Following are brief descriptions of long-lasting drug candidates that are available for licensing.

PEG~SN-38 (PLX038). We have a novel, slow-releasing PEGylated SN-38 (PEG~SN-38) that has entered Phase 1 clinical trials at MD Anderson as an anti-cancer agent. SN-38 is the active metabolite of the anti-cancer agent irinotecan (CPT-11) and is a potent inhibitor of topoisomerase I.. In animal models, the ProLynx PEG~SN-38 conjugate PLX038 shows a unique combination of the most desirable features of a topo I inhibitor: (i) it has a very long half-life and very low Cmax; (ii) it does not require liver metabolism and thus has minimal intestinal toxicity; (iii) it accumulates in solid tumors; and (iv) it shows high therapeutic efficacy. In contrast, none of the competing SN-38 or CPT-11 prodrugs provide delivery of SN-38 that maintains the drug over the target threshold for protracted periods; nor are they able to since their residence times are limited by the short cleavage half-lives of the ester linkage used (~12 to 24 h); further, Cmax and the peak-to-trough excursions are high. We believe these characteristics of PLX038 will translate into higher efficacy rates combined with an improved safety profile in cancer patients.

Prolynx retains all non-Asian rights to this PEG~SN-38 conjugate, which represent about 80% of anticipated global sales. We are seeking a pharma partner who shares our conviction that this drug is superior to the alternatives, and will take initiative in moving it forward aggressively in Phase 2 and pivotal clinical trials. For more information click here.

Subcutaneous long-acting octreotide. Octreotide is a cyclic octapeptide that is used to treat acromegaly and neuroendocrine tumors. It is commercially available as a thrice-daily subcutaneous (s.c.) immediate release injectable, and a long acting release formulation (Sandostatin LAR ®) that is injected intramuscularly (i.m.) each month. Yearly sales of Sandostatin LAR are currently about $1.5 billion.

There are several shortcomings of Sandostatin LAR. First, the PLGA formulation requires dry storage and a multi-step reconstitution at the time of injection. Second, the 2.5 mL deep intra-gluteal injection requires a large 1½ inch 20 gauge needle and must be administered monthly by a health care professional; not surprisingly, significant discomfort occurs at the injection site. Certainly, a considerable number of patients and physicians would welcome a patient-administered, relatively painless s.c. injection of a long-acting octreotide.

We have attached octreotide to 40 um hydrogel microspheres via our -eliminative linkers that can be administered s.c. through a small-bore 27 gauge needle. In an animal model, we can increase the half-life of octreotide to over 350 hours and maintain drug concentrations above therapeutic levels for prolonged periods. Pharmacokinetic simulations indicate that the hydrogel-octreotide microspheres will easily support weekly subcutaneous dosing in humans. Our data indicates that our hydrogel-octreotide conjugate should have the pharmacokinetic benefits of Sandostatin LAR, without its shortcomings. The ProLynx once-weekly s.c. octreotide is being readied for preclinical toxicology studies.

Once-Monthly GLP-1 Agonist.  Agonists of the glucagon like-1 (GLP-1) receptor are an important treatment for type 2 diabetes and potentially useful anti-obesity agents. In 2013, GLP-1 agonists achieved sales of $3.2 billion and sales are expected to reach >$12 billion by 2024. Since the first twice-daily agonist Byetta was approved in 2005, a number of once-daily or once-weekly administered agonists have been developed and approved by the FDA. A current challenge is the development of even longer acting GLP-1 agonists.

We have developed an ultra-long acting delivery system for a GLP-1 agonist that is suitable for once-monthly administration. The agonist is covalently attached to 40 um hydrogel microspheres by a self-cleaving β-eliminative linker; upon subcutaneous injection the linker slowly cleaves and releases the drug. The serum half-lives for released GLP-1 agonist is ~30 days. Simulations indicate that this conjugate will support monthly administration in the human, thus representing the first viable once-monthly GLP-1 agonists. The ProLynx once-monthly GLP-1 agonist being readied for preclinical toxicology studies.