Tim Heise, Germany
Profil -Moderator of 1 Session
Presenter of 3 Presentations
IMMUNOGENICITY AND OTHER SAFETY PARAMETERS FOLLOWING MULTIPLE SC DOSES OF DASIGLUCAGON
Abstract
Background and Aims
Parenteral administration of therapeutic peptides can be associated with generation of anti-drug antibodies (ADAs). The antibodies can be neutralising or non-neutralising, which is of importance for drug safety and efficacy for indications where the peptide is to be administered repeatedly. A special risk for analogues of human peptides is cross reactivity towards the endogenous peptide.
Methods
In the ADA Phase 3 trial, the immunogenicity of dasiglucagon (0.6 mg) was tested. The reference product was GlucaGen® (1 mg). Patients were randomly assigned in a 1:1 ratio to receive 3 SC injections of either dasiglucagon or GlucaGen®, with 1 week between doses. Blood samples for ADA analysis were taken before each of the three doses and 35, 60 and 104 days after the first dose. In total 111 T1DM patients received at least one dose and 102 patients completed all three doses.
Results
The primary endpoint was the overall ADA incidence. No patient had any confirmed treatment-induced or treatment-boosted ADA response at any measuring time after dosing. Nausea and vomiting were the most commonly reported IMP-related AEs, reported with similar frequencies for dasiglucagon and GlucaGen® (nausea: 46% and 43%, vomiting: 21% and 15%, respectively). There were no injection site reactions after dasiglucagon administration, whereas eight injection site reactions in 6 patients were noted in the GlucaGen® group.
Conclusions
In conclusion, dasiglucagon had a low potential for generation of ADAs. The low potential for generation of ADA’s and low potential for injection site reactions are of particular importance for the chronic indications pursued with dasiglucagon.
READY-TO-USE DASIGLUCAGON INJECTION AS A FAST AND EFFECTIVE TREATMENT FOR SEVERE HYPOGLYCEMIA
Abstract
Background and Aims
Severe hypoglycemia is a feared complication of insulin therapy and requires urgent assistance. Dasiglucagon is a peptide analog of human glucagon, stable in aqueous solution, in development for treatment of severe hypoglycemia via a ready-to-use auto-injector.
Methods
In this pivotal Phase 3 trial, the clinical efficacy and safety of 0.6 mg dasiglucagon were compared to placebo and with reference to GlucaGen®. In total, 168 patients with T1D were randomized (2:1:1) and dosed following induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery, defined as first PG increase ≥20 mg/dL after treatment initiation.
Results
Data showed dasiglucagon 0.6mg rapidly increased PG. The median time to recovery was 10 min for dasiglucagon and 12 and 40 min for GlucaGen® and placebo, respectively. In the dasiglucagon arm, 65% of patients had recovered within 10 min vs 49% of patients receiving GlucaGen®. Similarly after 15 min, 99% of patients treated with dasiglucagon had recovered vs 95% of patients treated with GlucaGen®. Nausea and vomiting were reported with similar frequencies for dasiglucagon and GlucaGen® (nausea: 55% and 53%, vomiting: 23% and 19%, respectively). Injection site reactions 30 minutes post dose were reported in 2%, 7% and 5% of patients in the dasiglucagon, GlucaGen® and placebo groups, respectively.
Conclusions
In conclusion, dasiglucagon 0.6mg was demonstrated to be a fast and effective treatment for severe hypoglycemia. The stability of dasiglucagon in aqueous formulation enables further development of dasiglucagon as a treatment option in the entire spectrum of mild, moderate and severe hypoglycemia.
How early is URLi (Ultra Rapid Lispro)?
Abstract
Background and Aims
While first generation prandial insulins have a significantly faster onset of action compared to regular human insulin, a further left-shift in the time-action profile of prandial insulins might help to improve postprandial blood glucose control even more. Ultra-rapid insulin lispro (URLi) was developed to more closely match physiological insulin secretion by adding two new excipients: a micro-dose of treprostinil causing local vasodilation and citrate enhancing local vascular permeability.
Methods
The presentation will summarise the currently available pharmacological and clinical trials with URLi.
Results
In comparison with insulin lispro (LIS), URLi showed a clear left-shift in the pharmacokinetic and pharmacodynamic profile with a faster onset of exposure and action, higher early and less late exposure and action. The faster absorption of URLi was confirmed in a comparative trial versus both conventional insulin aspart (ASP) and faster insulin aspart (FIA). The faster onset and offset of URLi led to improved post-prandial glucose (PPG) concentrations versus LIS, ASP and (non-significantly) versus FIA. Of note, URLi’s PPG profile more closely matched that of healthy subjects in the first 2-3 hours post-meal. Improvements in PPGs were also observed in larger clinical phase 3 trials vs. LIS.
Conclusions
URLi shows the fastest insulin absorption and shortest exposure duration compared to LIS, ASP and FIA leading to greater glucose lowering effects with statistically significant improvements in PPG excursions vs. LIS and ASP.