Dasiglucagon—A Next-Generation Glucagon Analog

Home , Dasiglucagon, Insulin glargine, Insulin glulisine

MRIGTEAIS RG N REGIMENS AND DRUGS THERAPIES: EMERGING

Diabetes Care Volume 44, June 2021 1361

Dasiglucagon—A Next-Generation Thomas R. Pieber,1 Ronnie Aronson,2 Ulrike Hovelmann,€ 3 Julie Willard,4 Glucagon Analog for Rapid and Leona Plum-Morschel,€ 5 Kim M. Knudsen,6 Benedikte Bandak,6 and Effective Treatment of Ramin Tehranchi6 Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial Diabetes Care 2021;44:1361–1367 | https://doi.org/10.2337/dc20-2995

OBJECTIVE To evaluate the efﬁcacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, deﬁned as an increase of $20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference.

RESULTS Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P < 0.001); the corresponding result 1Medical University of Graz, Graz, Austria for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, 2LMC Diabetes and Endocrinology, Toronto, Ontario, plasma glucose recovery was achieved within 15 min in all but one participant Canada (99%), superior to placebo (2%; P < 0.001) and similar to glucagon (95%). Similar 3Profil, Neuss, Germany 4 outcomes were observed for the other investigated time points at 10, 20, and 30 ProSciento, San Diego, CA 5Profil, Mainz, Germany min after dosing. The most frequent adverse effects were nausea and vomiting, 6Zealand Pharma, Søborg, Denmark as expected with glucagon treatment. Corresponding author: Thomas R. Pieber, [email protected] CONCLUSIONS Received 9 December 2020 and Accepted 11 Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults March 2021 with type 1 diabetes, with safety and tolerability similar to those reported for Clinical trial reg. no. NCT03378635, clinicaltrials.gov reconstituted glucagon injection. The ready-to-use, aqueous formulation of This article contains supplementary material online dasiglucagon offers the potential to provide rapid and reliable treatment of at https://doi.org/10.2337/figshare.14207960. severe hypoglycemia. © 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Glucagon is well established as a first-line pharmaceutical emergency treatment for More information is available at https:// severe (level 3) hypoglycemia in people with diabetes. Rescue glucagon can be www.diabetesjournals.org/content/license. 1362 Dasiglucagon Phase 3 Trial in Type 1 Diabetes Diabetes Care Volume 44, June 2021

carried by patients or caregivers, provid- of native glucagon. In adults with type Trial product was for this trial was ad- ing them with a valuable safety mea- 1 diabetes, dasiglucagon rapidly and ministered via prefilled syringe. sure. As the only prescription treatment effectively restored euglycemia after The trial was performed in accor- for severe hypoglycemia that is not lim- insulin-induced hypoglycemia at doses dance with the Declaration of Helsinki, ited to dosing by health care professio- from 0.1 to 1.0 mg (9). The present International Conference on Harmonisa- nals, glucagon has been recommended phase 3 trial was conducted to dem- tion guidelines, and Good Clinical Prac- in the most recent American Diabetes onstrate the efficacy and safety of a tice. An institutional review board or Association treatment guidelines (1) to single subcutaneous dose of 0.6 mg independent ethics committee approved be prescribed for all individuals at in- dasiglucagon as a treatment for severe the trial at each center, and all partici- creased risk of level 2 hypoglycemia, hypoglycemia in those with type 1 pants provided written informed consent fi < de ned as blood glucose 54 mg/dL diabetes. before undergoing any trial procedures (<3.0 mmol/L), so it is available if need- or assessments. ed. Caregivers, school personnel, or RESEARCH DESIGN AND METHODS family members of these individuals are Participants advised that they should know where Trial Design – This trial used a multicenter, random- The trial included adults (aged 18 75 glucagon treatment is stored and when years, inclusive) with type 1 diabetes re- and how to administer it. ized, placebo-controlled, double-blind, parallel-group design in a clinical receiving stable insulin therapy and with Despite these recommendations, glu- HbA <10% (85.8 mmol/mol). Partici- search inpatient setting. The trial was 1c cagon is underused for the treatment of pants were excluded if they had previ- conducted in two centers in Germany severe hypoglycemia in individuals with ously received dasiglucagon, had an and one in each of the following: Aus- diabetes, even when available to well- allergy to any trial product, or had experi- – tria, the U.S., and Canada. It included informed patients and caregivers (2 4). enced hypoglycemia with seizure during three parallel treatment arms, with par- This underuse may be at least partly at- the preceding year or severe hypoglyce- ticipants randomly assigned 2:1:1 to re- tributable to the fact that the majority mia during the preceding month. Partici- ceive a single subcutaneous dose of 0.6 of glucagon for prescription use is pants were also excluded if they had provided in glucagon emergency kits mg dasiglucagon, placebo, or 1.0 mg re- used β-blockers, indomethacin, warfarin, (Glucagon for Injection, Eli Lilly and Com- constituted lyophilized glucagon (Gluca- or anticholinergic drugs daily during the pany; GlucaGen HypoKit, Novo Nordisk) Gen; 1 mg/mL glucagon for injection). 28 days before screening. that require multistep reconstitution be- The primary objective of the trial was to fore subcutaneous or intramuscular injec- demonstrate superiority of dasiglucagon Procedures tion. The complexity of the multistep over placebo; reconstituted glucagon Participants were screened between 30 reconstitution process is a known barrier was included as a reference. Randomi- and 3 days before dosing. Eligible partic- to timely, accurate, and effective adminis- fi zation was performed using a xed- ipants attended a single dosing visit and tration of glucagon, often resulting in block randomization scheme, which was a safety follow-up visit 28 days after both delays and inaccurate dosing and generated before the trial began by dosing. The dosing visit required an the potential for total failure in dose ad- an independent statistician/programmer overnight stay in the center before dos- ministration (3,5,6). More recently, ready- who was not a member of the trial to-use glucagon products for subcutane- ing. Participants fasted from 2200 h but team; the investigators were unaware were allowed to have small amounts of ous injection (Gvoke; formulation in the of the block size of the randomization organic solvent DMSO) and intranasal dry carbohydrates (up to 20 g total) to pre- scheme. Randomization was stratified ’ powder administration (Baqsimi) have vent hypoglycemia. Participants insulin by injection site (abdomen, buttocks, or become available. These newer products therapy was stopped in advance accord- thigh) via an interactive web response fi have unique benefit-risk profiles because ing to prede ned timelines: insulin de- system. Dasiglucagon and placebo were of the characteristics of drug formulation gludec and insulin glargine U300 48 provided in ready-to-use aqueous for- and/or mode of administration (7,8). h before dosing, other long-acting insu- mulations, and glucagon was provided The next-generation glucagon analog lins 24 h before dosing, and insulin NPH dasiglucagon is the first glucagon as a lyophilized powder requiring recon- and short-acting insulins (except insulin product to be provided in a ready-to- stitution. Because the medications were glulisine) 16 h before dosing. Insulin use, aqueous formulation. Like endog- different in appearance, the preparation pumps were stopped on the morning of enous glucagon, dasiglucagon is com- and administration of trial medication the dosing day (insulin glulisine) or at posed of 29 amino acids, but with were performed by unblinded trial per- least 6 h before dosing (other insulins). seven amino acid substitutions com- sonnel who were not involved in any Intravenous insulin glulisine was admin- pared with endogenous glucagon to other trial procedures or assessments. istered at 150% of the participant’susual increase the physical and chemical The tested aqueous formulation of dasi- basal rate, with adjustments to achieve a stability in aqueous media. Aqueous glucagon contained 1 mg dasiglucagon controlled decline in plasma glucose, tar- formulation is thereby enabled, elimi- per mL, and hence, the injected volume getingaplasmaglucoselevelof55mg/ nating the need for reconstitution be- was 0.6 mL (similar for placebo). dL (3.1 mmol/L). Plasma glucose concen- fore injection. Dasiglucagon maintains Dasiglucagon is developed for com- trations were measured using glucose specificity for the glucagon receptor mercialization in two presentations: a analyzers (YSI 2300; Yellow Springs Instru- and has potency comparable to that prefilled syringe and an autoinjector. ments, Yellow Springs, OH; or Super GL care.diabetesjournals.org Pieber and Associates 1363

analyzer; Dr. Muller€ Ger€atebau GmbH, expected to be >20 min, which would details are provided in Supplementary Freital, Germany). After the start of the result in a power >90%. Fig. 1. A majority of participants were insulin infusion, plasma glucose was mea- Theprimaryendpointwastimefrom male (63%), White (92%), and non-His- sured approximately every 10 min while dosing to plasma glucose recovery, de- panic (96%). Mean age was 39.1 years plasma glucose was >110 mg/dL (6.1 fined as time to first increase in plasma (range, 18–71 years), mean BMI was 2 mmol/L) and approximately every 5 min glucose of $20 mg/dL (1.1 mmol/L) 26.1 kg/m ,meanHbA1c was 7.4% once plasma glucose was #110 mg/dL. from baseline (time of injection) without (57 mmol/mol), and mean duration of The insulin infusion was stopped rescue intravenous glucose. Individuals diabetes was 20.0 years. Demographic once the glucose concentration was were considered not to have recovered data and baseline diabetes characteris- <60 mg/dL (3.3 mmol/L). After 5 min if rescue intravenous glucose was ad- tics were similar across the three treat- and if plasma glucose was $45 mg/dL ministered or if recovery was not ment groups (Table 1). and <60 mg/dL (2.5–3.3 mmol/L), the achieved within 45 min. In addition to trial drug was administered by subcuta- theobservedtimetorecovery,asup- Efficacy neous injection, with location assigned portive analysis using linear interpola- Results for plasma glucose recovery are to the abdomen, buttock, or thigh. Seri- tion between observed time points shown in Table 2. Median (95% CI) time al blood samples for central laboratory before and after plasma glucose recov- from dosing to plasma glucose recovery plasma glucose assessments were taken ery occurred was prespecified to find an was 10 min for dasiglucagon (10, 10) com- predose and at predefined intervals at individual’struetimetoplasmaglucose pared with 40 min for placebo (30, 40) 4, 6, 8, 10, 12, 15, 17, 20, 25, 30, 40, recovery (i.e., the predicted time of an (P < 0.001). Median time to plasma glu- 50, 60, 75, and 90 min after dosing. exact 20 mg/dL increase in plasma glucose recovery for the reference glucagon Blood samples for pharmacokinetic cose). The primary end point was sum- product was 12 min (10, 12). A one minus measurements (data not shown) and marized by treatment group using Kaplan-Meier plot is shown in Fig. 1A. safety assessment were taken predose survival analysis methods (median time Using linear interpolation to estimate and at predefined intervals up to 120 to event and mean time to event when the true time to plasma glucose recov- and 300 min after dosing, respectively. no censoring occurred). The treatment ery, median (95% CI) time to recovery Antidrug antibody (ADA) samples were group difference between dasiglucagon was 9.0 min for dasiglucagon (8.4, 9.7), analyzed using a multitiered testing ap- and placebo was evaluated inferentially 33.7 min for placebo (26.1, 36.1), and proach. In tier 1, screening for antidasiglu- using a two-sided log-rank test stratified 10.0 min for glucagon (9.0, 10.6). cagon antibodies was conducted based on by injection site. Time to recovery is dis- A high proportion of dasiglucagon- an ELISA. The same assay with inclusion of played as cumulative recovery (i.e., as treated participants achieved plasma excess dasiglucagon was used as confirma- one minus Kaplan-Meier estimate). The glucose recovery within predefined tory analysis in tier 2. Confirmed positive influence of injection site was evaluated time points; 65%, 99%, and 99% of par- samples were analyzed for in vitro neutral- in a proportional hazards model, includ- ticipants recovered within 10, 15, izing activity in a cell-based assay (tier 3). ing treatment group and injection site and 20 min after dose administration, Finally, ADA-positive samples were titrated as categorical effects and baseline plas- respectively. The single dasiglucagon- using the tier 1 assay. A similar set of as- ma glucose as a continuous covariate. treated participant who did not recover says were used to analyze ADA-positive The key secondary end points of within 20 min closely approached the samples for antibodies cross-reacting with achievement of plasma glucose recov- recovery threshold, with a plasma glu- glucagon. ery within 30, 20, 15, and 10 min were cose increase from baseline to 20 min compared between treatment groups of 19.98 mg/mL (1.1 mmol/L). In con- Statistical Analysis using Fisher’sexacttest.Thekeysec- trast, only one (2%) participant in the The sample size was set to 78 partici- ondary end points of plasma glucose placebo group recovered within 15 min, pants treated with dasiglucagon, with a change from baseline at 30, 20, 15, and with 47% of participants achieving re- total of 156 participants completing the 10 min were analyzed using an ANCOVA covery within 30 min after injection dosing visit. In a phase 2 trial, median model. The treatment group differences (Table 2). Pairwise comparisons of the time to plasma glucose recovery (glu- between dasiglucagon and placebo for proportion of participants achieving glucose increase of 20 mg/dL) was approx- the primary and key secondary end cose recovery were significantly in favor imately 10 min with dasiglucagon. With points were tested in a prespecified or- of dasiglucagon versus placebo at 10, a 2:1:1 randomization for dasiglucagon der (as listed above) using a hierarchical 15, 20, and 30 min (P < 0.001 for each to placebo to glucagon in this trial, and testing approach to control for multiplicity. time point). In the reference glucagon assuming an exponential time-to-recov- group, recovery rates were 49%, 95%, ery distribution with median times of RESULTS and 98% after 10, 15, and 20 min, re- 10 min for dasiglucagon and at least 20 Participant Disposition and spectively. Intravenous glucose rescue min for placebo, a two-sided log-rank Characteristics was not required by participants in the test was expected to detect a difference Between December 2017 and May dasiglucagon or glucagon groups but between dasiglucagon and placebo with 2018, 170 participants were randomly was required by seven (16%) partici- 90% power at a 5% significance level, assigned, of whom 168 received a single pants in the placebo group. given a follow-up time of 45 min. Medi- dose of trial drug (dasiglucagon, n =82; Plasma glucose increase from base- an time to recovery for placebo was placebo, n =43;andglucagon,n =43); line is shown for the three treatment 1364 Dasiglucagon Phase 3 Trial in Type 1 Diabetes Diabetes Care Volume 44, June 2021

Table 1—Demographic data and baseline diabetes characteristics bodies were no longer evident 17 Dasiglucagon Placebo Glucagon months after dosing. (n = 82) (n = 43) (n = 43) Sex, n (%) CONCLUSIONS Male 50 (61) 27 (63) 28 (65) In this phase 3 trial, a single subcutane- Female 32 (39) 16 (37) 15 (35) ous dose of 0.6 mg dasiglucagon re- Race, n (%) White 76 (93) 39 (91) 39 (91) sulted in rapid and sustained reversal of Other 6 (7) 4 (9) 4 (9) insulin-induced hypoglycemia in adults Age, years, median (range) 37.0 (18–71) 36.0 (18–65) 38.0 (23–66) with type 1 diabetes. Dasiglucagon Weight, kg 78.3 (13.5) 79.5 (12.9) 80.7 (15.1) treatment resulted in significant treat- fi BMI, kg/m2 26.1 (4.13) 26.1 (3.34) 25.9 (3.42) ment bene ts relative to placebo across all key end points comprising time to HbA1c, % 7.52 (0.95) 7.17 (0.74) 7.41 (0.97) plasma glucose recovery, proportion of Diabetes duration, years 21.5 (12.32) 18.3 (11.02) 18.7 (11.17) participants achieving recovery, and Plasma glucose, mg/dL 58.9 (5.59) 58.8 (4.44) 58.5 (5.11) change in plasma glucose from baseline. Data are mean (SD) unless otherwise indicated. Median time from injection to plasma glucose recovery (defined as first increase in plasma glucose of $20 mg/dL groups in Fig. 2. After 30 min, mean both active treatment groups and in this [1.1 mmol/L]) was 10 min for dasigluca- plasma glucose increase from baseline trial setting, nausea generally occurred gon and 12 min for glucagon, with cor- was 90.9 mg/mL for dasiglucagon com- 1to3hafterdosingandlasted<3 responding values of 9.0 vs. 10.0 min pared with 19.1 mg/mL for placebo; the hinmostcases.Vomitingtendedtooc- when applying linear interpolation to corresponding mean increase for the cur later than nausea, with most events estimatethetruetimetoplasmaglu- reference glucagon product was 88.5 occurring between 2 and 3 h after injec- cose recovery. A numerically greater mg/mL. Plasma glucose change from tion and lasting <3 h. No serious or fa- proportion of participants achieved baseline was significantly greater for da- tal adverse events occurred. plasma glucose recovery within 10, 15, siglucagon than placebo at 10, 15, 20, and Local tolerability assessments showed and 20 min after dasiglucagon administra- 30 min (P < 0.001 for each time point). few events: two events in two (2%) par- tion (65%, 99%, and 99%, respectively) Injection site (abdomen, buttock, or ticipants in the dasiglucagon group, two compared with those receiving reference thigh) did not influence time to plasma events in two (5%) participants in the glucagon treatment (49%, 95%, and 98%, glucose recovery across the three treat- placebo group, and three events in respectively). By comparison, in a similar ment groups (P = 0.152). three (7%) participants in the glucagon clinical trial comparing intranasal and in- group. All injection site reactions were tramuscular glucagon (where success was Safety mild and transient (e.g., redness, ede- definedasanincreaseinplasmaglucose The safety profiles of both dasiglucagon ma, and pain on palpation). to $70 or $20 mg/dL from the glucose and glucagon were consistent with One participant in the dasiglucagon nadir), the respective proportions of par- the known adverse effects of glucagon grouptestedpositiveforADAsatthe ticipants achieving recovery within 10, 15, treatment, with the most common 28-day follow-up visit. The antibodies and 20 min of dosing were 21%, 71%, drug-related adverse events of nausea, had a low titer, were nonneutralizing and 90% with intranasal glucagon and vomiting, and headache comparable be- in vitro, and did not cross-react with 48%, 86%, and 100% with intramuscular tween treatment groups (Table 3). In glucagon. These nonneutralizing anti- glucagon (10).

Table 2—Plasma glucose recovery Dasiglucagon Placebo Glucagon (n = 82) (n = 43) (n = 43) Time to recovery,* minutes (primary end point) 10 (10, 10) 40 (30, 40) 12 (10, 12) P < 0.001† True time to recovery* estimated using linear interpolation, minutes 9.0 (8.4, 9.7) 33.7 (26.1, 36.1) 10.0 (9.0, 10.6) P < 0.001† Proportion of patients achieving plasma glucose recovery* within, % 30 min 100 47 100 20 min 99 14 98 15 min 99 2 95 10 min 65 0 49 P < 0.001 for all tests† Data are median (95% CI) unless otherwise indicated. *Deﬁned as ﬁrst increase in plasma glucose of $20 mg/dL from baseline without administration of rescue intravenous glucose (censoring at 45 min). †Test relative to placebo. care.diabetesjournals.org Pieber and Associates 1365

Actual In the current trial, the speed and ef- A ficacy of dasiglucagon in achieving plas- 100% ma glucose recovery were fully on par with those of reconstituted glucagon. 75% Importantly, time to response in this trial was measured from the time of injection and as such did not capture the 50% benefit of being able to administer the ready-to-use dasiglucagon preparation 25% directly as opposed to having to recon- stituteglucagonbeforeinjection,which Percent recovered is associated with high rates of unsuc- 0% cessful injection and delayed dosing 0 4 6 8 10 12 15 17 20 25 30 40 45 (5,6). A similar benefitofavoidingthe Minutes after dosing reconstitution step is obtained with the currently marketed ready-to-use gluca- Interpolated gon products for subcutaneous injection B (Gvoke) or intranasal dry powder ad- 100% ministration (Baqsimi). Although they represent an improvement relative to 75% the hypo kit products, these newer products have unique benefit-risk pro- fi 50% les because of the characteristics of drug formulation and/or mode of administration, with injection site edema 25% and pain being more prevalent for

Percent recovered Gvoke and nasal and ocular adverse 0% events being more prevalent for 0 4 6 8 10 12 15 17 20 25 30 40 45 Baqsimi, both relative to reconstituted glucagon (7,8). Within the referenced Minutes after dosing summaries, both of these newer prod- Dasiglucagon 0.6 mg Placebo GlucaGen® 1.0 mg ucts are characterized by a prolonged time from product administration to Figure 1—One minus Kaplan-Meier plots of time to plasma glucose recovery. Plasma glucose re- achievement of plasma glucose target fi covery was de ned as an increase from baseline of at least 20 mg/dL without rescue intrave- when compared with reconstituted nous glucose. A: Time to plasma glucose recovery. B: Estimated true time to plasma glucose – recovery (linear interpolation). glucagon (prolonged by 3 4 min for Gvoke (7) and by 1–4 min for Baqsimi (8)). No head-to-head trials comparing these products versus dasiglucagon have been conducted; however, in this trial, dasiglucagon showed no delay in 120 6.66 time elapsed from product administra- 100 5.55 tion to plasma glucose target achievement compared with reconstituted 80 4.44 glucagon. With the combination of 60 3.33 the ready-to-use formulation and the rapid and effective reversal of hypo- 40 2.22 glycemia, dasiglucagon may provide (mmol/L) fi fi 20 1.11 signi cant bene t to patients for the most clinically relevant parameter of 0 0 from baseline (mg/dL) time elapsed from initiating product

Increase in plasma glucose handling to achieving recovery from 0 6 10 15 20 30 40 severe hypoglycemia. Minutes after dosing Glucagon is widely known to be underused as a treatment for severe hypoglyce- Dasiglucagon 0.6 mg Placebo GlucaGen® 1.0 mg mia (4,11), with only a small proportion of Figure 2—Mean increase in plasma glucose (mg/dL) shown as change from baseline with 95% insulin-treated patients being prescribed glu- CIs after a single dose of 0.6 mg dasiglucagon (red), placebo (orange), or 1.0 mg glucagon (gray). cagon rescue medication from the start of The horizontal line represents the deﬁnition of plasma glucose recovery used for the primary insulin therapy (2). Prescribers may be end point (an increase from baseline of at least 20 mg/dL). more conﬁdent in prescribing a ready-to- 1366 Dasiglucagon Phase 3 Trial in Type 1 Diabetes Diabetes Care Volume 44, June 2021

Table 3—Adverse events conflicts of interest relevant to this article Dasiglucagon Placebo Glucagon were reported. (n = 82) (n = 43) (n = 43) Zealand Pharma sponsored this trial and was involved in the design and conduct of All adverse events 66 (80) 14 (33) 32 (74) the trial and analysis and interpretation of Drug-related* adverse events 52 (63) 3 (7) 27 (63) the data, including collection, management, Most commonly reported† and statistical analysis of the data. T.R.P., R.A., U.H., J.W., drug-related* adverse events Author Contributions. and L.P.-M. were involved in conducting the Nausea 45 (55) 1 (2) 23 (53) trial. T.R.P. and R.T. wrote the manuscript. All Vomiting 19 (23) 1 (2) 9 (21) authors reviewed, edited, and approved the Headache 8 (10) 1 (2) 4 (9) manuscript for submission. T.R.P. and K.M.K. Injection site erythema 1 (1) 2 (5) 2 (5) are guarantors of this work and, as such, had Data are n (%). *Possibly or probably drug-related adverse events, as reported by the inves- full access to all data in the trial and take re- tigator. †Occurring in $5% of participants in any treatment group. sponsibility for the integrity of the data and the accuracy of the data analyses. T.R.P., R.A., U.H., J.W., and L.P.-M. are the principal investigators from the five participat- ing sites. use glucagon analog such as dasigluca- elimination of residual injected insulin Prior Presentation. Parts of this trial were gon. A ready-to-use product is likely to predosing. A stable confirmed period of presentedinabstractformatthe79thSci- increase the probability of successfully hypoglycemia before dosing, as well as entific Sessions of the American Diabetes – administering the drug, especially for blinding of investigators and partici- Association, San Francisco, CA, 7 11 June fi 2019, and at the 13th International Confer- nonmedical caregivers, who often nd pants, also reduced any potential bias. ence on Advanced Technologies & Treat- the complexity of reconstitution highly Adverse event review throughout a pro- ments for Diabetes, Madrid, Spain, 19–22 stressful in an emergency situation longed follow-up period and systematic February 2020. (3,4). The simplicity of dosing and review of injection sites were helpful in short time to hypoglycemia recovery determining the full adverse effect pro- References achieved with dasiglucagon may also file. However, the therapy was assessed 1. American Diabetes Association. Standards of result in fewer cases of severe and Medical Care in Diabetes-2020 abridged for in a highly controlled investigational in- primary care providers. Clin Diabetes 2020;38: persistent hypoglycemia that require patient setting, which may not fully re- 10–38 additional medical intervention, which flect real-world settings. Additional 2. Mitchell BD, He X, Sturdy IM, Cagle AP, would be expected to reduce the investigations should explore the effica- Settles JA. Glucagon prescription patterns in overall cost burden of treatment. The cy and safety of dasiglucagon in real-life patients with either type 1 or 2 diabetes with cost of treating a severe hypoglycemic newly prescribed insulin. Endocr Pract 2016;22: situations. 123–135 event in an emergency medical or In conclusion, this randomized, con- 3. Harris G, Diment A, Sulway M, Wilkinson M. hospital setting is substantial, includ- trolled clinical trial demonstrated that da- Glucagon administration – underevaluated ing direct costs (e.g., hospital treat- siglucagon provided rapid and effective and undertaught. Pract Diabetes Int 2001;18: – ment, ambulance, primary health care reversal of hypoglycemia in adults with 22 25 professional contacts, and treatment 4. Kedia N. Treatment of severe diabetic type 1 diabetes. The ready-to-use, aque- hypoglycemia with glucagon: an underutilized at home) that may exceed $1,100 and ous formulation of dasiglucagon offers therapeutic approach. Diabetes Metab Syndr indirect costs (e.g., expected produc- the potential to provide rapid and reli- Obes 2011;4:337–346 tivity loss) as high as $580 per event able treatment of severe hypoglycemia. 5. Valentine V, Newswanger B, Prestrelski S, (12). In contrast, for severe hypo- Andre AD, Garibaldi M. Human factors usability glycemic episodes that require only and validation studies of a glucagon autoinjector Acknowledgments. The authors acknowl- in a simulated severe hypoglycemia rescue nonmedical assistance (e.g., by a rela- edge patients who participated in the trial situation. Diabetes Technol Ther 2019;21: tive or caregiver), the cost of treatment and contributed to the outcome of the trial, 522–530 has been estimated at <$250 (12). A as well as Fiona Swain of Mediwrite Ltd. for 6. Settles JA, Gerety GF, Spaepen E, Suico JG, model of the potential downstream providing medical writing support (funded by Child CJ. Nasal glucagon delivery is more health care savings of successful nonho- Zealand Pharma). successful than injectable delivery: a simulated Duality of Interest. This trial was sponsored severe hypoglycemia rescue. Endocr Pract 2020; spital glucagon use (13) has shown a by Zealand Pharma. T.R.P. has received re- 26:407–415 potential cost savings of >$1,000 per search funding (paid to university) from Zea- 7. U.S. Food and Drug Administration. Gvoke episode. land Pharma, AstraZeneca, Novo Nordisk, and summary basis of approval, application 212097: The safety profile of dasiglucagon Sanofi and consulting fees from Adocia, Are- clinical review. Accessed 6 April 2021. Available was comparable to that of reconstituted cor, AstraZeneca, Eli Lilly, Novo Nordisk, at www.fda.gov/media/132052/download Sanofi, and The Longevity Lab. R.A. has re- 8. U.S. Food and Drug Administration. Baqsimi lyophilized (reference) glucagon. Nausea ceived research support from Novo Nordisk, summary basis of approval, application 210134: and vomiting were the most frequently Becton Dickinson Technologies, Eli Lilly, Zea- clinical review. Accessed 6 April 2021. Available at reported adverse events, consistent land Pharma, Xeris, Insulet, Dexcom, and Tan- www.accessdata.fda.gov/drugsatfda_docs/nda/ with these gastrointestinal events being dem Diabetes and consulting fees from 2019/210134Orig1s000MedR.pdf fi € well-known adverse effects of glucagon Sano , Novo Nordisk, Boehringer Ingelheim, 9. Hovelmann U, Bysted BV, Mouritzen U, Eli Lilly, and Gilead. U.H., J.W., and L.P.-M. et al. Pharmacokinetic and pharmacodynamic treatment. have received research support from Zealand characteristics of dasiglucagon, a novel soluble The strengths of this trial include the Pharma. K.M.K., B.B., and R.T. are employees and stable glucagon analog. Diabetes Care 2018; multicenter design and the rigorous of Zealand Pharma. No other potential 41:531–537 care.diabetesjournals.org Pieber and Associates 1367

10. Rickels MR, Ruedy KJ, Foster NC, et al.; T1D 11. Pearson T. Glucagon as a treatment of diabetes in the United States. J Med Econ Exchange Intranasal Glucagon Investigators. severe hypoglycemia: safe and efﬁcacious but 2015;18:420–432 Intranasal glucagon for treatment of insulin- underutilized. Diabetes Educ 2008;34:128–134 13. Leinwand B, Hughes KE, Inocencio T. The induced hypoglycemia in adults with type 1 12. Foos V, Varol N, Curtis BH, et al. Economic health service and economic impact of glucagon diabetes: a randomized crossover noninferiority impact of severe and non-severe hypo- rescue administration during severe hypoglycemic study. Diabetes Care 2016;39:264–270 glycemia in patients with type 1 and type 2 events. Value Health 2014;17:A352