First Tau Imaging Agent for Alzheimer Disease FDA-Approved

Charles Ganley, MD, director, Office of Specialty Medicine, Center for Drug Evaluation and Research, FDA

Charles Ganley, MD

The FDA has approved the use of intravenous imaging agent flortaucipir F18 (Tauvid; Avid Radiopharmaceuticals) to help image tau pathology in the brain for adult patients with cognitive impairment who are being evaluated for Alzheimer disease.¹

The indication supports flortaucipir F18 to be used with positron emission tomography (PET) imaging of the brain to assess distribution and density of aggregated tau neurofibrillary tangles (NFTs), a primary marker of Alzheimer disease. The safety and effectiveness of the imaging agent were evaluated in a pair of clinical studies, in which each had 5 evaluators read and interpret the imaging.

“Alzheimer disease is a devastating condition that affects millions of Americans. This approval will provide health care professionals with a new type of brain scan to use in patients being evaluated for Alzheimer disease,” said Charles Ganley, MD, director, Office of Specialty Medicine, Center for Drug Evaluation and Research, FDA, in a statement. “While there are FDA approved imaging drugs for amyloid pathology, this is the first drug approved for imaging tau pathology, 1 of the 2 neuropathological hallmarks of Alzheimer disease, and represents a major advance for patients with cognitive impairment being evaluated for the condition.”

The FDA noted that as of now, Alzheimer disease can only be definitively diagnosed by postmortem pathologic evaluation of a patient’s brain, and 3 imaging agents are approved for postmortem amyloid pathology with PET scans.

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The data from the 2 clinical trials assessing the flortaucipir F18 tracer included more than 300 patients, including those with terminal illness who agreed to participate in a postmortem brain donation program, as well as those with mild cognitive impairment (MCI). Those findings suggested that the tau tracer can support a pathological diagnosis of Alzheimer disease by identifying the underlying presence of NFTs at the B3 level (Braak stages V to VI) and high levels of Alzheimer disease neuropathologic change (ADNC) per National Institute on Aging—Alzheimer Association (NIA–AA) criteria.^2,3

The first study, Study A16, enrolled 156 terminally ill patients, of which 64 died within 9 months of their brain scan. The reading of those scans was compared to postmortem readings from independent pathologists who evaluated the density and distribution of NFTs in the same brain. The data suggested that the flortaucipir F18 images had a high probability of correctly evaluating patients with tau pathology and had an average-to-high probability of correctly evaluating patients without tau pathology.²

The second study, the FR01 Validation Study, included those from the first study, in addition to 18 additional patients with terminal illness and 159 patients with cognitive impairment who were being assessed for Alzheimer disease. This assessment judged agreement between evaluations from each clinician scan reader, with perfect reader agreement rated as 1 and no reader agreement as 0. Data showed that reader agreement was 0.87 across all 241 patients.¹

A separate subgroup analysis with the 82 terminally ill individuals with or without dementia diagnosed postmortem and the 159 patients with cognitive impairment showed that reader agreement was 0.90 for the patients in the indicated population and 0.82 in the terminally ill patients.¹ All told, B3 level NFTs sensitivity was 89.1% (95% CI, 77.0—95.3) and specificity was 86.1% (95% CI, 71.3–93.9), and high Alzheimer disease neuropathologic change (ADNC) level sensitivity was 95.1% (95% CI, 83.9–98.7) and specificity was 82.9% (95% CI, 68.7–91.5).³

Of the 64 patients in the primary cohort from A16, the mean age was 82.5 (standard deviation [SD], 9.6) years. In total, 77% (n = 49) had dementia, 2% (n = 1) had MCI, and 22% (n = 14) had normal cognition. Among the 156 enrolled participants, 9% (n = 14) experienced at least 1 treatment-emergent adverse event (AE).

The scans in the subgroup analysis predicted a B3 level of tau pathology with sensitivity ranging from 92.3% (95% CI, 79.7—97.3) to 100.0% (95% CI, 91.0–100.0) and specificity ranging from 52.0% (95% CI, 33.5–70.0) to 92.0% (95% CI, 75.0–97.8). Elevated levels of ADNC was predicted with sensitivity of 94.7% (95% CI, 82.7–98.5) to 100.0% (95% CI, 90.8–100.0) and specificity of 50.0% (95% CI, 32.1–67.9) to 92.3% (95% CI, 75.9–97.9).

For that full cohort data set, authors Adam S. Fleisher, MD, MAS, et al. noted that all 5 readers met the success criteria, defined as having ≥3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. For NFTs, sensitivity ranged from 89.1% (95% CI, 77.0—95.3) to 93.5% (95% CI, 82.5–97.8) and specificity from 66.7% (95% CI, 50.3–79.8) to 94.4% (95% CI, 81.9–98.5). For a high level of ADNC, sensitivity ranged from 95.1% (95% CI, 83.9—98.7) to 97.6% (95% CI 87.4–99.6) and specificity from 65.9% (95% CI, 50.5–78.4) to 90.2% (95% CI, 77.5–96.1).

The FDA noted that the most common AEs in patients using the tracer were headache, injection site pain, and increased blood pressure. It is not indicated for use in the evaluation of patients for chronic traumatic encephalopathy.¹

REFERENCES

1. FDA Approves First Drug to Image Tau Pathology in Patients Being Evaluated for Alzheimer’s Disease. News release. FDA; May 28, 2020. Accessed May 28, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-image-tau-pathology-patients-being-evaluated-alzheimers-disease

2. Clark CM, Pontecorvo MJ, Beach TG, et al; AV-45-A16 Study Group. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 2012;11(8):669-678. doi:10.1016/S1474-4422(12)70142-4

3. Fleisher AS, Pontecorvo MJ, Devous Sr MD, et al. Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes. JAMA Neurol. Published online April 27, 2020. doi:10.1001/jamaneurol.2020.0528