Delving into the Latest Updates on PEN-866 with Synapse

Overview

Basic Info

Drug Type

Small molecule-drug conjugates

Synonyms

Hsp90-targeted sn-38 conjugate pen-866, Locnartecan

+ [4]

Target

HSP90 x TOP1

Mechanism

HSP90 inhibitors(Heat shock 90kDa proteins inhibitors), TOP1 inhibitors(DNA topoisomerase I inhibitors)

Therapeutic Areas

NeoplasmsRespiratory Diseases

Active Indication

Solid tumorNon-Small Cell Lung CancerSmall Cell Lung Cancer

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmCervical Squamous Cell Carcinoma+ [7]

Originator Organization

Madrigal Pharmaceuticals, Inc.

Active Organization

SciClone Pharmaceuticals (China) Co., LtdSciClone Pharmaceuticals (Holdings) Ltd.

SciClone Pharmaceuticals LLC

Inactive Organization

Tarveda Therapeutics, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC49H49N7O9

InChIKeyQTPZAEAYDWMVJO-GGCSAXROSA-N

CAS Registry1472614-83-7

View All Structures (2)

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Background:
The drug PEN-866 can remain in tumor cells longer than it does in normal cells. It also may be more effective than other drugs at treating Ewing sarcoma and rhabdomyosarcoma. Researchers want to learn if combining PEN-866 with other drugs can treat certain cancers in adolescents and young adults.
Objective:
To learn if the combination of PEN-866 with vincristine and temozolomide can be used to treat adolescents and young adults with solid tumors that have returned after or did not respond to standard treatments, or for which there are no standard treatments.
Eligibility:
People ages 12-39 years who have solid tumors, Ewing sarcoma, or rhabdomyosarcoma that returned after or did not respond to standard treatments.
Design:
Participants will be screened with a medical history, physical exam, and eye exam. They will have heart function tests. They may have imaging scans of the chest, abdomen, and pelvis. They will give blood and urine samples. They may have a tumor biopsy. Some samples will be used for genetic testing. Some screening tests will be repeated during the study.
Participants will get 3 drugs for up to 18 cycles. Each cycle lasts 21 days. They will get PEN-866 and vincristine by IV infusion (a tube in their vein) on Days 1 and 8 of each cycle. They will take temozolomide by mouth on Days 1-5 of each cycle.
Participants will complete questionnaires about their physical, mental, and social health.
Participants will have a follow-up visit 30 days after treatment ends. They may be contacted by phone or email for the rest of their life.

Start Date31 Oct 2024

Sponsor / Collaborator

National Cancer Institute

NCT03221400 / Unknown statusPhase 1/2

A Phase 1/2a, Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of PEN-866 in Patients With Advanced Solid Malignancies

Protocol PEN-866-001 is an open-label, multi-center, first-in-human Phase 1/2a study evaluating PEN-866 in patients with advanced solid malignancies whose disease has progressed after treatment with previous anticancer therapies.

Start Date29 Aug 2017

Sponsor / Collaborator

Tarveda Therapeutics, Inc.

100 Clinical Results associated with PEN-866

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100 Translational Medicine associated with PEN-866

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100 Patents (Medical) associated with PEN-866

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5

Literatures (Medical) associated with PEN-866

17 Jan 2017·Oncotarget

Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models

Article

Author: Cai, Kathy Q. ; Handorf, Elizabeth ; Beglyarova, Natalya ; Proia, David A. ; Restifo, Diana ; Campbell, Kerry ; Skobeleva, Natalia ; Bobrov, Egor ; Golemis, Erica A. ; Astsaturov, Igor ; Khazak, Vladimir

The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the "undruggable" KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA-12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA-12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest.Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists.

15 Oct 2016·Clinical Cancer ResearchQ1 · MEDICINE

A Novel HSP90 Inhibitor–Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer

Q1 · MEDICINE

Article

Author: Duncan, James S. ; Egleston, Brian L. ; Golemis, Erica A. ; Gaponova, Anna V. ; Kopp, Meghan C. ; Skobeleva, Natalia ; Ogawa, Luisa S. ; Proia, David A. ; Duncan, Kelly E. ; Deneka, Alexander Y. ; Nikonova, Anna S. ; Khazak, Vladimir ; Kudinov, Alexander E. ; Cai, Kathy Q. ; Boumber, Yanis

AbstractPurpose: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12% to 13% of total lung cancers, with median survival of <2 years. No targeted therapies have proven effective in SCLC. Although most patients respond initially to cytotoxic chemotherapies, resistance rapidly emerges, response to second-line agents is limited, and dose-limiting toxicities (DLT) are a major issue. This study performs preclinical evaluation of a new compound, STA-8666, in SCLC.Experimental Design: To avoid DLT for useful cytotoxic agents, the recently developed drug STA-8666 combines a chemical moiety targeting active HSP90 (concentrated in tumors) fused via cleavable linker to SN38, the active metabolite of irinotecan. We compare potency and mechanism of action of STA-8666 and irinotecan in vitro and in vivo.Results: In two SCLC xenograft and patient-derived xenograft models, STA-8666 was tolerated without side effects up to 150 mg/kg. At this dose, STA-8666 controlled or eliminated established tumors whether used in a first-line setting or in tumors that had progressed following treatment on standard first- and second-line agents for SCLC. At 50 mg/kg, STA-8666 strongly enhanced the action of carboplatin. Pharmacokinetic profiling confirmed durable STA-8666 exposure in tumors compared with irinotecan. STA-8666 induced a more rapid, robust, and stable induction of cell-cycle arrest, expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and apoptosis in vitro and in vivo, in comparison with irinotecan.Conclusions: Together, these results strongly support clinical development of STA-8666 for use in the first- or second-line setting for SCLC. Clin Cancer Res; 22(20); 5120–9. ©2016 AACR.

04 Oct 2016·Oncotarget

STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma

Article

Author: Trepel, Jane ; Helman, Lee J. ; Lee, Sunmin ; Mendoza, Arnulfo ; Neckers, Len ; Proia, David A. ; Edessa, Leah D. ; Baumgart, Joshua T. ; Heske, Christine M.

Long-term survival in patients with metastatic, relapsed, or recurrent Ewing sarcoma and rhabdomyosarcoma is dismal. Irinotecan, a topoisomerase 1 inhibitor, has activity in these sarcomas, but due to poor bioavailability of its active metabolite (SN-38) has had limited clinical efficacy. In this study we have evaluated the efficacy and toxicity of STA-8666, a novel drug conjugate which uses an HSP90 inhibitor to facilitate intracellular, tumor-targeted delivery of the topoisomerase 1 inhibitor SN-38, thus preferentially delivering and concentrating SN-38 within tumor tissue. We present in vivo evidence from mouse xenograft models that STA-8666 results in more persistent inhibition of topoisomerase 1 and prolonged DNA damage compared to irinotecan. This translates into superior antitumor efficacy and survival in multiple aggressive models of both diseases in mouse xenografts, as well as in an irinotecan-resistant model of pediatric osteosarcoma, demonstrated by dramatic tumor shrinkage, durable remission and prolonged complete regressions following short-term treatment, compared to conventional irinotecan. Gene expression analysis performed on xenograft tumors treated with either irinotecan or STA-8666 showed that STA-8666 affected expression of DNA damage and repair genes more robustly than irinotecan. These results suggest that STA-8666 may be a promising new agent for patients with pediatric-type sarcoma.

1

News (Medical) associated with PEN-866

17 Sep 2021

·endpts.com

Philip Morris gets shareholder backing in Vectura saga; Tarveda strikes exclusive licensing agreement with SciClone

Tobacco giant Philip Morris now has crossed the 50% threshold it needs for shareholder backing for its controversial, $1.5 billion takeover of asthma inhaler maker Vectura. Investors have accepted a $2.28-per-share offer from the company behind Marlboro cigarettes, according to Sky News — and those investors represent nearly 75% of the company’s shares. Acquiring the British inhaler maker is only a part of Philip Morris’ long term plan to develop “smoke-free” products, with a desire to ultimately become a “broader healthcare and wellness” company. The deal, which was alongside a rival offer from private equity firm Carlyle, has already received regulatory clearances. The latest step in the takeover process means its offer cannot be withdrawn — effectively sealing the deal. The company said it was extending its offer until the end of the month to give remaining Vectura shareholders time to accept its proposal. Massachusetts biotech Tarveda has expanded its recent partnership with SciClone Pharmaceuticals. Tarveda’s exclusive license agreement with SciClone, which builds upon the partnership signed in March of 2020 for anti-tumor conjugate PEN-866, allows SciClone to send a mini drug portfolio of conjugates through R&D and commercialization in certain Asian markets, such as China, Taiwan, Macau and Hong Kong. The portfolio will consist of preclinical products such as a PI3K inhibitor with an undisclosed payload moiety, a linker and an HSP90-binding moiety. SciClone will pay Tarveda an upfront fee as part of the expansion, along with making an equity investment, providing additional milestone payments and leaving open the possibility for royalties. Specific numbers and percentages were not publicly disclosed. Tarveda president and CEO Brian Roberts said in a statement, “We are excited to expand our relationship with SciClone Pharmaceuticals … SciClone Pharmaceuticals has proven to be a reliable and outstanding partner with deep product, regulatory and commercialization experience in Greater China and we are thrilled to broaden our partnership beyond PEN-866.”

Collaborate

100 Deals associated with PEN-866

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16186

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 2	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Advanced Malignant Solid Neoplasm	Phase 2	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Pancreatic Ductal Adenocarcinoma	Phase 2	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Small Cell Lung Cancer	Phase 2	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Squamous cell carcinoma of vulva	Phase 2	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Cervical Squamous Cell Carcinoma	Discovery	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Gastroesophageal junction adenocarcinoma	Discovery	US	Tarveda Therapeutics, Inc.	29 Aug 2017
Squamous Cell Carcinoma of the Penis	Discovery	US	Tarveda Therapeutics, Inc.	29 Aug 2017
stomach adenocarcinoma	Discovery	US	Tarveda Therapeutics, Inc.	29 Aug 2017
uterus adenocarcinoma	Discovery	US	Tarveda Therapeutics, Inc.	29 Aug 2017