Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome: A Randomized Clinical Trial

Abstract

Importance: Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease.

Objective: To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

Design, setting, and participants: Two parallel-design, double-blind, placebo-controlled phase 1 randomized clinical trials in AD and 4RT were conducted from December 20, 2013, through May 4, 2017, at the University of California, San Francisco, and University of Alabama at Birmingham. A total of 94 patients with clinically diagnosed AD (n = 39) and 4RT (n = 55) were screened; of these, 3 refused to participate, and 10 with AD and 11 with 4RT did not meet inclusion criteria. A total of 29 patients with AD, 14 with PSP, and 30 with β-amyloid-negative CBS (determined on positron emission tomography findings) were enrolled. Data were analyzed from December 20, 2013, through May 4, 2017, based on modified intention to treat.

Interventions: Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2 of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension.

Main outcomes and measures: Primary end points were safety and tolerability (maximal tolerated dose) of TPI-287. Secondary and exploratory end points included TPI-287 levels in cerebrospinal fluid (CSF) and changes on biomarker, clinical, and neuropsychology measures.

Results: A total of 68 participants (38 men [56%]; median age, 65 [range, 50-85] years) were included in the modified intention-to-treat analysis, of whom 26 had AD (14 women [54%]; median age, 63 [range, 50-76] years), and 42 had 4RT (16 women [38%]; median age, 69 [range, 54-83] years). Three severe anaphylactoid reactions occurred in TPI-287-treated patients with AD, whereas none were seen in patients with 4RT, leading to a maximal tolerated dose of 6.3 mg/m2 for AD and 20.0 mg/m2 for 4RT. More falls (3 in the placebo group vs 11 in the TPI-287 group) and a dose-related worsening of dementia symptoms (mean [SD] in the CDR plus NACC FTLD-SB [Clinical Dementia Rating scale sum of boxes with frontotemporal dementia measures], 0.5 [1.8] in the placebo group vs 0.7 [1.6] in the TPI-287 group; median difference, 1.5 [95% CI, 0-2.5]; P = .03) were seen in patients with 4RT. Despite undetectable TPI-287 levels in CSF, CSF biomarkers demonstrated decreased chitinase-3-like protein-1 (YKL-40) levels in the 4RT treatment arm (mean [SD], -8.4 [26.0] ng/mL) compared with placebo (mean [SD], 10.4 [42.3] ng/mL; median difference, -14.6 [95% CI, -30.0 to 0.2] ng/mL; P = .048, Mann-Whitney test).

Conclusions and relevance: In this randomized clinical trial, TPI-287 was less tolerated in patients with AD than in those with 4RT owing to the presence of anaphylactoid reactions. The ability to reveal different tau therapeutic effects in various tauopathy syndromes suggests that basket trials are a valuable approach to tau therapeutic early clinical development.

Trial registration: ClinicalTrials.gov identifiers: NCT019666666 and NCT02133846.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tsai reported receiving research support from the University of California and grant K23AG055688 from the National Institute of Aging (NIA); consulting for ExpertConnect and Grifols; and current employment at Denali Therapeutics. Dr Z. Miller reported receiving research support from grant K23 AG048291 from the NIA, with additional funds from the Hellman Research Scientist Award, and the Arking Foundation for Frontotemporal Dementia. Dr Rojas reported serving as a site principal investigator for clinical trials sponsored by Eli Lilly and Company and receiving support from the National Institutes of Health (NIH). Dr Ljubenkov reported serving as a site principal investigator for clinical trials sponsored by AbbVie, Inc, and Alector, Inc. Dr Rosen reported receiving research support from Biogen, Inc, and the NIH and consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals. Dr Rabinovici reported receiving research support from Avid Radiopharmaceuticals, Eli Lilly and Company, GE Healthcare, and Life Molecular Imaging; receiving consulting fees from Eisai Co, Ltd, Genentech, Inc, Merck & Co, and Roche Diagnostics; and receiving an honorarium as associate editor for JAMA Neurology. Dr Fagan reported receiving research funding from the NIA of the NIH, Biogen, Inc, Centene Corporation, Fujirebio, Inc, and Roche Diagnostics; serving as a member of the scientific advisory boards for Roche Diagnostics, Genentech, Inc, and AbbVie, Inc; and consulting for Araclon/Grifols, Diadem Pharmacy, and DiamiR. Dr Geldmacher reported receiving grants from UCSF during the conduct of the study and grants from Biogen, grants from Bristol-Myers Squibb, grants from Eisai, grants and personal fees from Genentech, grants from AbbVie, grants from Neurim, grants from Janssen, grants from Lilly, and personal fees from Grifols outside the submitted work. Dr Powers reported receiving grants from Alzheimer's Association, grants from Corticobasal Degeneration Solutions, and grants and nonfinancial support from Cortice Bioscience during the conduct of the study. Dr Shamloo reported receiving grants from the NIH during the conduct of the study. Dr B. L. Miller reported being the medical director for John Douglas French Foundation and scientific director for the Tau Consortium; serving on the Director/Medical Advisory Board of the Larry L. Hillblom Foundation and as a Scientific Advisory Board Member for the National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia (United Kingdom); and serving as a board member for the American Brain Foundation. Dr Roberson reported receiving research support from grants RF1AG059405, RF1AG059009, and R01NS075487 from the NIH, Bluefield Project to Cure Frontotemporal Dementia, Alzheimer’s Drug Discovery Foundation, BrightFocus Foundation, Weston Brain Institute, the Alzheimer’s Association, AbbVie, Inc, Alector, Inc, Avid Radiopharmaceuticals, Biogen, Inc, Bristol-Myers Squibb, C2N, Eli Lilly and Company, and Roche Diagnostics; consulting for Applied Genetic Technologies Corporation, AVROBIO, Inc, Biogen, Inc, and Novartis International AG; and owning intellectual property related to tau. Dr Boxer reported research support from grants U54NS092089, R01AG038791, U01AG045390, and U24AG057437 from the NIH, Tau Research Consortium, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, and the Alzheimer’s Association; serving as a consultant for Aeton, AbbVie, Inc, AGTC, Alector, Inc, Amgen, Inc, Arkuda Therapeutics, Arvinas, Inc, Eisai Co, Ltd, Ionis Pharmaceuticals, iPierian, Inc, Janssen Pharmaceutica, Lundbeck Pharmaceuticals, Merck & Co, Novartis International AG, Pinteon Therapeutics, Inc, Passage Bio, Samumed, LLC, Third Rock Ventures, Toyama Chemical Co, UCB, and Wave Neuroscience; owing stock options in Alector, Inc, and Arvinas, Inc; and receiving research support from Avid Radiopharmaceuticals, Biogen, Inc, Bristol-Myers Squibb, C2N, Cortice Biosciences, Inc, Eli Lilly and Company, Forum Pharmaceuticals, Inc, Genentech, Inc, Janssen Pharmaceutica, Pfizer, Inc, Roche Diagnostics, and TauRx Therapeutics, Ltd. No other disclosures were reported.

Figures

Figure 1.. Trial Profile

AD indicates Alzheimer disease; CBS, corticobasal syndrome; mITT, modified intention to treat; OLE, open-label extension; PSP, progressive supranuclear palsy; and 4RT, 4-Repeat Tauopathy.

Figure 2.. Baseline Cerebrospinal Fluid Biomarker and Volumetric Magnetic Resonance Imaging Measurements

Data are expressed as medians with 25% and 75% quartile bars. A, Differences in cerebrospinal fluid (CSF) levels of β-amyloid 1-42 (Aβ42), phosphorylated tau (p-tau), and neurofilament light chain (NfL) at baseline among diagnostic groups with Alzheimer disease (AD), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). B, Differences in brain volume among AD, CBS, and PSP compared with a group of 44 age- and sex-matched healthy control participants. All maps thresholded at P < .05 (familywise error). GM indicates gray matter; WM, white matter. Color scale bars indicate t scores. aP < .001 compared with CBS cohort. bP < .001 compared with PSP cohort. cP = .001 compared with CBS cohort. dP = .03 compared with PSP cohort.