Zealand Pharma A/S · OMXCOP:ZEAL
Zealand Pharma A/S — Investor Day (2015)
50 slides from Zealand Pharma A/S's investor day presentation, 2015
Slide 1: Hypoglycemia: Therapeutic Challenges and Solutions
Hypoglycemia: Therapeutic Challenges and Solutions Howard Wolpert, MD Senior Physician, Joslin Diabetes Center Associate Professor, Harvard Medical School Director, Joslin Institute for Technology Translation
Slide 2: Diabetes Technology Timeline
Diabetes Technology Timeline: Convergence of insulin pumps & continuous glucose monitoring (CGM) to a closed loop system 1922 Insulin CLOSED LOOP: Smart Insulin • Artificial beta cell pump Delivery • Mechanical system 1978 • Stem cell Insulin pump Glucose 1970 Monitoring Ames meter Blood test 1912 R
Slide 3: Trade-off between Complications & Hypoglycemia
Trade-off between Complications & Hypoglycemia Rate pf progression of retinopathy 120 Rate of severe hypoglycaemia 12 (per 100 patient years) (per 100 patient years) 10 8 6 60 4 2 0 0 0 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5 HbA1c (%) DCCT Research Group, 1993
Slide 4: How have patients reacted to the implications of the DCCT?
“How have patients reacted to the implications of the DCCT ?” Concerns of motivated patients about intensifying glycemic control: • More frequent hypoglycemic reactions 73% • Weight gain 60% • Maintaining long-term effort 45% • More frequent home glucose monitoring 22% Thompson, 1996
Slide 5: Effects of Hypoglycemia
Effects of Hypoglycemia • Work and driving performance impaired > motor vehicle accidents • Social activities affected Arterialized Venous Blood Glucose (mg/dL) 90 80 mg/dL Inhibition of • Anxiety, perspiration, endogenous tremulousness insulin secretion 72 • Visual blurring, numbness, 70 mg/dL feel
Slide 6: Scope of the Problem
Scope of the Problem: Data from UK Hypoglycaemia Study Group Proportion of each group experiencing at least one severe hypoglycemic event during 9-12 months of follow-up Frier, Nat Rev Endocrionol 2014
Slide 7: Hospital Admissions for Hyperglycemia and Hypoglycemia among Medicare Beneficiaries
Hospital Admissions for Hyperglycemia and Hypoglycemia among Medicare Beneficiaries, 1999 to 2011 Hypoglycemia Hyperglycemia Hypoglycemia rates two-fold higher for older patients (≥75 years) compared to younger patients (65-74 years) Lipska et al, JAMA Int Med,published online May 17, 2014
Slide 8: Total Charges for Severe Hypoglycemia Hospitalizations in US
Total Charges for Severe Hypoglycemia Hospitalizations in US Type 2 Diabetes Total hospitalizations = 248,422 Charges per hospitalization = $48,569 Total charges = $12.07 billion Type 1 Diabetes Total hospitalizations = 20,839 Charges per hospitalization = $46,039 Total charges = $0.96 billion Avera
Slide 9: Severe Hypoglycemia
Severe Hypoglycemia Risk Factors: • Hypoglycemia unawareness (inability to recognize when glucose is low): up to 6 fold increase • Previous severe hypoglycemic events i.e. severe hypoglycemia clusters in same individual • Older age
Slide 10: Hypoglycemia in the Elderly
Hypoglycemia in the Elderly Hypoglycemia in community-living older adults (> 70 years) with A1C>8%, detected by CGM Patients with hypoglycemia (65 % of 40 subjects) Patients with A1C 8-9 % 14 (54 %) Patients with A1C > 9 % 12 (46 %) Severity of hypoglycemic episodes 60-69 mg/dl 100 % 50-59 mg/dl 73
Slide 11: Hypoglycemia Unawareness is Induced by Recurrent Hypoglycemia
Hypoglycemia Unawareness is Induced by Recurrent Hypoglycemia Single Episode of Hypoglycemia > Reduced Symptomatic and Hormonal Responses to Hypoglycemia 100 6.0 GLUCOSE NORADRENALINE 1.80 mmol/l 80 mmol/l mg/dL 4.0 60 1.20 2.0 40 0.60 SYMPTOMS 40 5000 ADRENALINE Score pmol/l 20 2500 0 0 Antecedent
Slide 12: Hypoglycemia-induced Autonomic Failure
Hypoglycemia-induced Autonomic Failure Vicious Cycle: Hypoglycemia induces hypoglycemia unawareness (inability to recognize hypoglycemia), predisposing to further hypoglycemia Recurrent Hypoglycemia Hypoglycemia Unawareness Clustering of severe hypoglycemia in the same individual
Slide 13: Meticulous Glucose Control Reverses Hypoglycemia-induced Autonomic Failure
Meticulous Glucose Control Reverses Hypoglycemia-induced Autonomic Failure 9 AUTONOMIC SYMPTOMS 6 Score 3 0 basal N= 12 non-diabetic N= 8 T1 DM 2 weeks volunteers 3 months 14 12 10 NEUROGLYCOPENIC Score 8 SYMPTOMS 6 4 2 0 0 60 120 180 240 300 360 Minutes Increasing hypoglycemia Fanelli, 1994
Slide 14: Injection-to-injection Variability in Absorption of Basal Insulins
Injection-to-injection Variability in Absorption of Basal Insulins: Contributes to Risk for Hypoglycemia Glucose infusion rate profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in the same patient NPH insulin Insulin glargine Insulin detemir Glucose infusion rate
Slide 15: More Predictable Insulin Pharmacodynamics with Pump
More Predictable Insulin Pharmacodynamics with Pump: Reduces Risk for Hypoglycemia Pump Gold Standard Detemir 27% Glargine 46% NPH Intrasubject Variability in Pharmacodynamics 59% Lepore, 2000 Heise, 2003
Slide 16: Meta-Analysis: Less Severe Hypo with CSII Pump vs MDI
Meta-Analysis: Less Severe Hypo with CSII Pump vs MDI Study Rate ratio (95%) Weight (%) Bode (poor control) 5.55 (3.57, 8.61) 5.84 Bode (good control) 10.50 (4.24, 26.01) 4.66 Kaderman 6.47 (3.09, 13.55) 5.11 Maniatis 1.29 (0.31, 5.42) 3.34 Rizvi 8.00 (1.84, 34.79) 3.26 Litton 5.75 (0.72, 45.97) 2.1
Slide 17: Continuous Glucose Monitoring (CGM) Technology
Continuous Glucose Monitoring (CGM) Technology • Sensor measures glucose in interstitial space • More complete picture of glucose patterns than intermittent, capillary blood glucose monitoring • Glucose alarms - threshold & predictive • Glucose trend/rate of change
Slide 18: Clinical Sites
Clinical Sites • Atlanta Diabetes Associates • Joslin Adults • Joslin Pediatrics • Kaiser Permanente So. California • Nemours Clinic • Stanford University • U. Colorado/Barbara Davis Diabetes Center • U. Iowa • U. Washington • Yale University
Slide 19: Improved Glucose Control with CGM
Improved Glucose Control with CGM Changes in HbA1c in ≥25-year olds CGM Control 0.1 +0.02 0 Change in HbA1c –0.1 –0.2 Difference: –0.53% –0.3 p value <0.001 –0.4 –0.5 –0.50 –0.6 JDRF CGM Study Group, 2008
Slide 20: Less Hypoglycemia despite Improved HbA1c
Less Hypoglycemia despite Improved HbA1c Percent < 50 mg/dL 2.5 p=0.10 2.2 2.0 1.6 1.6 1.5 Percent p=0.001 1.0 0.8 0.5 0 Baseline 26 weeks Baseline 26 weeks CGM Control JDRF CGM Study Group, 2008
Slide 21: Increased Risk for Hypoglycemia Overnight
Increased Risk for Hypoglycemia Overnight 3.5 Baseline 3.1 3.0 26 weeks 2.5 2.2 2.0 2.0 Percent 2.0 1.6 1.5 1.0 0.8 0.9 0.7 0.7 0.7 0.5 0 Overall MN– 6am– Noon– 6pm– 6am Noon 6pm MN
Slide 22: Limitations of CGM Hypo Threshold Alarms
Limitations of CGM Hypo Threshold Alarms: Trade-off between sensitivity & specificity Modeling analysis based on: glucose decline at 1 mg/dL/min & q 5 min sampling frequency Clinical challenge in setting alarm thresholds: Derive benefit from CGM alarms.... but minimize alarm fatigue Noujaim, 2007
Slide 23: Is the Mechanical Closed Loop the Solution for Hypoglycemia?
Is the Mechanical Closed Loop the Solution for Hypoglycemia? INSULIN GLUCOSE PUMP SENSOR 0.8 146
Slide 24: Mechanical Control Systems can't Compete with Normal Physiology
Mechanical Control Systems can’t Compete with Normal Physiology Insulin Glucose Bonner-Weir, 1982
Slide 25: Delayed Absorption Kinetics of Subcutaneous-delivered Insulin
Delayed Absorption Kinetics of Subcutaneous-delivered Insulin Risk for late post-meal 400 hypoglycemia from delayed 300 absorption of insulin Insulin (pmol/L) 200 100 0 0 60 120 180 240 300 Time (minutes) Insulin levels after Insulin levels after mixed meal in a subcutaneous injection non-diabetic s
Slide 26: Delays associated with Mechanical Closed Loop Control
Delays associated with Mechanical Closed Loop Control Absorption of SC Insulin action insulin (~50 min) (~30 min) INSULIN GLUCOSE PUMP SENSOR 0.8 146
Slide 27: Physiologic Delay between Blood and Interstitial Glucose
Physiologic Delay between Blood and Interstitial Glucose adds to the Delay in Mechanical Closed Loop Systems Current monitors: capillary glucose Continuous sensors: interstitial glucose Capillary & interstitial glucose do not always correspond: • ~ 5-30 minute delay in equilibration • ↑ glucose afte
Slide 28: Mechanical Closed Loop Cannot Respond to Rapid Glucose Changes
Because of Delays Mechanical Closed Loop Cannot Respond to Rapid Glucose Changes Absorption of SC Insulin action insulin (~50 min) (~30 min) INSULIN GLUCOSE PUMP SENSOR 0.8 146 Physiologic lag & signal processing delay (0 - 30 min)
Slide 29: Implications of Delays for Closed Loop Control
Implications of Delays for Closed Loop Control: Delayed insulin delivery > early post-meal hyperglycemia Prolonged insulin ‘tail’ > risk for late post-meal hypoglycemia Solutions: • Manual/patient-activated insulin bolus pre-meal • Glucagon to prevent late post-meal hypoglycemia (Bi-hormonal closed
Slide 30: Mechanical Closed Loop Systems can't Mimic Physiologic Changes during Exercise
Mechanical Closed Loop Systems can’t Mimic Physiologic changes needed to Maintain Glucose Levels during Exercise • Healthy subjects • Bicycle ergometer at fixed work load DecreaseGlucagon Solution: insulin + Glucose release increase epinephrine injection/infusion by the liver Aarnio, 2001
Slide 31: Severe Hypoglycemia
Severe Hypoglycemia Risk Factors: • Hypoglycemia unawareness (inability to recognize when glucose is low): up to 6 fold increase • Previous severe hypoglycemic events i.e. severe hypoglycemia clusters in same individual • Older age Barriers to prevention and treatment: • Current treatment (glucagon
Slide 32: Current Glucagon Kits are Complex and Impractical
Current Glucagon Kits are Complex and Impractical • Glucagon not stable in aqueous solution Glucagon Emergency Kit • Current glucagon emergency kits consist of lyophilized glucagon and diluent • Nine steps to reconstitute glucagon prior to administration • Process is complex and challenging for the
Slide 33: Glucose data analytics: Best practices 2014
Glucose data analytics: Best practices 2014 • Time-consuming, inefficient • Isolated glucose data without contextual information • Systems cannot be applied for population-based screening to identify patients at high risk from hypoglycemia In contrast, care systems can use A1c to track patients with
Slide 34: Glooko System for Uploading Data from Blood Glucose Meters
Glooko System for Uploading Data from Blood Glucose Meters Can upload data from 30+ different blood glucose meters
Slide 35: HypoMap system v1: key components
HypoMap system v1: key components Automatically identifies hypo events from glucose data stream 5 5 Prompts patient for contextual information related to hypo events Synthesizes glucose and contextual information into data reports
Slide 36: The app: Identifies hypoglycemic measurements
The app: 1) Identifies hypoglycemic measurements (BG < 70 mg/dL) 2) Prompts the patient to record contextual information about the hypo event (associated symptoms, cause, treatment)
Slide 37: Patient with normal hypoglycemic warning symptoms
Patient with normal hypoglycemic warning symptoms
Slide 38: Neuroglycopenic symptoms are the first indicator of hypoglycemia
Neuroglycopenic symptoms are the first indicator of hypoglycemia. Patient with hypoglycemic unawareness i.e. no autonomic warning symptoms
Slide 39: Patient is prompted to record possible causes of hypoglycemia
Patient is prompted to record possible causes of hypoglycemia
Slide 40: Patient is prompted to record possible causes of hypoglycemia
Patient is prompted to record possible causes of hypoglycemia Tool to engage patient in considering cause(s) for glycemic excursion
Slide 41: Patient is prompted to record treatment of hypoglycemia
Patient is prompted to record treatment of hypoglycemia
Slide 42: Glucose Tablet
Glucose Tablet [How many glucose tablets di. |
Slide 43: Over-treatment is a common cause of hyperglycemia following hypoglycemic events
In practice, over-treatment is a common cause of hyperglycemia following hypoglycemic events Tool to reinforce appropriate treatment of hypoglycemia
Slide 44: Option to record if assistance was needed
On the treatment screen, there is also an option to record if assistance was needed for treatment (i.e. severe hypo event)
Slide 45: Care management system notified about severe hypo
Care management system notified in near real-time about severe hypo, so that clinic follow- up can be scheduled soon after the event
Slide 46: Hypo Awareness Zone: intact ability to recognize hypos
Hypo Awareness Zone Individuals with intact ability to recognize hypos: Signals in “Hypo awareness zone”
Slide 47: Hypo Awareness Zone: individuals with unawareness
Hypo Awareness Zone Individuals with unawareness: “Hypo awareness zone” is empty
Slide 48: Prompt patients with hypo unawareness to improve recognition
Prompt patients with hypo unawareness to improve their hypoglycemia recognition by identifying their individual-specific neuroglycopenic symptoms
Slide 49: Displays collected contextual information from each hypo episode
Displays collected contextual information from each hypo episode, and glucose data for 12 hours before and after the episode • Provides detailed information to enhance clinical decision-making • Turns hypo events into teachable moments, improving patient insights into how to prevent and treat hypos
Slide 50: Conclusion
Conclusion • Despite therapeutic advances, hypoglycemia remains a major, life-threatening complication of intensive diabetes management • Improved therapeutic tools are needed