Delving into the Latest Updates on ARC-100 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

NBT 287, NBT-287, TPI 287

+ [1]

Target

Tubulin

Mechanism

Tubulin inhibitors

Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication

GlioblastomaMedulloblastomaNeuroblastoma

Inactive Indication

Alzheimer DiseaseBrain metastasesBreast Cancer+ [15]

Originator Organization

Cortice Biosciences, Inc.

Active Organization

Tapestry Pharmaceuticals, Inc.

Cortice Biosciences, Inc.

Inactive Organization

The University of California, San Francisco

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC46H63NO15

InChIKeyFDTAUJJRHBRHIJ-FDJAAIFISA-N

CAS Registry849213-15-6

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Sequential Cohort, Dose-Ranging Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TPI 287 in Patients With Primary Four Repeat Tauopathies: Corticobasal Syndrome or Progressive Supranuclear Palsy

The purpose of this study is to determine the safety and tolerability [maximum tolerated dose (MTD) within planned dosing range] of intravenous (IV) infusions of TPI 287 administered once every 3 weeks for 9 weeks (for a total of 4 infusions) in patients with primary four repeat tauopathies (4RT), corticobasal syndrome (CBS; also called corticobasal degeneration, CBD) or progressive supranuclear palsy (PSP).

Start Date01 May 2014

Sponsor / Collaborator

The University of California, San Francisco

[+2]

NCT02047214 / TerminatedPhase 2

Phase 2 Dose-Escalation Study of TPI 287 in Combination With Bevacizumab in Adults With Recurrent or Progressive Glioblastoma Following a Bevacizumab-Containing Regimen

The purpose of this study is to evaluate the safety, maximum tolerated dose (MTD), and efficacy of TPI 287 in combination with Avastin (bevacizumab) in subjects who have glioblastoma multiforme (GBM) that has progressed following prior radiation and temozolomide (TMZ) therapy and that has progressed following prior bevacizumab therapy.

Start Date01 Jan 2014

Sponsor / Collaborator

Cortice Biosciences, Inc.

100 Clinical Results associated with ARC-100

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100 Translational Medicine associated with ARC-100

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100 Patents (Medical) associated with ARC-100

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9

Literatures (Medical) associated with ARC-100

01 Feb 2023·Cancer chemotherapy and pharmacology

The CNS-penetrating taxane drug TPI 287 potentiates antiglioma activity of the AURKA inhibitor alisertib in vivo

Article

Author: Teer, Landon ; Lehman, Norman L ; Hey, Andrew J ; Williams, Brian J ; Kakar, Aastha ; Schier, Leslie M ; Sak, Müge ; Chen, Joseph ; Al-Kawaaz, Mustafa N G ; Wilson, Megan J ; Zumbar, Cory T

INTRODUCTION:

Glioblastoma (GBM) has a very poor prognosis despite current treatment. We previously found cytotoxic synergy between the AURKA inhibitor alisertib and the CNS-penetrating taxane TPI 287 against GBM tumor cells in vitro.

METHODS:

We used an orthotopic human GBM xenograft mouse model to test if TPI 287 potentiates alisertib in vivo. Western blotting, immunohistochemistry, siRNA knockdown, annexin V binding, and 3-dimensional Matrigel invasion assays were used to investigate potential mechanisms of alisertib and TPI 287 treatment interactions.

RESULTS:

Alisertib + TPI 287 combination therapy significantly prolonged animal survival compared to vehicle (p = 0.011), but only marginally compared to alisertib alone. Alisertib, TPI 287, and combined alisertib + TPI 287 reduced animal tumor volume compared to vehicle-treated controls. This was statistically significant for the combination therapy at 4 weeks (p < 0.0001). Alisertib + TPI 287 treatment decreased anti-apoptotic Bcl-2 protein levels in vivo and in vitro. Expression of the pro-apoptotic protein Bak was significantly increased by combination treatment (p < 0.0001). Pro-apoptotic Bim and Bak knockdown by siRNA decreased apoptosis by alisertib + TPI 287 in GB9, GB30, and U87 cells (p = 0.0005 to 0.0381). Although alisertib and TPI 287 significantly reduced GBM cell invasion (p < 0.0001), their combination was no more effective than TPI 287 alone.

CONCLUSIONS:

Results suggest that apoptosis is the dominant mechanism of potentiation of GBM growth inhibition by alisertib + TPI 287, in part through effects on Bcl-2 family proteins, providing a rationale for further laboratory testing of an AURKA inhibitor plus TPI 287 as a potential therapy against GBM.

01 Feb 2020·JAMA neurologyQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Geldmacher, David S. ; Koestler, Mary ; Powers, Ryan ; Hare, Emma ; Shamloo, Merhdad ; Jung, Joo In ; Rosen, Howard J. ; Tsai, Richard M. ; Chuu, Emmeline L. ; Luong, Phi N. ; Mumford, Paige ; Rabinovici, Gil D. ; Wolf, Amy ; Boxer, Adam L. ; Miller, Zachary ; Ljubenkov, Peter A. ; Natelson-Love, Marissa ; Miller, Bruce L. ; Fagan, Anne M. ; Cobigo, Yann ; Wang, Ping ; Rojas, Julio C. ; McKinley, Emily C. ; Roberson, Erik D. ; Brown, Jesse A.

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.

01 May 2018·Journal of neuro-oncologyQ2 · MEDICINE

The CNS penetrating taxane TPI 287 and the AURKA inhibitor alisertib induce synergistic apoptosis in glioblastoma cells

Q2 · MEDICINE

Article

Author: Urio, Sara ; Lehman, Norman L ; Mifsud, Caroline S ; McElroy, Joseph P ; Bryant, William M ; Dalton, Hailey M ; Li, Xiaohui ; King, Paul D ; Sak, Muge ; Zumbar, Cory T ; Usubalieva, Aisulu ; Farmer, George

Glioblastoma is a highly malignant disease in critical need of expanded treatment options. The AURKA inhibitor alisertib exhibits antiproliferative activity against glioblastoma in vitro and in vivo. Unlike current clinically used taxane drugs, the novel taxane TPI 287 penetrates the CNS. We tested for interactions between three selective AURKA inhibitors and TPI 287 against standard U87 and U1242 cells and primary glioblastoma neurospheres using colony formation assays. Bliss and Chou-Talalay analyses were utilized to statistically test for synergism. Morphological analysis, flow cytometry and annexin V binding were employed to examine cell cycle and apoptotic effects of these drug combinations. TPI 287 not only potentiated the cytotoxicity of the AURKA inhibitors alisertib, MLN8054 and TC-A2317, but was often potently synergistic. Morphologic and biochemical analysis of the combined effects of alisertib and TPI 287 consistently revealed synergistic induction of apoptosis. While each agent alone induces a mitotic block, slippage occurs allowing some tumor cells to avoid apoptosis. Combination treatment greatly attenuated mitotic slippage, committing the majority of cells to apoptosis. Alisertib and TPI 287 demonstrate significant synergism against glioblastoma cells largely attributable to a synergistic effect in inducing apoptosis. These results provide compelling rationale for clinical testing of alisertib and/or other AURKA inhibitors for potential combination use with TPI 287 against glioblastoma and other CNS neoplasms.

1

News (Medical) associated with ARC-100

26 Dec 2007

·www.biospace.com

Tapestry Pharmaceuticals, Inc. Receives Notice Regarding Minimum Bid Price Rule

BOULDER, Colo., Dec. 21 /PRNewswire-FirstCall/ -- Tapestry Pharmaceuticals, Inc. today announced that it received notice on December 18, 2007 from the Nasdaq Stock Market that the minimum bid price of its common stock had fallen below $1.00 for 30 consecutive business days and that Tapestry was therefore not in compliance with Marketplace Rule 4310(c)(4). In accordance with the Nasdaq Marketplace Rule 4310(c)(8)(D), Tapestry has until June 16, 2008, which is 180 calendar days from December 18, 2007, to regain compliance. This notification does not have immediate affect on the listing of the Company's common stock. Tapestry can regain compliance with the minimum bid price rule if the bid price of its common stock closes at $1.00 or higher for a minimum of ten consecutive business days during the initial 180-day period, although Nasdaq may, in its discretion, require Tapestry to maintain a bid price of at least $1.00 per share for a period in excess of ten consecutive business days (but generally no more than 20 consecutive business days) before determining that Tapestry has demonstrated the ability to maintain long-term compliance. If compliance is not achieved by June 16, 2008, Tapestry will be eligible for an additional 180-day compliance period if it meets the Nasdaq Capital Market initial listing criteria as set forth in Marketplace Rule 4310(c) other than the minimum bid price requirement. If Tapestry is not eligible for an additional compliance period, or does not regain compliance during any additional compliance period, Nasdaq will provide written notice to Tapestry that its securities will be delisted. At such time, Tapestry would be able to appeal the delisting determination to a Nasdaq Listing Qualifications Panel. There can be no assurance that Tapestry will be able to regain compliance with the Nasdaq listing requirements or that its securities will not be delisted from the Nasdaq Capital Market on a basis other than failure to maintain a minimum bid price. About Tapestry Pharmaceuticals, Inc. Tapestry Pharmaceuticals, Inc. is a biopharmaceutical company focused on the development of proprietary therapies for the treatment of cancer. Tapestry's lead candidate, TPI 287 is in multiple Phase 2 clinical studies at this time. For more information about Tapestry and its technologies, visit Tapestry's website at glink@tapestrypharma.comlilian@sternir.comtapestry@schwartz-pr.com CONTACT: Gordon Link, Senior Vice President, Chief Financial Officer of Tapestry Pharmaceuticals, Inc., +1-303-516-8500, glink@tapestrypharma.com; or Investor: Lilian Stern of Stern Investor Relations, Inc., +1-212-362-1200, lilian@sternir.com, for Tapestry Pharmaceuticals, Inc.; or Media: Dana Conti of Schwartz Communications, +1-781-684-0770, tapestry@schwartz-pr.com, for Tapestry Pharmaceuticals, Inc. Web site:

100 Deals associated with ARC-100

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Glioblastoma	Phase 2	US	Cortice Biosciences, Inc.	01 Jan 2014
Metastatic melanoma	Phase 2	US	Cortice Biosciences, Inc.	01 Sep 2013
Refractory Neuroblastoma	Phase 2	US	Cortice Biosciences, Inc.	01 Dec 2011
Medulloblastoma	Phase 2	US	Cortice Biosciences, Inc.	01 Dec 2011
Breast Cancer	Phase 2	US	Cortice Biosciences, Inc.	16 Aug 2011
Breast Carcinoma Metastatic in the Brain	Phase 2	US	Cortice Biosciences, Inc.	16 Aug 2011
Glioblastoma Multiforme	Phase 2	US	Cortice Biosciences, Inc.	01 Apr 2010
Pancreatic carcinoma non-resectable	Phase 2	US	Cortice Biosciences, Inc.	01 Oct 2007
Pancreatic carcinoma non-resectable	Phase 2	ES	Cortice Biosciences, Inc.	01 Oct 2007
Prostatic cancer metastatic	Phase 2	US	Cortice Biosciences, Inc.	01 Jan 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02133846 \| NCT01966666 (Pubmed \| JAMA Neurol) Manual	Phase 1	Alzheimer Disease \| Corticobasal degeneration \| Supranuclear Palsy, Progressive	68	TPI-287	oeqifmmncy(mukqblmkdo) = bkctcnvoys ynokrxdxcj (svsoosqkzy ) View more	Positive	01 Feb 2020
NCT02133846 \| NCT01966666 (Pubmed \| JAMA Neurol) Manual	Phase 1		68	Placebo	oeqifmmncy(mukqblmkdo) = vxwnfdyiyy ynokrxdxcj (svsoosqkzy ) View more	Positive	01 Feb 2020
NCT01582152 (CTgov)	Phase 1/2	Recurrent Glioblastoma	12	TPI+Bevacizumab (TPI 287 160 mg/m2 + Bevacizumab)	szkyhxnvgy(mbjecaxidu) = hlnzfqozav oijnuiexud (gdnurizpti, iqoqkveqkc - xedjhwyjhr) View more	-	05 Jun 2019
NCT01582152 (CTgov)	Phase 1/2	Recurrent Glioblastoma	12	TPI+Bevacizumab (TPI 287 140 mg/m2 + Bevacizumab)	szkyhxnvgy(mbjecaxidu) = ipgimiedhy oijnuiexud (gdnurizpti, fhuaxolskl - apeoxvyumh) View more	-	05 Jun 2019
NCT01332630 (CTgov)	Phase 2	Breast Carcinoma Metastatic in the Brain \| Breast Cancer	24	TPI 287+Ranitidine+Benadryl+Dexamethasone	azrzykxghb(sdvsoksgmj) = fjzuwabuzr gygzzxzhlh (nrdjbztsuk, fkzhcjnopw - ddqblllnau) View more	-	10 Jul 2018
NCT01933815 (ASCO2017) Manual	Phase 1/2	Recurrent Glioblastoma	24	bevacizumab+TPI 287	whaxypsytd(hnykajgkgz) = eyvaywnlfc hnyktrzfva (vcifpgydxs ) View more	Positive	05 Jun 2017
NCT01067066 (Pubmed \| Melanoma Res) Manual	Phase 1	Metastatic melanoma	21	temozolomide+TPI 287	dioqvljbpt(zrkimkghne) = neuropathy and six patients experienced grade III neuropathy xuwbbhxkim (pjrrfqulhn ) View more	Positive	01 Dec 2016
NCT01113463 (CTgov)	Phase 2	Glioblastoma Multiforme	17	TPI 287	qefgnzxyna(hncmpfpahq) = mgcbfndphw zktvswpgnb (ombprzkirw, fpzkpkshff - opxtgtwoxh) View more	-	31 Oct 2016
NCT01505608 (CTgov)	Phase 1/2	-	14	Temozolomide+Irinotecan (Arm A- Temozolomide and Irinotecan)	ckdlfblyxr(bndobjlper) = llskpggmdv tngjmttyce (fnqtrvverv, sspxglilth - iuggattrnu) View more	-	28 Oct 2016
NCT01505608 (CTgov)	Phase 1/2	-	14	Temozolomide+TPI 287+Irinotecan (Arm B- Temozolomide/Irinotecan + TPI 287)	vqqbvllqly(azpyhevrpp) = jioezjtghb egrhtcftjc (ctmovicjfk, vjhgxenrzm - nartmgffta)	-	28 Oct 2016
NCT01483820 (CTgov)	Phase 1/2	Refractory Neuroblastoma \| Medulloblastoma	8	TPI 287	ddgxriptyx(uqlrbhrtdg) = pkgmvfubce upsytewziy (hycohgheqf, qlysbcpnkk - czsyqpajsz) View more	-	28 Oct 2016
NCT00867568 (CTgov)	Phase 1	Refractory Neuroblastoma \| Medulloblastoma	18	TPI 287	zvslpdmdhp(uzwpdtlcin) = edrecnqfdb spnsyzhlph (jejtrdalpx, nfnbrmzigd - ulxepysgvu) View more	-	28 Oct 2016
NCT02187822 (ASCO2015)	Phase 1	Breast Carcinoma Metastatic in the Brain \| Lung Cancer with Brain Metastasis	36	TPI 287	ymfjpgvndo(zrjjpehjlc) = zbehlieijp wbjipqffxv (kysdzdhhmc )	-	20 May 2015
NCT02187822 (ASCO2015)	Phase 1		36	TPI 287 (FSRT)	ymfjpgvndo(zrjjpehjlc) = ckwumnwhkq wbjipqffxv (kysdzdhhmc )	-	20 May 2015