Novel Formulations to Modify Mealtime Insulin Kinetics Alan Krasner, Roderike Pohl, Patrick Simms, Philip Pichotta, Robert Hauser, Errol De Souza Biodel, Inc. Danbury, CT
Disclosure All authors are employees and shareholders in Biodel, Inc. 1
Normal Appearance of Circulating Insulin After Meals Clock Time (hours) Source: Polonsky et al, J. Clin. Invest., 81, 1988 2
How do We Measure Success? Estimates of normal response to mixed meal Caveats: Do not account for physiologic portal delivery Do not account for other variables which may influence postprandial glycemia, e.g., GLP-1/Glucagon tone Estimates of normal plasma insulin appearance after a meal Time to half maximal insulin concentration (T 5%early ): 15-18 minutes Time to maximal insulin concentration (T max ): 3-45 minutes Currently available prandial insulins do not match curves of insulin appearance after meals seen in normal, non-diabetic individuals. Humalog : T 5%-early : 2-26 minutes; T max : 55-66 minutes What is the best way to measure speed of absorption? Pharmacokinetics: T 5%-early? T max? AUC -3min? AUC -6min? Pharmacodynamics (Glucose Infusion Rate? Meal Study?) How much tail do we want and how do we measure it? Is the shape of the curve important? Do we want a smooth hump? Shoulder? 3
Faster Absorption Through Formation of Monomers Zn 2+ EDTA Citrate Monomer Human Insulin or Analog: Hexamer formation BIOD Formulations: EDTA Zn chelation BIOD Formulations: Citrate masks charges 4
EDTA/citrate shift equilibrium toward monomerized insulin DLS Size Distributions vs. Dilution Factor 7. Mean insulin Size Distribution (nm) 6. 5. 4. 3. 2. 1. 5 1 15 Dilution factor RHI BIOD-95 RI2 (diluted.1 N HCl) (acidified RHI) J Diabetes Sci Technol 212; 6(4):755-763 5
Formulations Evaluated in Clinical Studies Active Ingredient Recombinant Human Insulin (RHI) BIOD-9 (EDTA, citrate) Two-part, U-25 Associated with approx. 5% subject discontinuation rate due to injection site discomfort BIOD-1 (EDTA, citrate) Liquid U-1 BIOD-123 (EDTA, citrate, MgSO 4 ) Liquid U-1 Insulin lispro BIOD-25 (EDTA, citrate, MgSO 4 ) Liquid U-1 All formulations above deliver more insulin earlier than Humalog (marketed formulation of insulin lispro) Choice of insulin active pharmaceutical ingredient (e.g., RHI vs. rapid-acting analog) may affect duration of tail and overall shape of PK curves BIOD-531 (RHI, EDTA, citrate, MgSO4) Liquid U-4 Evaluated in diabetic swine model, now in Phase 1 6
BIOD-9 Pilot Study: Aim and Methods Aim: Characterize the PK/PD profile of BIOD-9 PK/PD of SC single administrations of - BIOD-9 (doses of 3, 6,12 U) - Regular Insulin (Humulin ) (12 U) - Insulin lispro (Humalog ) (12 U) Ten fasting healthy volunteers Five way crossover, three different insulin formulations Injections by syringe in the abdomen 7
Pharmacodynamic Profile 12 1 Baseline corr. Glucose infusion rate (mg/kg/min) 12 U Humulin 12 U Humalog 12 U BIOD-9 8 6 4 2 Time (h) 1 2 3 4 5 6 7 8 Diabetologia 51:162-166, 28 8
Pharmacodynamic Profile 12 1 Baseline corr. Glucose infusion rate (mg/kg/min) 3 U BIOD-9 6 U BIOD-9 12 U BIOD-9 8 6 4 2 1 2 3 4 5 6 7 8 Diabetologia 51:162-166, 28 Time (h) 9
Pharmacokinetic Profile -12 min 12U Humulin 12U BIOD-9 12U Humalog % Insulin Cmax 1 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 1 11 12 Time (min) Diabetologia 51:162-166, 28 1
Meal Study: Aim and Subjects Aim: Do the observed improvements in PK/PD parameters of BIOD-9 translate into improved postprandial metabolic control? Primary objective was to compare the maximal post-prandial glucose concentration and the time to maximal post prandial blood glucose concentrations between the different insulin treatments. 11
Meal Study Study Design 18 Patients with Type 1 Diabetes 4 Hours Baseline, patients BG stabilized by glucose clamp (target 12 mg/dl), glucose turned off prior to meal Administration of study drug followed by standardized meal and continuous glucose monitoring for 8 h Four different study days, three different insulin formulations: - Patient specific dose of Humulin R - Same dose of Humalog - Same dose of BIOD-9 - One half dose of BIOD-9 12
Prandial Glucose Responses Blood Glucose (mg/dl) 2 19 18 17 16 15 14 13 12 11 1 Meal 9 8 7 18 Patients Average Blood Glucose RHI Humulin (Humulin (RHI) R) Humalog (Lispro) Linjeta BIOD-9 6-3 3 6 9 12 15 18 21 24 27 3 33 36 Time (min) BIOD-9 Linjeta Humalog Humulin R (RHI) Ideal Range Journal of Diabetes Science and Technology 211;5(3):681-686 13
BIOD-1 (U-1, Liquid) Compared to Humalog Pharmacokinetics 1 Linjeta Humalog Percent Mean C max 9 8 7 6 5 4 3 2 N= 43 patients with T1DM Dose of each insulin=12 U 1 9 8 7 6 5 4 3 2 1 3 6 9 12 Diab, Obes, Metab. 14:222-227, 212 1 6 12 18 24 3 36 42 48 Time (minutes) 14
Toleration Assessments of BIOD-1, BIOD- 9 and Humalog Variable BIOD-1 (U-1, liquid) Mean ± SEM BIOD-9 (U-25, two-part) Humalog P-value BIOD-1 vs. BIOD- 9 VAS 1 17.3 ±2.5 22. ±2.8 5.3 ±1..41* Absolute Severity 2.85 ±.1 1.7 ±.1.19 ±.5.17* Relative Severity 3 3.3 ±.8 3.49 ±.8 2.73 ±.7.19* 1 Visual Analog Scale (VAS) from (no discomfort) to 1 (worst possible discomfort) (mm) 2 Absolute: =None 1=Mild 2=Moderate 3=Severe 3 Relative to usual mealtime insulin: 1=Much Less 2=Less 3=Equal 4=Increased 5=Much Increased 15
Improving Local Toleration of EDTA/citrate Formulations Hypothesis: Na 2 EDTA causes transient calcium sequestration in the subcutaneous space, promoting neuronal depolarization and stinging Testing this hypothesis Formulation variants made with calcium-edta tested in clinic (BIOD-125) Formulation variants made with magnesium sulfate also tested in clinic (BIOD-123) Magnesium has been shown to have nerve membrane stabilizing properties similar to calcium Magnesium is an N-methyl-D-aspartate antagonist Surgical wound infiltration with magnesium shown to reduce pain and opioid consumption 16
Phase 1 Evaluation of BIOD-123, BIOD-125 Compared to Lispro in Subjects with T1 DM Single center, double blind, crossover: BIOD-123, BIOD-125 vs. Lispro - PK, PD (glucose clamp), Toleration (n=12) Visit 1 (screening) Visit 2 (1 st dosing visit) BIOD-123 Visit 3 (2 nd dosing visit) BIOD-123 Visit 4 (3 rd dosing visit) BIOD-123 Visit 5 (Final visit) 3-28 days BIOD-125 BIOD-125 BIOD-125 1-21 days LIS 3-28 days wash-out period LIS 3-28 days wash-out period LIS Dose=.2 U/Kg 17
Comparison of Pharmacokinetic Profiles of BIOD 123, BIOD 125 and Lispro Administered by SC Injection (n=12) 12 BIOD-123 BIOD-125 Lispro Humalog (3-11) 1 8 6 4 12 1 8 6 4 2 6 12 18 24 3 36 42 48 1 2 3 4 5 6 Time (min) 18 Insulin Concentration (% of Cmax) 2
Injection Site Tolerability Profiles of BIOD-123, BIOD-125 vs. Lispro Visual Analog Scale (mm) 25 2 15 1 5 BIOD-123 BIOD-125 Lispro * Treatment Metrics Lispro BIOD-123 BIOD-125 Tolerability (VAS 1mm) 1.8 ± 1.1 3.6 ± 2.1 6.8 ± 2.9* Absolute Severity Score.17 ±.11.36 ±.15.5 ±.19 Relative Severity Score 2.92 ±.8 2.91 ±.25 3.8 ±.26 Injection site discomfort was measured on a Visual Analog Scale (VAS) from (no discomfort) to 1 (worst possible discomfort) (mm). Data represents mean ± standard error, *p <.5 vs. Lispro a. Absolute Severity Score: =none, 1=mild, 2=moderate, 3=severe b. Relative Severity Score: 1=much less, 2=less, 3=equal, 4=increased, 5=greatly increased 19
BIOD-123 Achieved Primary Endpoint and Showed Statistically Significant Lower Glucose Excursions Open-Label Phase 2 Study at 32 U.S. Sites in 132 Type1 Patients Central Randomization BIOD-123 + Glargine (Lantus ) n = 65 Screening 2 weeks Lispro (Humalog ) + Glargine n = 66 6 weeks titration 12 weeks relative stable dosing HbA1c: Primary Non-inferiority Analysis HbA1c (%) Change from Baseline.1 -.1 -.2 -.3 -.4 BIOD-123 (n=65) Lispro (n=66) 6 Week 12 18 Mean ± SE Difference in HbA1c Change from Baseline to Final.5.4.3.2.1 -.1 LS Mean difference:.17 95% CI: -.1 to.35 Change from Baseline Glucose (mg/dl) Liquid Meal Challenge Blood Glucose Excursions 8 6 4 2 3 min 6 min BIOD-123 9 min 12 min 1 8 6 4 2 Maximal Glucose Excursion (mg/dl) LS Mean difference 2.8 p =.34 2
Adverse Events in Phase 2 Study 3-21 No reports of severe pain in either treatment arm or drop outs due to injection site pain In this open label study there was an increased report of mostly mild pain in the BIOD-123 arm Phase 2 Open Label Study Incidence of Treatment-Emergent Adverse Events with Incidence > 5% Preferred Term BIOD-123 (n=65) n (%) Lispro (n=66) n (%) p-value Hypoglycemia 65 (1.) 66 (1.) NS Injection Site Hematoma 4 (6.2) 5 (7.6) NS Injection Site Pain 1 (15.4) 1 (1.5) <.5 Influenza 4 (6.2) 2 (3.) NS Nasopharyngitis 11 (16.9) 11 (16.7) NS Sinus Congestion (.) 4 (6.1) NS Upper Respiratory Tract Infection 13 (2.) 8 (12.1) NS Previous blinded pain studies showed no statistical difference (On tolerability VAS 1mm, BIOD-123 scored 3.6 ± 2.1 vs. 1.8 ± 1.1 for Humalog ) Visual Analog Scale (mm) 25 2 15 1 5 Blinded Phase 1 Tolerability Study BIOD-123 Humalog 21
Humalog, NovoLog and Apidra Analogs Formulated with BIOD-1 Excipients Have an Ultra-Rapid-Acting Insulin Pharmacokinetic Profile in Diabetic Swine Insulin (uu/ml) 16 14 12 1 8 6 4 2 Humalog Humalog plus EDTA and citric acid Insulin (uu/ml) 16 14 12 1 8 6 4 2 NovoLog NovoLog plus EDTA and citric acid 4 8 12 16 2 24 4 8 12 16 2 24 Time (minutes) Time (minutes) 16 Insulin (uu/ml) 14 12 1 8 6 4 Apidra Apidra plus EDTA and citric acid 2 4 8 12 16 2 24 Source: 21 EASD 46 th Annual Meeting, Stockholm, Sweden pp. S384 Time (minutes) Preclinical study : Pharmacokinetic profiles in diabetic swine 22
In Man, Lispro Based* BIOD-25 Demonstrated a More Rapid In and Rapid Out vs. Humalog 8 BIOD-25 Humalog 8 Insulin Concentration (µu/ml) 6 4 2 6 4 2 1 2 3 4 5 6 6 12 18 24 3 36 42 48 Time (min) * Biodel excipients added to commercial Humalog to create BIOD-25 23
Pharmacokinetic Parameters: BIOD-25 (lispro formulation) vs. Humalog Variable BIOD-25 N=11 Humalog N=1 P-value BIOD-25 vs. Humalog Absorption Early ½ T max (minutes) T max (minutes) AUC ins-3 min (mu*min/l) 14.6 ± 1.9 (12.9) 4.9 ± 6.1 (4.) 1185 ± 133 (126) 24.9 ± 2.9 (22.6) 62.5 ± 8.4 (6.) 596 ± 126 (652).1.25.2 Decline from peak concentration Late ½ T max (minutes) 142.6 ± 16.5 (137.8) 166.4 ± 1.6 (183.2).4 Data represent the Mean ± SEM; Median Values are presented in parentheses. 24
Injection Site Tolerability BIOD-25 (with MgSO 4 ) vs. BIOD- 238 (without MgSO 4 ) vs Humalog BIOD-238 BIOD-25 Humalog Tolerability (VAS 1mm) 24.2 ± 7. 2.7 ± 1.6 8.2 ± 4.5 Visual Analog Scale (mm) 35 3 25 2 15 1 5 * BIOD-238 BIOD-25 Humalog Absolute 1 Severity Score Relative 2 Severity Score 1.1 ±.2.1 ±.1.5 ±.2 3.6 ±.3 2.9 ±.2 3.2 ±.1 1 Absolute: =None 1=Mild 2=Moderate 3=Severe 2 Relative to usual mealtime insulin: 1=Much Less 2=Less 3=Equal 4=Increased 5=Much Increased Injection Site Discomfort Severity None Mild Moderate Severe Primary endpoint of injection site discomfort was measured on a Visual Analog Scale (VAS) from (no discomfort) to 1 (worst possible discomfort) (mm). Data represent means ± standard error, *p <.5 vs. Humalog BIOD-238 (n=1) BIOD-25 (n=11) Humalog (n=1) 2 (18.2%) 6 (54.5%) 3 (27.3%) 1 (9.9%) 1 (9.1%) 6 (6.%) 3 (3.%) 1 (1.%) 25
Concentrated Insulin Room for Improvement? The use of concentrated (U-5R) insulin is increasing Used in patients with high insulin dose requirements (> 2 units/day) Lower volume, more comfortable injections that equivalent doses of U-1 Prandial and basal coverage in one injection, however prandial component is even slower than regular U-1 insulin Diabetes Care. 211 Dec;34(12):2496-51. doi: 1.2337/dc11-721. Epub 211 Oct 12. 26
Concentrated Ultra-Rapid-Acting Insulin: BIOD-531 Concentrated U-4 formulation RHI Disodium EDTA Citrate Magnesium sulfate 27
BIOD-53* Vs. Humulin R U-5R Dose.25 U/kg PK and PD Profiles in Diabetic Swine 14 Mean Baseline subtracted glucose and insulin (+/-SEM) 12 Insulin (uu/ml) 1 8 6 4 2 Lilly U-5R BIOD-53* Study.19 Lilly U-5R (n=1) BIOD-53 (n=9) C max 135.5±22.7 155.4±15.6 T max 94±17.1 41.7±12.2* T 5%early 26.9±5. 11.4±2.4* AUC 2161±313 21535±434 *p<.5-2 Glucose (mg/dl) -4-6 -8-1 -12-14 -16-18 Lilly U-5R BIOD-53* 5 1 15 2 25 3 35 4 45 5 Time (min) *BIOD-53 and 531 are similar formulations aside from the presence of Magnesium sulfate in 531 28
BIOD-531 Vs. Humalog 75/25 Dose.25 U/kg PK and PD Profile in Diabetic Swine 14 Humalog 75:25 75/25 BIOD-531 Insulin (uu/ml) Glucose (mg/dl) 12 1 8 6 4 2-5 -1-15 -2-25 -3 Study.28 Humalog 75/25 (n=1) BIOD-531* (n=1) C max 55±5 131±21* T max 86±19 79±18 T 5%early 35±6 24.6±5 AUC 9673±1167 2188±4192* *p<.5 6 12 18 24 3 36 42 48 Time (min) 29
Summary Formulating human insulin or insulin lispro with EDTA and citrate accelerates insulin absorption Human insulin vs. lispro may affect the duration of washout or tail and shape of PK curve Clinical data suggest that these formulations can be demonstrated to be safe and effective with improved postprandial glucose control relative to approved prandial insulins Concentrated versions of these formulations may be of use in patients with type 2 diabetes and moderate to severe insulin resistance 3