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BEL-0222 (PEG-SN38) – Oncology.


BEL-0222 (PEG-SN38 or firtecan pegol) is a Phase III-ready oncologic that is a PEGylated conjugate of SN38, which is the active moiety of irinotecan, a topoisomerase I (“Topo I”)-inhibitor. BEL-0222 (PEG-SN38) has been shown to down-modulate HIF-1α, a subunit of HIF-1. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of gene products essential for tumor invasion, migration, angiogenesis and production of vascular endothelial growth factor (VEGF).

This proprietary conjugate delivers improved clinical properties compared to other Topo I-inhibitors, including parenteral delivery, increased solubility, higher exposure, more profound deoxyribonucleic acid (DNA) damage, inhibition of angiogenesis, and longer half-life compared with native SN38. PEG-SN38 leverages Belrose’s proprietary “releasable linker” PEGylation platform that increases bioavailability, extends the half-life and is engineered to release the native molecule as the linkers are enzymatically cleaved.

Promise of PEG-SN38

PEG-SN38 (PEGylated SN38) is a topoisomerase 1 inhibitor
  • Preclinical data indicates it is superior to irinotecan in all tumor models evaluated
  • Delivers an improved clinical profile
    • Water soluble prodrug of SN38
    • Created by PEGylating SN38 (insoluble) with 4-arm PEG
    • Enables parenteral delivery of SN38 – Avoids use of “irinotecan” prodrug, which has inherent toxicity and confers inter-subject variability in pharmacokinetics (PK)
    • Passive localization to tumor due to enhanced permeability and retention effect
    • Provides “depot” sink in plasma and tumor, with controlled, sustained SN38 release
  • Has longer half-life and greater tumor exposure/residence time


Mechanism of Action / Advantages

As a therapeutic class, Topo I-inhibitors are agents designed to interfere with the action of the topoisomerase enzyme topoisomerase I, which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

Topo I-inhibitors are widely-used as cancer chemotherapy treatments. Research suggests that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death. Topoisomerase inhibitors can also function as antibacterial agents.

One class of Topo I-inhibitor, Camptothecins, are among the most effective anticancer agents recently introduced into clinical practice. Camptothecin derivatives approved by the US FDA include (a) topotecan (Hycamtin), which is approved for the treatment of ovarian and lung cancer, and (b) irinotecan (CPT11), which is approved for the treatment of colon cancer.

PEG-SN38 has produced positive responses in clinical trials for metastatic breast cancer and pediatric neuroblastoma. PEG-SN38 has completed multiple Phase I studies, three Phase II studies and has demonstrated a strong safety profile.

The most promising development opportunities for PEG-SN38 include the following:

Potential Indications for PEG-SN38

Based on Phase 1 and Phase 2 clinical trials, Belrose believes the most promising indications for PEG-SN38 include the following:
  • Metastatic breast cancer (heavily pretreated) as a single agent
    • Results of Phase 2 trial confirm that PEG-SN38 is active
    • Phase 3 ready
    • Opportunities to develop companion diagnostic are underway
    • Available data indicates that PEG-SN38 may be suitable for multiple agent therapy
  • Neuroblastoma (heavily pretreated) as a single agent following disease progression on topoisomerase 1 targeting agents
    • Results of Phase 1 trial are promising
    • Phase 2 nonrandomized trial may be pivotal
  • Other solid cancers
    • Activity highly likely in other cancers in which irinotecan is active
    • Promicing potential treatment for gastric, brain, nonsmall and small cell lung, pancreatic, ovarian and other cancer types


Clinical Trial Overview

Belrose is currently working with the US FDA to confirm the requirements for pivotal clinical trials and other requirements to support approval of BEL-0222 for treatment of:

  • Pediatric Neuroblastoma; and
  • Triple Negative Breast Cancer.

BEL-0222 received orphan drug designation for “Treatment of neuroblastoma” and Belrose is currently seeking designation for “Treatment of Triple Negative Breast Cancer”.

Based on FDA input received to date, we anticipate launching each of these pivotal Phase II/III studies in Q1 2014.


Selected Articles on BEL-0222

Phase I Trial of Polyethylene Glycol (PEG) Conjugated SN38 in Children with Recurrent or Refractory Neuroblastoma (NB) and Other Solid Tumors
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Final analysis of Phase 2 study of EZN-2208 (PEG-SN38) in metastatic breast cancer (MBC) demonstrates activity in patients with triple negative breast cancer (TNBC) and in platinum pretreated patients
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EZN-2208, a novel anticancer agent, in patients with advanced malignancies; a Phase 1 dose-escalation Study
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Pharmacokinetics of EZN-2208, a novel anticancer agent, in patients with advanced malignancies
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Phase 1, first-in-human, dose-escalation study of EZN-2208, a novel anticancer agent, in patients with advanced malignancies
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A novel polyethyleneglycol-SN38 conjugate, EZN-2208, downregulates HIF-1a
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EZN-2208 A Novel PEGylated SN-38 Drug Conjugate
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PEG-SN38 CCR Article- Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11–Refractory Model (Clinical Cancer Research)
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EZN-2208 Phase 2 MBC Poster SABCS — December 2011
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ENZ-2208 04 PEG-SN38 CRC Phase 2 ASCO GI 2012 Poster
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