Delving into the Latest Updates on ASC-06 with Synapse

Overview

Basic Info

Drug Type

siRNA

Synonyms

ALN VSP, ALN-VSP

+ [1]

Target

KIF11 x VEGF-A

Mechanism

KIF11 inhibitors(Kinesin-like protein 1 inhibitors), VEGF-A inhibitors(Vascular endothelial growth factor A inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Solid tumor

Inactive Indication

Advanced Malignant Solid NeoplasmLiver CancerMalignant ascites

Originator Organization

Alnylam Pharmaceuticals, Inc.

Active Organization

Arbutus Biopharma Corp.

Inactive Organization

Alnylam Pharmaceuticals, Inc.

Ascletis Pharma, Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

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Sequence Code 29830285Sense strand

Sequence Code 254615900Antisense strand

Sequence Code 29402701Sense strand

Sequence Code 29830281Antisense strand

OBJECTIVETo establish an improved method for stereotactic location of the supraoptic nucleus in rats.METHODSTwenty-four SD rats were randomly divided into experimental group (12 rats) and control group (12 rats) for oblique (20° to the left) stereotactic puncture (OSP group) and vertical stereotactic puncture (VSP group), respectively, both targeting the supraoptic nucleus (SON). The surgical data and postoperative (within 24) mortality of the rats were compared between the two groups.RESULTSThe nucleus locating time was longer in OSP group than in VSP group (59.55∓3.64s vs 27.44∓2.18 s, P=0.000), and the postoperative mortality rate of the rats did not differ significantly between the groups (0 vs 44.4%, P=0.082). In OSP group, compared with VSP group, the procedure was associated with a lowered rupture rate of the superior sagittal sinus (11.1% vs 88.9%, P=0.003), a shortened hemostatic time after craniotomy (52.89∓24.05 s vs 157.445 ime a s, P=0.000) and after puncture (24.33 reas 45 s vs 133.89∓28.81 s, P=0.000), and also a shortened operation time (178.89 on tims vs 362.44 timees, P=0.000).CONCLUSIONThe improved method for locating supraoptic nucleus in rats is convenient, stable and reproducible, and helps to avoid important blood vessels and specific nuclei according to the needs of different experiments and allows the operators to choose different surgical paths.

01 Oct 2014·Nanomedicine

siRNA Nanoparticles: The Future of RNAi Therapeutics for Oncology?

Author: Chou, Szu-Ting ; Mixson, A James

siRNA clinical trials: state of the art With the emergence of siRNA-based nanomedicine as a powerful therapeutic strategy for cancers, seven of these therapeutics have now advanced to clinical trials. Carriers of siRNA therapeutics include transferrin-modified cyclodextrin (CALAA-01, Arrowhead Research Corporation, CA, USA), in vivo jetPEI (SNS01-T; Sevion Technologies, NJ, USA), cationic liposomes (ALN-VSP02, Alnylam Pharmaceuticals, MA, USA; TKM080301, Tekmira Pharmaceuticals, Burnaby, Canada; Atu027, Silence Therapeutics, London, UK; and DCRMYC, Dicerna Pharmaceuticals, Watertown, MA, USA) and neutral liposomes (siRNA–EphA2–1,2-dioleoyl-sn-glycero3-phosphocholine [DOPC], MD Anderson Cancer Center, TX, USA ). Among those in clinical trials, the cationic lipoplex targeting MYC1a (DCR-MYC) is the only nanoplex that requires the Dicer enzyme in order to obtain functional siRNA. In 2008, the transferrin-modified cyclodextrin polyplex (CALAA-01) was the first siRNA nanoparticle to be approved for cancer clinical trials. In a preclinical mouse study, a single dose of the cyclodextrin nanoplex targeting luciferase mRNA reduced its activity by 80% [1]. More importantly, melanoma patients receiving CALAA-01 in a Phase I clinical trial showed a 50–80% reduction in the RRM2 mRNA compared with mRNA from untreated tumor tissues [2]. Although this study showed promise, the development of CALAA-01 has been delayed and no results have been reported. SNS01-T is a polyethyleneimine (PEI)based (in vivo JetPEI) nanoparticle containing siRNAs targeting EIF5A and decoy plasmids expressing nonhypusinable eIF5A mutants for treatment of multiple myeloma and non-Hodgkin’s B-cell lymphoma [3]. Francis and colleagues have shown that SNS01-T enhances the antitumor efficacy of lenalidomide and bortezomib in a xenograft model [3]. An open-label, Phase I/II doseescalation study that includes 15 patients is currently underway. Sevion technologies, the manufacturer of SNS01-T, has reported no dose-limiting toxicities in four patients at a dose of 0.2 mg/kg of the nanoparticle. Cationic lipid nanoparticles (LNPs) have effectively downregulated oncogenes in malignant hepatomas (CDH16, PLK1, VEGF and MYC1a) and prostate tumors (PKN3) [4]. While LNPs have a circulation half-life that is longer than 18 h [5], most lipoplexes are ultimately internalized by the liver and spleen. Although the accumulation of lipoplexes may lead to tissue toxicity in these organs at higher dosages, they appear to be well-tolerated by humans at defined dosages. In Phase I clinical trials, the maximum tolerated doses were 0.336, 0.75 and 1.25 mg/kg for Atu027, TKM080301 and ALN-VSP02, respectively. As a result, LNPs targeting PKN3 (Atu027) and PLK1 (TKM080301) have been advanced to Phase II trials. Neutral DOPC liposomes have been used to target ovarian cancers (EPHA2, PTK2, and IL8) and melanoma (thrombin receptor) [6]. While siRNA–EphA2–DOPC inhibited tumor growth by approximately siRNA nanoparticles: the future of RNAi therapeutics for oncology?

01 Dec 2013·Nature MedicineQ1 · MEDICINE

Kinesin inhibitor marches toward first-in-class pivotal trial

Q1 · MEDICINE

Author: Owens, Brian

Array is also looking at a potential biomarker, alpha-1 acidic glycoprotein (AAG), which is often elevated in people with multiple myeloma.AAG is a ′cleanup′ protein in the blood serum that can bind to ARRY-520, rendering it ineffective.In a 32-person trial in which patients with myeloma received ARRY-520 alone, 5 of the 21 participants with low AAG levels showed a reduction in M protein that lasted for more than 8 mo on average, whereas none of the 5 participants with high AAG levels experienced such a favorable response.According to Koch, the findings, which will also be presented at the Dec. ASH meeting, suggest that AAG levels could help indicate who might be a good candidate for the drug. "There are very few mechanisms that show such strong single-agent activity," he says.Array is not the only company that has faith in the KSP pathway.At least two other companies, ArQule and Alnylam Pharmaceuticals, both based in the Boston area, are developing compounds that target KSP.ArQule′s ARQ 621 is being tested in both hematol. and solid tumor cancers, while Alnylam′s ALN-VSP is focused on liver cancer.ALN-VSP is unique among these drugs, as it does not target the KSP protein directly, but uses RNA interference to prevent it from being expressed in the first place.(ARQ 621, like ARRY-520, is a typical small mol. that′s administered i.v.) So far, both have only been tested in phase 1 trials.At first, ARRY-500 will probably be used only in people with myeloma who have failed on other drugs.But Andy Robbins, Array′s senior vice-president of com. and strategy, hopes that KSP inhibitors like ARRY-520 will one day form a frontline therapy, alongside the two entrenched classes of therapies: immunomodulators such as Revlimid (lenalidomide) and proteosome inhibitors such as Kyprolis and Velcade. "We have the potential to be a third backbone treatment," he says.

100 Deals associated with ASC-06

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Cancer	Phase 3	-	Ascletis Pharma, Inc.	-
Malignant ascites	Phase 2	ES	Alnylam Pharmaceuticals, Inc.	10 Mar 2009
Advanced Malignant Solid Neoplasm	Phase 2	ES	Alnylam Pharmaceuticals, Inc.	01 Mar 2009
Advanced Malignant Solid Neoplasm	Phase 2	US	Alnylam Pharmaceuticals, Inc.	01 Mar 2009
Liver Cancer	Phase 2	-	Ascletis Pharma, Inc.	-
Solid tumor	Preclinical	CA	Arbutus Biopharma Corp.	20 May 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2012	Phase 1	Neoplasms	37	ALN-VSP02	(yrbxsmxpii) = buvdrlhvsc wuluphltwd (fywqdceauv )	-	20 May 2012
ASCO2011	Phase 1	Liver Cancer	-	ALN-VSP02	crvgmybjqq(bzcahghzcm) = mlfghwozwm vadaatfrkj (wisllwjbgx ) View more	-	20 May 2011