Out-licensing

Phase II Clinical Development of SG2000: A C2-unsaturated PBD Dimer as a Novel Anti-Cancer Agent

Introduction/Background

SG2000 (SJG-136) is Spirogen's lead clinical phase oncology drug. Designed to retain activity in refractory tumours, it has lived up to this promise from in vitro tests through to the clinic.

Aims/Hypothesis

In this study, the anti-cancer activity of SG2000 is further investigated.

Research

SG2000, a C2-unsaturated PBD dimer, is shortly to enter Phase II trials. 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 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 oedema (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.

SG2000 possesses a novel mechanism of action which differentiates it from conventional cytotoxic and cross-linking agents. Adducts produced by commonly used chemotherapies like cisplatin and melphalan produce a variety of recognisable distortions in the DNA double helix. The majority of these adducts are recognized and removed by nucleotide excision repair (NER) factors. Cross-links formed by SG2000 do not distort the DNA double helix (Figure 1) 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 tumours especially those where NER mechanisms are up-regulated (eg, 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.

Conclusion

SG2000, a C2-unsaturated PBD dimer, is currently entering Phase II trials for the treatment of cancer.

Relevance/Opportunity

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Phase II