21 Jan 2008

Can an FDA-approved arthritis drug double as a therapy for Alzheimer disease? Claiming it did in a patient, a case report published in the January 9 Journal of Neuroinflammation generated a wave of media attention that splashed across television, the BBC, newspapers and out to numerous online sources and blogs. The coverage ran the gamut from breathless approval to stern criticism. Some headlines announced “Extraordinary Breakthrough-Alzheimer’s Symptoms Reversed in Minutes,” other outlets reprinted the press release, CNN’s Sanjay Gupta balanced promise and caveats, and a blogger posted his open letter to the study authors in which he charged “This, gentlemen, appears to be a sham.” So what is a reader to make of it? The Alzforum looked behind the initial media accounts to report the story in greater depth. Scientists in the field were intrigued about the approach of inhibiting certain cytokines to treat inflammation in AD, yet also expressed reservations about the way these studies were conducted.

The present paper was submitted to J. Neuroinflammation, an open-access journal published by BioMedCentral, on November 29, 2007. It describes the response of an 81-year-old physician who met diagnostic criteria for probable AD and came to the principal investigator’s medical practice in October of 2007. The patient received weekly injections of etanercept (marketed under the name Enbrel®), a biologic drug that binds and neutralizes tumor necrosis factor α (TNFα). The paper’s authors are Edward Tobinick, a dermatologist and internist who runs a private medical group in Los Angeles, and Hyman Gross, a neurologist in private practice in Santa Monica, California. The paper is freely available and therefore not summarized in detail here. In brief, the authors report that this patient visibly and measurably improved within minutes of receiving drug injections into the back of the neck, and that his improvement lasted throughout a 7-week assessment period during which he received one injection every week for the first 5 weeks. Tobinick and Gross hypothesize that the man’s cognitive improvement might be due to etanercept’s ability to quench the action of excess TNFα at the brain’s synapses.

In an accompanying editorial, Sue Griffin of the University of Arkansas School of Medical Sciences in Little Rock speculates that this drug might be able to counteract “gliotransmission” in the human brain, i.e., the effects on synaptic activity of TNFα released by activated glial cells. In an unusually personal editorial, Griffin recounts her journey to Tobinick’s practice to observe the treatment herself, writing: “…—I was amazed!” Griffin is editor-in-chief of J. Neuroinflammation; the news bureau at her institution issued the press release. Griffin argues for larger, double-blind follow-up studies to explore both etanercept and the delivery method used by Tobinick and Gross. The present paper followed publication in 2006 of an open-label pilot study of 15 patients. This study did not assess patients’ cognition so soon after they had received the injection, but did claim to provide proof-of-concept that 6 months of weekly etanercept administration improved the performance of patients on the MMSE, ADAS-Cog, and SIB assessment tools (Tobinick et al., 2006). In this paper, one patient, an 80-year-old study participant, was reported to have died suddenly and without obvious cause during the last week of the trial.

When asked about this study, seven independent academic investigators who were not involved in it all said that the scientific rationale behind targeting TNFα to dampen inflammation in AD and some other neurological conditions is valid. Case reports have led to the development of new drugs before, and the independent scientists all agreed that formal clinical research should be pursued. At the same time, they expressed unease about the way in which these studies were performed. “The use of etanercept in this fashion is an interesting idea; however, I believe these studies should be done in randomized controlled trials, so the field can know how to interpret the data,” said David Holtzman, who chairs the neurology department at Washington University in St. Louis, Missouri. Some criticized the way the study was publicized. “This is exciting but very preliminary information,” said Cynthia Lemere, associate professor of Neurology at Brigham and Women’s Hospital in Boston. “The appropriate way to pursue it at this stage is to apply to FDA and NIH for support to run a rigorous trial, not to promote it to the general public.”

These comments encompass a range of specific concerns scientists raised. For one, none of the studies reported so far included controls. Controls could include injecting placebo, i.e., sterile saline, in the exact same way that etanercept is injected. This would test whether any response is due to the drug or to something else about the procedure. One reason why this is important is that patients with probable Alzheimer disease have been noted to have strong placebo effects, as occurs in other diseases. “I never fail to be dismayed at the magnitude of placebo effects in Alzheimer disease; they are remarkably large,” said Ben Barres, a professor of neurobiology and leader in glial cell research at Stanford University in Palo Alto, California (see comment below.) Another reason is that symptoms in Alzheimer disease patients are known to vary widely over time. The long-term trajectory of this progressive disease is invariably downward, but within that slow overall decline, patients show frequent ups and downs in cognitive function. Patients change not only because of their disease but also in response to things around them—stress, the environment, changes in daily routines, Holtzman explained. This zigzag pattern of overall decline renders it nearly impossible to interpret observations of any intervention done without controls, especially in a single case.

If follow-up studies substantiate that the observed effect is due to etanercept, fundamental scientific questions about where and how the treatment works remain to be addressed. Toward that goal, other controls could include peripheral administration of etanercept. Side-by-side comparisons of delivery modes and uptake/metabolism in plasma and cerebrospinal fluid (CSF) would begin to address issues around whether the injection used in this study is the best way to deliver the drug. Scientists interviewed questioned whether etanercept reaches the brain and acts there, or instead reduces TNFα in a more indirect fashion from outside the central nervous system (CNS, see comment by Greg Cole below). According to his papers, Tobinick injected etanercept between the spinous processes of the C6 and 7 vertebrae in the neck in such a way that the needle does not penetrate the CSF space itself but deposits the drug around one of the membranes covering the spinal cord. There are numerous veins in this region, which are proposed to allow some transport into the brain. To enhance this transport, the patients were laid on their backs, with their feet higher than their heads, for 5 minutes after the injection. Tobinick calls this type of injection “perispinal extrathecal” administration. This administration involves a shallower injection than the better known and widely used lumbar puncture farther down the spine, which some physicians consider safer in part because it is less likely to rupture veins.

There is no formal published data yet to show that the perispinal injection does indeed cause brain uptake of TNFα. Scientists in the laboratory of Pat McGeer took up this question and have unpublished results. (A noted researcher at the University of British Columbia, Vancouver, McGeer was one of the pioneers who established the concept of inflammation in neurologic disease and advanced it as a therapeutic target. To date, most controlled trials of anti-inflammatory drugs have been negative, but research is ongoing.) The Canadian scientists imaged the brains of rats injected with labeled etanercept. They were able to detect etanercept in the CSF but not the brain parenchyma, where neurons and synapses are located (see comment below).

In addition to determining whether this special injection is effective at delivering etanercept to the brain’s synapses, one might study whether its inherent risk is necessary, said Murali Doraiswamy, chief of biological psychiatry Duke University Medical Center in Durham, North Carolina. Published evidence from a large randomized, controlled trial of people with psoriasis suggests that etanercept given peripherally (it usually is injected under the skin) can ameliorate depression, mood, and other brain-related symptoms (Tyring et al., 2006). This leads some researchers to wonder whether some small fraction of etanercept—a large molecule generally considered unable to cross the blood-brain barrier—might somehow get across, or act on brain TNFα levels indirectly from the outside. Monkey studies with labeled etanercept would be suitable to answer these questions in preparation for formal clinical trials, said Lemere.

A related question concerns whether people with AD truly have elevated TNFα levels in their CSF. Several studies have reported such findings while some others have not, and some researchers noted having measured elevated CSF TNFα in some AD patients but not in others. As yet, scientists have not come to a general consensus that CSF TNFα is elevated in AD, as they have, for example, for tau or oxidative products called isoprostanes. The relationship between peripheral (i.e., plasma) and central (i.e., CSF) levels of TNFα in AD needs to be sorted out (e.g., see Cole comment below).

Edward Tobinick is a board-certified dermatologist and internist, who has been active in laser hair removal prior to developing an interest in the use of etanercept for CNS indications. The hair removal clinic at which Tobinick is medical director, the Institute of Laser Medicine, is in the same building as the Institute for Neurological Research, the medical group that sees AD patients for etanercept treatment; both are in suites 205-210 at 100 UCLA Medical Plaza. Etanercept is approved for rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and the skin disease psoriasis. Tobinick has previously disclosed that he owns stock in Amgen, the owner of etanercept. He holds numerous patents on delivery methods of etanercept for neurologic conditions (e.g., United States Patent 7,214,658).

As of January 2008, the Medical Board of California lists Tobinick as being on probation. Details of the disciplinary action were not available in time for this news article, but the Board’s April 2007 newsletter [.pdf] on page 20 published a paragraph indicating that Tobinick was charged with unprofessional conduct relating to advertising an unproven treatment for back pain. Tobinick published uncontrolled open-label treatment results suggesting that etanercept might serve to ameliorate disc-related pain (Tobinick et al., 2004). Researchers at Johns Hopkins University, Baltimore, Maryland, tested these observations with a double-blind, placebo-controlled dose-response trial. Last summer they reported that etanercept injection was not effective for this indication (Cohen et al., 2007).

A related area of uncertainty pertains to the distinctions between clinical practice and research. Physicians routinely prescribe drugs off-label, and charge for the drug, as part of their medical practice. This is a common practice tolerated by the FDA. In contrast, when the intent is to study a drug for a new indication, i.e., to collect and publish data, it is treated as research, and as such becomes subject to approval by an institutional review board (IRB). IRBs often mandate that the physicians submit their study protocols to the FDA for review. In an interview, an FDA official was unable to say whether an investigational new drug (IND) exemption had been submitted for the study of perispinal etanercept in AD, as IND issuances are confidential. The official pointed out that typically under IRB and IND rules, patients cannot be charged for the treatment given in a research study. Attempts to clarify how the interrelated issues of IRB rules, payment, and treatment versus research were handled in these studies were unsuccessful. According to the published papers, the patient described in this month’s case report was treated as part of clinical practice. The 2006 paper of the pilot study notes that a central institutional review board, a form of IRB often used for multicenter trials, approved the study, and that the families of the study subjects supplied the study drug.

Most media reports presented the work as a “UCLA study.” Tobinick lists a UCLA e-mail address on the manuscript, and the private medical group where he works full-time is located in a building at UCLA’s medical plaza. According to the UCLA media office, Tobinick is a voluntary assistant clinical professor with UCLA’s Division of Dermatology. The office stated that his etanercept study did not go through the UCLA IRB. Greg Cole, associate director of the UCLA Alzheimer Disease Center (ADC), said that the center had nothing to do with Tobinick’s etanercept work. (Cole is known for his research on inflammation and cytokine action in AD. He studies, among other things, curcumin, a spice that has anti-TNFα activity and is being tested in a 12-month Phase 2 clinical trial at UCLA.) The J. Neuroinflammation paper identifies coauthor Gross as being at the Department of Neurology, University of Southern California, School of Medicine. That university’s website does not list Gross as a faculty physician in the neurology department. John Weiner, media representative at USC Health Sciences, said that Gross is not on USC’s regular, paid faculty but has a voluntary appointment. Weiner added that such voluntary associations are similar to “adjunct” appointments at other academic institutions.

Amgen, the maker of etanercept, distanced itself from the study. A statement regarding Tobinick and Gross’s study on the company website noted: “This study was not supported nor endorsed by Amgen. While Amgen and others have long recognized the potential for TNF inhibitors to have an effect on neurological conditions, we have carefully examined this study and believe that at this time there is insufficient scientific data to support the use of a TNF inhibitor as a means of treating Alzheimer's disease.” Reached by telephone, Amgen spokeswoman Sonia Fiorenza confirmed that this statement referred not only to the present paper, but that Amgen had studied etanercept’s potential for treating AD internally, as well. “As common sense would suggest, we have looked very closely at this,” Fiorenza said. According to Amgen’s 2006 Annual Report, etanercept (Enbrel®) sales that year totaled $2.9 billion.

On January 15, this reporter e-mailed Tobinick questions relating to long-term cognitive effects, the precise nature of the injection, IRB approval, patient payment for treatment, total number of patients who responded vs. who did not, and other issues for an author Q&A in the format the Alzforum frequently publishes. Dr. Tobinick requested a phone conversation instead, but during the subsequent call declined to take questions. In a later e-mail, Tobinick noted that he is in discussions with academic medical centers.—Gabrielle Strobel.

References:
Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008 Jan 9;5(1):2. Abstract

Griffin WS. Perispinal etanercept: Potential as an Alzheimer therapeutic. J Neuroinflammation. 2008 Jan 10;5(1):3. Abstract

Comments

- Ben Barres
- Posted: 21 Jan 2008
Overall, my comment is one of strong doubt because of the possibility that the observed improvement is a placebo effect, and because of the lack of double-blind information. That said, TNFα is a microglial-derived, secreted protein that is likely to be elevated in Alzheimer’s. Given that it is a known inducer of complement proteins such as C1q, it is a provocative idea that TNFα might be playing some role in enhancing neuroinflammation and perhaps even complement-mediated synapse loss in neurodegenerative diseases such as Alzheimer’s.

Until a double-blind trial is run, we simply do not know whether TNFα antibodies will be useful for AD. Given that these antibodies are reasonably safe, I am all for doing a real trial to find out. One big caveat is that most antibodies cannot get across the blood-brain barrier.

One more point: in clinical practice, elderly patients occasionally come to the emergency room with a bladder infection presenting as stupor or coma. The infectious agent or the inflammatory response to them depresses brain function, and these patients quickly become alert on antibiotics. Perhaps there is some inflammatory response in AD that, when suppressed, enables patients to suddenly do better.

View all comments by Ben Barres

- Pat McGeer
- Posted: 21 Jan 2008
Dr. Ed Tobinick has developed a revolutionary approach to deal with the neuroinflammatory damage which occurs in AD. He has administered Enbrel®, a soluble TNF blocker which is too large to cross the blood-brain barrier, perispinally to AD patients. The clinical results he reports are too dramatic to be overlooked by clinicians who plod along prescribing drugs that do not deal with the underlying pathology and which, at best, are only marginally effective in some individuals. Confirmation is urgently required to determine if, for the first time, there is a treatment for AD that really works. Dr. Tobinick reports almost immediate results so, at the start, a long-term trial with hundreds of patients is not needed. Let us hope that clinicians with access to patients will soon test the method and report whether or not they can confirm Tobinick’s results.

Dr. Tobinick himself might want to provide control data by injecting placebo. As for our group, we did PET scans on rats injected by Dr. Tobinick with radiolabeled antibody. In this experiment, etanercept rapidly reached the CSF but not the brain parenchyma.

View all comments by Pat McGeer

- Gregory Cole
  UCLA/VA
- Posted: 21 Jan 2008
I have been told that patients of colleagues received this treatment and it did not help them. I also have been told that the patients pay for it out of pocket, and that it is expensive. Last year the UCLA ADRC invited Dr. Tobinick to present his results to us. Dr. Tobinick’s presentation was for the most part a literature review on TNFα and inflammation. There was very little data and no formal study. Dr. Tobinick showed a videotape of a woman who performed poorly on simple directed tasks such as counting backwards from 10, then she was said to be treated, then she did better within 15 to 30 minutes. Since Amgen owns the drug, we called our contacts there, who said they had taken a look at this work and decided it did not merit follow-up. I asked Dr. Tobinick about Amgen—after all, if it worked, they would make money off it—and he said he presented to them and they didn’t follow up.

There are several other issues:

1. No controls for placebo or test/retest, nothing formal to show a real drug effect.

2. A response so rapid that most TNF mechanisms could not be involved. It would have to be an immediate immuno-neutralization and signal transduction effect.

3. Tony Wyss-Coray's panel finds low, not high, plasma TNFα as a diagnostic marker for AD (Ray et al., 2007). So a plasma effect would be in the opposite direction from normal but still might lower central TNFα. I think we can agree that most of the antibody would go to the periphery. This matters because TNFα can cross the BBB, so etanercept would lower peripheral TNF, which may be a significant source for brain TNFα and still have an effect. It is entirely possible that injection via another route would produce the same benefit in patients who have high peripheral TNFα.

4. For the case report with an N = 1 and sudden improvement, it is hard to conclude that there is any real phenomenon to explain. But for the previously published open-label study with 15 patients, there are more interesting results to follow up on. In that study, they found evidence of a more gradual and continuing improvement in cognitive measures with no improvement of MMSE scores at 1 month, but then improvement at 2 months. That would be consistent with a more plausible, slower time course for an anti-TNFα effect.

References:

Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007 Nov;13(11):1359-62. PubMed.

View all comments by Gregory Cole

- Tony Wyss-Coray
  Stanford University Medical School
- Posted: 21 Jan 2008
- Paper: Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.
The role of TNFα in the brain is complex. Although there is a lot of indirect evidence that TNFα is detrimental in AD, this protein can be neuroprotective and has been shown to mediate synaptic scaling, a process that helps cells to readjust synaptic strength after prolonged activity (Stellwagen and Malenka, 2006). Given these diverse functions, we cannot yet say what increased or decreased levels in plasma or CSF mean for this disease.

I think we should be cautious with inhibiting TNFα in AD, as AD is not an acute inflammatory disease.

References:

Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. PubMed.

View all comments by Tony Wyss-Coray

- Linda Van Eldik
  University of Kentucky
- Posted: 22 Jan 2008
- Paper: Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration.
Dr. Ed Tobinick reports clinical improvement in AD patients administered etanercept, a macromolecular drug that interferes with TNFα activity. His recent Journal of Neuroinflammation paper reports the unexpected and intriguing finding that perispinal administration of etanercept leads to observable clinical improvement in AD patients within minutes. This case report of one patient follows up an earlier 2006 report in Medscape General Medicine. In that pilot study, 15 patients with mild to severe AD were treated once weekly with etanercept by perispinal administration for 6 months, and showed significant and sustained improvement in three different cognitive tests. Dr. Tobinick himself has raised several caveats related to the study, such as the possibility that the rapid effects are related to mood elevation or improved alertness, the lack of a control group treated with placebo, and the unconventional drug delivery method. The clinical observations are sufficiently intriguing to warrant analysis in a randomized, double-blind, placebo-controlled clinical trial.

These initial clinical observations from a feasibility study are consistent with the hypothesis that cytokine levels and activity need to be tightly regulated in the brain, and that cytokine dysregulation might be a pathophysiology progression mechanism that can be targeted in new therapeutic development. The mechanisms behind how etanercept treatment influences cognition, especially the rapidity of the effects in the recent study, are not known and are one of many parameters that need to be studied in more detail. However, a number of testable hypotheses can be proposed and rapidly tested in preclinical animal models in parallel with planning for future clinical trials.
The clinical observations also indicate the critical need for small molecule therapeutics that modulate cytokine production. This critical need is amplified when one realizes that current cytokine-modulating drugs are macromolecules, and using macromolecules as a therapeutic approach has a number of disadvantages for clinical use in chronic CNS disorders, such as high cost and inconvenient dosing regimens. Clearly, there is an unmet need for small molecule, orally active, brain-penetrant, anti-cytokine compounds to test as potential new classes of AD therapeutics.

View all comments by Linda Van Eldik

- Lon S. Schneider
  University of Southern California Keck School of Medicine
- Posted: 24 Jan 2008
The media have been tripping over themselves about a single case report of what they have pegged as etanercept’s Lazarus-like effect in one patient. To add but one headline to the ones cited as examples in Gabrielle Strobel’s news story, the Methuselah Foundation quotes the author as saying, "the patients improve literally before your eyes" (Enbrel Works Fast Against Alzheimer's Disease?, accessed January 18, 2007).

No matter how strong the underlying science or rationale of why an antagonist to TNFα might help, case reports tell so little and mislead so much. The circumstances of this one are particularly concerning, touting immediate and huge cognitive benefits using a perispinal injection process possibly covered by 17 patents owned by the author. The patient was treated just last October 30 for 7 weeks, with his final assessment on December 19 and journal publication the first week of January.

Now 12 weeks later, would it be presumptuous to ask how the patient is doing? As reported, he was severely demented and confused before treatment, and after extrathecal infusion and being tilted head-below-his-heart for 5 minutes, improved markedly to a level of about moderate dementia in about 1 hour.

I wonder what was the rush to publish this case when 1.5 years ago, the same authors published a 16-patient case series where they exampled one patient with a MMSE of 0 who had even greater effects than this most current case, i.e., a 34-point improvement on the Severe Impairment Battery, and apparently sustained over 6 months. What deadline were they trying to meet?

They state in their case report that they had many similar experiences: “It should also be emphasized that rapid cognitive improvement following perispinal etanercept is not limited to the patient of the present report, but has, in fact, been commonly observed in multiple patients during the authors’ now more than 3-year clinical experience utilizing perispinal etanercept for treatment of probable Alzheimer’s disease.” Why didn’t they report these patients as well and earlier? How many other patients were treated and not reported? Did they have any failures, any non-responders? If you value one case, you have got to value them all.

Uncontrolled case reports at best suggest hypotheses, regardless of how large the effects seem to be. If the efficacy of etanercept is even a fraction as great as that reported in this case or as the average 5-point ADAS-cog or 16-point SIB improvement over 6 months reported previously, then a simple and small double-blind placebo-controlled trial could be done very easily and quickly (preferably by independent investigators). The legal and ethical issues enumerated by Gabrielle Strobel should not be underestimated.

Disclosure: Consultant with Wyeth, co-marketers with Amgen of Enbrel®.

References:

Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006;8(2):25. PubMed.

Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation. 2008;5:2. PubMed.

Tobinick E. Perispinal etanercept for treatment of Alzheimer's disease. Curr Alzheimer Res. 2007 Dec;4(5):550-2. PubMed.

View all comments by Lon S. Schneider

- David Jensen
- Posted: 30 Jan 2008
While I am happy that the Alzforum linked to my blog, I don't feel that you sufficiently nailed the point down here ... that is, extraordinary "wow" headlines have no place in press releases about medical research. This is unfair to those with the disease, or to their caregivers. In this blogger's opinion, these authors lost all credibility when someone labeled their science with a headline like "Alzheimer's Symptoms Reversed In Minutes."—Dave Jensen, author, Sham vs. Wham

View all comments by David Jensen

- Gerard Roberts
- Posted: 01 Feb 2008
Should elderly Alzheimer disease patients be exposed to off-label administration of a drug that has been shown to be largely unable to cross the blood-brain barrier (e.g., Tweedie et al., 2007), but which lowers the immune system, leaving these patients more vulnerable to infections? See etanercept prescribing information.

References:

Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res. 2007 Sep;4(4):378-85. PubMed.

View all comments by Gerard Roberts

- Diane Stephenson
  Critical Path Institute
- Posted: 01 Nov 2011
Having spent some 25 years in industry focused on advancing therapies to treat patients with neurodegenerative diseases, I am very keenly aware of the critical importance for rigorous clinical trials.

I do think, however, that Etanercept is deserving of further study. There is now a wealth of evidence from preclinical studies in acute and chronic neurodegenerative conditions that elevated TNF exacerbates injury. Dr. Clive Holmes demonstrated that the single best predictor of cognitive decline in AD patients is serum TNF levels (Holmes et al., 2009), a finding that has since been confirmed in larger numbers of subjects. These results suggest that targeting patients with elevated TNF levels might be a strategy for identifying what patients to treat with anti-TNF therapies. Such an approach, if combined with neuroimaging biomarkers for patient enrichment (ARF related news story) and molecular neuroimaging tools to assess neuroinflammation (peripheral benzodiazepine receptor radiotracers) suggests a path forward for designing innovative trials that address key hypotheses.

Numerous comments highlight the concern about lack of BBB permeation of anti-TNF antibodies. This stands in contrast to the growing investment in industry now that is being placed on therapeutic antibody approaches to deliver disease-modifying therapies (reviewed by Paul, 2011).

Note the reference on ClinicalTrials.gov to the study of the safety and tolerability of Etanercept in AD (STEADI-09), which is actively recruiting patients.

References:

Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009 Sep 8;73(10):768-74. PubMed.

Paul SM. Therapeutic antibodies for brain disorders. Sci Transl Med. 2011 May 25;3(84):84ps20. PubMed.

View all comments by Diane Stephenson

- Gregory Cole
  UCLA/VA
- Posted: 10 Nov 2011
Reply to comment by Diane Stephenson
In general, the recent GWAS data provide a compelling rationale
for some causal modulatory role for the immune system in the development of
AD. But they don't clarify what this role is. It may be a positive role in
amyloid clearance or a negative role related to neurodegeneration.

The paper by Holmes et al. on which Diane Stephenson comments adds to a rationale to
focus on TNFα, which is known to "orchestrate" inflammation in various
models. That paper argues that TNFα plays a role in the rate
of cognitive decline in AD, but most anti-inflammatory trials in AD patients
have failed.

The reports that some AD patients treated with anti-TNFα
antibodies have had a favorable response are difficult to evaluate without a
larger, more controlled clinical trial without any potential conflict of
interest concerns.

The issue with all anti-inflammatory interventions remains confounded by conflicting information about which population might
benefit. For example, the ADAPT trial results now argue that persons with
cognitive decline won't benefit from conventional NSAIDs like naproxen, while
the paper by Holmes et al. suggests that anti-TNF therapy with antibody or even
a small molecule like curcumin might actually help a subset of patients with
established AD. This is really an empirical question.

View all comments by Gregory Cole