Type 1 Diabetes:2012 and Beyond

Tom Blevins MDTexas Diabetes and Endocrinology

Austin, Texas

Stem Cell Breakthrough • In a breakthrough that signifies a move toward a

cure for type 1 diabetes, Australian researchers have identified stem cells in the pancreas that can be turned into insulin-producing cells....

• Identified and isolated stem cells from the adult pancreas, and then developed a way to coax them into insulin-producing cells that can secrete insulin in response to glucose.

• 2012

BCG• In the study, six insulin-dependent adults with

type 1 diabetes received either two doses of BCG or two fake vaccinations.

• In the three patients who received the vaccine:– "Bad" anti-insulin T cells began dying off.– New "good" regulatory T cells increased.– There were signs of new, albeit temporary, insulin

production from pancreatic beta cells.• The vaccine was safe.

Vitamin D Deficiency Linked to Type 1 Diabetes

• (Nov, 2012) — A study led by researchers from the University of California, San Diego School of Medicine has found a correlation between vitamin D3 serum levels and subsequent incidence of Type 1 diabetes.

• The six-year study of blood levels of nearly 2,000 individuals suggests a preventive role for vitamin D3 in this disease.

Quest to prolong the action of insulin

• 1930’s-- development of protamine zinc insulin • Lente, NPH, and ultralente were developed as suspensions

to prolong action by delaying absorption• Glargine and detemir were developed to prolong

subcutaneous absorption by altering amino acid structure (glargine) or adding fatty acylated side chains (detemir)

“Ideal” Basal Insulin• The “ideal” longer acting insulin may be expected to

– Reduced variability– Lower risk of hypoglycemia, – Reduce the need for twice-daily injections– Provide minimal peak activity– Restore physiologic distribution of the 2-fold portal to systemic

insulin levels • Subcutaneous systemic absorption results in similar portal and systemic

levels• With current insulins, reduced hepatic insulin action must be balanced

with excess peripheral insulin action to maintain glucose homeostasis.

Basal Insulins in Development

Insulin Degludec-Novel Basal Insulin

• Forms a depot of soluble multi-hexamers at the injection site • Half-life of ~25 hours and a consistent glucose-lowering effect

of >42 hours

Insulin Degludec

Degludec: Basal-Bolus Type 1

LY2605541

Pharmacodynamic Profiles of LY2605541

Heise, et al, Poster ADA 2012

Better Glycemic Control and Weight Loss with the Novel Long-Acting Basal InsulinLY2605541 Compared with Insulin Glargine in Patients with Type 1 Diabetes

Julio Rosenstock, Richard M. Bergenstal, Thomas Blevins, Linda A. Morrow, Melvin J. Prince, Yongming Qu,Vikram P. Sinha, Daniel C. Howey, Scott J.Jacober

ADA, 2012, abstracts/poster session

Change in A1c

ADA, 2012, abstracts/poster session

Change in Weight

ADA, 2012, abstracts/poster session

Prandial (Pre-meal) Insulin

Injected Prandial Insulin

Rapid Actingor

Very Rapid Acting (Warp Speed?)

Do We Need Ultrafast Insulin?• Current analog insulin is slower than the physiologic prandial insulin

response of healthy individuals– Typical time to peak insulin concentration is 45-60 minutes for healthy subjects

vs. 60-100 minutes for analog prandial insulin • Tail of insulin action is longer than physiologic response and leads to 3- 6

hour post meal hypoglycemia (including nocturnal hypoglycemia)• Prandial control is elusive for even “well-controlled” patients

– Majority of patients fail to achieve Post-Prandial Glucose (PPG) goals • Current analog insulin requires approximately 15-20 minutes meal delay

Hyaluronin and Hyaluronidase

Hyaluronan (hyaluronic acid) Structure/Function• Until the late 1970s, hyaluronan was described as a "

goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix

• Large (Mega Dalton), repeating sugar polymer found in interstitial tissues

• Forms barrier to bulk fluid flow in interstitial space

• Human body turns over more than 5 grams/day (1/3rd of total body pool)

Hyaluronidase Mechanism of Action• Catalyzes the rapid depolymerization of hyaluronan

• Locally-acting, transient removal of the hyaluronan barrier to enhance the dispersion of coinjected drugs

• Rapid dispersion enhances insulin dissociation kinetics and accelerated absorption into the systemic circulation

rHuPH20 disperses SC administered drugs

SC administered drug depot

2323

Pharmacokinetic Results

• The three marketed rapid acting analog insulins have similar time exposure profiles

Morrow et al. ADA oral presentation 2010

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Pharmacokinetic Results

• Faster Out: – Insulin exposure after 2 hours decreased by 43%, 54%, and 57% for PH20

coinjection with glulisine, lispro and aspart, respectively (all P < 0.0001)

• Faster In (Primary Endpoint): – With rHuPH20 insulin exposure in the 1st hour was 191%, 229%, and 246%

of control for glulisine, lispro and aspart, respectively (all P < 0.0001)

Morrow et al. ADA oral presentation 2010

Human Hyaluronidase + Rapid Analog Insulin (RAI) Improves Postprandial Glycemic Control in Type 1 Diabetes

Compared to Insulin Lispro Alone

IRL B. HIRSCH, JAY S SKYLER, SATISH GARG, THOMAS BLEVINS, DANIEL E VAUGHN, DOUGLAS B MUCHMORE

University of Washington, Seattle, WA;University of Miami, Miami, FL;

University of Colorado Denver, Aurora, CO;Texas Diabetes and Endocrinology, Austin, TX;

Halozyme Therapeutics, San Diego, CA

Hirsch et al, ADA 2012 Poster

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T1DM: Improved Prandial Control with Analog-PH20 Demonstrated Throughout Study

Overall mean PPG change (90 minutes) from pre-meal baseline, routine SMBG monitoring throughout each treatment phase.

Meal % Reduction in Glycemic Excursion

Breakfast 73% (p=.017)

Lunch 34% (p=.44)

Dinner 219% (p=.040)

Overall 82% (p=.0045)

Confidential

Artificial Pancreas

Closed loop “automatic” systems (pump-sensor)

Is Hypoglycemia a Challenge?

• Do some of your adults or children with diabetes suffer from:

– Hypoglycaemia Unawareness?– Nocturnal Hypoglycaemia?– Or a fear of Hypoglycaemia?

Medtronic MiniMed Guardian® REAL-Time Continuous Glucose Monitoring System

How to Address this Challenge?

• Current Therapy Options– CSII vs MDI – Continuous Glucose Monitoring (CGM)

• Advanced Therapy Options– Sensor-augmented Pumps– Automatic Insulin Shut-off Mechanism

Diabetes Technology Explosion

CSII Reduces Incidents of Severe Hypoglycaemia1/4

1 Rudolph JW, Hirsch IB. Endocrine Pract 2002: 8; 401 – 4052 Bode, BW et al., Diabetes Care 1996, 19:325-7. 3 Boland, EA et al., Diabetes Care 1999, 22:1779 - 84. 4 Pickup JC & Sutton, AJ. Diabet Med 2008;25:765-774

1 2 3

Severe Hypoglycaemic Episodes: CSII vs MDI

CGM Alerts Reduce Duration of Hypoglycaemic Excursions1

• 71 Type 1 patients wore sensors over a 12-day period• Multi-Center RCT where patients were randomised to:

1. Alert Group• Alerts On 50%• Alerts Off 50%

2. Control Group• Alerts Off

CGM alerts improve glycemic control

1. Bode et al. 2004 Diab.Tech & Therapeutics 6(2): 105-113.

Period 1Period 2

Min

utes

per

eve

nt 69.664.4 63.8

0

20

40

60

80

Alert Group Control Group

Alertsoff

Alerts on

33.6

Alertsoff

Alertsoff

p=0.004 p=0.03

Sensor Report

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The Road to Closing the Loop

The Road to Closing the Loop

1. Low Glucose Suspend2. Predictive low glucose3. High glucose bolus4. Predictive high glucose bolus5. True closed loop

How Does Low Glucose Suspend Work?

• User settable: On/Off • Range: Trigger at <50 mg/dl

• Fictional illustration of Low Glucose Suspend function in use

• Suspends insulin infusion for a 2-hour period

• All other sensor functions and alerts remain operational during insulin suspension

• Reduces the severity of hypoglycemia • Complements the CGM alerts• Provides an additional safety measure for

an unresponsive patient

Low Glucose Suspend is the first component of the closed loop

LGS – CareLinkTM Therapy Management Software Tracing

Introducing the MiniMed Paradigm® Veo™ SystemA new era in diabetes management

• Greater protection from severe hypoglycaemia– Automatic insulin shut-off mechanism –

Low Glucose Suspend (LGS)

• Greater protection from glycaemic excursions– CGM-ready insulin pump

• Combined CSII and CGM offer clinical benefits1

– CGM alerts • Give early warnings of glycaemic excursions• Reduce the duration of hypoglycaemic excursions2

– Improved sensor sensitivity in the hypoglycaemic range

• Closing the loop – First device to offer sensor-driven adjustments to insulin delivery

2. Bode B., et al. Diabetes Technology and Therapeutics. Volume 6, Number 2, 2004

1. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008;25:765-774

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Veo system: patient view

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Examples of Successful Inductions

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Effect of LGS on hypoglycemia

By means of %SG for individual users**

  LGS Off LGS On p

Mean 151.34 156.04 0.050

STD 60.07 54.84  0.028

%SG<50 1.33 0.92 0.001%SG<60 3.58 2.63 0.140

%SG<70 6.73 5.48 0.433

%SG<80 11.39 10.05 0.866

Reduction in severe hypoglycemic blood glucose levels is observed with LGS

Fig. Comparison of low sensor BG when LGS is OFF vs. ON

**”Characterization of the Low Glucose Suspend Feature of the Medtronic Paradigm Veo Insulin Pump and Events Preceding its Activation” . To be presented by Dr. Fran Kaufman at the ADA conference 2011

Percent time SG <= 50 Percent time SG <= 80

Fictional illustration of alerts in use

Studies Done at Here in Austin at Texas Diabetes and Endocrinology

• Basal Insulin– Degludec– Basal insulin lispro (BIL)

• Rapid, pre-meal insulin (warp speed)– Halozyme– Biodel

• Insulin pump-LGS (low glucose suspend)

Studies- ongoing or coming up for Type 1’s

• Sanofi U300- Lantus pen – Concentrated insulin, lower volume – 3 units for every 1 traditional unit

• Halozyme- Insulin pump with very rapid acting insulin• Eli Lily BIL basal insulin flex dosing

– Given in the am or pm-flat profile• Liraglutide in Type 1’s

– The agent that lowers glucose and glucagon with weight loss in Type 2 diabetes

• Novo Degludec– Long acting, basal insulin with flat profile.

“Smart Insulin”

• “Smart Insulin” works via competitive binding – insulin (orange lines), attached to a sugar group (orange hexagons),

binds with a sugar-binding molecule (blue circle) in solution. – When glucose (blue hexagons) in the body is high, it competes with

insulin to bind to the sugar-binding molecules, displacing insulin and releasing it into the bloodstream as needed

Q and A