Background

TPI 287 is a tubulin-binding and microtubule-stabilizing drug that is being clinically developed by Cortice Biosciences, formerly Archer Biosciences. TPI 287 is an abeo-taxane—a synthetic derivative of the taxane diterpenoid drugs used in cancer therapy, such as paclitaxel. Unlike most taxanes, TPI 287 crosses the blood-brain barrier. It has been reported to accumulate in the brain over plasma, possibly because it is a poor substrate for the P-glycoprotein, aka multi-drug-resistance protein, which is located on epithelial cells of the blood-brain barrier and pumps drugs back out of the brain. For this reason TPI 287 is being evaluated for the treatment of brain cancer and primary tumors that have metastasized to the brain (Fitzgerald et al., 2012). 

TPI 287 is also being evaluated for tauopathies. The physiological function of the protein tau includes stabilization of microtubules, and destabilization of these cytoskeletal components related to tau dysfunction is considered an important step in the axonal and dendritic degeneration that leads to neuronal death (for review, see Zempel and Mandelkow, 2014). Prior taxane drugs, e.g. epothilone D, have been tested in Alzheimer's disease, a tauopathy.

Findings

In November 2013, the University of California, San Francisco, began a Phase 1 trial of TPI 287 in 33 patients with mild to moderate Alzheimer's disease whose screening MRI was consistent with this diagnosis. Participants received intravenous infusions of one of three doses of TPI 287 or placebo once every three weeks for nine weeks; those who completed this regimen could opt to continue into an open-label extension comprising three additional infusions and safety monitoring. The primary goal of this study was to determine the maximal tolerated dose of this drug. The secondary goal was to measure drug exposure in plasma and CSF; additional outcome measures included CSF Aβ/tau biomarkers, MRI, and cognitive, behavioral, disability, and safety measures. 

In May 2014, UCSF and the University of Alabama, Birmingham, began a Phase 1 study of TPI 287 in 66 patients who have a primary four-repeat tauopathy, either corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP). To determine eligibility, this study used consensus criteria for PSP and CBD plus an MRI consistent with the clinical diagnosis. People with cortical amyloid on PET scans were excluded to limit the treatment group to participants with pure tau pathology. Like the AD trial, this study aimed to determine the maximum tolerated dose with a nine-week regimen of four infusions of one of three doses of TPI 287 or placebo, plus an optional six-week, open-label extension. It also used largely the same outcome measures. This study was supported by CBD Solutions and the Tau Consortium. In May 2015, reflecting the difficulty of enrolling patients with these rare tauopathies, the enrollment target was cut back to 44 and the age limit increased to 85.

Results of both trials were presented at CTAD (Dec 2017 conference news) and subsequently published (Tsai et al., 2019). A total of 29 AD, 14 PSP, and 30 CBS patients received doses of 2, 6.3, or 20 mg/meter2 TPI 287, or placebo. Three AD patients on the high dose suffered severe allergic reactions; the maximum tolerated dose for this group was 6.3 mg/meter². On exploratory cognitive endpoints, MMSE scores declined less in the treated AD group than placebo; however, the placebo group declined faster than expected on MMSE, which may explain the difference. No other endpoints changed significantly.

The CBD/PSP group suffered no allergic reactions; their maximum tolerated dose was 20 mg/meter². TPI 287, however, caused more falls in CBD and PSP patients, and this cohort had a dose-related worsening on the Clinical Dementia Rating-sum of boxes at three months.

The drug was undetectable in CSF one week after the last infusion.  Among the exploratory biomarkers, only YKL-40, a marker of inflammation, was significantly lower in CSF in the drug-treated CBD/PSP group compared with placebo.

TPI 287 has also been tested in Phase 1 and 2 for a range of cancers, but no trials are currently active.

For all clinical trials of TPI 287, see clinicaltrials.gov.