PE0139: A super-long-acting basal insulin for once-weekly administration

PhaseBio is developing PE0139, a novel, super-long-acting basal insulin for the treatment of hyperglycemia associated with diabetes dosed as a once-weekly injection. PE0139 is a fully mature, native insulin molecule (B and A chains) genetically fused to our ELP biopolymer. The compound is manufactured using PhaseBio’s ELP-based E. coliexpression system, where refolding of the drug occurs naturally in the cytosol. Importantly, PE0139 is in a simple formulation that facilitates co-formulation with GLP-1 receptor agonists, including PhaseBio’s proprietary GLP-1, PB1023, and other GLP-1 receptor agonists.

phasebio_pe0139-1

PE0139 is expressed as a genetic fusion of proinsulin and the ELP1-120 biopolymer. During downstream processing, the proinsulin is converted into mature insulin.

PE0139 for Type 2 Diabetes

In nonclinical models of diabetes, PE0139 has demonstrated a flat pharmacokinetic (PK) curve with a long elimination phase and a reduction in blood glucose of significantly greater duration than with insulin glargine. A phase 1 single ascending dose study of PE0139 in adults with type 2 diabetes demonstrated prolonged exposure to the drug that would enable once-weekly administration and a low peak-to-trough ratio, which is particularly important for basal insulin.

A phase 2a multiple ascending dose study of PE0139 was initiated in 4Q2015.

PE0139 / Weekly GLP-1 Combination for Type 2 Diabetes

A combination of a GLP-1 receptor agonist and a basal insulin has the potential to enhance efficacy (greater reduction in HbA1c) and safety (reduced incidence of hypoglycemia), while minimizing weight gain normally associated with insulin administration. PhaseBio’s weekly basal insulin, PE0139, and our weekly GLP-1, PB1023, have the opportunity to be the first combination product administered via a single weekly injection on the market. The products are stable in the same simple liquid formulation and are fully compatible when co-formulated in one vial. In addition, PE0139 is formulated in a simple aqueous solution making it amenable to formulation with other weekly GLP-1 receptor agonists.

The PE0139 / PB1023 combination has demonstrated a strong synergistic effect in a model of type 2 diabetes (db/db mice). Subtherapeutic doses of the two compounds normalize blood sugar levels when combined, as shown below:

pb_synergy-peo139-2

Diabetic mice (db/db) were fasted for 3.5 hours and then injected with sub-therapeutic subcutaneous doses of the compounds, or a combination of the two compounds (time 0). Four hours later, an intraperitoneal glucose tolerance test (IPGTT) evaluated the post-prandial glucose response.

Future clinical studies will examine the efficacy of PE0139 co-formulated with PB1023 or another GLP-1 receptor agonist.