NEWS BRIEFING Adjunctive Therapies in Type 1 and Type 2 Diabetes

Transcription

1 NEWS BRIEFING Adjunctive Therapies in Type 1 and Type 2 Diabetes Moderated by: Bernard Zinman, MD, CM, FRCPC, FACP Lunenfeld-Tanenbaum Research Institute and University of Toronto Mount Sinai Hospital 1

2 EMBARGO POLICY All recordings are for personal use only and not for rebroadcast online or in any format. Information presented today in this briefing is under embargo until the end of the formal scientific presentation here at the conference. Please consult the top of each press release for embargo dates and times. Tweeting is not permitted from the news briefing or any sessions. The Association s social media team will be monitoring all channels. 2

3 212-OR 52-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Adults with Type 1 Diabetes (intandem1, NCT ) John B. Buse, MD, PhD University of North Carolina School of Medicine Chapel Hill, NC This study was funded and conducted by Lexicon Pharmaceuticals Inc. Lexicon Pharmaceuticals Inc., and Sanofi have entered a license agreement effective November 2015 and are collaborating on the development and commercialization of sotagliflozin. 3

4 Presenter Disclosures Consultant: Employee: Research Support: Speaker s Bureau: Stock Options: None None AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Lexicon, Novo Nordisk, Sanofi, Theracos, and vtv Therapeutics None Mellitus Health, PhaseBio Pharmaceuticals Adocia, AstraZeneca, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Lexicon, Metavention, NovaTarg, Novo Nordisk, Sanofi, Senseonics, and vtv Therapeutics 4

5 Sotagliflozin: First-in-Class Dual SGLT1 and SGLT2 Inhibitor SGLT1 is the primary transporter for absorption of glucose and galactose in the GI tract. 1 Inhibition blunts and delays post-meal glucose excursion. 2 SGLT2 is expressed in the kidney, where it reabsorbs 90% of filtered glucose. 3 Inhibition reduces renal glucose reabsorption. 4 GI, gastrointestinal; SGLT, sodium-dependent glucose transporter. 5

6 intandem1: Trial Overview Randomized, double-blind Treatment Primary Endpoint Secondary Endpoints Key Inclusion Criteria 793 patients from 75 North American sites Placebo (PBO) Sotagliflozin (SOTA) 200 mg SOTA 400 mg Change in A1C from baseline to Week 24 Net benefit (% with A1C <7.0% and no severe hypoglycemia and no diabetic ketoacidosis), weight, bolus insulin, fasting plasma glucose, patient-reported outcomes at 24 and 52 weeks T1D for at least a year; age 18 years Insulin pump or multiple daily injection (MDI) therapy A1C prior to insulin optimization 7 11% Characteristic Patient Population PBO SOTA 200 mg SOTA 400 mg Pts randomized, n A1C, % Age, yrs: mean Mean BMI, kg/m %Pump / %MDI a 60/40 59/41 60/40 Mean total daily insulin, U/kg BMI body mass index a Pump vs MDI was a stratification factor.

7 A1C, LSM Change from Baseline ± SE (%) intandem1: Change from Baseline in A1C over 52 Weeks 0.8 Screening = 8.2% - 8.3% DB CT IDMC, A1C masked 24-Week Difference from PBO -0.36% (-0.45, -0.27); P< % (-0.50, -0.32); P<0.001 Baseline = 7.5% - 7.6% DB EXT No IDMC, A1C not masked 52-Week Difference from PBO -0.25% (-0.37, -0.14); P< % (-0.43, -0.20); P< Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg

8 Proportion of Patients (%) Net Benefit Patients with A1C <7.0% at Week 52, Without Severe Hypoglycemia or Diabetic Ketoacidosis (5.7, 21.2) P< (-0.3,14.7) P= Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg 8

9 Summary of Safety Outcomes Over 52 Weeks (Safety Population) Placebo n=268 Sotagliflozin 200 mg n=263 Sotagliflozin 400 mg n=262 Any TEAE, n (%) 216 (80.6) 215 (81.7) 209 (79.8) TEAEs leading to study discontinuation, n (%) 11 (4.1) 13 (4.9) 17 (6.5) Treatment-emergent serious adverse events, n (%) 20 (7.5) 27 (10.3) 29 (11.1) Death, n (%) 1 (0.4) 0 0 Patients with 1 DKA event*, n (%) 1 (0.4) 9 (3.4) 11 (4.2) Patients with 1 Severe hypoglycemia event, n 26 (9.7) 17 (6.5) 17 (6.5) (%) Diarrhea, n (%) 18 (6.7) 22 (8.4) 27 (10.3) Genital mycotic infection, n (%) 9 (3.4) 24 (9.1) 34 (13.0) *Defined as an adjudicator assessment as Yes, with certainty or Yes, probably 9

10 intandem1: Summary of 52-Week Results Addition of sotagliflozin to intensified insulin therapy for 1 year in patients with T1D reduced A1C and improved clinical outcomes beyond A1C, including: Reduction in fasting plasma glucose Reduction in weight Lower incidence of severe hypoglycemia (low glucose levels) At 52 weeks, more patients receiving sotagliflozin vs placebo achieved A1C targets without severe hypoglycemia or diabetic ketoacidosis Significant difference from placebo in patient-reported outcomes related to improved treatment satisfaction was maintained at 52 weeks The small but increased risk of DKA can be potentially mitigated with proper education and ketone monitoring Sotagliflozin is effective in subjects with T1D and has an acceptable benefit-risk profile 10

11 213-OR Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type 1 Diabetes: DEPICT-2 Study Chantal Mathieu, MD, PhD University of Leuven Belgium 11

12 Presenter Disclosures Advisory boards: AstraZeneca, Boehringer Ingelheim, Bristol- Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, ActoBio Therapeutics, Janssen Pharmaceuticals, Medtronic, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, Sanofi and UCB Speaker s Bureau: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi Research support: Abbott, Eli Lilly, ActoBio Therapeutics, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche and Sanofi The DEPICT 2 study was sponsored by AstraZeneca 12

13 Type 1 Diabetes Autoimmune disease: destruction of insulin-producing beta-cell in the pancreas, resulting in need for life-long insulin therapy Some 1.25 million Americans are living with T1D, including about 200,000 youth (less than 20 years old) In U.S., less than 50% of people with T1D achieve target A1c levels Even at target A1c, T1D patients experience wide glycemic variability Hypoglycemia remains the major barrier to optimal glycemic control, with severe/fatal episodes Growing problem of overweight/obesity in T1D Unmet need: Improved A1c, without more hypoglycemia or weight gain and with more stable glucose profiles, safely Lancet, 2006, March; 367: ; Diabetes Care 2015 Jun; 38(6): ; J Pediatr Jun;156(6):923-9; J Pediatr Jun;156(6):

14 SGLT2 inhibitors: preventing glucose reabsorption from urine 14

15 DEPICT-2: Study design Adults with T1D not well controlled PLACEBO Dapagliflozin 5mg PLACEBO Dapagliflozin 5mg 14 countries: Argentina, Belgium, Canada, Chile, Germany, Japan, Netherlands, Norway, Poland, Russian Federation, Sweden, Switzerland, United Kingdom, and United States. Dapagliflozin 10mg 6 months Double Blind Dapagliflozin 10mg 6 months 15

16 Primary endpoint: Stable reduction in A1c Secondary endpoints: Reduction in weight Difference vs. placebo (95% CI) DAPA 5 mg: 3.40 % ( 4.18, 2.63) DAPA 10 mg: 3.74 % ( 4.49, 2.99) p-value for both: < Difference vs. placebo (95% CI) Reduction in insulin dose DAPA 5 mg: 0.37 % ( 0.49, 0.26) DAPA 10 mg: 0.42 % ( 0.53, 0.30) p-value for both: < Difference vs. placebo (95% CI) DAPA 5 mg: % ( 13.73, 7.72) DAPA 10 mg: % ( 14.04, 8.02) p-value for both: <

17 Secondary Composite Endpoint: HbA1c Reduction 0.5% Without Severe Hypoglycemia Odds ratio: 2.71 (95% CI: 1.81, 4.06); p< Odds ratio: 3.07 (95% CI: 2.05, 4.60); p< Patients with a 0.5% reduction in HbA1c without severe hypoglycemia, % Dapagliflozin 5 mg + INS (N=271) Dapagliflozin 10 mg + INS (N=270) Placebo + Insulin (N=272) Longitudinal repeated measures mixed model with direct likelihood

18 Secondary CGM Endpoints 24-hour interstitial glucose reading, mg/dl Baseline mean (SD) Adjusted mean change at Week 24 (SE) Difference vs placebo DAPA 5 mg + INS (N=252*) (28.68) 6.46 (1.83) ( 20.26, 11.05) p< DAPA 10 mg + INS (N=255*) (28.09) (1.83) ( 24.34, 15.14) p< PBO + INS (N=257*) (28.95) 9.20 (1.85) MAGE, mg/dl Baseline mean (SD) Adjusted mean change at Week 24 (SE) Difference vs placebo (29.60) (1.90) 9.85 ( 14.66, 5.03) p< (29.85) 9.68 (1.91) 9.36 ( 14.16, 4.55) p= (29.29) 0.33 (1.93) 24-hour interstitial glucose within > mg/dl, % Baseline mean (SD) Adjusted mean change at Week 24 (SE) Difference vs placebo (12.43) 5.92 (0.82) 9.02 (6.97, 11.06) p< (11.83) 7.60 (0.82) (8.66, 12.74) p< (12.55) 3.10 (0.83)

19 Adverse Events Overall well tolerated Expected increase in genital infections No increase in (severe) adverse events No increase in (severe) hypoglycemia Increase in diabetic ketoacidosis (DKA) Dapagliflozin 5mg Dapagliflozin 10mg Placebo N=271 N=270 N=272 Events of definite DKA, n Patients with definite DKA, n (%) 7 (2.6) 6 (2.2) 0 19

20 Conclusions of DEPICT 2 Analogous to the previously published results of DEPICT 1 1 : o the DEPICT 2 study showed that in adults with T1D, compared to placebo: o Dapagliflozin 5 and 10 mg as add-on to insulin reduced HbA1c, with less daily insulin requirements and with weight reduction o Odds of reaching a drop in A1c >0.5% without severe hypoglycemia were higher with dapagliflozin (OR ) o CMG showed more stable glycemic levels with dapagliflozin o No increase in (severe) hypoglycemia with dapagliflozin o DKA events were rare, but higher in dapagliflozin-treated patients 1. Dandona et al. Lancet Diabetes Endocrinology 2017 Unmet need: Improved A1c, without more hypoglycemia or weight gain and with more stable glucose profiles, safely 20

21 3-LB Liraglutide as an Additional Treatment to Insulin in Patients with Type 1 Diabetes Mellitus A 52-Week Randomized Double-Blinded Placebo-Controlled Clinical Trial Paresh Dandona, MD, PhD, FRCP, FACP, FACC, FACE State University of New York at Buffalo Head, Division of Endocrinology 21

22 Presenter Disclosures Nothing to disclose 22

23 Background Previously demonstrated that a 12-week addition of Liraglutide to insulin therapy in patients with well controlled type 1 diabetes results in an improvement in glycemic control, weight loss and a reduction in systolic blood pressure, along with a reduction in mean insulin requirements 1-year randomized study investigating the effects of Liraglutide in patients with type 1 diabetes 23

24 Hypothesis Treatment with Liraglutide in patients with type 1 diabetes decreases HbA1c, fasting and the overall mean glucose concentrations while decreasing the dose of insulin required In order to compare these values, a continuous glucose monitoring system (Dexcom) was utilized 24

25 Methods Double-blind, placebo-controlled, randomized, one-year trial 46 adults (average age 47.6 years) with T1D participated in the study At the beginning of the trial, the patients had an average HbA1c level of 7.92, and an average body mass index of 28.9 Kg/m2 Patients were randomized: o 26 patients received daily injections of 1.8 mg of Liraglutide o 20 patients received daily injections of a placebo Continuous glucose monitoring (CGM) was performed for four weeks before treatment and at the end of treatment. 25

26 Results C-peptide concentrations were nondetectible at the beginning and at the end of the study At the end of 52-week treatment with Liraglutide, placebo adjusted HbA1c fell significantly by 0.57±0.17% (p=0.006 vs. placebo) from 7.920±0.15 to 7.45±0.12% (p=0.009) There was significant weight loss by 2.5±0.9 kg (placebo adjusted, p=0.041 vs. placebo) and fall in SBP by 9±3mmHg (p=0.031) 26

27 Conclusions Liraglutide treatment for 1 year in type 1 diabetes patients reduced HbA1c by 0.57% compared to placebo with concurrent fall in insulin dose (mainly bolus) and fall in fasting and weekly glucose levels There was a significant fall in systolic blood pressure and body weight There was no significant change in C-peptide following 1 year treatment Further analysis is required to provide possible mechanism underlying the improvement in glycemia The addition of Liraglutide to insulin treatment in type 1 diabetes significantly reduced HbA1c, mean and fasting blood glucose, blood pressure and body weight without significant increase in hypoglycemia Type 1 DM patients may benefit from the addition of liraglutide as an adjunct therapy to insulin 27

28 Restoring Insulin Secretion Study The RISE Consortium

29 Restoring Insulin Secretion (RISE) Study Overview and Comparison of Youth and Adults Steven E. Kahn, MB, ChB Professor of Medicine VA Puget Sound Health Care System University of Washington Seattle, WA Pediatric Medication Study Kristen J. Nadeau, MD, MS Professor of Pediatrics University of Colorado Anschutz Medical Campus Aurora, CO 29

30 Presenter Disclosures Steven Kahn Paid consultant on advisory boards for Novo Nordisk Kristen Nadeau No conflict of interest 30

31 The Problem of Type 2 Diabetes The prevalence of type 2 diabetes is increasing dramatically worldwide Type 2 diabetes is an emerging problem in youth The racial/ethnic distribution is similar in youth and adults Indirect evidence suggests the disease in youth is more aggressive than in adults 31

32 Pathogenesis of Impaired Glucose Tolerance and Type 2 Diabetes The elevated blood glucose observed in impaired glucose tolerance (prediabetes) and type 2 diabetes is caused by: Insulin resistance, i.e. insulin is not able to increase glucose uptake by tissues effectively, and Pancreatic -cell dysfunction, i.e. insulin (and its coproduct C-peptide) release are not appropriate. 32

33 Restoring Insulin Secretion (RISE) Study Fasting glucose (mg/dl) < Normal Impaired Diabetes < hour glucose (mg/dl) 33

34 RISE Randomized Study Populations Pediatric Medication Adult Medication Adult Surgery All randomized Not taking metformin at baseline Baseline analyses

35 Insulin Sensitivity and β-cell Responses in Youth and Adults 35

36 OGTT Glucose, C-peptide and Insulin Profiles in Youth vs. Adults Glucose C-peptide Insulin Beta-cell response Insulin sensitivity 36

37 1/Fasting Insulin (1/[µU/mL]) Early C-peptide Response (ng/ml) OGTT-Derived Insulin Sensitivity and Early C-peptide Response in Youth vs. Adults Insulin Sensitivity Beta-cell Response p<0.001 p<0.001 Youth Adults Youth Adults 37

38 Summary: Youth vs. Adults In RISE participants with impaired glucose tolerance or early type 2 diabetes: Insulin sensitivity in youth was approximately half that of adults Youth had β-cell responses that were greater than adults These differences may provide an explanation for the more aggressive disease course in youth 38

39 Pediatric Medication Study 39

40 Pediatric Medication Study Protocols: Study Phases and Key Time Points Hyperglycemic Clamp OGTT Hyperglycemic Clamp OGTT Screening Run-in (3 weeks) Glargine followed by metformin or Metformin alone Washout (3 months) Baseline Randomization 12 months 15 months The RISE Consortium: Diabetes Care 37: ;

41 Measurements from the Hyperglycemic Clamp Insulin sensitivity (M/I) Beta-cell responses o Acute C-peptide Response to Glucose (ACPR g ) o Steady state C-peptide o Acute C-peptide Response to Arginine (ACPR max )... 41

42 β-cell Response Potential Changes in β-cell Responses and Insulin Sensitivity with Interventions Insulin Sensitivity 42

43 β-cell Function Continues to Decline Despite Use of Interventions that Lower Glucose -cell Secretory Capacity Hyperglycemia ~450 mg/dl+ Arginine 43

44 HbA1c (%) HbA1c Increases Over Time by Treatment Active Treatment Washout p<0.05 compared to baseline 5 Baseline Month 3 Month 6 Month 9 Month 12 Month 15 Glargine/Metformin Metformin 44

45 What Have We Learned from the RISE Pediatric Medication Study? Despite early intervention in youth with IGT or recently diagnosed type 2 diabetes, -cell dysfunction progressed and was worse than at baseline. These findings contrast with those published in adults showing an improvement in -cell function with metformin and with insulin for diabetes prevention and treatment. 45

46 Thanks Thanks to the RISE participants who, by volunteering, are furthering our ability to reduce the burden of diabetes Funding and scientific input from NIDDK, Department of Veterans Affairs and Kaiser Permanente Southern California. Additional financial and material support from ADA, Allergan, Apollo Endosurgery, Abbott Laboratories and Novo Nordisk A/S. 46

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