(Pram) and Insulin A21G Improves Post-Prandial Glucose Vs Novolog

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ADO09, A Co-Formulation Of Pramlintide (Pram) and Insulin A21G improves Post-Prandial Glucose Vs Novolog® in Type 1 Diabetes (T1DM) G.Meiffren¹, G.Andersen², R.Eloy¹, C.Seroussi¹, C.Mégret¹, S.Famulla², Y.-P Chan¹, M.Gaudier¹, O.Soula¹, J.H. DeVries²,T.Heise² (1 Adocia, Lyon, France ; 2 Profil, Neuss, Germany)

Introduction & Background Overall safety Outpatient period results - CGM metrics o ADO09 (M1Pram) is a co-formulation of pramlintide and insulin A21G o Both treatments were well tolerated without any treatment-related serious adverse events o Most of the CGM metrics (TiR [70-180], TiR [80-140], mean blood glucose per day), were significantly improved developed to leverage the beneficial effects of pramlintide on post-prandial (Table 2). As expected M1Pram had numerically more, mostly gastrointestinal adverse events with M1Pram (Table 4). Postprandial and mean 24-hour glucose profiles were improved with M1Pram (Fig. 3) glucose without additional injections than insulin aspart Table 4: CGM metrics, all days. Significant differences are marked in bold Objective and design o No severe hypoglycemia were seen, slightly more hypoglycemic events occurred with M1Pram Ratio of LSMean* o To compare the effect of M1Pram and insulin aspart (Novolog®, Novo than with aspart (Table 3) Difference Parameter Treatment LS Mean M1Pram / Aspart P-value Nordisk) on post-prandial glucose control, glycemic control assessed by Table 2: Incidence of adverse events throughout the trial (M1Pram-Aspart) (95% CI) CGM and safety/tolerability M1Pram Aspart M1Pram (N=24) 16.50 o Double-blind, single center, randomized, 2 period cross-over trial comparing (N=25) (N=23) TIR [70-180 mg/dL] (h) 1.05 (1.01;1.10) +51 mins 0.0134 pre-meal M1Pram vs aspart over 24 days Number of Subjects (%) / Number of Events Aspart (N=22) 15.65 o Key endpoints: Mixed meal tolerance test (MMTTs) at day 24 and CGM Adverse Events 20 (80 %) / 47 10 (43 %) / 23 M1Pram (N=24) 9.66 metrics of 21 T1DM subjects Moderate and Severe Adverse Events 7 (28 %) / 8 2 (8 %) / 3 TIR [80-140 mg/dL] (h) 1.14 (1.06;1.22) +70 mins 0.0017 Aspart (N=22) 8.50 Methods Drug Related* Adverse Events 14 (56 %) / 34 4 (17 %) / 9 o Basal insulin: insulin degludec (Tresiba®, Novo Nordisk) optimized during a *Possible or probable, as assessed by the Investigator M1Pram (N=24) 0.69 run-in phase of 28 days Serious Adverse Event (unlikely related) 1 (4%) / 1 0 Time < 70 mg/dL (h) 1.31 (1.00;1.72) +10 mins 0.0464 o Dosing period: 3 inpatient days and 21 outpatient days with Aspart (N=22) 0.53 Drug Related Adverse Events leading to permanent 2 interim visits (Figure 1) 2 (8 %) 0 Discontinuation of Study Drug M1Pram (N=24) 0.15 o CGM: Dexcom® G6 CGM unblinded to patients from the start of the run-in Time < 54 mg/dL (h) 1.06 (0.65;2.15) <1 min 0.8045 phase to the end of the trial Table 3: Incidence of hypoglycemic events during the outpatient period Aspart (N=22) 0.14 o IMP titration: done by subjects, supported by study physicians and a titration M1Pram Aspart M1Pram (N=24) 149.98 guidance Mean BG per Day (mg/dL) 0.95 (0.93;0.97) -8.19 mg/dL 0.0001 (N=25) (N=23) o Statistical Analyses: Comparisons were done with a linear mixed-effect Category Aspart (N=22) 158.17 model with treatment, period, and sequence as fixed effects and subject Number of Subjects (%) / Number of Events within sequence as random effect, with a significance level of 5%. For Overall 21 (84 %) / 142 18 (78 %) / 115 Figure 3: Mean CGM during outpatient days at mealtime (0-4h) and over 24h endpoints not normally or log-normally distributed, comparisons were done 180 ) Daytime (6:00 am to 11:59 pm) 19 (76 %) / 117 18 (79 %) / 109 Breakfast Aspart M1Pram 170 L

non-parametrically with the Wilcoxon Signed Rank Test ) d

At night (midnight to 05:59 am) 15 (60 %) / 25 5 (21 %) / 6 160 / Mean CGM Profiles (Outpatient periods) dL Figure 1: Trial overview 150 g

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( 180 Day-1 to Day-1 to 130 Day 4 to Day 23 to Wash-out Day 4 to Day 23 to Meal Test - Plasma Glucose

Day 3 Day 3 M Run-in Day 22 Day 24 period 5 Day 22 Day 24 120 Aspart M1Pram

phase with to 7 days- Follow 0 1 2 3 4 G Screen- (3 days at (3 days at o Incremental plasma glucose AUCs on day 24 were reduced by >100% after 1h and 2h (both 180 170

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ing visit clinical site) clinical site) Lunch Aspart M1Pram (28 days outpatient+3 site Meal test keeping outpatient+3 site Meal test visit p<0.001) and by 39% after 4h with M1Pram vs aspart (Figure 2) 170 Rando.+ Rando.+ y max) visits at Site at degludec visits at Site at meal test meal test 160 b 160

at D10 & D17 D24+PK/PD basal at D10 & D17 D24+PK/PD

D1+PK/PD D1+PK/PD o Similarly, ∆PGmax was reduced by 19 mg/dL (p=0.01) and ∆PG_1h by 70 mg/dL (p<0.001) 150 e

140 s Period 1: M1Pram or aspart CGM Period 2: Aspart or M1Pram (Figure 2)

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Demographic data 180 g

Dinner Aspart M1Pram 140 Mean Blood Glucose Concentration  SEM 170 l

o34 T1D subjects were screened, 28 randomized, 26 exposed and 22 completed a

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Female/Male (n) 8/20 White race (%) 100 c 8 baseline Insulin dose & body weight

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Age (years) 40.4 ± 11.70 HbA1c (%) 7.3 ± 0.77 7

g o On the last outpatient day, mean daily bolus doses were 4 U lower (-18%, p<0.0001) with M1Pram d

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o compared to aspart. No change in basal insulin dose was allowed after run-in period per protocol

Weight (kg) 76.7 ± 9.49 C-peptide (nmol/L) 0.06 ± 0.050 6 L

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B o Height (cm) 176.7 ± 9.50 Diabetes duration (years) 20.4 ± 12.53 5 M1Pram induced a 0.7 kg weight loss from beginning to the end of the 23-day treatment period (p=0.01). 0 1 2 3 4 No significant change was seen with aspart (p=0.96) time (h) Conclusion: ADO09 (M1Pram) combines the established characteristics of pramlintide and insulin in one injection. In this short-term trial ADO09 was well-tolerated and significantly improved postprandial glucose in a test meal and CGM-metrics including TiR and mean glucose in an outpatient setting with lower prandial insulin doses compared to aspart and significant weight loss.

This study was sponsored by Adocia and performed by Profil American Diabetes Association, 80th Scientific Session – June 12-16,2020 NCT# NCT03981627 - EudraCT Trial Number:2019-000980-25 ADO09, A Co-Formulation Of Pramlintide (Pram) and Insulin A21G improves Post-Prandial Glucose Vs Novolog® in Type 1 Diabetes (T1DM)

G.Meiffren¹, G.Andersen², R.Eloy¹, C.Seroussi¹, C.Mégret¹, S.Famulla², Y.-P Chan¹, M.Gaudier¹, O.Soula¹, J.H. DeVries²,T.Heise²

1 Adocia, Lyon, France ; 2 Profil, Neuss, Germany Introduction & Background

o ADO09 (M1Pram) is a co-formulation of pramlintide and insulin A21G developed to leverage the beneficial effects of pramlintide on post-prandial glucose without additional injections

Objective and design o To compare the effect of M1Pram and insulin aspart (Novolog®, Novo Nordisk) on post-prandial glucose control, glycemic control assessed by CGM and safety/tolerability o Double-blind, single center, randomized, 2 24 days period cross-over trial comparing pre-meal M1Pram vs aspart over 24 days o Key endpoints: Mixed meal tolerance test (MMTTs) at day 24 and CGM metrics of 21 T1DM subjects Figure 1: Trial overview

Day-1 to Day-1 to Day 4 to Day 23 to Wash-out Day 4 to Day 23 to Day 3 Day 3 Run-in Day 22 Day 24 period 5 to 7 Day 22 Day 24 phase with days-Subj. Screen- (3 days at (3 days at Follow degludec 21 days 1.5 days at keeping 21 days 1.5 days at ing visit clinical site) clinical site) -up (28 days outpatient+3 site Meal test degludec outpatient+3 site Meal test Rando.+ meal Rando.+ meal visit max) visits at Site at basal visits at Site at test test at D10 & D17 D24+PK/PD at D10 & D17 D24+PK/PD D1+PK/PD D1+PK/PD

Period 1: M1Pram or aspart CGM Period 2: Aspart or M1Pram

This study was sponsored by Adocia and performed by Profil American Diabetes Association, 80th Scientific Session – June 12-16,2020 NCT# NCT03981627 - EudraCT Trial Number:2019-000980-25 Methods

o Basal insulin: insulin degludec (Tresiba®, Novo Nordisk) optimized during a run-in phase of 28 days o Dosing period: 3 inpatient days and 21 outpatient days with 2 interim visits (Figure 1) o CGM: Dexcom® G6 CGM unblinded to patients from the start of the run-in phase to the end of the trial o IMP titration: done by subjects, supported by study physicians and a titration guidance o Statistical Analyses: Comparisons were done with a linear mixed-effect model with treatment, period, and sequence as fixed effects and subject within sequence as random effect, with a significance level of 5%. For endpoints not normally or log-normally distributed, comparisons were done non-parametrically with the Wilcoxon Signed Rank Test Subjects disposition and Demographic data o 34 T1D subjects were screened, 28 randomized, 26 exposed, 22 completed the trial and 21 included in the per protocol analysis. (Table 1)

Table 1: Patients’ Characteristics (n=28; mean±SD, unless stated otherwise)

Female/Male (n) 8/20 White race (%) 100 Age (years) 40.4 ± 11.70 HbA1c (%) 7.3 ± 0.77 Weight (kg) 76.7 ± 9.49 C-peptide (nmol/L) 0.06 ± 0.050 Height (cm) 176.7 ± 9.50 Diabetes duration (years) 20.4 ± 12.53 Overall safety oBoth treatments were well tolerated without any treatment-related serious adverse events (Table 2). As expected M1Pram had numerically more, mostly gastrointestinal adverse events than insulin aspart oNo severe hypoglycemia were seen, slightly more hypoglycemic events occurred with M1Pram than with aspart (Table 3) Table 2: Incidence of adverse events throughout the trial M1Pram Aspart (N=25) (N=23) Number of Subjects (%) / Number of Events Adverse Events 20 (80 %) / 47 10 (43 %) / 23 Moderate and Severe Adverse Events 7 (28 %) / 8 2 (8 %) / 3 Drug Related* Adverse Events 14 (56 %) / 34 4 (17 %) / 9 *Possible or probable, as assessed by the Investigator Serious Adverse Event (unlikely related) 1 (4%) / 1 0 Drug Related Adverse Events leading to permanent Discontinuation of Study Drug 2 (8 %) 0 Table 3: Incidence of hypoglycemic events during the outpatient period M1Pram Aspart Category (N=25) (N=23) Number of Subjects (%) / Number of Events Overall 21 (84 %) / 142 18 (78 %) / 115 Daytime (6:00 am to 11:59 pm) 19 (76 %) / 117 18 (79 %) / 109 At night (midnight to 05:59 am) 15 (60 %) / 25 5 (21 %) / 6 Meal Test – Plasma Glucose Meal Test - Plasma Glucose o Incremental plasma glucose AUCs on day 24 were reduced by >100% after 1h and 2h (both p<0.001) and by 39% after 4h with M1Pram vs aspart (Figure 2) o Similarly, ∆PGmax was reduced by 19 mg/dL (p=0.01) and ∆PG_1h by 70 mg/dL (p<0.001) (Figure 2)

Figure 2: M1Pram improves post prandial glucose control Mean Blood Glucose Concentration  SEM

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CGM metrics o Most of the CGM metrics (TiR [70-180], TiR [80-140], mean blood glucose per day), were significantly improved with M1Pram (Table 4). Postprandial and mean 24-hour glucose profiles were improved with M1Pram (Fig. 3)

Table 4: CGM metrics, all days. Significant differences are marked in bold Figure 3: Mean CGM during outpatient days at mealtime (0-4h) and over 24h Ratio of LSMean* Difference Parameter Treatment LS Mean M1Pram / Aspart P-value 180 Breakfast Aspart M1Pram (M1Pram-Aspart) 170

(95% CI) ) 160

M1Pram (N=24) 16.50 dL 150 )

TIR [70-180 mg/dL] (h) 1.05 (1.01;1.10) +51 mins 0.0134 140 L d

Aspart (N=22) 15.65 130 / Mean CGM Profiles (Outpatient periods) g

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M1Pram (N=24) 9.66 ( 180 TIR [80-140 mg/dL] (h) 1.14 (1.06;1.22) +70 mins 0.0017 0 1 2 3 4 180 M Aspart M1Pram

Aspart (N=22) 8.50 Lunch Aspart M1Pram G

170 170

M1Pram (N=24) 0.69 160 y

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Time < 70 mg/dL (h) 1.31 (1.00;1.72) +10 mins 0.0464 150 e

Aspart (N=22) 0.53 140 s o 150 130 c

M1Pram (N=24) 0.15 u l

Time < 54 mg/dL (h) 1.06 (0.65;2.15) <1 min 0.8045 120 g

140 glucose by glucose by (mg/ CGM 0.14 0 1 2 3 4 l Aspart (N=22) a

180 i t

Dinner Aspart M1Pram i 170 t 130

M1Pram (N=24) 149.98 s 160 r 0 4 8 12 16 20 24

Mean BG per Day (mg/dL) 0.95 (0.93;0.97) -8.19 mg/dL 0.0001 e Aspart (N=22) 158.17 t

150 n time (h) I 140 Interstitial 130 120 0 1 2 3 4 time (h) Insulin dose & body weight o On the last outpatient day, mean daily bolus doses were 4 U lower (-18%, p<0.0001) with M1Pram compared to aspart. No change in basal insulin dose was allowed after run-in period per protocol

o M1Pram induced a 0.7 kg weight loss from beginning to the end of the 23-day treatment period (p=0.01). No significant change was seen with aspart (p=0.96) Conclusion

ADO09 (M1Pram) combines the established characteristics of pramlintide and insulin in one injection.

In this short-term trial ADO09 was well-tolerated and significantly improved postprandial glucose in a test meal and CGM-metrics including TiR and mean glucose in an outpatient setting with lower prandial insulin doses compared to aspart and significant weight loss.