Last week our team joined an exciting and busy 54th EASD Annual Meeting in Berlin. We would like to give you a brief overview about those orals and posters presenting results from clinical trials Profil had been involved in.
Profil’s contributions to the scientific sessions: 7 posters and 4 oral presentations
Topics:
- Nasal glucagon
- Ultra rapid insulins (Ultra rapid lispro (URLi); BioChaperone Lispro)
- Mixed insulin (BioChaperone Combo)
- Dual GLP-1/Glucagon receptor agonist (MEDI0382)
Nasal glucagon
Nasal glucagon (NG) instead of injectable glucagon as a rescue medication for the treatment of severe hypoglycaemia – this might make life easier for relatives during an emergency situation as it avoids cumbersome reconstitution and injection of currently available glucagon formulations.
PD Dr. Leona Plum-Mörschel, Chief Executive Officer, Profil Mainz, in an oral presentation provided the results of a randomised, two-period crossover trial in adult participants with type 1 diabetes [1]. The study compared a novel drug-device combination product consisting of a dry powder spray formulation with 3-mg synthetic glucagon contained within a single-use device to 1 mg intramuscular glucagon (IMG). Hypoglycaemia (PG<3.3 mmol/L) was induced by intravenous insulin infusion, and 5 min after stopping insulin either NG or IMG was administered, followed by multiple plasma glucose (PG) measurements up to 90 min. Local tolerability of NG was assessed by means of a Nasal and Non-Nasal Symptom Questionnaire (NNSQ).
The study showed non-inferiority of NG to IMG, and all participants achieved treatment success by 25 min (defined as an increase in PG to ≥3.9 mmol/L or an increase of ≥1.1 mmol/L from the PG nadir within 30 min of receiving glucagon) – with a mean time to treatment success of 11.4 min (NG) and 9.8 min (IMG).
There were no deaths or other serious adverse events (AEs). 48 AEs occurred after NG vs 51 after IMG, most were mild and transient and of similar frequency (nausea 31% NG; 42% IMG, vomiting 14% NG, 17% IMG). After NG, ≥10% symptoms from the NNSQ included watery eyes, nasal itching, nasal congestion, runny nose, sneezing, red eyes, itchy eyes and itching of throat.
In conclusion, nasal glucagon was as efficacious and safe as intramuscular glucagon for the treatment of insulin-induced hypoglycaemia in adults, thus supporting the use of nasal glucagon as a rescue treatment for severe hypoglycaemia.
Ultra rapid insulins
A total of two oral presentations and four posters were related to Profil’s EASD contributions on ultra rapid insulins, i.e. ultra rapid lispro (URLi) and BioChaperone Lispro (BCLIS).
a) Ultra rapid lispro (URLi)
Profil’s ultra rapid lispro (URLi) EASD contributions comprised a 2-part, randomised, double-blind phase 1b study that evaluated pharmacokinetic (PK) and pharmacodynamic (PD) differences between URLi and lispro in 30 participants with type 1 diabetes [2].
URLi reduced postprandial glucose excursions vs lispro at multiple meal-to-dose timing intervals (-15, 0, +15 min; solid mixed meal tolerance tests; MMTT).
The PK and PD profiles for URLi and lispro were sustained after two weeks of outpatient dosing. Comparable numbers of hypoglycaemic events were observed for both treatments during MMTTs. During two weeks of outpatient dosing, the number of events was numerically lower for URLi vs lispro. Local tolerability was similar between treatments.
Dr. Christoph Kapitza, Chief Executive Officer, Profil, presented the results of a corresponding trial with URLi in 30 people with type 2 diabetes [3]. This study also demonstrated both reduced postprandial glucose excursions with URLi vs lispro at multiple meal-to-dose timing intervals and sustained PK and PD profiles as above. More hypoglycaemic events occurred with URLi during MMTTs but these were mild and mostly asymptomatic. Only few events were seen in either group during the two weeks of outpatient dosing – with no differences between treatments and similar local tolerability.
A third double-blind, randomised crossover trial looked at the PK and PD of URLi vs lispro via insulin pump (CSII) in 24 adult participants with type 1 diabetes [4]. URLi showed faster insulin absorption compared to lispro and a trend toward improved postprandial glucose control. No differences were observed in the number or severity of hypoglycaemic events or local tolerability between URLi and lispro.
b) BioChaperone Lispro (BCLIS)
Profil’s EASD contributions on BioChaperone Lispro (BCLIS) included an oral presentation on a double-blind, randomised, 3-period crossover glucose clamp phase 1 trial in 43 adult subjects with type 1 diabetes [5]. The study exhibited ultra-rapid PD and PK properties of BCLIS compared to insulin aspart and favorable profiles compared to the ultra-rapid faster insulin aspart formulation in insulin pumps. All three formulations were safe and well tolerated.
Dr. Tim Heise, Lead Scientist, Profil, presented the results of a pooled analysis of clinical trials investigating the PK of BCLIS vs lispro in subjects with type 1 and type 2 diabetes [6].
Insulin absorption was consistently faster with BCLIS than with lispro as indicated by reaching early half-maximum insulin levels 10.0 (95% confidence interval [-14.3;-5.8] and time to maximum levels (tmax) 8.4 [-9.6;-7.2] min earlier (p<0.0001 for both comparisons). Early insulin exposure was significantly greater for BCLIS for up to 2 hours after administration. BCLIS also shwed faster offset of exposure than conventional lispro. This applied to both people with type 1 and type 2 diabetes.
An open-label trial in 12 healthy volunteers investigated the PK properties as well as safety and tolerability of a single subcutaneous (s.c.) dose of BioChaperone 222 (BC222), the new excipient enabling the ultra-rapid BioChaperone Lispro formulation [7].
BC222 was completely absorbed after s.c. injection and rapidly excreted by the kidneys.
Mixed insulin (BioChaperone Combo)
Dr. Theresa Herbrand, Research Physician, Scientific Study Advisor, Profil, presented the results of a double-blind, double-dummy, crossover trial in 39 people with type 2 diabetes [8]. They were randomised to receive the three study insulins (BioChaperone Combo (BC Combo), lispro Mix25, separate glargine and lispro (G+L) administrations) immediately before a standardized solid meal test.
BC Combo demonstrated superior postprandial glucose control with numerically fewer subjects experiencing hypoglycaemia compared to both lispro Mix25 and separate G+L injections.
Dual GLP-1/Glucagon receptor agonist (MEDI0382)
Profil was involved in one oral presentation and two posters on the dual GLP-1/Glucagon receptor agonist MEDI0382.
The oral presentation provided results of a randomised double-blind placebo controlled phase 2a trial investigating efficacy of MEDI0382 and tolerability in different titration regimens in 65 subjects with type 2 diabetes [9]. MEDI0382 administered for up to 49 days resulted in significant weight loss and rapid reduction in both fasting and postprandial glucose levels. Tolerability in the first cohort was comparable to that of marketed GLP-1 analogs; lengthening the titration interval did not improve gastrointestinal tolerability.
One poster showed results of a cohort study (cohorts 1-5) of MEDI0382 in 61 subjects with type 2 diabetes receiving different dosing levels and uptitration schedules [10]. MEDI0382 administered for up to 22 days revealed a marked reduction in both fasting and postprandial glucose with weight reduction and an acceptable tolerability profile (nausea and vomiting more frequently with MEDI0382 vs placebo, not dose related).
Another poster referred to a placebo-controlled, double-blind study in 51 obese/overweight patients with type 2 diabetes (BMI 27-40 kg/m²) [11]. As above, MEDI0382 normalized fasting and postprandial blood glucose, significantly reduced body weight and had an acceptable safety profile over 41 days of dosing in these participants.