Quick Reversal of Symptoms in Alzheimer's Case Claimed with Etanercept

LOS ANGELES, Jan. 11 -- A single dose of the anti-inflammatory drug etanercept (Enbrel) produced significant improvement within minutes in an Alzheimer's disease patient, researchers here said.
Also point out that the principal author owns stock in the manufacturer of etanercept, and has multiple issued and pending patents, which describe the parenteral and perispinal use of etanercept for the treatment of Alzheimer's disease.
The remarkable, though limited, recovery occurred in an 81-year-old man who received etanercept by perispinal injection into his neck, reported Edward L. Tobinick, M.D., of the Institute for Neurological Research, and Hyman Gross, M.D., of the University of Southern California, in the Journal of Neuroinflammation.
The treatment was predicated on a controversial theory that etanercept's activity against tumor necrosis factor reduces glial cell-mediated brain inflammation and the cognitive deficits to which the inflammation contributes.
The authors hypothesized "that excess TNF-alpha in Alzheimer's disease interferes with the synaptic regulatory functions of TNF-alpha. When TNF-alpha is in a normal physiologic range synaptic scaling is enabled, thereby preserving optimal functioning of the brain's neural network."
When TNF-alpha is overexpressed, because of glial activation, it is postulated that the synaptic regulatory activities of TNF-alpha are disturbed. Synaptic dysfunction is hypothesized to result from this dysregulation, which may provide a basis for reduced functional connectivity between brain regions in Alzheimer's.
Immediately prior to treatment, the man was unable even to guess at the current year and could not say what state he was in. He performed poorly on standard tests of memory and cognitive ability.
Ten minutes later, the researchers wrote, "he was noticeably calmer, less frustrated, and more attentive. He was able to correctly identify the state as California, and he identified the year as 2006."
In fact, the year was 2007, but Dr. Tobinick said in an interview that the near-miss represented improvement from the man's prior condition.
According to the report, the man showed additional improvement over the next several hours. At a formal cognitive examination that began two hours after dosing, he showed markedly better performance on tests that required him to identify pictures, list words beginning with the letter F, and name as many animals as possible in one minute.
Before dosing, the man was able to list five words beginning with F in one minute, with five perseveratory responses and one neologism. He could only list "dog" and "cat" as animals in one minute. On the Boston Naming Test, he could identify one of 10 pictures.
At the post-dose exam, he identified nine Boston test pictures, listed eight words beginning with F with one perseveratory response, and named five animals.
He showed similar improvements on some additional cognitive and memory tests, though not all. He also appeared to be more aware of his faulty responses, the researchers said.
The patient received additional etanercept doses weekly for five weeks. At week seven, he was retested and showed continued improvement over baseline performance.
That the man had Alzheimer's disease was supported by extensive testing including positron emission tomography, which found substantial cortical atrophy and areas of low metabolism.
The report followed an open-label study Dr. Tobinick published in 2006, which involved 15 patients receiving the perispinal etanercept injections. Those patients showed improvements in cognitive performance lasting the full six months of the study.
W. Sue T. Griffin, M.D., of the University of Arkansas, the Journal of Neuroinflammation's co-editor, wrote in an editorial that the case report "is hopefully the first of many articles attesting to the benefit of direct-to-the-brain delivery of anti-cytokine therapies."
She added that she had visited Dr. Tobinick's clinic last November to witness the treatment first-hand.
"I noticed clinical improvement in each of the three patients within minutes following treatment," Dr. Griffin said. "My first impression was that there was a clear, easily discernible, difference in each. They were more cheerful, more at ease, and more attentive."
Other Alzheimer's disease researchers were more skeptical.
"The Alzheimer's field has plenty of open-label studies and case reports of improvement that have not panned out into new useful treatments," said Paul B. Rosenberg, M.D., of Johns Hopkins. Without confirmation in a controlled trial, "you shouldn't get too excited," he said.
P. Murali Doraiswamy, M.D., of Duke, made a similar point. "Unless one does a controlled study, one can never get a good handle on efficacy and safety." He said that it was common to see rapid but transient improvements with unusual chronic conditions.
However, both researchers agreed that central nervous system inflammation and anti-cytokine therapies are "a promising area for study," as Dr. Doraiswamy put it.
"It's not phony baloney," Dr. Rosenberg said. "This drug ought to be studied."
However, he questioned the necessity for the perispinal delivery method Dr. Tobinick has used.
It involves placing the needle tip near the spinal cord without penetrating its outer sheath. Dr. Tobinick said the method is not used for other procedures elsewhere and requires special training.
He insisted that it's necessary to the treatment's success. He said it allows the drug to cross the blood-brain barrier without physically compromising it, as an intrathecal injection would. He said the etanercept molecule is too large to cross the blood-brain barrier when delivered systemically.
But Dr. Rosenberg said he was not persuaded. He said a study of etanercept in psoriasis had found that the drug had antidepressant effects, suggesting it's available in the brain after ordinary systemic dosing.
Dr. Tobinick said a controlled trial of perispinal etanercept in Alzheimer's disease has been funded and is now being designed in collaboration with an academic institution, which he declined to identify.
Etanercept's manufacturer, Amgen, maintained a hands-off attitude toward the research. It issued a statement saying it did not endorse or support Dr. Tobinick's program. A spokeswoman said the company had no plans to conduct or fund studies on the drug's possible use in Alzheimer's disease.
She said the company has determined there is not scientific justification to warrant further effort.
"We looked carefully at the data," she said. "Right now, we don't think it's a viable option."
However, she added that Amgen might reconsider its position when new data come along.
The case report had no outside funding sources. The patient paid for treatment as part of Dr. Tobinick's clinical practice.
Dr. Tobinick reported owning stock in Amgen and holds issued and pending patents on parenteral and perispinal use of etanercept for the treatment of Alzheimer's disease and other neurological disorders.

Additional source: Journal of NeuroinflammationSource reference: Tobinick E, et al "Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration" J Neuroinflammation 2008; DOI: 10.1186/1742-2094-5-2. Additional source: Journal of NeuroinflammationSource reference: Griffin S, "Perispinal etanercept: potential as an Alzheimer therapeutic" J Neuroinflammation 2008; DOI: 10.1186/1742-2094-5-3.