SG2000 - Oncology
SG2000 (formerly known as SJG-136) is a highly potent DNA interactive molecule that has demonstrated promising anti-tumor activity in multiple tumor types across a number of preclinical and clinical studies.
SG2000 is a highly potent C2-unsaturated pyrrolobenzodiazepine (PBD) dimer. PBDs are naturally occurring anti-tumor molecules, which can be isolated from various streptomyces species. SG 2000 is a synthetic version of PBD which was rationally designed by Spirogen, an Auven Therapeutics portfolio Company.
SG2000 is currently in a Phase II NCI sponsored study in platinum resistant and refractory ovarian cancer. Details of the ongoing study can be found at: NCT01200797. Further trials are planned in Europe.
In four Phase I trials, a total of 69 patients were treated with SG2000 on various schedules. Three objective partial responses were seen in refractory ovarian carcinoma (64% decrease), ALL (84% blasts reduced to 10%) and a poorly differentiated carcinoma (>30% decrease). Furthermore, 16 cases of stable diseases were noted across all centres. These trials all involved heavily pre-treated patients and dose escalation.
The primary dose limiting toxicities (DLTs) were recorded as fatigue and lower limb edema (atypical VLS). Transient elevated LFTs were observed; myelotoxicity was not seen. These DLTs were reversible upon treatment cessation and a short prophylactic course of dexamethasone was adequate to ameliorate the worst of the symptoms. A Phase II dose is recommended as 30 μg/m2 i.v. daily for three days every three weeks.
Mechanism of Action
SG2000 possesses a novel mechanism of action which differentiates it from conventional cytotoxic and cross-linking agents. Adducts i.e. a piece of DNA that is bonded to a cancer-causing chemical are produced by commonly used chemotherapies like cisplatin and melphalan results in a variety of recognizable distortions in the DNA double helix. The majority of these adducts are recognized and removed by nucleotide excision repair (NER) factors. SG2000 has been rationally designed so that cross-links formed by this molecule do not distort the DNA double helix and so are able to ‘slip under the radar’ of NER. SG2000-induced cross-links persist and permit the molecule to exert its effect longer. This property makes SG2000 highly active in refractory tumors especially those where NER mechanisms are up-regulated (e.g., cisplatin resistance). Eventually, adducts are removed by homologous recombination repair (HRR) and defects in this system can be exploited to increase the potency of SG2000. Biomarker stratification processes based on defective DNA repair mechanisms promise to provide a significant boost to clinical efficacy.
Development program funding
The development program has benefited from more than $20 million of investment to date, including significant sponsorship from Cancer Research UK and the National Cancer Institute in the USA.