular intervention, it can recommend covering the intervention, not covering it, or restricting its use in specific ways. For instance, it advocated coverage of the Left Ventricular Assist Device, an invasive treatment that is almost but not quite an artificial heart, but it required a detailed informed consent process that included a social worker and palliative care expert along with the patient, family, and cardiac surgeon. Ultimately, Medicare approved coverage for the device but set reimbursement at $70,000 (the manufacturer’s price was closer to $200,000) and limited insertion of the device to a handful of medical centers across the country. 

            Medicare is required by federal law to provide coverage for anything that is “reasonable and necessary” for “the diagnosis or treatment of an illness or injury.” Despite years of often contentious debate, there is no precise definition of what this means. The FDA, by contrast, approves drugs and devices if they are “safe and effective.” In the case of aducanumab, it is arguable whether the drug is truly safe and effective, but surely it would be reasonable and necessary for Medicare to restrict the use of aducanumab to early disease (the only group in whom it was tested) and to require an elaborate informed consent process. While Medicare, by established custom, does not reject coverage based on cost-benefit analysis, it could set the price at a level comparable to those of the existing, only marginally beneficial drug treatments for Alzheimer’s disease, drugs such as rivastigmine (brand name Exelon, which has a yearly retail cost, when given as the brand name drug, of $823) and donepezil (brand name Aricept, which has a yearly retail cost, when given as the brand name drug, of $5380).

            Given the controversy swelling around Biogen’s new Alzheimer’s drug, the case for Medicare initiating the National Coverage Decision process is strong. The only reason for failing to do so is external pressure, whether by the manufacturer, by members of Congress under the influence of the pharmaceutical industry, or by the public. If CMS opts against this path or convenes MEDCAC only to reject its advice,* as the FDA did with its advisory committee, that would be a compelling reason to make CMS an independent agency, along the lines of the National Science Foundation, that is under control of a bipartisan board and whose director is independent of the President.

 

            *Between when this essay was drafted on July 9 and edited for publication today, CMS has in fact decided to proceed with a National Coverage Decision.

Deja Vu All Over Again?

 

The big news in geriatrics this week was the FDA  approval granted to a drug against Alzheimer's disease, the first new drug in 20 years. It reminded me of the day in 1986 when the initial report about what would be the very first FDA-approved drug against this disease appeared.

It was November 13, 1986 and I had been a practicing geriatrician for four years. My weekly copy of the New England Journal of Medicine had arrived right on time, as it did every Thursday. I scanned the table of contents and one article immediately jumped out at me. It had the suitably serious, scientific-sounding title “Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.”

 

During four years  of clinical practice—plus a year of geriatrics fellowship and three years doing an internal medicine residency—I had encountered patients with what we then called “SDAT,” (senile dementia of the Alzheimer’s type) and which we now simple call Alzheimer’s disease. The cognitive impairments of dementia were to me, to family members of the afflicted, and often to the affected themselves, among the saddest of the many disorders that develop among older individuals. Death, while also very sad, was part of the natural order of things, especially when it came after a long and rich life. But dementia in general and Alzheimer’s disease in particular was devastating because it attacked personality; some would say it assaulted personhood itself. While I would go on to spend much of my career thinking about how best to enable people with dementia (as well as those with physical frailty) to live meaningful lives despite their limitations, I recognized then and continue to believe today that the condition is a scourge that we should strive to prevent, eradicate, or at least ameliorate.

 

The medication described in the 1986 NEJM article would ultimately be approved by the FDA under the name of Tacrine for treatment of mild to moderate Alzheimer’s disease; it would be supplanted by its first cousin, the drug donepezil, brand name Aricept; and Aricept would top $2 billion in US sales by the time it came off patent in 2013. The story of the drug’s development says volumes about Americans’ desperation for a medical fix to Alzheimer’s, about big business, and about our regulatory system. Both the similarities and the differences between the Tacrine story and the tale of the new drug approved by the FDA for the treatment of Alzheimer’s are illuminating.

That 1986 study ostensibly showing that Tacrine led to improvements in cognition as well as to overall functioning was based on a whopping 17 patients, only 14 of whom actually completed the study. Its lead author was Dr. William Summers, a psychiatrist at UCLA medical center who had never before published anything of importance and had done very little research altogether. The scientific community immediately began questioning not only Summers’ credibility but also his methodology. Did the 17 patients actually have compelling evidence of an Alzheimer’s diagnosis? Did the “global assessment rating” used to measure outcomes translate into meaningful improvement?

 

After Summers filed for FDA approval for his drug,the FDA investigated Summers and his lab. The agency issued a rare “interim report” in 1991 in which it criticized Summers for the absence of documentation that the study was actually performed as  claimed in the NEJM  paper.  It questioned the randomization process and whether the physicians were, as asserted by Summers, blinded to what drug the patient was receiving. The best the FDA could say was that there was “no clear evidence of purposeful misrepresentation.”

 

In response, the public vilified the FDA, claiming the agency was “heartlessly impeding the relief of suffering.” David Kessler, the FDA director, received hate mail.

 

Approval of the drug came, but only after the release in 1992 of a larger more carefully conducted study by the “Tacrine Collaborative.” The trial lasted for 12 weeks and was carried out at 23 centers involving 468 patients. The results, published in the Journal of the American Medical Association, showed a statistically significant improvement in cognition and in overall function, whether measured by physicians or caregivers. And so, the first drug was approved for treatment of Alzheimer’s disease. Sales soared.  But questions continued to plague use of the drug—a subsequent study, for example, testing the effectiveness of a higher dose of the drug,  found that the higher dose was more effective than lower doses—but more than 2/3 of the patients dropped out of the study. Tacrine was soon effectively replaced by donepezil (Aricept), another cholinesterase inhibitor that differed only from Tacrine in that it is taken once a day rather than twice and has fewer gastrointestinal side effects. Patients and families demanded these drugs, which were soon followed by chemically slightly different but no more effective agents such as Excelon; the drug companies advertised them widely and made a small fortune on their  sales; but clinicians remained skeptical. I, for one, believe that the cholinesterase inhibitors are next to useless. None of the numerous studies of the drugs carried out since 1986 have persuaded me otherwise.

 

Fast forward to 2021 and the approval by the FDA of aducanumab under the brand name of Aduhelm. This is a completely different kind of treatment. Tacrine and Aricept are cholinesterase-inhibitors: they work by increasing the level of the neurotransmitter, acetylcholine, which is dramatically reduced in Alzheimer’s. They are given orally and were never terribly expensive, although Aricept got cheaper when the generic version became available. Side effects, particularly in the case of Aricept, are modest and consist of nausea and very rarely of liver enzyme abnormalities.  The new drug, by contrast, is a monoclonal antibody that works to mop up deposits of beta-amyloid from the brain, the chemical widely thought to cause Alzheimer’s disease. It must be given intravenously once a month. The average yearly cost will be set at $56,000. Two years ago, its manufacturer, Biogen, stopped an ongoing clinical trial of the drug after interim analysis failed to demonstrate efficacy. The drug company then re-analyzed the data and claimed it was effective after all, but an FDA Advisory Panel, convened in  November, 2020 unanimously concluded there was insufficient evidence of significant benefit to proceed. 

 

Multiple other monoclonal antibodies targeting beta amyloid have also failed, leading some to suggest that by the time these drugs are given to patients, it’s already too late. Or maybe beta amyloid is a marker for the disease and not the cause of the disease. It is in this setting, that the FDA approval of aducanumab is something of a surprise.

What is particularly striking about today’s FDA approval is that it is not based on the clinical effectiveness of the drug. Rather, it is based on its ability to clear the brain of amyloid deposits. There is a long tradition of requiring that drugs cause improvement in clinically meaningful outcomes, not just in “surrogate markers.” Cholesterol-lowering drugs were approved based on their ability to prevent heart attacks, not just on their ability to lower blood cholesterol levels. Antihypertensive drugs were approved based on their effectiveness in reducing strokes, not just on their capacity to lower blood pressure. To be sure, the FDA is holding off on full, unconditional approval until it sees the results of a yet to be performed large clinical trial demonstrating long-term benefit of amyloid plaque reduction. In the meantime, anxious patients and their families will submit to monthly injections of a drug that has been shown to cause symptomatic brain swelling, manifested by nausea, vomiting, visual problems, headaches and sometimes small strokes, in 40 percent of cases. 

We are a long way from the trials and tribulations of tacrine, but in the end, is the tale of aducanumab any less disturbing? In both cases, there was enormous pressure by the public to approve a drug that offered hope, some hope, however slim, of ameliorating this terrible disease. In both cases, the FDA, after seemingly acting based on scientific considerations alone, seemed to succumb to external pressures. And in both cases, the pharmaceutical industry stood to gain enormously by release of the drug. The FDA currently has an acting director: President Biden has yet to name a new, permanent head. Maybe it's time for the FDA director to become a civil servant, selected by the FDA members, rather than a political appointee. At the very least, the new director, when chosen, should take a long hard look at decision-making within the organization.

Have We Been Barking Up the Wrong Tree?

More of my blog posts deal with dementia than with any other subject and the news about Alzheimer’s disease over the years has been largely dispiriting, so who would have thought that I would leap at the opportunity to write about a new diagnostic test. But with so much of the medical literature relentlessly focused on COVID-19, it’s reassuring to realize that research on other subjects is continuing. The new study does not report a treatment, let alone a cure for Alzheimer’s disease. Furthermore, the prospect of screening healthy individuals to determine their future risk of developing progressive cognitive impairment is ethically fraught. Nonetheless, in the current climate, this report is good news.

It’s good news, and not just because it indicates that not all medical scientists have retooled as corona virus researchers, though it does that. It’s good news, and not just because it means it will be possible to target intervention studies to high risk individuals will permit studies to be carried out on smaller numbers of people and over a shorter period of time, though it means that. It’s good news because it shines a bright light on a long-neglected character in the Alzheimer’s story, the tau protein. 

Back in 1906, when Alois Alzheimer peered into his microscope at tissue from the brain of a patient who had died of the disorder of cognition that would one day bear his name, he identified two unusual substances that he described as plaques and tangles. The plaques, which were located between neurons, would ultimately be found to be composed of a protein known as amyloid. The neurofibrillary tangles, which were located inside the nerve cell bodies, would eventually be identified as a protein called tau. These two substances have been recognized as the hallmarks of Alzheimer’s disease for over a century.

For years, the roles of amyloid and tau were hotly debated. Some researchers felt that amyloid was the result of Alzheimer’s; others were confident it was the cause. Some scientists were more interested in studying amyloid; others directed their efforts towards tau. But over the course of the last 25 years, amyloid has gained the upper hand. Study after study has sought to improve cognition in Alzheimer’s disease by ridding the brain of amyloid-laden plaques—and each time, the approach failed. 

A great deal of excitement was engendered by immunotherapy back in 2001: the idea was to stimulate the body to create antibodies against amyloid with what was essentially a vaccine—but the study had to be stopped because a subset of patients developed meningitis. Then there was enthusiasm about the use of monoclonal antibodies. Several such antibodies have made it to phase 3 trials in which their efficacy was compared to placebo. In 2014, two studies of Bapineuzumab showed no benefit. In 2018, Solznezumab was tried for individuals with mild Alzheimer’s and it was unsuccessful. In the same year, additional negative results were reported for Verubecestat in people with mild to moderate Alzheimer’s. 

All these negative studies don’t exonerate amyloid. Maybe the trials are initiated too late in the course of these disease’s development. Maybe the dose is too low. But with anti-amyloid strategies repeatedly striking out, I can’t help but wonder, as have others who know much more about the science than I do, that we’re looking at the wrong target.

Which is why the new study that focuses on tau is exciting. The authors found that their tau antibody test was able to diagnose Alzheimer’s disease as well as or better than more invasive existing tests—when they used the test in patients all of whom had some kind of neurodegenerative disease. That is, the test did well in answering the question: is this person being tested more likely to have Alzheimer’s or, say, Parkinson’s? That’s a very different question from: is this person normal or does he have Alzheimer’s? Not only was the population in which the test was studied composed exclusively of patients with some neurologic condition, not only did the population include a much larger proportion of people with Alzheimer’s than would be found in the general population, but the subjects were far from ethnically or racially diverse. So, it’s a long way from the article in JAMA to a widely useful diagnostic test.

Despite the test’s preliminary nature, it is a compelling piece of evidence that tau should get more attention. Two weeks before the on-line publication of the JAMA study, a small Swiss pharmaceutical company, AC Immune, announced that together with Johnson & Johnson, it was launching a trial of a vaccine designed to stimulate the body to produce antibodies against tau—leading its stock price to soar by 18.9 percent. Just a few weeks earlier, the giant Swiss pharmaceutical company, Roche, announced it, too, was investing in the development of an anti-tau vaccine. 

It’s too early to say whether the attack on tau will fizzle, much like the previous attacks on amyloid. But maybe, just maybe, it will be a rousing success.

Rescinding the DNR order--for anti-amyloid drugs

The pharmaceutical firm Biogen issued a stunning press release this week: it would seek FDA approval for its anti-Alzheimer’s drug, Aducanumab—the very same drug the company had pronounced a failure just last March, after preliminary analyses indicated the drug was very unlikely to achieve its objectives. Dennis Selkoe, a prominent Alzheimer’s researcher at the Brigham and Women’s Hospital in Boston, wrote in STAT (a health-oriented news website owned by the Boston Globe) that he believed that “aducanumab is the breakthrough we have been waiting for.” But is it?

Aducanumab is by no means the first drug studied that targets beta amyloid, a protein widely believed to play an important role in the development of Alzheimer’s disease. An article in Nature Reviews (Drug Discovery), published shortly after the first analysis of the Aducanumab data, put the drug in perspective: a monoclonal antibody that binds to beta amyloid, it is the fourth such drug to make it to a Stage III clinical trial. And all three of its predecessors, as well as another five anti-amyloid drugs that have a different mechanism of action, were abysmal failures leading Nature Reviews to proclaim "Anti-Amyloid Failures Stack Up as Alzheimer's Antibody Flops." Maybe what this new analysis of the Aducanumab data has done is to reverse the Do-Not-Resuscitate label previously attached to monoclonal antibodies and instead put them on life support. So, what, exactly, does the new data analysis show? 

The details will be released to the FDA when Biogen files with the FDA to approve the drug. Thus far what we know is what Biogen has included in its press release. Biogen conducted two randomized, double blind, controlled studies, giving the monoclonal antibody (presumably by injection, like other monoclonal antibodies) or placebo to a total of 3285 patients and following them, some for 78 weeks. One study, sporting the acronym ENGAGE, produced negative results even upon re-analysis, although a subset of ENGAGE patients who received a high dose of the drug appeared to respond. The other study, named EMERGE, showed a reduction in the rate of clinical decline in treated patients compared to those receiving placebo. In other words, the study patients did not improve nor did they plateau; rather, they got worse more slowly. Unfortunately, the press release doesn’t report the absolute magnitude of the change, opting instead to say that the scores on the Mini-Mental State Examination (MMSE), a commonly used measure of cognition, fell 15 percent less with treatment than with placebo. Similarly, the rating on the ADAS-Cog13, another measure of cognitive function, declined 27 percent less in those on the drug. Finally, and perhaps most encouragingly, the decline in the ability to perform basic daily tasks (as measured by the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory) was 40 percent lower in those receiving Aducanumab than in their counterparts who received placebo. 

These are not spectacularly impressive results—the patients continued to worsen and the difference between treated individuals and untreated individuals, at least on measures such as the MMSE, was very small. But what we don’t know is whether the slowed rate of decline will persist over time or whether, as with drugs that are currently on the market such as donepezil (Aricept), there is a one-time effect. We don’t know whether the effect would be greater if the medication were used earlier in the progression of Alzheimer’s disease, perhaps in people with mild cognitive impairment. We don’t know whether the drug will prove to be more effective in those with “pure” Alzheimer’s disease, that is, without concurrent vascular changes. 

What we can predict is that if the drug is approved by the FDA, Biogen, whose stock price soared after the press release, will aggressively market the drug. An estimated 5.8 million Americans have Alzheimer’s disease, according to Alzheimer’s Association statistics released in 2019: since the time from diagnosis to death is 5-7 years, roughly one-fifth of the affected individuals or over a million people likely have early Alzheimer’s and are potential Aducanumab consumers. This could be a dream come true for the pharmaceutical company--a blockbuster specialty drug. (Blockbuster drugs are prescribed to at least one million people a year and specialty drugs are very expensive biologicals such as monoclonal antibodies). And if the sales price for the drug is anything like that of other newly marketed monoclonal antibodies, it may be upwards of $1000 per month (Dupilumab, brand name Dupixent, a new monoclonal antibody used in the treatment of asthma and/or nasal polyps, has a list price of $37,000 per year). 

Biogen stockholders will benefit enormously; how much people with Alzheimer’s disease will benefit is less clear. But on a more positive note, as Dennis Selkoe commented in STAT, for the first time we have evidence that it is possible both to design molecules that target amyloid and to administer them to real people with minimal toxicity and some evidence of benefit. That truly is good news.

Clearing the Air

I’ve been reading “The Uninhabitable Earth: Life After Warming,” an extensively researched account of where we are headed that begins with the warning: “It is much, much worse than you think.” When I got to the chapter depressingly entitled “Unbreathable Air,” I encountered the following shocking sentence: “Pollution has been linked with increased mental illness in children and the likelihood of dementia in adults.” Now I’ve seen all kinds of things associated with dementia: head trauma, assorted medications (anticholinergic drugs, anti-anxiety drugs, and anti-ulcer drugs), aluminum. Some of those links have become well-established over time, such as head trauma. Some of have been totally debunked, such as aluminum. Others are questionable and I’ve written about them on this blog (drugs). But air pollution? This was a new one to me. 

Most likely, I figured, it would prove to be another spurious association. Probably, I thought, there was some other factor that was associated with both air pollution and dementia. The alleged connection would be like the link between washing machines and colon cancer—a favorite example of a “confounder” from my medical school epidemiology class. People who own washing machines, it turns out, do have a higher rate of colon cancer than people who don’t. But they also vary in where they live and what they eat, which is far more important than their possessing a washing machine. Surely air pollution was likewise a marker for something that did matter. But then, as I read on in Wallace’s book, I came to an even more dramatic statement: “An enormous study in Taiwan found that, for every single unit of additional air pollution, the relative risk of Alzheimer’s doubled.” This I had to look into.

The “enormous study in Taiwan” was published in a minor but respectable journal, the Journal of Alzheimer’s Disease in 2015. It was large: it was a cohort study of 95,690 adults aged 65 and older followed prospectively for 10 years beginning in 2001. Not only was it large, but it was a random sample drawn from Taiwan’s National Insurance Research Database comprised of 23 million people, or 99 percent of the entire Taiwanese population. Moreover, Taiwan has 70 EPA monitoring stations distributed over the island, allowing it to have reasonably accurate measures of both ozone exposure and small (less than 2.5 micrometers) particulate measure. Finally, the population is fairly stable over time, allowing for fairly good estimates of exposure based on home address. The conclusion? The risk of newly diagnosed Alzheimer’s disease (adjusting relevant co-morbidities such as stroke, hypertension, and diabetes) rose steadily with the rate of exposure to ozone or small particulate matter—going up, for example by 211 percent for each 10.91 ppb increase in ozone.

Taiwan isn’t the only place where a relationship between air pollution and dementia has been discovered. In 2017, a similar study entitled “Exposure to Ambient Air Pollution and the Incidence of Dementia: A Cohort Study,” appeared in Environmental International. Carried out in Ontario, Canada and involving a cohort of just over two million adults, this analysis attributed just over six percent of all dementia cases to air pollution. 

Neither study is conclusive, but they’re awfully suggestive. I wondered if there had been any further work on this subject since Wallace wrote his book. Lo and behold, a systematic review was just published by Peters et al from Australia, also in the Journal of Alzheimer’s Disease. These authors found thirteen reasonably well-conducted studies bearing on the question. They concluded that small particulate matter (containing nitrogen) and carbon monoxide are both associated with an increased risk of dementia. 

These reports are very disturbing in light of the Trump administration’s systematic assault on air pollution regulation. According to an article just published in the New York Times, 85 environmental rules are being rolled back, including 24 in the arena of air pollution. Of these 24, 10 have already been undone and another 14 are “in process.” 

We already know that climate change will have an enormous impact on health, principally through its multitudinous indirect effects—for example, by causing drought, which in turn affects agricultural productivity, which in turn results in death. Now there may be another health risk to add to the list of adverse effects of environmental harm. Dementia is such an enormous public health problem that even measures that only slightly affect the risk of developing this devastating condition may be worthwhile. But the good news is that air pollution is an area where we can intervene. We even know how to. The last thing we should be doing is unraveling the progress we have made. So, speak up, tell your senators and representatives to act, and vote wisely to decrease the pollution that threatens us all.

Treatment for Alzheimer's or False Alarm?

The most promising treatment of Alzheimer’s disease to date uses monoclonal antibodies to rid the brain of amyloid plaques. These plaques are widely thought to be crucial in the development of Alzheimer’s disease, the form of dementia that afflicts over 5 million Americans—and, unless we find a way to cure or prevent it, will afflict millions more in the coming years. Researchers hope that these drugs will prove to be “disease-modifying,” that they will disrupt the cascade of events that produces the symptoms of the disease. 

So far, the studies of monoclonal antibodies in this setting have been very disappointing: Bapinezumab: 3 failed trials. Solanezumab: 3 failed trials. Crenezumab: 1 failed trial. In the past year, three major pharmaceutical companies, Eli Lilly, AstraZeneca, and Merck, all stopped development of the monoclonal antibodies they were testing against Alzheimer’s disease. Another company, Pfizer, closed its neurodegenerative disease research section entirely. Now we learn that a Phase II trial of the as yet unnamed agent “BAN2401” actually “looks promising.” How promising?

Like its cousins, BAN2401 is a “humanized monoclonal antibody.” That means an antibody that was developed in mice and modified so it wouldn’t be rejected as alien by the human immune system. Now mice don’t normally get Alzheimer’s disease but certain strains have been genetically engineered so that they do. Using the genetically engineered mouse model, a monoclonal antibody was created that binds to amyloid. Today, this chemical is called BAN2401; when it enters the next stage of assessment, it will presumably acquire a name that ends in “zumab” to indicate it is just such a humanized monoclonal antibody. So, what do we know about this nameless entity?

We know that BAN2401 made it through a Phase I trial that tested its safety, tolerability, and pharmacokinetics in 80 people with mild to moderate dementia. We know it then entered Phase II of testing in people aged 50-90 with evidence of amyloid on their PET scans and either mild Alzheimer’s disease or mild cognitive impairment (a condition that is not dementia but often evolves into dementia). Five different dose regimens were administered intravenously and compared to placebo in terms of their effects on cognition and on brain amyloid deposits on PET scan. We know that when the preliminary results were announced last December, no cognitive benefit was reported. But now, after 18 months of study, the final results are in. They were presented at the Alzheimer’s Association International Conference in Chicago this past week.

What we don’t know is how this study will fare when subjected to peer review. We don’t know what the final paper will look like. But here’s what I can glean from the press release by Eisai, the company that collaborated with Biogen to develop and test the drug, and the reports by the news media:

--The amount of amyloid in the brain (as measured by PET scan) decreased with all the doses tested. The more drug, the greater the change. The findings were statistically significant. 

--There was no discernible effect on cognitive function except in the 161 people who were treated with the highest dose of BAN2401. In those 161 people, cognitive function deteriorated over time, just as it did in all the other groups, but it deteriorated less.

--Cognitive function was measured in a way that differs from the way it has been measured in other studies of treatments for Alzheimer’s disease. The researchers used a composite measure made up of several scales, each of which has been individually validated as a way to assess mental status, but only one of which is regularly used to report the outcome of clinical trials of Alzheimer’s drugs. 

--The patients tested included a mix of people with mild dementia and people with mild cognitive impairment (who don’t actually have dementia but aren’t entirely normal either) and the study had no way to determine whether the effectiveness of BAN2401 was any different in the two subgroups.

What does all this mean? The PET scan changes indicate that the monoclonal antibodies were successful in destroying amyloid deposits in the brain. That doesn’t prove that whatever effect the drug had was due to its amyloid-busting, but it’s suggestive. It also indicates that to the extent that the drug was a failure, it wasn’t a failure because it didn’t destroy amyloid. 

How should we interpret the cognitive changes? It’s hard to know, given that the researchers used a non-standard means of measuring clinical decline (a test they called ADCOMS). We cannot, for example, say that BAN2401 is better than one of the other monoclonal antibodies that was deemed a failure since nobody looked at the effect of the other drug on the “ADCOMS.” What we can say is that a 30 percent change in the rate of decline may be statistically significant but clinically, it’s a lot less impressive. Everyone  deteriorated, including those given the highest dose regimen; they just deteriorated a little less. How much of a difference actually occurred depends on the absolute decline: suppose the score went from 100 at baseline to 80 at the end of the study in the controls (I don’t know what the actual numbers are, so this is hypothetical). A 30 percent difference in the rate of decline means that the score in the treated group dropped from 100 to 86.  Is that clinically meaningful? Probably not.

So, no, BAN2401 is not likely to likely to dramatically change the course of Alzheimer’s disease. I hope the FDA does not allow the drug’s manufacturers catapult it into a clinical trial prematurely, before it goes through Phase 3 testing. But it has taught us a few valuable lessons. 

We now know that monoclonal antibodies can be designed that destroy amyloid plaques in the brain. We know that only the highest tolerated dose of the drug has any chance of being clinically useful. We should also realize the importance of studying patients with early dementia and those with MCI separately—it’s possible that using monoclonal antibodies once dementia has set in is too late, and I suppose that it’s also possible that using them before dementia has developed is too early. Finally, the study reminds us of the importance of a uniform methodology in conducting this kind of work. If the test that was previously regarded as the gold standard, the ADAS-Cog, is not the right test to use, then researchers need to agree on that and decide collectively what test to use instead. 

ABC News reported the drug as “giving patients hope” and showing “big promise.” Fortune magazine asserted that “world leaders want to end Alzheimer’s by 2025; a new drug breakthrough means we just might.” Investors are closer to the mark: Eisai’s stock price fell 10 percent after the data were reported.

The Secret to Staying Sharp

The last time that NIH requested a review of the data on preventing cognitive decline in old age (including Mild Cognitive Impairment, Alzheimer’s type dementia, and “usual” age-related cognitive deterioration) was in 2010. At that time, the systematic review of the published literature (performed by the Agency for Healthcare Research and Quality) and the associated state of the science conference (convened by NIH) concluded there was insufficient evidence to make any recommendations about interventions to prevent cognitive decline and dementia.

Now, the NIA has asked the National Academies of Science, Engineering, and Medicine to commission a new systematic review of the data and, based on that review, to issue recommendations about prevention. Its report, optimistically entitled, “Preventing Cognitive Decline and Dementia: A Way Forward,” was just released.  Alas, while the commission bent over backwards to find beneficial interventions, adding observational, non-experimental studies, risk factor analysis, and neurobiological work to the randomized controlled trials (RCTs) that were supposed to provide the evidence for their conclusions, it was forced to conclude, once again, that  the review “identified no specific interventions that are supported by sufficient evidence to justify mounting out an assertive public health campaign to encourage people to adopt them for the purpose of preventing cognitive decline and dementia.” The best the group could come up with was that the review did “find some degree of support for the benefit of three classes of intervention: cognitive training, blood pressure management in people with hypertension, and increased physical activity.

If we examine these three domains, what we find is not entirely encouraging. The arena of cognitive training (brain games, crossword puzzles, studying a foreign language, etc.) had the greatest degree of evidence. There is good evidence that it can improve performance in a trained task—that is, if you work at generating synonyms for words over and over again, you will get better at finding synonyms, at least in the short term. What is less clear is whether the benefits are sustained, whether training in one domain yields benefits in other domains, and whether it translates at all into improvement in daily functioning, in areas such as shopping, cooking, or paying bills. The good news, such as it is, about cognitive training, derives principally from one study, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE), which provides moderately strong evidence of effectiveness in the training domain after 2 years but low strength evidence after 5 or 10 years. The improvements that were found failed to translate into areas other than the one where training was provided.

Perhaps surprisingly, given the strong evidence that blood pressure control in people with hypertension is beneficial in preventing stroke and coronary artery disease, vigorous blood pressure treatment did not so readily translate into prevention or delay of any form of cognitive decline in old age. One British study did show efficacy. Given that blood pressure treatment is already recommended for other reasons, encouraging its use in the hope that it might also help fend off cognitive decline evidently seemed harmless enough to the committee.

The story on exercise is similar to that on blood pressure control: the RCT data are inconsistent, but there’s at least some data that shows a positive effect. Exercise studies are problematic because they so often utilize different forms of exercise and prescribe varying duration and frequency of exercise. Nonetheless, given the evidence that exercise is useful to promote mobility and to prevent depression, and that some studies find it beneficial in preventing cognitive decline, the committee opted to include exercise in its short list of interventions for which there is “some degree of support.”

The main justification, it seems to me, for subtitling this report “A Way Forward” is the section on recommendations for future research. The areas that have shown some promise deserve further study. And that study, as well as all other avenues that might be pursued, should be methodologically sound. That means acknowledging the deficiencies of existing work and avoiding those flaws in the future.

I suppose that whether this report is encouraging or not depends on whether you are a glass half full or half empty sort of a person. I will certainly continue to exercise regularly and challenge my mind, as long as I am able to. If I develop high blood pressure, I’ll want it adequately controlled. But I won’t kid myself that any of these measures will get me off the hook. And I will continue to support ongoing research in preventing or delaying cognitive decline in old age. But I won’t hold my breath. So far, the secret to staying sharp is that there isn't one.

Brave New World of Genetic Testing

In a provocative piece in the NY Times last week, science writer Gina Kolata suggests that the long term care insurance industry may be in a “death spiral.” The culprit, she argues, is genetic testing, which got a boost last month when the FDA approved testing by the company 23andMe. Previously best known for providing genealogical information to those who send in a saliva sample and a $99 fee, the personal genomics company is now authorized to provide information about genetic risk factors as well—for only an additional $26.

One of the ten conditions about which companies may offer information is Alzheimer’s disease. And perhaps the best established genetic risk factor for late-onset Alzheimer’s disease (sometimes called LOAD) is apoE. A gene that codes for a protein involved in cholesterol metabolism, apoE comes in three varieties, prosaically named apoE2, apoE3, and apoE4. Everyone has two copies of the apoE gene, so there are six possible genotypes, of which the most common are E2/E2, E3/E3, E4/E4, E2/E3, and E3/E4. The majority of people (63 percent, in one study of the distribution of the allele in 9 different populations) are E3/E3.

But while there is no way to definitively predict who will develop Alzheimer’s disease, fully 40 percent of people who develop LOAD are among the 25-30 percent of people who carry the e4 variant of the gene. And roughly half the residents of nursing homes have Alzheimer’s disease. As a result, according to spokesmen from the industry, a growing number of people are seeking testing from 23andMe to see if they have the e4 gene. If they have it, they buy long term care insurance. If they don’t, they take their chances.

If this trend continues—and as of 2017, 2 million people have obtained the direct to consumer genetic analyses---the pool of people buying long term care insurance could be heavily weighted towards those who actually will develop the disease. The health insurance industry, however, as consumers are perhaps finally coming to understand in the ongoing Obamacare wars, depends on pooled risk; it only works if the people who buy insurance include some people who will get sick and others who won’t. 

The reason the direct-to-consumer marketing of genetic information potentially spells doom for the long term care industry is that Americans are protected by the Genetic Information Nondiscrimination Privacy Act, which prevents insurers from requiring gene tests or using the results of genetic testing in coverage decisions. That means that ordinary people, without any physician input, can find out if they are at high risk, they can make decisions about buying coverage based on that assessment—and the insurance companies are powerless to intervene. If most of the people who are destined to get Alzheimer’s disease end up with insurance, the insurance company will end up paying out a lot more than they originally anticipated—leading to enormous increases in the rates or bankruptcy of the industry.

Now there are plenty of other reasons that the long term care insurance industry may collapse, and a good number of pre-existing reasons why it’s a poorly designed program. The amount of money it actually provides people is rarely enough to cover their actual costs, whether of home or institutional care. There are many barriers in the way of people using their benefits—for example, many policies require three months of disability before they kick in, which may be three months too long, especially if they are only going to be in a nursing home for three months. And Medicaid is currently available as a back up to pay for institutional care, provided people have “spent down” their personal savings, so the value of long term care insurance derives from its ability to shelter assets.

Analyzing the value of long term care insurance is a conversation for another blog post. But the point I want to make today is that before you rush out and get tested for Apo E, you should be aware of the limited predictive value of the test. While the likelihood of getting LOAD if you are one of the 2.6 percent of the population who have two copies of E4 is 91 percent, the likelihood of getting LOAD if you are one of the 22 percent of the population with one copy of the E4 allele falls to 47 percent. And if you are one of the 76 percent of the population with no E4 alleles, you still have a 20 percent of getting Alzheimer’s. Because the poor “negative predictive value”—because even with a negative test, you have a substantial risk of getting the disorder—physicians and organizations such as the Alzheimer’s Association have for years recommended against routine Apo E screening.

Interestingly, Apo E determination has been available to Europeans as a direct to consumer test for years. A study to find out what the short- and long-term psychological consequences were for patients with a positive test. Though the study only looked at people who requested testing, it found that there were no significant adverse consequences of getting bad news. So fear that you will become anxious or depressed is probably not grounds for resisting the impulse to be tested for Apo E4. But you should remember that it’s just a risk factor—and one over which you have no control—and plenty of people who test negative will still develop Alzheimer’s disease.

Quack, Quack--if it Sounds Like a Duck....

When Lydia Pinkham (1819-1883) began selling her patent medicine in the mid-nineteenth century, she advertised it as a panacea for all sorts of “female complaints.” Whether you suffered from “neurasthenia,” from menstrual cramps, from infertility, or from postmenopausal depression, Lydia Pinkham’s Vegetable Compound was the drug for you. It made Mrs. Pinkham and her descendants a bundle: as described by James Harvey Young in his book, Toadstool Millionaires, the remedy grossed $300,000 in the year of her death and in 1925, it earned a profit of $3.8 million. I’m not sure what that is in 2017 dollars, but it’s a lot.

Other patent medicines made similarly broad claims of effectiveness and were likewise lucrative for their developers. Warner’s "Safe Cure" stated on the label that it treated “Bright’s disease (nephritis), urinary disorders, female complaints, general debility, malaria,” and “all disorders caused by disordered kidneys and liver.”

These potions remained unregulated until the passage of the Pure Food and Drug Act in 1906, at which point the labels were required to be “truthful” about their ingredients. In particular, 11 dangerous substances including morphine, cocaine, and alcohol, which were frequently found in patent medicines (even in cough syrup for children) needed to be explicitly listed. There would be no evidence of efficacy required for another 32 years.

In the intervening years, both physicians and the public gradually began to appreciate that any drug that was touted as the treatment or even the cure for as many as ten distinct diseases was almost invariably a fraud and the disseminator of claims of its miraculous properties a quack. No one drug can plausibly have so many unrelated beneficial properties. Today, we are afflicted with the inverse of the one-drug-many-cures scam. We are bombarded with claims that a single disease can have many unconnected causes. And the disease for which such assertions are most commonly made is Alzheimer’s disease.

A few years ago, the media was all riled up by an article purporting to show that the anti-anxiety drugs, benzodiazepines,  were associated with an increased risk of Alzheimer’s disease. A year later, we learned that anti-allergy medicines and some antidepressants had also been associated with developing Alzheimer’s. Last year, the culprit was the class of anti-ulcer medications, proton pump inhibitors (drugs such as omeprazole). And now, instead of a medication, we have soda and other sugar-laden beverages allegedly leading to stroke and dementia.

Really? Do all these substances launch innocent people on the path towards dementia?

To be fair, there are disorders with multiple well-established risk factors. Coronary artery disease, for example, is associated with elevated cholesterol, diabetes, high blood pressure, and smoking. But in this case, we understand something of how the disease develops and how each of these risk factors affects that pathway. High blood pressure damages the lining of the coronary arteries, and the resulting areas of inflammation tend to trap cholesterol, producing plaques, etc. 

There are also single substances that produce diffuse toxicity: cigarette smoking has been associated with lung cancer, bladder cancer, and cancers of the head and neck (three very different types of cancer), as well as with heart disease and stroke. But again, we understand the mechanism of action that is responsible for the disparate effects. 

In the case of dementia, the connection between benzodiazepines and dementia, allergy medicine and dementia, proton pump inhibitors and dementia, and now soda and dementia, is purely statistical. Nobody has made a plausible argument for how each of these agents might work to trigger Alzheimer’s—even though we now know quite a bit about how the disease develops. No one has made a good argument because they haven't found one.

Nor is there a persuasive statistical argument. The studies based on which all these factors have been implicated in causing dementia are retrospective, non-randomized studies. The authors try to control for various “confounding factors” that might be the real explanation for the association, but they might not know what the relevant factor is or they might not be able to figure out if it was present or not. For example, maybe people who were ultimately diagnosed with Alzheimer’s disease were more likely than others to have taken benzodiazepines a few years before their diagnosis because they were already exhibiting very early symptoms, and those symptoms created anxiety.

Much exciting research is underway on Alzheimer’s disease, research that may someday result in treatment, prevention, or even cure. But fishing expeditions to come up with a commonly used drug or other substance as an explanation of this complex disease are a distraction. We don’t need people abandoning their ulcer medication or their allergy treatment out of an ill-founded fear that they are bringing dementia upon themselves. Stirring up hysteria—and potentially depriving individuals of good drugs—is a really bad idea.

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