Perispinal Etanercept Produces Rapid Improvement in Primary Progressive Aphasia: Identification of a Novel, Rapidly Reversible TNF-Mediated Pathophysiologic Mechanism

Edward Tobinick, MD

Disclosures

June 10, 2008

Discussion

The data reported here, along with confirmatory clinical experience of more than 3 years duration in patients with Alzheimer's disease, provide the first preliminary evidence that perispinal etanercept may have potential therapeutic utility for selected patients with PPA.[26,27,28] In addition, these data, combined with those from previous reports, suggest that positive clinical effects may begin rapidly, within minutes, thereby suggesting the participation of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in PPA and Alzheimer's disease.[26,27,28]

Of particular note in this patient is the more than 10-point improvement in the activities of daily living (ADL) over the course of 1 month following the initiation of perispinal etanercept, as measured by the ADCS-ADL and the ADCS-ADL sev.[32,33] The ADCS-ADL was developed by a subcommittee of the ADCS composed of clinicians with expertise in dementia assessment and clinical trials to assess a wide range of ADL.[32] Functional assessment of ADL is a critical element of patient care and may also be used to quantify the clinical relevance of cognitive or other effects of a drug intervention.[32] Treatment that enhances cognitive function should lead to an improvement in ADCS-ADL.[32] The ADCS-ADL is a standard instrument used in clinical trials for Alzheimer's disease. It has broad applicability, good test-retest reliability, and sensitivity to detect change in disease progression.[32] A modified version, the ADCS-ADL modified for severe dementia (ADCS-ADLsev, also called the ADCS-ADL19), has been developed and validated for patients with severe dementia.[33] The ADCS-ADL is scored from 0 to 78; the ADCS-ADLsev is scored from 0 to 54, with lower scores indicating more severe functional impairment. The initial scores of the patient, 16/78 on the ADCS-ADL and 15/54 on the ADCS-ADLsev, both indicate severe dementia. A 2006 meta-analysis of memantine for Alzheimer's disease and other forms of dementia documents the use of the ADCS-ADLsev instrument in multiple studies; in two 4- to 6-week studies with a total of 126 patients, the effect size was -1.34 points.[34]

As an example of the use of the ADCS-ADLsev in clinical trials, this inventory was used as one of the main outcome measures in a 24-week trial of memantine given to a group of patients with moderate to severe Alzheimer's disease who were already receiving donepezil.[35] During the course of the 24 weeks, scores of the placebo group declined by 3.4 points in the ADCS-ADLsev, while the scores in the group treated with memantine declined by 2.0 points, a significant difference (P = .03).[35] In a 28-week study of memantine in another group of patients with moderate to severe Alzheimer's disease, the memantine group also declined less than the placebo group (-3.1 vs -5.2, P = .02).[36] The effects in these studies, although small, were statistically significant. A more recent 24-week study of memantine did not show a significant difference from the placebo group with respect to ADCS-ADLsev.[37]

As recently discussed, the rapid effects noted may occur through modulation of synaptic mechanisms that have been dysregulated by excess TNF-alpha.[28] This hypothesis is supported by recent evidence suggesting both a role for TNF in the amyloid oligomer disruption of long-term potentiation and other memory mechanisms and its function as a gliotransmitter.[3,4,38,39]

Further study will be necessary to characterize response rates, dosing schedules, and duration of response in patients with PPA and to determine whether patients with PPA associated with frontotemporal dementia respond in a different manner from patients with PPA associated with Alzheimer's disease.

Potential side effects of the use of perispinal etanercept for the treatment of dementia, an off-label use, include all of the risks inherent in the use of etanercept for its labeled indications, which may include death, infection, decreased blood cell counts, congestive heart failure, lymphoma, demyelinating disease, and reactivation of tuberculosis.[40] PPD skin testing before initiation of etanercept treatment is mandatory, and a black box warning highlighting the risk of tuberculosis, sepsis, and severe infection has been added to the package insert.

The unmet medical need in primary progressive aphasia, with not even a single approved therapeutic agent; the scientific rationale, including basic science and clinical data; and these promising preliminary results together support the initiation of further clinical study. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying PPA and related forms of dementia and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in both PPA and Alzheimer's disease.

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