Drugs

https://doi.org/10.1007/s40265-021-01531-z

ADISINSIGHT REPORT

Dasiglucagon: First Approval

Hannah A. Blair1

© Springer Nature Switzerland AG 2021

Abstract
Dasiglucagon ­(Zegalogue®) is an antihypoglycaemic agent being developed by Zealand Pharma for the treatment of hypo-
glycaemia, type 1 diabetes mellitus (T1DM) management and congenital hyperinsulinism. In March 2021, dasiglucagon
received its first approval in the USA for the treatment of severe hypoglycaemia in paediatric and adult patients with diabetes
aged 6 years and above. Dasiglucagon, a glucagon analogue, is available as a single-dose autoinjector or prefilled syringe
for subcutaneous injection. This article summarizes the milestones in the development of dasiglucagon leading to this first
approval for hypoglycaemia.

Digital Features for this AdisInsight Report can be found at https://​
doi.​org/​10.​6084/​m9.​figsh​are.​14498​250.
Dasiglucagon (Zegalogue®): Key points 
Antihypoglycaemic agent being developed by Zealand
Pharma for the treatment of hypoglycaemia, T1DM man-
agement and congenital hyperinsulinism
Received its first approval on 22 March 2021 in the USA
Approved for the treatment of severe hypoglycaemia in
paediatric and adult patients with diabetes aged 6 years
and above
1 Introduction
Glucagon is commonly used as a rescue treatment for
severe hypoglycaemia in patients with type 1 diabetes mel-
litus (T1DM) [1]. However, native glucagon is unstable and
undergoes degradation in aqueous solutions, leading to a
This profile has been extracted and modified from the AdisInsight
database. AdisInsight tracks drug development worldwide through
the entire development process, from discovery, through pre-
clinical and clinical studies to market launch and beyond.
loss of bioactivity [1]. Commercially available glucagon
emergency kits contain powdered glucagon that must be
reconstituted in aqueous solution prior to injection, which
may result in delayed rescue and user error [1, 2]. Dasigluca-
gon ­(Zegalogue®) is a glucagon analogue and antihypogly-
caemic agent with improved solubility and stability in an
aqueous liquid formulation [1, 2].
Dasiglucagon is being developed by Zealand Pharma for the
treatment of hypoglycaemia, T1DM management and congeni-
tal hyperinsulinism. On 22 March 2021, dasiglucagon received
its first global approval in the USA, where it is indicated for
the treatment of severe hypoglycaemia in paediatric and adult
patients with diabetes aged 6 years and above [3, 4]. Dasigluca-
gon is available as a solution for subcutaneous injection in a
single-use autoinjector or prefilled syringe [3]. The recom-
mended dose is 0.6 mg administered into the outer upper arm,
lower abdomen, buttocks or thigh. If no response is observed
after 15 min, a second 0.6 mg dose from a new device may
be administered while waiting for emergency assistance [3].
Dasiglucagon is in phase II/III development for T1DM
management in the USA. Phase III development is ongoing
in various countries for the treatment of congenital hyperin-
sulinism, for which dasiglucagon has been granted Orphan
Drug (US and EU) and Rare Pediatric Disease (US) designa-
tions [5].

* Hannah A. Blair 1.1 Company Agreements

dru@adis.com
1
Springer Nature, Private Bag 65901, Mairangi Bay, In June 2016, Zealand Pharma entered into an agreement
Auckland 0754, New Zealand with Beta Bionics to collaborate on the development of a

Vol.:(0123456789)
 H. A. Blair

NDA submitted in USA (Mar)

NDA accepted in USA (May)

Preclinical studies initiated (Jun 2013) Approved in USA (Mar)

Phase I trials initiated (Dec 2014) US PDUFA goal date (Mar)

2017 2018 2019 2020 2021

NCT03378635
NCT03667053
NCT03688711
NCT03984370
NCT04449692
Phase III trials in hypoglycaemia (Zealand Pharma)
Phase II trial in hypoglycaemia (University Hospital, Gentofte, Copenhagen)
Phase II trial in hypoglycaemia (Steno Diabetes Center, Copenhagen)

Key milestones in the development of dasiglucagon, focusing on its use in the treatment of hypoglycaemia. NDA New Drug Application,
PDUFA Prescription Drug User Fee Act

bihormonal artificial pancreas system for the treatment of
T1DM [6]. The advanced bionic pancreas platform technol-
ogy was developed at Boston University and integrated into
a pocket-sized wearable medical device, the ­iLet®. Zealand
Pharma reported that it will evaluate a multiple-dose indi-
cation of dasiglucagon with the ­iLet® [6]. The companies
boosted their collaboration in December 2017 [7]. In Janu-
ary 2019, Zealand Pharma announced the completion of a
strategic equity investment in Beta Bionics, further strength-
ening the collaboration to advance with the phase III pro-
gram for ­iLet® [8].
native glucagon [9]. In glucose intolerant mice, a continu-
ous 2-week subcutaneous infusion of dasiglucagon reduced
insulin secretion which was corrected for by glucagon-like
peptide 1 [11]. In patients with T1DM, subcutaneous dasi-
glucagon rapidly and dose-dependently increased plasma
glucose concentrations across a dose range of 0.1–1 mg,
which is comparable to commercial glucagon [12, 13].
Administration of dasiglucagon at plasma concentrations
more than fivefold above therapeutic concentrations was not
associated with clinically relevant QT interval prolongation
[3].

2.2 Pharmacokinetics
2 Scientific Summary
The pharmacokinetic profile of dasiglucagon is character-
ized by a dose-dependent and rapid increase in plasma con-
2.1 Pharmacodynamics
centrations [12]. Dasiglucagon is rapidly absorbed following
subcutaneous injection, with a time to maximum plasma con-
Dasiglucagon is a novel peptide analogue of human gluca-
centration ­(tmax) of ≈ 35 min and a half-life (­ t½) of ≈ 30 min
gon [1]. It comprises 29 amino acids, with seven substitu-
[3, 12]. In patients with T1DM, t­ max and t­ ½ were longer with
tions that increase solubility and physicochemical stability
dasiglucagon than with commercial glucagon under both
[1]. As a glucagon receptor agonist, dasiglucagon activates
hypoglycaemic [12] and euglycaemic [13] conditions. The
glucagon receptors in the liver, thereby increasing blood
apparent volume of distribution of dasiglucagon is 47–57 L
glucose concentrations and stimulating glycogen breakdown
[3]. Like human glucagon, dasiglucagon is eliminated via
and the release of glucose [3]. The antihypoglycaemic activ-
proteolytic degradation pathways in the blood, liver and kid-
ity of dasiglucagon is dependent on hepatic glycogen stores
ney [3].
[3]. In vitro, dasiglucagon and native glucagon have similar
Concomitant administration of dasiglucagon with
receptor potency at the human glucagon receptor [9].
β-blockers may result in a transient increase in heart rate
Subcutaneous administration of dasiglucagon increased
and BP [3]. The antihypoglycaemic activity of dasiglucagon
blood glucose concentrations in animal models of hypo-
may be reduced when it is coadministered with indometha-
glycaemia [9, 10]. In hypoglycaemic rats, dasiglucagon
cin. Dasiglucagon may increase the anticoagulant effect of
was associated with a dose-dependent and rapid increase
warfarin [3].
in blood glucose concentrations that was similar to that of
Dasiglucagon: First Approval

Features and properties of dasiglucagon

Alternative names ZP-4207; ZP-GA-1; ­Zegalogue®

Class Antihypoglycaemics; peptides
Mechanism of action Glucagon receptor agonists
Route of administration Subcutaneous
Pharmacodynamics Activates hepatic glucagon receptors; ↑ blood glucose concentrations; stimulates glycogen breakdown and the
release of glucose from the liver
Pharmacokinetics Dose-dependent and rapid ↑ in plasma concentration; t­max ≈ 35 min; volume of distribution 47–57 L; half-life
≈ 30 min; undergoes proteolytic degradation in the blood, liver and kidney
Most frequent adverse events Nausea, vomiting, headache, injection site pain, diarrhoea
ATC codes
WHO ATC code A16A (other alimentary tract and metabolism products)
EphMRA ATC code A16A (other alimentary tract and metabolism products)
Chemical name H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-
Trp-Leu-Glu-Ser-Thr-OH

↑ indicates increase/s, tmax time to maximum plasma concentration

2.3 Therapeutic Trials for ≥ 1  year. Following induction of hypoglycaemia,

2.3.1 Hypoglycaemia
The efficacy of dasiglucagon for the treatment of severe
hypoglycaemia was demonstrated in a randomized,
double-blind, phase  III trial in patients with T1DM
(NCT03378635) [14]. Time to plasma glucose recovery
(primary endpoint) was shorter for dasiglucagon than for
placebo. The median time to recovery (defined as first
plasma glucose increase of ≥ 20 mg/dL after treatment
initiation without rescue glucose) was 10 min with dasi-
glucagon, 12 min with reference glucagon and 40 min
with placebo; the difference between dasiglucagon and
placebo was statistically significant (p < 0.001). In this
study, 170  patients were randomized 2:1:1 to receive
subcutaneous dasiglucagon 0.6 mg, reference glucagon
­(GlucaGen®) 1 mg or placebo following induced hypogly-
caemia. After 10 min, 65% of patients in the dasiglucagon
group had recovered, compared with 49% of those in the
reference glucagon group. After 15 min, 99% of dasigluca-
gon recipients and 95% of reference glucagon recipients
had recovered [14].
In another randomized, double-blind, phase III trial
in patients with T1DM (NCT03688711), dasiglucagon
was a fast and effective treatment for severe hypoglycae-
mia [15]. The median time to plasma glucose recovery
(primary endpoint) was significantly shorter with dasi-
glucagon than with placebo (10 vs 35 min; p < 0.0001).
The median estimated true time to recovery was 9.3 min
with dasiglucagon and 25.8 min with placebo. This study
enrolled patients aged 18–70 years with a glycated hae-
moglobin level of < 10% who had been receiving insulin
45  patients were randomized to receive subcutaneous
dasiglucagon 0.6 mg (n = 34) or placebo (n = 10) via an
autoinjector. Significantly (p ≤ 0.001) more dasiglucagon
than placebo recipients experienced plasma glucose recov-
ery (i.e. increase of ≥ 20 mg/dL) within 10 (62 vs 0%),
15 (88 vs 0%), 20 (94 vs 10%) and 30 (97 vs 50%) min.
The increase in plasma glucose from baseline was also
significantly (p ≤ 0.001) higher with dasiglucagon versus
placebo at all timepoints [15].
A further randomized, double-blind, phase  III trial
evaluated the efficacy of dasiglucagon for the treatment
of severe hypoglycaemia in paediatric patients with T1DM
(NCT03667053) [16]. The median time to plasma glucose
recovery (primary endpoint) was 10 min with dasigluca-
gon, 30 min with placebo (p < 0.001) and 10 min with
reference glucagon. The median estimated true time to
recovery was 8.7 min with dasiglucagon, 29.3 min with
placebo and 9.8  min with reference glucagon. In this
study, 16 children aged 6–11 years and 25 children aged
12–17 years were randomized 2:1:1 to subcutaneous dasi-
glucagon 0.6 mg, reference glucagon ­(GlucaGen®) or pla-
cebo following induced hypoglycaemia [16].
The effects of dasiglucagon on postprandial hypoglycae-
mia after Roux-en-Y gastric bypass (RYGB) were assessed
in a phase II proof-of-concept study (NCT03984370) [17].
Compared with placebo, dasiglucagon 80 and 200 µg signifi-
cantly (p < 0.05) increased nadir plasma glucose (70 and 81
vs 54 mg/dL) and decreased the time spent in hypoglycaemia
(plasma glucose < 70 mg/dL; 27.5 and 14.0 vs 62.0 min). This
randomized, double-blind, crossover study enrolled ten RYGB-
operated patients aged 29–67 years with confirmed symptomatic
postprandial hypoglycaemia. On three separate treatment days,
 H. A. Blair
patients received a standard liquid mixed meal, with a subcuta-
neous injection of dasiglucagon 80 µg, dasiglucagon 200 µg or
placebo after the postprandial plasma glucose peak. The time
spent in level 2 hypoglycaemia (< 56 mg/dL) was 0 min with
dasiglucagon 200 µg, 7 min with dasiglucagon 80 µg and 31 min
with placebo; the difference between dasiglucagon 200 µg and
placebo was statistically significant (p = 0.01) [17].
2.3.2 T1DM Management
The efficacy of a bihormonal bionic pancreas (BHBP) using
insulin and dasiglucagon versus an insulin-only bionic pancreas
(IOBP) in 12 adults with T1DM was investigated in a phase II/
III feasibility trial (NCT03840278) [18, 19]. The mean glucose
level, as measured by continuous glucose monitoring (CGM),
was 139 mg/dL during the BHBP period versus 149 mg/dL
during the IOBP period (p = 0.004). This randomized, two-
period crossover study compared the performance of the ­iLet®
in the BHBP and IOBP configurations for one week each [18,
19]. Patients used their typical insulin analogue (insulin lispro
or insulin aspart) during both periods, and micro-doses of dasi-
glucagon were delivered during the BHBP period [19]. The
percentage of time the CGM glucose level was < 54 mg/dL
(i.e. hypoglycaemia) was not significantly different between
the BHBP and IOBP periods (0.2 vs 0.6%) [19]. Patients
spent 79% of the time with their CGM glucose level in range
(70–180 mg/dL) on days 2–7 of use during the BHBP period,
compared with 71% during the IOBP period (p < 0.01) [18].
The proportion of patients with a mean CGM glucose level of
< 154 mg/dL (corresponding to a glycated haemoglobin level
of 7%) was 90% during the BHBP period and 50% during the
IOBP period [18].
The antihypoglycaemic efficacy of dasiglucagon deliv-
ered by the i­ Let® bihormonal artificial pancreas (BHAP) was
also evaluated in a phase IIa trial in 12 adults with T1DM
(NCT02971228) [20, 21]. There were no statistically sig-
nificant differences between dasiglucagon and recombinant
human glucagon in the percentage of time with a glucose of
level of < 60 mg/dL (13 vs 20%) and in the 70–180 mg/dL
range (71 vs 62%). This randomized, crossover study com-
prised two 8-h study periods; during each, the BHAP was
stress-tested under conditions that increased the need for
glucagon [20]. Fasted patients had their first meal at lunchtime
and were given extra insulin (up to twice the normal basal
rate), after which they performed 30 min of structured exer-
cise to initiate the administration of glucagon by the BHAP
[20, 21].
2.3.3 Congenital Hyperinsulinism
The efficacy of dasiglucagon for reducing hypoglycaemia
in children with congenital hyperinsulinism was assessed
in a randomized, multicentre, open-label, phase III trial
(NCT03777176) [22]. There were no significant differ-
ences between dasiglucagon + standard of care (SOC) and
SOC alone in the weekly number of hypoglycaemic events
(plasma glucose < 70 mg/dL) as detected by self-monitored
plasma glucose (primary endpoint). In this study, 32 chil-
dren from 3 months to 12 years of age received a subcutane-
ous infusion of dasiglucagon (starting at 10 µg/h) + SOC
or SOC alone for 4 weeks. Thereafter, all patients received
dasiglucagon + SOC until week  8. The hypoglycaemia
event rate decreased from ≈ 9 events/week at baseline to
3 events/week at week 8 in both treatment groups. In a post
hoc exploratory analysis, all measures of hypoglycaemia
(including the hypoglycaemia event rate and the percentage
of time in hypoglycaemia) as measured by blinded CGM
were reduced by 40–50% with dasiglucagon + SOC versus
SOC alone (all p < 0.05) [22].
2.4 Adverse Events
Dasiglucagon was generally well tolerated when used
to treat severe hypoglycaemia in patients with T1DM in
phase III trials [14–16]. In adults, adverse events (AEs)
occurring within 12 h of treatment in ≥ 2% of dasiglucagon
recipients and at a higher frequency than with placebo were
nausea (57 vs 4%), vomiting (25 vs 2%), headache (11 vs
4%), diarrhoea (5 vs 0%) and injection site pain (2 vs 0%)
[3]. Similar AEs were seen in paediatric patients: nausea
(65 vs 0%), vomiting (50 vs 0%), headache (10 vs 0%) and
injection site pain (5 vs 0%). Other AEs occurring within
12 h of treatment with dasiglucagon included bradycardia,
hypertension, hypotension, orthostatic intolerance, palpita-
tions and presyncope [3].
Administration of glucagon products is known to cause nausea
and vomiting [16, 23]. Rates of these AEs were generally similar
for dasiglucagon and commercial glucagon in adults (nausea 55
vs 53% and vomiting 23 vs 21% in NCT03378635 [14]; nausea
46 vs 43% and vomiting 21 vs 15% in NCT03216226 [24]) and
in children aged 6–11 years (nausea 25 vs 50% and vomiting 25
vs 25%) [16], but not in children aged 12–17 years (nausea 92 vs
17% and vomiting 67 vs 0%) [16].
Dasiglucagon was also considered to be safe and well
tolerated in children with congenital hyperinsulinism [22].
In a phase III trial, dasiglucagon + SOC was associated with
higher rates of gastrointestinal and skin AEs than SOC alone
[22].
As with all therapeutic peptides, dasiglucagon has the
potential for immunogenicity [3]. In clinical trials, treat-
ment-emergent anti-drug antibodies (ADAs) were detected
in four (< 1%) dasiglucagon recipients. One of these patients
had ADAs with transient neutralizing activity and cross-
reactivity against human glucagon [3]. In a randomized,
double-blind, phase  III safety trial in 112  patients with
T1DM (NCT03216226), dasiglucagon was not associated
Dasiglucagon: First Approval

Key clinical trials of dasiglucagon

Drug(s) Indication(s) Phase Status Location(s) Sponsor (collaborator) Identifier(s)

Dasiglucagon Hypoglycaemia III Completed Multinational Zealand Pharma NCT03378635;

EudraCT2017-002449-31
Dasiglucagon Hypoglycaemia III Completed USA Zealand Pharma NCT03688711
Dasiglucagon Hypoglycaemia III Completed Multinational Zealand Pharma NCT03667053;
EudraCT2018-000892-33
Dasiglucagon Hypoglycaemia, III Completed Multinational Zealand Pharma NCT03216226;
T1DM (SynteractHCR) EudraCT2017-000062-30
Dasiglucagon Hypoglycaemia, III Completed Canada Zealand Pharma NCT03895697
T1DM
Dasiglucagon Congenital III Completed Multinational Zealand Pharma NCT03777176;
hyperinsulinism EudraCT2017-004547-21
Dasiglucagon Congenital III Recruiting Multinational Zealand Pharma NCT03941236;
hyperinsulinism EudraCT2017-004546-15
Dasiglucagon, T1DM II/III Completed USA Massachusetts General NCT03840278
insulin aspart, Hospital (Beta Bionics,
insulin lispro Zealand Pharma)
Dasiglucagon Congenital II/III Recruiting Multinational Zealand Pharma NCT04172441;
hyperinsulinism EudraCT2017-004545-24
Dasiglucagon Hypoglycaemia II Completed Denmark University Hospital, Gentofte, NCT03984370
Copenhagen
Dasiglucagon T1DM II Completed Germany Zealand Pharma NCT02916251;
EudraCT2016-002617-21
Dasiglucagon Hypoglycaemia II Completed Germany Zealand Pharma NCT02660008;
EudraCT2015-005287-41
Dasiglucagon Hypoglycaemia II Completed USA Zealand Pharma (Massachusetts NCT02971228
General Hospital, Beta Bionics)
Dasiglucagon Hypoglycaemia II Completed Denmark Steno Diabetes Center NCT04449692;
Copenhagen EudraCT2020-000551-12
Dasiglucagon Hypoglycaemia II Not yet Denmark University Hospital, Gentofte, SHERRY; NCT04836273;
recruiting Copenhagen (Zealand EudraCT2020-005241-16
Pharma)
Dasiglucagon Hypoglycaemia II Not yet Denmark Steno Diabetes Center NCT04764968;
recruiting Copenhagen EudraCT2020-005745-16
Dasiglucagon Hypoglycaemia II Not yet Unknown Zealand Pharma NCT04824872
recruiting

T1DM type 1 diabetes mellitus

with the development of ADAs [23]. The overall ADA inci-
dence, calculated as a percentage of the combined results
of treatment-induced ADA-positive patients and treatment-
boosted ADA-positive patients relative to the total number
of evaluable patients (primary endpoint), was zero. This
study enrolled patients aged 18–70 years with a glycated
haemoglobin level of < 10% who had been receiving insu-
lin for ≥ 1 year. They were randomized to receive repeated
single doses of subcutaneous dasiglucagon 0.6 mg (n = 57)
or commercial glucagon 1.0 mg (­ GlucaGen®; n = 55) at
weeks 1, 2 and 3. No injection site reactions were reported
in the dasiglucagon group, while eight injection site reac-
tions were reported in six commercial glucagon recipients.
There were no serious drug-related AEs and no AEs leading
to treatment discontinuation [23].
2.5 Ongoing Clinical Trials
A phase II trial plans to evaluate the efficacy, safety and fea-
sibility of pen-administered low-dose dasiglucagon to treat
or prevent episodes of mild hypoglycaemia in insulin pump-
treated patients with T1DM (NCT04764968). This rand-
omized, open-label, two-period crossover study is expected
to start in April 2021 and has an estimated study completion
date of March 2022.
The efficacy, safety and tolerability of dasiglucagon for
the treatment of postprandial hypoglycaemia after RYGB
surgery will be investigated in a phase II proof-of-concept
trial (SHERRY; NCT04836273) and in another phase II trial
(NCT0482487). A phase II/III trial (NCT04172441) is currently
underway to evaluate the efficacy and safety of dasiglucagon in
 H. A. Blair
children under the age of 365 days with congenital hyperinsu-
linism. Recruitment is also underway in a phase III extension
trial (NCT03941236) assessing the long-term safety and effi-
cacy of dasiglucagon in children aged from 6 weeks to 13 years
with congenital hyperinsulinism who completed one of two
lead-in trials (NCT04172441 or NCT03777176).
10. Castle J, Elander M, O’Halloran S. Long-term safety and tolerabil-
3 Current Status
Dasiglucagon received its first approval on 22 March 2021
in the USA for the treatment of severe hypoglycaemia in
paediatric and adult patients with diabetes aged 6 years and
above [4].
Declarations  dasiglucagon consistently increase plasma glucose levels from
Funding  The preparation of this review was not supported by any
external funding.
Authorship and Conflict of Interest  During the peer review process the
manufacturer of the agent under review was offered an opportunity to
comment on the article. Changes resulting from any comments received
were made by the authors on the basis of scientific completeness and
accuracy. Hannah Blair is a salaried employee of Adis International
Ltd/Springer Nature, and declares no relevant conflicts of interest. All
authors contributed to the review and are responsible for the article
content.
Ethics Approval, Consent to Participate, Consent to Publish, Availability
of Data and Material, Code Availability  Not applicable.
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