Excitement Fades for Off-Label Alzheimer’s Treatment

The results of the trial were so dramatic that even some seasoned leaders in the field of Alzheimer’s research grew excited: After years of failed “breakthrough” drugs, researchers thought they may have finally discovered the drug that would restore memory and brain function to patients with Alzheimer’s dementia.[1]

The study, published online by a group of Case Western University scientists in February 2012,[2] described how mice with a genetically induced form of Alzheimer’s disease had experienced an enormous reduction in the number of amyloid plaques, structures in the brain that are the telltale feature of Alzheimer’s disease. The results were seen after treatment with bexarotene (TARGRETIN),[3] a toxic drug approved by the Food and Drug Administration (FDA) in 1999[4] to treat cancer.[5] Amyloid plaques are widely believed to interfere with brain function and to play a key role in causing Alzheimer’s dementia.

Now, a year and a half later, the outlook for this once-exciting treatment has grown quite dim. The primary problem is that the study’s findings cannot be replicated by other qualified scientists. Five different teams of researchers have worked exhaustively to reproduce the results of the Case Western study, and none have seen the sweeping reduction in amyloid or the memory improvements observed during the first trial.[6]

The bexarotene story is not uncommon: Countless Alzheimer’s treatments have failed following initially promising results in animal trials. What makes this story so striking, however, is the degree to which one preliminary study spread like wildfire through the popular media and Internet, raising the hopes of families already desperate for an elusive cure before quietly fizzling out in the face of a mounting body of opposing evidence. Understanding this story, and the mystery of why so many Alzheimer’s drugs have failed, may help prevent your family from being victimized by a potentially risky unapproved Alzheimer’s treatment as well as the plethora of approved Alzheimer’s drugs lacking evidence of any meaningful benefit.

Promising results

The initial Case Western study involved feeding bexarotene to a group of mice that had been genetically altered to develop the symptoms of Alzheimer’s disease.[7] After 14 days of bexarotene treatment, 75 percent of the plaques in the brains of these mice had melted away.[8] The effects, while stunning in the short term, appeared temporary and vanished after three months of treatment.[9] However, researchers were heartened by another sign: Mice treated with bexarotene for various periods — including up to three months — seemed to perform better on memory tests and appeared to be better at building nests and responding to smells, two behaviors that are lost as dementia progresses in genetically modified mice.[10]

Within days of the Case Western publication, media outlets were buzzing with news about the study. It was even featured in an article posted on the website of the widely watched television program, “The Dr. Oz Show,” starring celebrity doctor Mehmet Oz.[11] The article compared the drug to the vaccine that had wiped out polio in the U.S. and much of the world.[12]

Almost immediately, patients were clamoring for clinical trials of this toxic drug, which is approved for use in cancer patients despite its association with pancreatitis, life-threatening liver failure, thyroid problems, immune system damage and cataracts.[13] The Case Western researchers announced that they had filed a patent on the drug for use in treating Alzheimer’s disease (the drug’s patent for cancer treatment expires in 2016) and were planning to start testing in humans within months.[14]

The great mystery of Alzheimer’s disease

Researchers had a good reason to be initially excited by the reduction in amyloid plaques. These structures are a hallmark characteristic of Alzheimer’s disease, appearing as multiple plaques (patches) in the brain made up of clustered protein fragments know as beta-amyloid peptides (amyloids).[15] Scientists have known about these plaques for more than a century but still know very little about where they originate, how they develop or what role they play in causing dementia.[16]

Healthy brains have a process for clearing away amyloids and preventing these protein fragments from building up into plaques.[17] Scientists have identified several abnormal variants of a particular protein, known as APOE, that appear to affect a person’s risk for Alzheimer’s disease by influencing the amyloid-clearing process.[18] People with one version of the gene, APOE4, are at higher risk for Alzheimer’s disease, and people with another version, APOE2, are relatively protected against the disease.[19]

The Case Western researchers, like many before them in the field of Alzheimer’s research, [20]had set out to test a tantalizing hypothesis: If Alzheimer’s dementia is caused by the buildup of amyloids, researchers should be able to delay or even reverse the symptoms of the disease by targeting the processes by which amyloids are created or destroyed.

It is a good hypothesis, with a lot of circumstantial evidence. The only problem? It has repeatedly failed to work. Time and again, Alzheimer’s treatments promising to attack the amyloid pathway and reduce the buildup of plaques have failed to yield meaningful results in clinical testing.[21] In 2012 and 2013, three promising drugs targeted at reducing amyloid buildup, solanezumab, bapineuzumab and an immunoglobulin (GAMMAGARD),[22] were were shown to be ineffective in phase 3 clinical trials involving Alzheimer’s patients. (GAMMAGARD has been approved for other conditions.[23]) Another drug, semagacestat,[24] was pulled from the development pipeline in 2010 after significantly worsening dementia symptoms during phase 3 testing. To make matters worse, semagacestat also increased the risk of skin cancer.[25]

Bexarotene promised to reduce the accumulation of amyloid plaques through a novel mechanism: By increasing production of APOE proteins, the Case Western researchers believed that they could enhance the body’s natural mechanisms for breaking down and clearing amyloids, potentially treating Alzheimer’s dementia effectively where other drugs have proven unsuccessful.[26]

We may never understand why the drug produced such promising results, only to defy replication after repeated, carefully designed attempts by qualified scientists. The Case Western authors stand by their initial findings, arguing that even if bexarotene does not remove amyloid plaques, it still improves behavior and memory.[27] However, subsequent research teams have poked holes in this part of the original study as well, pointing out that one of the memory tests used by the Case Western researchers may have been flawed.

The bexarotene story highlights gaps in knowledge about Alzheimer’s disease itself. Researchers still lack insight into the true role amyloids play in influencing brain function. Are they mere waste products, clogging our synapses and preventing our neurons from communicating?[28] Or are they, as some evidence suggests, critically involved in our neurological processes in ways we still do not fully understand?[29]

An uncertain path forward

The lingering uncertainties remaining in the field of Alzheimer’s research offer little comfort to the families of 5.4 million Americans currently suffering from the disease, a number that will only increase as the U.S. population ages.[30]

Some researchers believe that Alzheimer’s drugs have not worked because researchers simply have not used them early enough, and advocate testing the drugs on subjects who have not yet experienced the symptoms of Alzheimer’s dementia.[31] This research raises entirely new ethical challenges, as it exposes healthy people without major symptoms (who may or may not develop dementia for years, if at all) to clinical trials that will most likely do little for their condition and, in a few tragic cases, could even worsen existing symptoms.

For now, human testing on bexarotene continues, despite the fact that some researchers involved in efforts to replicate the bexarotene results in animals have called for a halt to clinical testing of this drug until more convincing animal data are collected.[32] Given the dubious animal data and the known risks of the drug, patients participating in such trials are much more likely to be harmed by this ineffective, toxic drug than helped by a “miracle” cure. Yet for families watching their loved ones slip away to this devastating illness, it may be difficult to heed cautious warnings and give up on the chance of a cure, no matter how bad the odds.

What You Can Do

There is no drug that is proven effective and safe at helping those with Alzheimer’s dementia. Several drug therapies are currently marketed to treat later-stage Alzheimer’s disease symptoms, but WorstPills.org has categorized each of these approved therapies as Do Not Use because they do not produce meaningful improvements in cognitive function and all carry harmful side effects.[33],[34],[35],[36]

The current best approach for patients with early signs of cognitive impairment that may indicate Alzheimer’s disease is to take general steps to stay mentally and physically healthy, including quitting smoking, eating a heart-healthy diet, and controlling blood pressure[37] and diabetes. Some studies show that people who make these healthy lifestyle choices have a lower risk of developing Alzheimer’s dementia, although the evidence of benefit is not always consistent, and researchers still know very little about how these lifestyle factors affect mental functioning.[38]

There also is a growing body of evidence that physical[39] and intellectual activity[40] may help delay the onset of dementia symptoms. (For one study on the effect of exercising, see text box below.)[41] Walking and other physical activity carry minimal risks, are widely available at low cost, and have an array of other physical and mental health benefits.[42]

You also may benefit from talking to a doctor about stopping sleeping pills, tranquilizers or antidepressants, as these drugs can cause side effects such as confusion and memory loss that mimic or worsen symptoms of dementia.[1],[44]

Avoid the temptation to seek off-label or unapproved medications based on stories of miraculous results, and be cautious about signing up for a clinical trial in search of a cure. As devastating as it is to suffer through Alzheimer’s disease, the last thing you or your family need is to become the victim of even greater harm from a failed Alzheimer’s treatment.

References

[1] The Dr. Oz Show. http://www.doctoroz.com/blog/mike-roizen-md/alzheimer-s-breakthrough-shows-promise. Accessed August 19, 2013.

[2] Cramer, P, et al. ApoE-directed therapeutics rapidly clear b-Amyloid and reverse deficits in AD mouse models. Science 2012; 335:1503.

[3] Ibid.

[4] Bexarotene. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed August 19, 2013.

[5] Bexarotene [drug label]. Esai Inc.

[6] LaClair, K, et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Molecular Neurodegeneration 2013, 8:18.

[7] Cramer, P, et al. ApoE-directed therapeutics rapidly clear b-Amyloid and reverse deficits in AD mouse models. Science 2012; 335:1503.

[8] Ibid.

[9] Ibid.

[10] Ibid.

[11] The Dr. Oz Show. http://www.doctoroz.com/blog/mike-roizen-md/alzheimer-s-breakthrough-shows-promise. Accessed August 19, 2013.

[12] Ibid.

[13] Bexarotene [drug label]. Esai Inc.

[14] Stix, G. Alzheimer's disease symptoms reversed in mice. Scientific American. February 9, 2012. http://www.scientificamerican.com/article.cfm?id=alzheimers-disease-sympto&page=2.

[15] LaFerla, F. Preclinical success against Alzheimer’s disease with an old drug. New England Journal of Medicine 2012; 367:6:570.

[16] Marchesi2012 (p1764)

[17] Cramer, P, et al. ApoE-directed therapeutics rapidly clear b-Amyloid and reverse deficits in AD mouse models. Science 2012; 335:1503.

[18] Ibid (p2)

[19] LaFerla, F. Preclinical success against Alzheimer’s disease with an old drug. New England Journal of Medicine 2012; 367:6:570.

[20] Marchesi, V. Alzheimer’s disease 2012: The great amyloid gamble. The American Journal of Pathology, 2012;180:5.

[21] Ibid.

[22] http://www.fiercebiotech.com/story/baxter-adds-gammagard-growing-roster-phiii-alzheimers-failures/2013-05-07 (use control “f” to find sentence on solanezumab and bapineuzumab).

[23] Gammagard Liquid. http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm089392.htm. Accessed August 19, 2013.

[24] Lilly halts development of semagacestat for Alzheimer's disease based on preliminary results of phase III clinical trials. http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=499794. Accessed August 19, 2013.

[25] Ibid.

[26] Cramer, P, et al. ApoE-directed therapeutics rapidly clear b-Amyloid and reverse deficits in AD mouse models. Science 2012;335:1503.

[27] Landreth et al., Response to comments on “ApoE-directed therapeutics rapidly clear b-Amyloid and reverse deficits in AD mouse models.” Science 2013;340:924.

[28] Dr. Oz Show (p1) http://www.doctoroz.com/blog/mike-roizen-md/alzheimer-s-breakthrough-shows-promise

[29] Marchesi, V. Alzheimer’s disease 2012: The great amyloid gamble. The American Journal of Pathology, 2012;180:5: 1765.

[30] Stix, G. Alzheimer's disease symptoms reversed in mice. Scientific American. February 9, 2012. http://www.scientificamerican.com/article.cfm?id=alzheimers-disease-sympto&page=2.

[31] Marchesi, V. Alzheimer’s disease 2012: The great amyloid gamble. The American Journal of Pathology, 2012;180:5:1762.

[32] LaClair, K, et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Molecular Neurodegeneration 2013, 8:18.

[33] WorstPills.org profile: ARICEPT. /monographs/view/128.

[34] WorstPills.org profile: EXELON. /monographs/view/129.

[35] WorstPills.org profile: NAMENDA. /monographs/view/130.

[36] WorstPills.org profile: HYDERGINE LC. /monographs/view/131.

[37] Blom K, Emmelot-Vonk MH, Koek HDL, The influence of vascular risk factors on cognitive decline in patients with dementia: A systematic review. Maturitas 2013.

[38] Daviglus ML, Plassman BL, Pirzada A, et al. Risk factors and preventive interventions for Alzheimer disease: state of the science. Arch Neurol 2011 Sep;68(9):1185-90.

[39] Lautenschlager NT, Cox KL, Flicker L, Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease. JAMA. 2008;300(9):1027-1037.

[40] Vemuri P, Lesnick TG, Przybelski SA, et al. Effect of lifestyle activities on Alzheimer Disease biomarkers and cognition. Ann Neurol 2012;72:730–738.

[41] Lautenschlager NT, Cox KL, Flicker L, Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease. JAMA. 2008;300(9):1027-1037.

[42] Ibid.

[43] WorstPills.org profile: HYDERGINE LC. /monographs/view/131.

[44] Ellison JM, A 60-year-old woman with mild memory impairment: review of mild cognitive impairment. JAMA 2008;300(13):1566-1574.

[45] Lautenschlager NT, Cox KL, Flicker L, Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease. JAMA. 2008;300(9):1027-1037.

[46] Ibid.