ZT-01, a novel SSTR2 antagonist to prevent nocturnal hypoglycemia in insulin dependent diabetes: results from Phase 1 studies and dose selection for a Phase 2 study in Type 1 diabetes (T1D).
Richard Liggins
Chief Scientific Officer, Zucara Therapeutics
ZT-01 is a novel somatostatin receptor type 2 antagonist peptide intended to restore the defective glucagon response to hypoglycemia in insulin-dependent diabetes. In a randomized, double-blinded placebo controlled Phase 1 study, ZT-01, injected subcutaneously, was evaluated in single ascending (40 healthy volunteers) and multiple daily (24 people with T1D) ascending doses (SAD and MAD cohorts) to demonstrate safety and determine pharmacokinetics. The effects of ZT-01 on glucagon counterregulation during hypoglycemia were determined in 23 adults with T1D, undergoing three hypoglycemic clamp procedures, in a crossover design, dosed with 3 or 20 mg ZT-01 or placebo 1 h prior to stepwise glucose clamp conditions using variable rate IV insulin infusion: euglycemia (90 ± 9 mg/dL), Level 1 (64 ± 5 mg/dL, L1), and Level 2 hypoglycemia (47 ± 4 mg/dL, L2).
In the SAD/MAD study, ZT-01 (6:2 active:placebo per cohort) was safe and well tolerated at doses ranging from 0.3 to 30 mg/day for up to 5 days. No serious adverse events (SAEs) were reported. The most common treatment emergent adverse events (TEAEs) were transient injection site reactions.
ZT-01 exposure was approximately dose-proportional. Mean t½ also increased with dose up to ~4.5 hours following a 30 mg dose.
In the hypoglycemic clamp study: following ZT-01, peak glucagon increased by up to 15.1 ± 10.5 and 27.1 ± 17.3 pg/mL in L1 and L2 hypoglycemia, respectively, compared with no increase in L1 and an 8.4 ± 8.4 pg/mL increase in L2 hypoglycemia following placebo (p<0.0001). A counterregulatory response of increased glucose level coinciding with an increased glucagon level was observed more frequently with ZT-01 than placebo. No clinically significant effects on other counterregulatory hormones or hypoglycemia symptoms were observed with ZT-01. A transient rise in glucagon and blood glucose was observed with ZT-01 post-dose prior to hypoglycemia. In the clamp study, no SAEs were reported and no TEAEs were observed with ZT-01.
Phase 1 studies showed ZT-01 was safe and well tolerated and demonstrated proof-of-concept that ZT-01 significantly enhances the defective counterregulatory response during hypoglycemia in people with T1D. These studies enabled dose selection for a Phase 2a study, assessing prevention of nocturnal hypoglycemia in people with T1D. A summary of dose selection and the Phase 2 study protocol will be presented.
Richard is the Chief Scientific Officer and a co-founder of Zucara (2014), and has led Zucara’s technology development from its discovery into Phase 2 clinical development. Dr. Liggins is co-inventor of aspects of Zucara’s intellectual property portfolio. Prior to Zucara, he was Senior Director of Advanced Projects at adMare BioInnovations (formerly CDRD), developing a portfolio of assets to commercialization, through NewCo formation or out-licensing.
Earlier in his career, he was a Research Scientist at Angiotech Pharmaceuticals, responsible for development of injectable formulations in clinical development. With a background in both drug and device development, Dr. Liggins has contributed to multiple IND filings, advancing programs from pre-clinical through Phase 2 development. Dr. Liggins has filed over 75 patent applications in 21 distinct patent families, resulting in 9 issued US patents and other international patents.
Dr. Liggins obtained his PhD in Pharmaceutical Sciences at the University of British Columbia in 1998.