Therapeutics

TPI 287

Overview

Name: TPI 287
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Corticobasal Degeneration, Progressive Supranuclear Palsy
U.S. FDA Status: Alzheimer's Disease (Phase 1), Corticobasal Degeneration (Phase 1), Progressive Supranuclear Palsy (Phase 1)
Company: Cortice Biosciences

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 receive intravenous infusions of one of three doses of TPI 287 or placebo once every three weeks for nine weeks; those who complete this regimen can opt to continue into an open-label extension comprising three additional infusions and safety monitoring. The primary goal of this study is to determine the maximal tolerated dose of this drug. The secondary goal is to measure drug exposure in plasma and CSF; additional outcome measures include CSF Aβ/tau biomarkers, MRI, and cognitive, behavioral, disability, and safety measures. This study is set to run until March 2017.

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, 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. Like the AD trial, this study aims 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 uses largely the same outcome measures. This study is 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. This study is set to run until spring 2017.

In addition, higher doses of TPI 287 are in trials for glio-, neuro- and medulloblastoma, as well as metastatic melanoma and breast cancer. Studies in pancreatic and prostate cancer have been terminated. For all clinical trials of TPI 27, see clinicaltrials.gov.

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References

Therapeutics Citations

  1. Epothilone D

Paper Citations

  1. . TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol Cancer Ther. 2012 Sep;11(9):1959-67. Epub 2012 May 23 PubMed.
  2. . Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci. 2014 Dec;37(12):721-32. Epub 2014 Sep 12 PubMed.

External Citations

  1. CBD Solutions
  2. Tau Consortium
  3. clinicaltrials.gov

Further Reading

Papers

  1. . Natural products as a rich source of tau-targeting drugs for Alzheimer's disease. Future Med Chem. 2012 Sep;4(13):1751-61. PubMed.
  2. . Progress from Alzheimer's tangles to pathological tau points towards more effective therapies now. J Alzheimers Dis. 2006;9(3 Suppl):257-62. PubMed.
  3. . Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies. J Med Chem. 2014 Jul 24;57(14):6116-27. Epub 2014 Jul 3 PubMed.
  4. . MT-Stabilizer, Dictyostatin, Exhibits Prolonged Brain Retention and Activity: Potential Therapeutic Implications. ACS Med Chem Lett. 2013 Sep 12;4(9):886-9. Epub 2013 Jul 23 PubMed.