Delving into the Latest Updates on Apatorsen with Synapse

Overview

Basic Info

Drug Type

Antisense oligonucleotides

Synonyms

Apatorsen Sodium, ISIS-306053, OGX-427

Target

Hsp27

Mechanism

Hsp27 inhibitors(Heat shock protein beta-1 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication

Bladder CancerNon-Small Cell Lung CancerPancreatic Cancer+ [1]

Inactive Indication

Advanced Lung Squamous Cell CarcinomaBreast CancerMetastatic castration-resistant prostate cancer+ [7]

Originator Organization

University of British Columbia

Active Organization

OncoGenex Pharmaceuticals, Inc.Ionis

University of British Columbia

Inactive Organization

Achieve Life Sciences, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Gene Sequence

Sequence Code 29963446

Source: *****

Within 10 years following definitive therapy for prostate cancer, ∼20-50% of patients (pts) experience biochemical recurrence (BCR) characterized by rising prostate-specific antigen (PSA) levels. Pts with high-risk BCR have an increased risk of mortality and improved therapies are needed. The objective of EMBARK was to evaluate the efficacy and safety of enzalutamide (enza) + androgen deprivation therapy (ADT) and enza monotherapy (mono) in pts with high-risk BCR.

METHODS:

EMBARK is a randomized, phase 3 study of pts with BCR considered high-risk: PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomized (1:1:1) to enza 160 mg/day + leuprolide acetate (LA) (double-blind), placebo (pbo) + LA (double-blind), or enza mono (open-label). LA 22.5 mg was administered every 12 weeks. If the PSA at week 36 was <0.2 ng/mL, therapy was stopped at week 37 and restarted when PSA was ≥2 ng/mL for pts with primary RP, and ≥5 ng/mL for pts without RP. The primary endpoint, determined by blinded, independent central review (BICR), was metastasis-free survival (MFS) with enza + LA vs pbo + LA. Key secondary endpoints were MFS of enza mono vs pbo + LA, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enza + LA or enza mono vs pbo + LA.

RESULTS:

1068 pts were randomized into the study (enza + LA, n=355; pbo + LA, n=358; enza mono, n=355). After median follow-up of 60.7 months, per BICR, MFS for enza + LA (HR 0.42; 95% CI 0.30-0.61; p<0.0001) and enza mono (HR 0.63; 95% CI 0.46-0.87; p=0.0049) were statistically superior to pbo + LA. Statistically significant improvements were also observed in risk of PSA progression (enza + LA: HR 0.07; 95% CI, 0.03-0.14; enza mono: HR 0.33; 95% CI, 0.23-0.49; both p<0.0001) and time to first use of new antineoplastic therapy (enza + LA: HR 0.36; 95% CI, 0.26-0.49; enza mono: HR 0.54; 95% CI, 0.41-0.71; both p<0.0001). Interim OS data trended in favor enza + LA (HR 0.59; 95% CI, 0.38-0.91; p=0.0153, did not cross interim efficacy boundary) and enza mono (HR 0.78; 95% CI, 0.52-1.17; p=0.2304). Fatigue and hot flash were the most common adverse events; no new safety signals were observed.

CONCLUSIONS:

In pts with high-risk BCR, enza + ADT and enza mono demonstrated a statistically significant and clinically meaningful improvement in MFS vs pbo + ADT. The safety profile of enza was consistent with results from previous clinical studies.

CLINICAL TRIAL REGISTRATION NUMBER:

NCT02319837.

SOURCE OF FUNDING:

Pfizer Inc. and Astellas Pharma Inc.Conflict of Interest and Disclosure Statement:Neal D. Shore reports grant support and consulting fees from AbbVie, Amgen, Astellas Pharma Inc., AstraZeneca, Bayer, Clovis Oncology, Dendreon Pharmaceuticals LLC, Ferring Pharmaceuticals, GenesisCare, Janssen Oncology, Merck, Myovant Sciences, Pfizer Inc., Sanofi-Genzyme, and Tolmar Pharmaceuticals, Inc. Murilo de Almeida Luz reports receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, Merck Sharp & Dohme, and Pfizer Inc.; being an advisory board member for Astellas Pharma Inc., Bayer, and Janssen; sponsored research from Bayer, Bristol Myers Squibb, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen, and Roche; receiving travel expenses from AstraZeneca, Bayer, Janssen, and Pfizer Inc. Ugo De Giorgi reports serving as a consultant for Janssen, Astellas Pharma Inc., Sanofi, Bayer, Pfizer Inc., Bristol Myers Squibb, Novartis, Ipsen, and Merck Sharp & Dohme. Martin Gleave reports stock or ownership interest in OncoGenex Technologies Inc., Sustained Therapeutics Inc., and Sikta Biopharma; is a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Genova Diagnostics (GDx), Janssen, Pfizer Inc., Roche, Sanofi, and TerSera Therapeutics LLC; and holds patents for OGX-011, OGX-427, ST-CP, and ST-POP. Geoffrey T. Gotto reports receiving honoraria from Amgen, Astellas Pharma Inc., Bayer, Ferring Pharmaceuticals, Janssen, and Merck; being a consultant or advisory board member for Amgen, Astellas Pharma Inc., Bayer, Janssen, and Merck; providing expert testimony for Janssen; and receiving support for travel, accommodation, and expenses from Janssen. Gabriel P. Haas reports being an employee of and shareholder in Astellas Pharma Inc. Miguel Ramirez-Backhaus reports serving as a consultant or advisory board member for Astellas Pharma Inc., Bayer, Janssen, and Karl Storz; receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, and GP Pharm. Antti Rannikko reports being a board member for the Ida Montin Foundation, and Orion Research Foundation; being an advisory board member for Bayer, Janssen, and Orion Pharma; being a stockholder and clinical advisor for Aqsens Health; being a clinical investigator for Astellas Pharma Inc., Bayer, Janssen, Orion Pharma, and RhoVac AB; and receiving competitive state research funding from HUS Helsinki University Hospital, Finnish Cancer Organizations, and the Jane and Aatos Erkko Foundation. Jamal Tazari, Yiyun Tang, and Fabian Zohren are employees of and shareholders in Pfizer Inc. Swetha Sridharan reports no conflicts of interest. Jennifer Sugg is an employee of Astellas Pharma Inc., and a shareholder in AstraZeneca. Ronald F. Tutrone, Jr. reports being an advisory board member for Bayer; and receiving speaker honoraria from Astellas Pharma Inc., Exosome Diagnostics, Inc., Myovant Sciences, and Pfizer Inc. Balaji Venugopal reports receiving honoraria from Bristol Myers Squibb, Eisai Co., Ltd, EUSA Pharma, Ipsen, Janssen, and Merck; being a consultant or advisory board member for Janssen, Merck Sharp & Dohme Oncology, and Pfizer Inc./EMD Serono; and receiving support for travel, accommodation, and expenses from EUSA Pharma, and Ipsen. Arnauld Villers reports receiving research grants from Astellas Pharma Inc., Ferring Pharmaceuticals, Ipsen, and Janssen. Henry H. Woo reports being an advisory board member for Astellas Pharma Inc., Bayer, Boston Scientific Corporation, and Mundipharma International Ltd; and reports receiving speaker honoraria from AbbVie, Astellas Pharma Inc., Boston Scientific Corporation, and Janssen. Stephen J. Freedland reports being a consultant for Astellas Pharma Inc., AstraZeneca, Bayer, Dendreon Pharmaceuticals LLC, Janssen, Merck, Myovant Sciences, Pfizer Inc., and Sanofi.

ACKNOWLEDGMENTS:

The authors thank all the patients, their families, and the investigators and investigational site members involved in this study.Editorial Acknowledgement:Medical writing and editorial support was provided by Julie B. Stimmel, PhD, Sinead Stewart, and Rosie Henderson, of Onyx (a Prime Global Agency), funded by Pfizer, Inc. and Astellas Pharma Inc., the co-developers of enzalutamide.Submission Category:prostate cancer.Sub-category:Advanced (including drug therapy).

01 Feb 2023·Molecular therapy : the journal of the American Society of Gene Therapy

DDX5 mRNA-targeting antisense oligonucleotide as a new promising therapeutic in combating castration-resistant prostate cancer

Article

Author: Cherif, Chaïma ; Audebert, Stéphane ; Taïeb, David ; Paris, Clément ; Baudelet, Emilie ; Fazli, Ladan ; Gleave, Martin ; Bertucci, François ; Bastide, Cyrille ; Lannes, François ; Finetti, Pascal ; Hamimed, Mourad ; Le, Thi Khanh ; Rocchi, Palma ; Omabe, Kenneth ; Barbolosi, Dominique

The heat shock protein 27 (Hsp27) has emerged as a principal factor of the castration-resistant prostate cancer (CRPC) progression. Also, an antisense oligonucleotide (ASO) against Hsp27 (OGX-427 or apatorsen) has been assessed in different clinical trials. Here, we illustrate that Hsp27 highly regulates the expression of the human DEAD-box protein 5 (DDX5), and we define DDX5 as a novel therapeutic target for CRPC treatment. DDX5 overexpression is strongly correlated with aggressive tumor features, notably with CRPC. DDX5 downregulation using a specific ASO-based inhibitor that acts on DDX5 mRNAs inhibits cell proliferation in preclinical models, and it particularly restores the treatment sensitivity of CRPC. Interestingly, through the identification and analysis of DDX5 protein interaction networks, we have identified some specific functions of DDX5 in CRPC that could contribute actively to tumor progression and therapeutic resistance. We first present the interactions of DDX5 and the Ku70/80 heterodimer and the transcription factor IIH, thereby uncovering DDX5 roles in different DNA repair pathways. Collectively, our study highlights critical functions of DDX5 contributing to CRPC progression and provides preclinical proof of concept that a combination of ASO-directed DDX5 inhibition with a DNA damage-inducing therapy can serve as a highly potential novel strategy to treat CRPC.

01 Dec 2019·The oncologistQ2 · MEDICINE

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial

Q2 · MEDICINE

Article

Author: Shipley, Dianna L. ; Spigel, David R. ; Waterhouse, David M. ; Hainsworth, John D. ; Page, Ray D. ; Mekhail, Tarek ; Jones, Suzanne F. ; Jacobs, Cindy ; Ward, Patrick J. ; Hemphill, Brian ; Shih, Kent C. ; McCleod, Michael ; Burris, Howard A. ; Whorf, Robert C. ; Stilwill, Joseph

Abstract:

Background:

This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC).

Methods:

Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity.

Results:

The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months.

Conclusion:

The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Implications for Practice:

This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

1

News (Medical) associated with Apatorsen

08 Mar 2007

·www.biospace.com

OncoGenex Technologies Inc. Withdraws Initial Public Offering

VANCOUVER, March 7 /PRNewswire/ - OncoGenex Technologies Inc. announced today that the company has withdrawn its registration statement from the U.S. Securities and Exchange Commission, citing market conditions as a deterrent to completing its initial public offering. "Due to the recent adverse market conditions, we have decided not to move forward with an initial public offering at this time," stated Scott Cormack, President and Chief Executive Officer of OncoGenex. "We anticipated pricing our initial public offering on February 27, coincidentally the same day that the equity markets suffered the largest one-day decline in four years. Given current market conditions, we believe it is in our shareholders' best interest to withdraw our initial public offering and continue to focus on delivering results from our phase 2 programs. "We have the resources to complete our five ongoing phase 2 clinical trials with our lead product candidate, OGX-011, in prostate, breast and non-small cell lung cancers," added Cormack. "We expect to have primary endpoint data from all five of these trials by the end of this year, and we look forward to reporting data in the appropriate forums." About OncoGenex OncoGenex is committed to the development and commercialization of new cancer therapies that address treatment resistance in cancer patients. OncoGenex currently has three product candidates in development: OGX-011, OGX-427 and OGX-225. These product candidates are designed to selectively inhibit the production of proteins that are associated with treatment resistance and that are over-produced in response to a variety of cancer treatments. OncoGenex' aim in targeting these particular proteins is to disable the tumor cells' adaptive defenses, render the tumor cells susceptible to attack with a variety of cancer therapies including chemotherapy, and facilitate tumor cell death. More information on OncoGenex and the company's pipeline is available at . Forward-looking Statements This press release may include forward-looking statements. Statements regarding future events, expectations and beliefs of management and other statements that do not express historical facts, are forward-looking statements. Words such as "believe", "may", "will", "estimate", "continue", "anticipate", "intend", "expect", "plan", "predict", "potential" and similar expressions, as they relate to OncoGenex, our business and our management, are intended to identify forward-looking statements. We have based these forward-looking statements largely on our current expectations and projections about future events and financial trends affecting the financial condition of our business. Forward-looking statements should not be read as a guarantee of future performance or results, and will not necessarily be accurate indications of the times at, or by, which such performance or results will be achieved. Forward-looking statements are based on information available at the time those statements are made and/or management's good faith belief as of that time with respect to future events, and are subject to risks and uncertainties that could cause actual performance or results to differ materially from those expressed in or suggested by the forward-looking statements. Important factors that could cause such differences include, but are not limited to: delays or unfavorable results from our current and planned clinical trials; our ability to establish and maintain intellectual property protection for our product candidates; our access to additional capital; our ability to enter into and maintain relationships with third parties, such as licensors, manufacturers, suppliers and those who conduct clinical trials for us; our ability to enroll patients for our clinical trials; our ability to implement and manage our sales and commercialization initiatives; the impact of competition and technological change; the timing of necessary regulatory clearances; coverage and reimbursement policies of governmental and private third-party payors, including the U.S. Medicare and Medicaid programs; general economic and business conditions, both nationally and in our markets; our ability to attract and retain key management and scientific personnel; existing and future regulations that affect our business; and other factors included in OncoGenex's filings with the United States Securities and Exchange Commission and the Canadian securities regulators. In light of these risks and uncertainties, forward-looking events and circumstances included in this presentation may not occur and actual results could differ materially from those anticipated or implied in the forward-looking statements. Forward-looking statements speak only as of the date the statements are made. You should not put undue reliance on any forward-looking statements. We assume no obligation to update forward-looking statements to reflect actual results, changes in assumptions or changes in other factors affecting forward-looking information, except to the extent required by applicable securities laws. If we do update one or more forward-looking statements, no inference should be drawn that we will make additional updates with respect to those or other forward-looking statements. CONTACT: OncoGenex Contact: Scott Cormack, President & CEO, (604) 630-5400, scormack@oncogenex.ca; Media Contact: Jason Spark, Porter Novelli Life Sciences, (619) 849-6005, jspark@pnlifesciences.com OncoGenex Technologies Inc. CONTACT: OncoGenex Contact: Scott Cormack, President & CEO, (604)630-5400, scormack@oncogenex.ca; Media Contact: Jason Spark, Porter NovelliLife Sciences, (619) 849-6005, jspark@pnlifesciences.com >>> Discuss This Story

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100 Deals associated with Apatorsen

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Lung Squamous Cell Carcinoma	Phase 2	GB	Achieve Life Sciences, Inc.	01 Jun 2014
Secondary malignant neoplasm of pancreas	Phase 2	US	Achieve Life Sciences, Inc.	01 Sep 2013
metastatic non-small cell lung cancer	Phase 2	US	Achieve Life Sciences, Inc.	01 Jul 2013
Non-squamous non-small cell lung cancer	Phase 2	US	Achieve Life Sciences, Inc.	01 Jul 2013
Recurrent Bladder Cancer	Phase 2	US	Achieve Life Sciences, Inc.	01 Apr 2013
Urothelial carcinoma recurrent	Phase 2	US	Achieve Life Sciences, Inc.	01 Apr 2013
Metastatic castration-resistant prostate cancer	Phase 2	US	Achieve Life Sciences, Inc.	01 Dec 2012
Metastatic castration-resistant prostate cancer	Phase 2	CA	Achieve Life Sciences, Inc.	01 Dec 2012
Salivary Gland Adenoma, Pleomorphic	Phase 2	US	Achieve Life Sciences, Inc.	01 Dec 2012
Salivary Gland Adenoma, Pleomorphic	Phase 2	CA	Achieve Life Sciences, Inc.	01 Dec 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01829113 (SPRUCE, Pubmed \| Oncologist) Manual	Phase 2	Non-squamous non-small cell lung cancer First line	155	Carboplatin+Pemetrexed+Apatorsen	yfjuymqzfg(qrbgdlrxmm) = nmbphyxtgf pujtdcmsnm (bejsxakalv ) View more	Negative	01 Dec 2019
				Carboplatin+Pemetrexed+Placebo	yfjuymqzfg(qrbgdlrxmm) = qomkjqagza pujtdcmsnm (bejsxakalv ) View more
NCT01681433 (GU12-159, CTgov)	Phase 2	Salivary Gland Adenoma, Pleomorphic \| Metastatic castration-resistant prostate cancer	72	OGX-427+Prednisone+Abiraterone Acetate (Experimental: Arm A)	clziccbkur(wghmmmqlxl) = nnzqppnfxu dpxhewlnfn (sjutuyzuod, rsfvynklel - nrrcgdipxt) View more	-	18 Oct 2018
				Prednisone+Abiraterone Acetate (Control Arm: Arm B)	clziccbkur(wghmmmqlxl) = bgrnttvxmq dpxhewlnfn (sjutuyzuod, yllqmvxyay - kbpihjroso) View more
NCT01829113 (SPRUCE, CTgov)	Phase 2	metastatic non-small cell lung cancer \| Non-squamous non-small cell lung cancer	155	OGX-427 (OGX-427)	dtcotlfwtl(zsoqqbxjjv) = usjznpdpoo dapywmnroc (acmihsgxnf, ydiqswtdpb - wwirmzsnik) View more	-	08 Jun 2018
				Placebo (Placebo)	dtcotlfwtl(zsoqqbxjjv) = dbwmurlkfc dapywmnroc (acmihsgxnf, iblrmlzygg - ijfjmqdaab) View more
NCT01780545 (Borealis-2, Pubmed) Manual	Phase 2	Metastatic urothelial carcinoma	200	docetaxel+Apatorsen	bezewzqsjy(yymoozslhh) = ikbcneoxaq lsjdzijbif (knprjifbqa )	Positive	01 May 2018
				docetaxel	bezewzqsjy(yymoozslhh) = gfnkrewleh lsjdzijbif (knprjifbqa )
NCT01120470 (Pubmed) Manual	Phase 2	Metastatic castration-resistant prostate cancer	74	apatorsen+prednisone	dpbtsnaqyf(jcbapfquxa) = vplpbpnnhs jlhtcxhvrb (qcnmqewste, 32.9 ~ 67.1) View more	Positive	01 Apr 2018
				prednisone	dpbtsnaqyf(jcbapfquxa) = vpiwhzjzxr jlhtcxhvrb (qcnmqewste, 26.3 ~ 59.2) View more
NCT01844817 (RAINIER, Pubmed \| Oncologist) Manual	Phase 2	Secondary malignant neoplasm of pancreas First line	132	Gemcitabine+Nab-Paclitaxel+Apatorsen	vzcctmzoza(puvadqqizs) = knpmpngkji hqzbojfluf (zdhjjfzfrp ) View more	Negative	01 Dec 2017
				Gemcitabine+Nab-Paclitaxel+Placebo	vzcctmzoza(puvadqqizs) = pxaxibietf hqzbojfluf (zdhjjfzfrp ) View more
NCT01844817 (RAINIER, CTgov)	Phase 2	Secondary malignant neoplasm of pancreas	132	OGX-427 (OGX-427)	coabfwqwgh(pbrudazuab) = euqkctwqik msfqqtzysv (qnbkmvmlfl, rkdfuhqtxr - ysasdoorun) View more	-	16 May 2017
				Placebo (Placebo)	coabfwqwgh(pbrudazuab) = qdifiqwzqr msfqqtzysv (qnbkmvmlfl, cyltvtvwuv - xwgierxzja) View more
NCT01780545 (GU12-160 \| Borealis-2, ASCO_GU2017)	Phase 2	Metastatic urothelial carcinoma	200	OGX-427 plus docetaxelOGX-427 plus docetaxel	nexjdpqgqv(xlwknmyxqw) = whzeienjpo mgzilqcmmr (okrtlcnime, 4.6 - 9.2)	Positive	29 Mar 2017
				Docetaxel alone	nexjdpqgqv(xlwknmyxqw) = syspaykimk mgzilqcmmr (okrtlcnime, 4.8 - 7.3)
NCT00487786 (Pubmed \| Ann Oncol) Manual	Phase 1	Castration-Resistant Prostatic Cancer \| Advanced cancer	42	apatorsen	nvvkrgfqpc(oycztrqdgt) = A maximum tolerated dose was not defined. tnmdazyqpm (kezbcpsmlk )	Positive	01 Jun 2016
				apatorsen (patients with CRPC)
ASCO2012	Phase 2	Metastatic castration-resistant prostate cancer	38	OGX-427 plus prednisoneOGX-427 plus prednisone	irxqnleqtg(dmunvkpzkj) = gzwicadjbt dvjiezbqvh (xhajzfkrcg ) View more	-	20 May 2012
				Prednisone	irxqnleqtg(dmunvkpzkj) = leevvvdnph dvjiezbqvh (xhajzfkrcg )