BEYOND INSULIN FOR GLYCEMIC TREATMENT OF TYPE 1 DIABETES

John B. Buse, MD, PhD

Verne S. Caviness Distinguished Professor

Chief, Division of Endocrinology

Director, Diabetes Center

Director, NC Translational and Clinical Sciences Institute

Executive Associate Dean, Clinical Research

University of North Carolina School of Medicine

T1D is a Burdensome Disease

1

People with T1D never get

a day off from managing it

It requires constant

monitoring of blood

glucose levels

People with T1D must wear

a pump or use injections to

dose insulin

It requires constant

management, 24 hours

a day

Must count the carbs and

account for everything

they eat

It is exhausting and

has long term

dangerous long-term

complications

Risk of nighttime hypoglycemia

and seizures

Risk of hypoglycemia

Comorbidities and Complications of T1D

Acute

• Hypoglycemia

• Diabetic Ketoacidosis (DKA)

Chronic

• Retinopathy

• Nephropathy

• Neuropathy

• Cardiovascular disease

The Impact of Diabetes Technology To Treat and

Manage T1D

CGM adoption continues to rise

(38% in 2018) in all age groups

No significant increase in

pump adoption

3Foster & T1D exchange clinic network (2019). DIABETES TECHNOLOGY & THERAPEUTICS

Despite Improved and More Widely Adopted Diabetes Technology, Clinical Outcomes Continue to Decline

What can be done now

▪ Support increased use of CGM in all ages and stages

▪ Transform device data to enhance self-management

(ex; decision support tools, etc.)

▪ Personalize treatment options (ex; adaptive algorithms,

open protocol, etc.)

▪ Use of adjunct therapies for added glycemic and

metabolic benefits

2016-18

2010-12

(Foster et al. Diabetes Technology and Therapeutics (2019) 21:66-72; DOI: 10.1089/dia.2018.0384)

Unmet Needs in Type 1 Diabetes

• A1C should be lower, particularly early in the course of the disease

• Weight is a concern for many patients and their providers

• Severe hypoglycemia is an important and immediate complication

• DKA remains an issue, even in patients who are apparently well managed

• While blindness and amputations have been largely eliminated in type 1 diabetes populations with good access to care, chronic kidney disease and cardiovascular disease remain important causes of morbidity and mortality

Will emerging technologies (closed loop, novel insulin analogs, glucose responsive insulin) solve these issues?

October 2019 9

Type 2 Diabetes Drugs in Type 1 DiabetesDrugs studied – improvements - harms

• Metformin: BMI (1), insulin, cholesterol – hypo, GI adverse events1

• Alpha-glucosidase inhibitors: nocturnal hypoglycemia, post-prandial hyperglycemia – GI

adverse events2

• Thiazolidinediones: insulin, mixed effects on progression – weight gain3

• GLP-1 receptor agonists: A1C (~0.3%), weight (~4 kg) – GI adverse effects, hypoglycemia,

ketosis4,5

• Pramlintide: A1C (~0.3%), weight (1.5-3 kg), PPG – GI adverse effects, hypoglycemia 5

• SGLT inhibitors: A1C (~0.4%), TIR improvement – DKA, genital infections 5

• GKA: A1C (~0.7%), TIR improvement – none reported thus far (only phase 2 data available

for 20 subjects)6

Exemplar references: 1. Vella S, et al. Diabetologia 2010; 53:809. Meng H, et al. Diabet Metab Res Rev 2018; Epub. Petrie JR, et al. Lancet D&E 2017; 5:597. 2. Raju B, et al. J Clin Endocrinol Metab. 2006; 91:2087-92. Riccardi G, et al. Diabet Med. 1999; 16:228. 3. Strowig SM, Raskin P. Diabetes Care. 2005; 28:1562. Shimada A, et al. Diabetes Metab Res Rev. 2011; 27:951. Yang Z, et al. Diabetes Res Clin Pract. 2009; 83:54-60.4. Wang W, et al Diabetes Ther 2017; 8:727. Ahren B, et al. Diabetes Care 2016; 39:1693. Mathieu C, et al. Diabetes Care 2016 39:1702.5. Warnes H, et al. Diabetes Ther. 2018; 9:1831-1851.6. Valcarce C, Freeman J, Dunn I, Dvergsten C, Soeder T and Buse J. Results from the sentinel and learning phase of the Simplici-T1 study, the first clinical trial to test activation of glucokinase as an adjunctive treatment for type 1 diabetes. Presented at 55th EASD conference, Barcelona, Spain, September 2019

October 2019 10

Injected Adjunctive Therapies

Physiologic Insulin and Amylin Secretion After Meals

Plasma insulin (pM)

Plasma amylin (pM)

30

25

20

15

10

5

7 am Midnight5 pm12 noon

Time

600

400

200

0

Meal Meal Meal

Koda et al, Diabetes. 1995; 44 (s1): 23BA.

Weyer et al. Curr Pharm Des. 2001;7:1353-1373

Amylin

Insulin

12

Pramlintide Reduces

FBG, PPG and Glucose Fluctuations

120

140

160

180

200

220

Glu

co

se

(m

g/d

L)

pre-bf post-bf pre-lu post-lu pre-di post-di bedtimeClinical Practice Study, 120 g SYMLIN

bf, breakfast; lu, lunch; di, dinner

N=166; *p-values for all data points <0.05

Edelman,S et al. Diabetes. 56 (Suppl 1):1826-P.

*

*

*

*

*

* *

insulin alone

insulin plus pramlintide

13

Pramlintide Summary

• A1C reduction versus placebo: 0 to -0.4%

• Insulin dose reduction: minimal

• Weight loss: 0 to 3 kg

• Hypoglycemia: Variable increase in severe hypoglycemia

• Substantial post-prandial glucose lowering

• Anecdotal improvement in sense of well-being

• GI adverse effects, particularly early in therapy

• Whether due to the need for taking an injection with each meal with waning adherence or due to tachyphylaxis, most patients did not continue on pramlintide long-term

Warnes H, et al. Diabetes Ther. 2018; 9:1831-1851.

Buse, personal observations

14

Liraglutide in Type 1 Diabetes:

Change in HbA1c from Baseline to End of Treatment

Data are estimated means. Full analysis setBL, baseline, HbA1c, glycosylated haemoglobin1. Mathieu C et al. Diabetes Care 2016;39:1702–1710; 2. Ahrén B et al. Diabetes Care 2016;39:1693–1701

HbA1c: –0.09% to –0.20%

Time since randomisation (week)

Hb

A1

c(%

) 8.0

7.0

0 8 12 16 20 26 32 38 44 52

HbA1c: –0.23% to –0.35%

7.5

7.6

7.7

7.8

7.9

8.0

8.1

8.2

0 8 12 16 20 26

Hb

A1

c(%

)

Time since randomisation (week)

Liraglutide 1.8 mg Liraglutide 1.2 mg Liraglutide 0.6 mg Placebo

ADJUNCT ONE1

ADJUNCT TWO2

7.2

7.4

7.6

7.8

8.2

8.4

Mean BL value Mean BL value

0.1299

0.0164

0.0019

p value vs placebo

0.0011

0.0021

<0.0001

p value vs placebo

15

Liraglutide in T1D: Conclusion

• “In conclusion, the current trial demonstrated that adding liraglutide to insulin

therapy for a population generally representative of people with type 1 diabetes

resulted in:

• better glycemic control, less insulin, greater body weight loss, and a greater proportion

of subjects achieving the ADA target of HbA1c <7%.”

• “This dose-dependent effect was accompanied by a higher rate of:

• symptomatic hypoglycemia and hyperglycemic episodes with ketosis, limiting the

clinical use of GLP1-RAs in people with type 1 diabetes.”

HbA1c, glycosylated haemoglobin

Mathieu C et al. Diabetes Care 2016;39:1702–1710

16

Oral Adjunctive Therapies

Meal

SGLT1 Glucose

Absorption

Glucose Filtration

Blood Glucose

Increased Urinary Glucose Excretion

X

Post-meal Glucose Levels

Zambrowicz et al 2012 Clin Pharmacol TherNishimura et al 2015 Cardiovasc Diabetol

Tissues

SGLT2(SGLT1)Glucose

Reabsorption

X

Intestinal SGLT1-Mediated Glucose Absorption

Renal SGLT2 (SGLT1) Mediated Glucose Reabsorption

October 2019 18

Study DEPICT1,2 inTandem3-5 EASE6

Drug, dose Dapagliflozin • 5 mg • 10 mg • Placebo

Sotagliflozin• 200 mg • 400 mg • Placebo

Empagliflozin• 2.5 mg• 10 mg• 25 mg• Placebo

3 SGLT Development Programs have Completed Phase 3:

DEPICT, inTandem, EASE

1. Dandona P, et al. Lancet Diabetes Endocrinol. 2017;5:864-876.

2. Mathieu C, et al. Diabetes Care. 2018;41:1938-1946.

3. Garg SK, et al. N Engl J Med. 2017;377:2337-2348.

4. Buse JB, et al. Diabetes Care. 2018;41:1970-1980.

5. Danne T, et al. Diabetes Care. 2018;41:1981-1990.

6. Rosenstock J, et al. Diabetes Care. 2018 Oct 4. [Epub ahead of print]

October 2019 19

*Lower doses retain much of the glycemic efficacy with lesser effect on weight and blood pressure.

Efficacy (Placebo Adjusted) At Highest Dose*

HbA1C reduction ~0.4%

Time in range (blinded CGM) ~3-hour increase

Time in hypoglycemia (CGM) No change or some reduction

Insulin dose 10%-15% reduction

Weight ~3-kg reduction

Systolic blood pressure ~3 mm Hg reduction

Patient reported outcomes Improved

To Summarize the Findings . . . (difficult to make precise efficacy comparisons across trials due to design and analysis differences)

In selected patients with T1D with inadequate glycemic control, consider the

use of an SGLT inhibitor as an adjunct to insulin therapy

20

Case: The ResultBefore: Glargine 46 Units/day + Aspart 30 Units/day; HbA1C: 8.8%

After: Glargine 32 Units/day + Aspart 24 Units/day + SGLT inhibitor

HbA1C: 6.5%; total daily dose reduced by ≈25%

14 pound weight loss

Statistics

Average glucose 148 mg/dL

Sensor usage 14 of 14 days

Calibrations per day 1.9

Standard deviation ±6.3 mg/dL

39% high

57% target

3% low

Target range 70 to 150 mg/dL

Nighttime 10 PM to 6 AM

39

57

3

Images courtesy of Satish K. Garg, MD.

Garg SK, Strumph P. N Engl J Med. 2018; 378:967-968

Comparison of Diabetic Ketoacidosis

Incidences in Phase 3 Studies

• Dapagliflozin and sotagliflozin are not approved in the US. Approved in the EU as oral

adjunctive treatments to insulin in T1D patients with BMI ≥ 27 (~1/4 of T1D patients).

• Empagliflozin EMDAC hearing scheduled November 13, 2019

22

DKA hazard ratios in SGLT2 trials of T1D

Goldenberg RM, et al. DOM. https://doi.org/10.1111/dom.13811

T1D SGLT inhibitor patient selection

Goldenberg RM, et al. DOM. https://doi.org/10.1111/dom.13811

T1D SGLTi Rx: Initial treatment

Goldenberg RM, et al. DOM. https://doi.org/10.1111/dom.13811

T1D SGLTi Rx: DKA risk mitigation

Goldenberg RM, et al. DOM. https://doi.org/10.1111/dom.13811

T1D SGLTi Rx: Wallet card (face)

Goldenberg RM, et al. DOM. https://doi.org/10.1111/dom.13811

T1D SGLTi Rx: Wallet card (back)

Goldenberg RM, et al. DOM. https://doi.org/10.1111/dom.13811

Investigational Agent

Glucokinase: The Physiological Glucose-sensor

vTv Therapeutics LLC, October 2019 30

❑ In humans, abnormal GK activity due to activating or inactivating mutations is linked to hyperglycemic and hypoglycemic conditions respectively

❑ In humans, loss of function mutations on the GKRP are associated with increased plasma lipids (Rees et al. J Clin Invest. (2012) 122, 205-217)

❑ In rodents, GKRP KO mice showed:▪ Decrease of GK expression in the liver▪ Glucose intolerance▪ Insulin resistance

Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator A. Vella, J. L. R. Freeman, I. Dunn, K. Keller, J. B. Buse and C. Valcarce, Science Translational Medicine 16 Jan 2019: Vol. 11, Issue 475, eaau3441. DOI: 10.1126/scitranslmed.aau3441

TTP399: The Importance of Tissue Selectivity and Preservation of Physiological Regulation to Avoid Pitfalls

vTv Therapeutics LLC, October 2019 31

▪ Based on genetic information, TTP399 was designed to avoid the expected pitfalls of GK activation:

• Liver selective: TTP399 does not activate GK in the beta-cells, i.e. no risk of hypoglycemia

• MoA preserves the natural interaction of GK-GKRP in the liver, i.e. no increase in lipids

Two essential criteria, validated by human mutations, to sustain glucose control without

causing hypoglycemia or hyperlipidemia

Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator A. Vella, J. L. R. Freeman, I. Dunn, K. Keller, J. B. Buse and C. Valcarce, Science Translational Medicine 16 Jan 2019: Vol. 11, Issue 475, eaau3441. DOI: 10.1126/scitranslmed.aau3441

❑ 11 clinical studies completed with TTP399 in healthy volunteers and T2DM patients ▪ 9 phase I studies ▪ 2 phase II studies ▪ Safety results included in TTP399 IB V7

❑ 1 ongoing clinical study with TTP399 in T1DM patients▪ Sentinel phase – 5 patients▪ Part 1 – 20 patients

❑ Approximately 500 subjects have received one or more doses of TTP399

❑ TTP399 was well tolerated at all doses tested

❑ The clinical results obtained to date are consistent with preclinical data and the MOA of a liver-selective GKA

Clinical Trials with TTP399

vTv Therapeutics LLC, October 2019 32

Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator A. Vella, J. L. R. Freeman, I. Dunn, K. Keller, J. B. Buse and C. Valcarce, Science Translational Medicine 16 Jan 2019: Vol. 11, Issue 475, eaau3441. DOI: 10.1126/scitranslmed.aau3441

TTP399-203 (Simplici-T1): Adaptive Phase 1b/2 Study Trial Design

vTv Therapeutics LLC, October 2019 33

Completed June 2019 Results expected in Q1 2020

Phase 2-Part 1 (Learning Phase)

Study Design:

▪ Double-blind Placebo control

▪ 12 weeks dosing 800mg QD

▪ ~20 adult subjects with T1D on CSII and CGM

▪ Primary Endpoint: change in HbA1c

TTP399 was well tolerated➢ No incidents of severe hypoglycemia or DKA➢ Indications of improved glycemic control, while

reducing insulin dose • Increase % time in range • Reduce % time in hyperglycemia without increasing

% time in hypoglycemia

Q1 2020June 2019

Phase 2-Part 2 (Confirming Phase)

Study Design:

▪ Double-blind Placebo control

▪ 12 weeks dosing 800mg QD

▪ ~90 adult subjects with T1D (all comers)

▪ Primary Endpoint: change in HbA1c

Phase 1 (Sentinels)

Study Design:

▪ Open-label

▪ 7 day dose escalation up to 1200mg QD

▪ 5 adult subjects with T1D on CSII and CGM

March 2018

ClinicalTrials.gov Identifier: NCT03335371

Valcarce C, Freeman J, Dunn I, Dvergsten C, Soeder T and Buse J. Results from the sentinel and learning

phase of the Simplici-T1 study, the first clinical trial to test activation of glucokinase as an adjunctive

treatment for type 1 diabetes. Presented at 55th EASD conference, Barcelona, Spain, September 2019

Subjects with Continuous Subcutaneous Insulin Infusion (CSII) and Continuous Glucose Monitoring (CGM)

• Multiple unmet needs in type 1 diabetes:

• A1C should be lower, particularly early in the course of the disease

• Weight is a concern for many patients and their providers

• Severe hypoglycemia is an important and immediate complication

• DKA remains an issue, even in patients who are apparently well managed

• Chronic kidney disease and cardiovascular disease in type 1 diabetes is high and completely

unaddressed by clinical trials

• Pramlintide FDA-approved but challenging to use

• Metformin, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists not moving

towards regulatory approval

• SGLT inhibitors partially address those unmet needs, but is the balance of efficacy and safety adequate

for FDA approval?

• GKA TTP339 shows promise as an adjunctive therapy in T1D

Summary

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