SN2310
 

Camptothecins are a class of cytotoxic drugs that act by the inhibition of topoisomerase I.  Irinotecan and topotecan are the two approved members of this class, with irinotecan responsible for the majority of sales. 

In September 2006, Sonus initiated a Phase I study of SN2310.  SN2310 is a prodrug of SN38, the active moiety of irinotecan.  SN2310 was synthesized by replacing the prodrug or carrier moiety of irinotecan responsible for cholinergic symptoms by a-tocopherol.  Compared to irinotecan, SN2310 is intended to provide prolonged exposure to SN38 for improved efficacy, while minimizing toxicities.

In preclinical studies, SN2310 has demonstrated improved anti-tumor effects when compared to irinotecan.  In the ongoing Phase I clinical trial, SN2310 has met the goals of (1) a substantially longer half-life of SN38, (2) a greater exposure (AUC) of SN38 at a given dose and (3) the absence of cholinergic symptoms, in particular early diarrhea, when compared to irinotecan.

DNA Methyl Transferase (DNMT) Inhibitor

Sonus has a program to identify novel DNMT inhibitors.  Cancer cells frequently have aberrant DNA methylation patterns and frequent methylation has been shown to have a poor prognosis.  Conversely, demethylation of DNA in cancer cells can lead to expression of aberrantly repressed genes and induction of cellular differentiation and apoptosis (cell death).  There is a growing interest in DNMT inhibitors that result in demethylation of DNA in cancer cells.  Such treatments are referred to as “epigenetic” therapy because they lead to changes in gene expression that do not involve changes in the DNA sequence.

There currently are two approved DNMT inhibitors: 5-azacytidine and 5-azadeoxycytidine (decitabine).  These compounds suffer from short half-lives and unwanted toxicity, in particular myelosuppression. 

Sonus has identified novel molecules that may act by DNMT inhibition and is in the process of selecting a lead to move towards the clinic.

5’-DFCR Prodrugs

Capecitabine is an approved prodrug of the antimetabolite 5-fluorouracil (5-FU).  Capecitabine has a complex metabolic pathway in vivo and its first metabolite is 5’-deoxyfluorocytidine (5’-DFCR).  Capecitabine is approved for the treatment of multiple solid tumors.

A published meta-analysis has demonstrated improved outcome in patients with colorectal cancer when 5-FU is administered by continuous infusion rather than by bolus.  The purpose of Sonus’ program is to more closely approximate 5-FU continuous infusion than is possible with capecitabine, resulting in greater efficacy and patient convenience.

Sonus is synthesizing novel prodrug constructs of 5’-DFCR in an attempt to meet these goals.

Monophosphorylated Nucleoside Prodrugs

Nucleosides are widely used for the treatment of cancer and viral disease.  Nucleosides need to undergo further metabolism to achieve the requisite activity.  Generation of the monophosphate (MP) of a nucleoside is commonly a rate limiting step in the biosynthesis of biologically active di- or triphosphate nucleosides.  Furthermore, it can also be one of the inherited or acquired mechanisms of resistance in tumor cells.  The goal of this program is to bypass such mechanisms of resistance by delivering to cells MP nucleosides.  Because of the construct of the carrier moiety of these prodrugs, it is also expected that such prodrugs will bypass the need for a nucleoside transporter, a second known mechanism of resistance to nucleosides in tumor cells.

This technology of MP mucleoside prodrugs is potentially applicable to a number of approved nucleosides for the treatment of cancer, e.g., gemcitabine, or viral diseases.  Furthermore, it may be applicable to nucleosides that were synthesized but not developed because they were poor substrates for kinases leading to suboptimal formation of MP nucleosides, and hence apparent lack of biological activity.

Licensing

In addition to internal research and development efforts described above in the “Sonus pipeline”, Sonus has an active in-licensing effort to identify promising  oncology therapeutics.  Of particular interest are small molecules that are near or in early clinical development.