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Inhaled GLP-1 and Exenatide: DifferentEffects on Pancreatic and Gastric Activity

Robert BaughmanRobert Baughman, Donald Costello, Mark Marino, , Donald Costello, Mark Marino, James Cassidy, Anders Boss, Christine Damico, Pamela Haworth, James Cassidy, Anders Boss, Christine Damico, Pamela Haworth, Peter C. Richardson, Peter C. Richardson, JeroenJeroen van de van de WeteringWetering, Andre A. van , Andre A. van VlietVliet

In compliance with the accrediting board policies, the American Diabetes Association requires the following disclosure to the participants:

Dr. Baughman is an employee and shareholder of Dr. Baughman is an employee and shareholder of MannKindMannKind Corporation, the trial Corporation, the trial sponsor. No clinical recommendations will be offered in this presponsor. No clinical recommendations will be offered in this presentation; the sentation; the content of which will be limited to scientific data and researchcontent of which will be limited to scientific data and research results.results.

Session Title: Incretin-Based Therapies (CT-OR03)

Publication No:160-OR

Date: June 07, 2009

Start Time: 08:30AM

Location: Room RO2, Convention Center

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GLP-1 Technosphere® MicroparticlesTechnosphereTechnosphere®®

microparticlesmicroparticlesGLPGLP--1 Technosphere1 Technosphere®®

++GLPGLP--1(71(7--36amide)36amide)

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MKC-253-0011.5 mg GLP-1 via oral inhalation in

6 fasted, healthy volunteers*

* Costello D, Baughman RA, Levy * Costello D, Baughman RA, Levy B, et al. Pulmonary B, et al. Pulmonary Administrations of GLPAdministrations of GLP--1 1 TechnosphereTechnosphere®® Powder Powder EllicitsEllicitsDoseDose--dependent Insulin dependent Insulin Response, Response, DiabetesDiabetes. . 5757(Suppl (Suppl 1):A1):A--59, 2008. 59, 2008.

GLP-1(7-36) Plasma Concentrations

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MKC-253-002 Study Design

Assessment of MKC253 activity in postprandial T2DMAssessment of MKC253 activity in postprandial T2DM

Primary objectivePrimary objectiveEvaluate effect of acute MKC253 Inhalation Powder Evaluate effect of acute MKC253 Inhalation Powder administration on postprandial glucose concentrations (AUCadministration on postprandial glucose concentrations (AUC00--240240))

Secondary objectivesSecondary objectivesEvaluate effect of MKC253 Inhalation Powder on Gastric Evaluate effect of MKC253 Inhalation Powder on Gastric emptying (emptying (1313CC--octanoate gastric motility breath test)octanoate gastric motility breath test)Measure GLPMeasure GLP--1 active, insulin, C1 active, insulin, C--peptide, peptide, glucagon concentrations glucagon concentrations Assess tolerability by evaluating reported adverse events (AE), Assess tolerability by evaluating reported adverse events (AE), vital signs, physical examinations, clinical laboratory tests, vital signs, physical examinations, clinical laboratory tests, pulmonary function tests (PFT), and electrocardiograms (ECG)pulmonary function tests (PFT), and electrocardiograms (ECG)

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MKC-253-002 Study Design

Key inclusion criteria: ♀♀ or ♂♂ T2 DM; 18T2 DM; 18--70 yrs; BMI 70 yrs; BMI ≤≤ 32 kg/m32 kg/m22; stable ; stable antidiabeticantidiabetic regimen X regimen X 8 wks; 8 wks; HbA1c 6.2 - 8.5%; fasting C-peptide ≥ 0.5 ng/mL; normal PFTsPFTs..

Key exclusion criteria: Tx w/any antidiabetic agent other than metformin, sulfonylurea, meglitinide or alpha glucosidase inhibitors within the preceding 12 weeks; serum Cr > ULN; sx of GI disease; hx of reactive airway disease.

Screening

1.5 mg GLP-1 fasted, #s 1-15

TIP fasted,#s 16-20

n = 20 randomized4 X 4 crossover, double-masked, double-dummy w/ 13C-octanoate gastric

motility testing

sc saline + + 1.5 mg GLP-1 + TIP, fed

sc saline + + TIP X 2, fed

sc 10 µg exenatide + TIP X 2 , fed

sc saline + + 1.5 mg GLP-1 X 2, fed

Injections 15 minutes before, inhalations immediately before and30 minutes after the meal (240 mL Boost High Protein and 1 muffin containing 13C-octanoate (total caloric value was 575 Kcal and contained a total of 24 g PRO, 97 gm CHO, 13 gm FAT).

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Mean GLP-1 Concentrations by treatment

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Mean Insulin Concentrations by treatment

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Mean C-peptide concentrations by treatment

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Baseline Adjusted Glucose by treatment

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Gastric Motility Breath TestSmall increase in emptying lag time with MKC253; greater change in

rate with exentatide

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Summary

MKC253 rapidly absorbed with a corresponding increase in insulinMKC253 rapidly absorbed with a corresponding increase in insulin; ; less insulin stimulation seen with less insulin stimulation seen with exenatideexenatide

Continued low incidence of adverse events with MKC253 relative tContinued low incidence of adverse events with MKC253 relative to o intravenous and sc GLPintravenous and sc GLP--11

Incidence of nausea < 5%Incidence of nausea < 5%No fatigue, No fatigue, dysphoriadysphoria or emesisor emesis

Limited effect on gastric emptying with MKC253 due to short Limited effect on gastric emptying with MKC253 due to short residence time; prolonged effect with residence time; prolonged effect with exenatideexenatide

MKC253 and MKC253 and exenatideexenatide work to control postprandial glucose by work to control postprandial glucose by different mechanismsdifferent mechanisms

GLPGLP--1 is another compound that has been shown to have different 1 is another compound that has been shown to have different PK and adverse event profiles when combined with Technosphere PK and adverse event profiles when combined with Technosphere microparticlesmicroparticles for oral inhalation.for oral inhalation.