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Medications Update – New and Emerging Therapies

WADE 2015 Annual Conference: Pathways to Positive Outcomes

Joshua J. Neumiller, PharmD, CDE, FASCPAssociate ProfessorDepartment of PharmacotherapyWashington State University

Disclosures to Participants

Conflicts of Interest and Financial Relationships Disclosures:

Presenter:

Joshua J. Neumiller, PharmD, CDE, FASCP - Speakers Bureau: Janssen Pharmaceuticals, Novo Nordisk; Advisory Board: Janssen Pharmaceuticals, Sanofi; Research Grant Support to WSU: AstraZeneca, Johnson & Johnson, Merck, Novo Nordisk.

Sponsorship / Commercial Support: None.

Non-Endorsement Of Products:

Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity.

Off-Label Use:

Participants will be notified by speakers to any product used for a purpose other than that for which it was approved by the Food and Drug Administration.

Learning Objectives

1. Identify new and emerging therapies for the treatment of diabetes mellitus;

2. Compare and contrast efficacy and safety data for SGLT-2 inhibitors currently available and in late-stage development; and

3. Discuss new and emerging insulin therapies and their potential place in therapy among currently available insulin products;

4. Outline emerging GLP-1 receptor agonist therapies and their potential role in combination therapy for people with type 1 and type 2 diabetes.

Pathophysiology of T2DM: The Ominous Octet

DeFronzo RA, Triplitt CL, et al. Diabetes Spectrum 2014;27(2):100-112.

ADA Standards of Medical Care in Diabetes – 2015. Diabetes Care. 2015.

SGLT-2 Inhibition

Glucose

Glomeruli

Blood Vessel

SGLT1

SGLT2

SGLT2 Inhibitor Urine

SGLT1

Small Intestine

Idris I, et al. Diabetes Obes Metab. 2009.

Inhibition of SGLT2 transporters in the proximal tubule blocks the reabsorption of filtered

glucose = increased glucose excretion via urine.

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Empagliflozin Monotherapy: A1C

Roden M, et al. Lancet Diabetes Endocrinol 2013;1:208-19.

Empagliflozin Monotherapy: Weight

Roden M, et al. Lancet Diabetes Endocrinol 2013;1:208-19.

ADA Standards of Medical Care in Diabetes – 2015. Diabetes Care. 2015.

Dapagliflozin vs. Glipizide as Add-on to Metformin

Nauck MA et al. Diabetes Care. 2011.

*Dapagliflozinnoninferior to

glipizide

Dapagliflozin vs. Glipizide as Add-on to Metformin

Nauck MA et al. Diabetes Care. 2011.

*P<0.0001*

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Canagliflozin versus Glimepiride as add-on to MET: A1C

Cefalu WT, et al. Poster presented at: The 73rd Scientific Session of the ADA, June 21-25, 2013, Chicago, IL.

Canagliflozin versus Glimepiride as add-on to MET: Weight

Cefalu WT, et al. Poster presented at: The 73rd Scientific Session of the ADA, June 21-25, 2013, Chicago, IL.

Canagliflozin and eGFR

Yale J, et al. Poster presented at: The 73rd Scientific Session of the ADA, June 21-25, 2013, Chicago, IL.

SGLT-2 Inhibitor Comparison/Contrast

Characteristic Canagliflozin Dapagliflozin Empagliflozin

Hypoglycemia Risk (monotherapy)

Low Low Low

Dose 100 mg daily before breakfast, Increase to

300 mg daily if needed

5 mg daily in the AM; Increase to 10 mg

daily if needed

10 mg daily in the AM; Increase to 25 mg if

needed

Weight Loss Loss Loss

SGLT-2 Inhibitors: Renal Dosing

Canagliflozin Prescribing Information. 2013.Dapagliflozin Prescribing Information. 2014.Empagliflozin Prescribing Information. 2014Woo V, et al. Poster presented at: The 73rd Scientific Session of the ADA, June 21-25, 2013, Chicago, IL.Kohan DE, et al. Kidney Int. 2013; doi: 10.1038/ki.2013.356. [Epub ahead of print]

Agent Dosing in CKD stages 3, 4 and 5 (non-dialysis)

Canagliflozin • eGFR ≥ 60 ml/min/1.73m2

No dosage adjustment needed• eGFR 45—59 ml/min/1.73m2

Do not exceed 100 mg/day PO• eGFR < 45 ml/min/1.73m2

Do not initiate and discontinue in patients currently receiving drug

Dapagliflozin Do not initiate and discontinue with eGFR <60 mL/min/1.73 m2

Empagliflozin • eGFR ≥ 45 ml/min/1.73m2

No dosage adjustment needed• eGFR < 45 ml/min/1.73m2

Do not initiate and discontinue in patients currently receiving drug

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Canagliflozin Efficacy

Woo V, et al. Poster presented at: The 73rd Scientific Session of the ADA, June 21-25, 2013, Chicago, IL.

SGLT-2 Late Developmental Pipeline

Agent Lead Company Phase

Ipragliflozin (ASP1941) Astellas Pharma 3

Luseogliflozin (TS071) Taisho Pharmaceutical 3

Tofogliflozin (CSG452) Chugai, Kowa, Sanofi 3

Ertugliflozin (PF-04971729) Pfizer, Merck & Co. 3

Sotagliflozin* Lexicon Pharmaceuticals 3

Nauck MA. Drug Design, Development and Therapy 2014;8:1335-1380.Bays H. Diabetes Ther 2013;4:195-220.Misra M, et al. JPP 2013;65:317-327.

*Dual SGLT-1/SGLT-2 Inhibitor

SGLT-2 Inhibitor Key Points• Unique MOA – have been studied in combination

with a variety of other medication classes• Oral administration• Low hypoglycemia risk as monotherapy – caution

when used with secretagogues or insulin• Can result in some weight loss and modest

decrease in BP• Common SE’s to be aware of:

– Genital mycotic infections – Lower UTIs– Urinary urgency– Orthostasis (especially in elderly, CKD, diuretic use)

• Watch volume status

New and Emerging Insulin Products

0 2 4 6 8 10 12 14 16 18 20 22 24

Pla

sm

a I

nsu

lin

Levels

Regular (6–10 hr)

NPH (10–20 hr)

Time (hr)

Glargine (~24 hr)

Aspart, Lispro, Glulisine, (4–5 hr)

Rosenstock J. Clin Cornerstone. 2001;4:50-61.

Detemir once daily(~24 hr)

Technosphere Insulin- Kinetics Curve

Technosphere Insulin Package Insert. 2014.

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Technosphere Insulin Package Insert. 2014.

Product Description

• Ultra rapid acting dry powder inhaled mealtime insulin for use in Type 1 and Type 2 Diabetes

• Use with caution in patients with history of smoking and/or lung cancer.

• Should not use in patients with chronic lung conditions• COPD

• ASTHMA• Assessment of pulmonary function recommended before starting, after 6 months and

annually

• Most common side effects: Hypoglycemia, Cough (25.6% vs. 19.7%), Throat Pain or Irritation (4.4% vs. 3.8%)

Available Strengths

• Currently availabile in two dosage strengths

• Strengths are converted to injected SC insulin units

• Supplied as cartridges in blister packs.

• 4 Unit equivalent (Blue)

• 8 Unit equivalent (Green)

Mankind Corporation, June 2014, [Afrezza® 4 unit cartidge], Retrieved from: http://www.mannkindcorp.com/collateral/documents/english-us/afrezza_medguide-ifu.pd

Mankind Corporation, June 2014, [Afrezza® 8 unit cartidge], Retrieved from: http://www.mannkindcorp.com/collateral/documents/english-us/afrezza_medguide-ifu.pd

Packaging/Storage• Keep packages in the refrigerator if not

actively using (good until expiration date)

• Sealed blister packaging good for 10 days outside refrigerator

• Opened blister section (strip of 3) good for 3 days once opened.

• Let all refrigerated materials come to room temperature for 10 minutes before use.

• Replace inhaler every 15 days.Mankind Corporation, June 2014, [Afrezza® cartridge blister pack diagram], Retrieved from: http://www.mannkindcorp.com/collateral/documents/english-us/afrezza_medguide-ifu.pd

Technosphere Insulin- Device Use

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Technosphere Insulin- Device Use Technosphere Insulin- Device Use

Other Select Emerging Prandial Insulins

• U200 Lispro – currently approved in Europe

• Pen device holds 3 mL of insulin – 600 total units per pen

• Possibly target people on larger volumes of mealtime insulin

• Faster-acting Insulin Aspart (FIAsp)

http://www.pipelinereview.com/index.php/2014100355623/Proteins-and-Peptides/European-Commission-Grants-Marketing-Authorisation-to-Humalog-200-units/ml-KwikPen-Insulin.html?utm_source=Closer+Look+Subscribers+2013&utm_campaign=5fbbdddc71-2014-10-03_%28HTML_LINKS%29_Intarcia%3B_Humal10_03_2014&utm_medium=email&utm_term=0_c55d924bf1-5fbbdddc71-411756565

U-300 Insulin Glargine• When compared to U-100 glargine, similar efficacy with less risk of

hypoglycemia

Bolli GB, et al. EDITION 3. Diabetes, Obesity and Metabolism. 2015;17:386-394.

U300 Insulin Glargine

• Type 2 DM (EDITION 1)• U300 Glargine vs. U100 Glargine in PM• Open label, 2 arm, parallel group over 1 year• End of Study

• U300- 1.03units/kg/day vs. U100- 0.9units/kg/day

Outcome U300 U100 P value

HbA1c (%) -0.86 -0.69 0.0074

FPG (mg/dl) -29.6 -26.0 NS

Weight (kg) 1.17(0.8-1.5) 1.4 (1.1-1.8) NS

Hypoglycemia

Severe 6.7% 7.5% ---

Any* 74.8% 82.8% RR 0.9(0.84-0.97)

Nocturnal** 44.6% 57.2% RR 0.78(0.68-0.89)

*<70mg/dl with symptoms; **Same definition, between 00:00-05:59hourRiddel MC, et al. Diabetes Care 2014;37(10):2755-2762.

U-300 Insulin Glargine: Determining Starting Dose

www.toujeopro.com

Prior Treatment: Start with:

Once-daily basal insulin 1:1 conversion

Twice-daily NPH 80% of total daily NPH dose

No current basal insulin 0.2 units/kg

• Available in SoloStar® Pen

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Long-acting Basal Insulin Analogs in Development

• Insulin degludec

• Phase 3

• Pegylated insulin lispro

• Phase 3

Degludec: Steady Release Occurs for More Than 24 Hours Following Injection

[Zn2+ ]

Insulin degludec

multihexamers

Zinc diffuses slowly, causing individual hexamers to disassemble, releasing

monomers.

Subcutaneous depot

Monomers are absorbed from the depot into the circulation. Slow

release

Jonassen I et al. Pharm Res. 2012;29(8):2104–1214.

BEGIN Basal-Bolus Type 2: A1C Over Time

6.0

6.5

7.0

7.5

8.0

8.5

9.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

A1

C (

%)

Time (weeks)

Treatment difference: noninferior

0

IDeg + IAsp (n = 744)

IGlar + IAsp (n = 248)

IDeg = insulin degludec; IGar = insulin glargine.

Garber A et al. Lancet. 2012;379(9825):1498–1507.

BEGIN Basal-Bolus Type 2: Confirmed Nocturnal Hypoglycemia

25% risk reductionRR: 0.75[0.58; 0.99]significant

Co

nfi

rmed

No

ctu

rnal

Hyp

ogl

ycem

ia

(Cu

mu

lati

ve N

um

ber

of

Even

ts p

er P

atie

nt-

year

)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Time (weeks)

0 4 8 12 16 20 24 28 32 36 40 44 48 52

IDeg + IAsp (n = 753)

IGlar + IAsp (n = 251)

Garber A et al. Lancet. 2012;379(9825):1498–1507.

PEGylated Insulin Lispro vs Insulin Glargine in Patients With T2D: Glucose Control at Week 12

• 12-week, randomized, open-label, Phase 2 study of

patients with T2D (A1C ≤10.5%), taking metformin

and/or sulfonylurea with once-daily basal insulin

PEGylated Lispro

(n=195)

Insulin Glargine

(n=95)

P Value

Change from

baseline at 12 weeks

Change from

baseline at 12 weeks

FBG (SMBG [mg/dL]) –25.9 ± 2.5 –24.5 ± 3.8 0.388

A1C level (%) –0.7 ± 0.1 –0.7 ± 0.1 0.197

FBG = fasting blood glucose.

Bergenstal RM et al. Diabetes Care. 2012;35(11):2140–2147.

With comparable glucose control

Bergenstal RM et al. Diabetes Care. 2012;35(11):2140–2147.

40

80

120

00 4 8 12

Cu

mu

lati

ve N

oct

urn

al

Hyp

ogl

ycem

ia E

ven

ts

(per

10

0 p

atie

nts

)

Week Since Randomization

Insulin glargine

PEGylated insulin lispro

PEGylated Insulin Lispro vs Insulin Glargine in Patients With T2D: Nocturnal Hypoglycemia

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–0.8

–0.6

–0.4

–0.2

0

0.2

0.4

Mea

n W

eigh

t Δ

(kg

)

Baseline 6 Weeks 12 Weeks

Insulin glargine

PEGylated insulin lispro

0.17

0.31

D = 0.84

–0.45

–0.58

*P <0.05 vsInsulin glargine

*

*

D = treatment difference.

Bergenstal RM et al. Diabetes Care. 2012;35(11):2140–2147.

PEGylated Insulin Lispro vs Insulin Glargine in Patients With T2D: Weight Change

GLP-1: effects in humans

GLP-1 is secreted fromL-cells of the jejunum

and ileum

That in turn…

Stimulates glucose-dependent insulin secretion

Suppresses glucagonsecretion

Slows gastric emptying

Leads to a reduction offood intake

After food ingestion…

Drucker. Curr Pharm Des 2001;7:1399-1412. Drucker. Mol Endocrinol 2003;17:161-171.

Drucker DJ. Cell Metab. 2006;3:153-165.

GLP-1 enhancement

GLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life:

exenatide

liraglutide

exenatide LAR

albiglutide

dulaglutide

Block DPP-4 to slow the

enzymatic degradation of

GLP-1:

sitagliptin

saxagliptin

linagliptin

alogliptin

Neumiller JJ. Med Clin North Am 2015;99(1):107-129.

Comparison & Contrast of Exenatide Products

Exenatide Once-

Weekly

Exenatide

Twice Daily

A1C reduction (%)

FPG reduction (mg/dL)

PPG reduction (mg/dL)

Achievement of A1C < 7%

1.9a

41b

96

77%d

1.5

25

124c

61%

Change in body weight (kg) -3.7 -3.6

A1C = hemoglobin A1c; FPG = fasting plasma glucose; PPG = postprandial glucoseaP=0.0023; bP < 0.0001; cP=0.0124; dP = 0.0039 versus comparator

Drucker DJ, et al. Lancet 2008;372(9645):1240-50.

Exenatide Once Weekly-Pen Device

• Same dosing, just new device

At least 15 minutes at room temp. prior to mixing steps

Major Steps in preparation

• Twist until mix diluent with microspheres (Audible Click Noted Upon Mixing)

• Gently move pen back and forth (oscillate) at least 80 times (about 1- 1 ½ minutes)

• Check Mixing Window for proper mixing-should see uniform color; If not-continue until uniform color seen in mixing window

• Twist until dosing plunger comes out of “Knob” and will hear a second “Click”

• Attach needle → ready for injection

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Albiglutide

• 97% homology to native GLP-1(7-36)

• 2 copies of a modified GLP-1 fused to human Albumin (C-terminus end of the modified GLP-1 sequence to the N-terminus of the human albumin)

• Resistant to DPP-4 metabolism- glycine replaces native GLP-1 alanine

• Half-life of 3.6-6.8 days

Eperzan, EMA, Accessed 12-11-14: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002735/WC500165119.pdf

• Dosing• 30mg Weekly• May increase to 50mg weekly

Albiglutide Efficacy vs Liraglutide

• Albi 50mg weekly versus Lira 1.8mg daily • At week 32 (n=422)• A1C: Albi -0.78%, Lira -0.99%

(difference 0.21%; 0.08—0.34; non-inferiority p value=0.0846)• GI SE: Albi 36%, Lira 49%• Injection site reactions: Albi 12.9%, Lira 5.4%

Pratley RE et al. Lancet Diabetes & Endo. 2014;2:289-297

Albiglutide- Device, Reconstitution, and Injection

• Storage of Pen Device• In refrigerator until expiration, and <4 weeks at room temp. • Pen needs 15 minutes at room temp before start mixing process

• Recommendation: take out next week’s dose when inject this week

• Injection site- subcutaneous delivery in abdomen, arm, or leg

• Must be injected within 8 hours of reconstitution• Inject weekly, without regard to meals

• “1” shows in window, twist until “2’” shows- slowly swirl 5 times, then let sit:

• 30mg dose- 15 minutes• 50mg dose- 30 minutes

Package Insert, GSK 2014, accessed 7-9-14, http://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF#nameddest=MG

Albiglutide-Injection Technique

Medication Guide, GSK 2014, accessed 7-9-14, http://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF#nameddest=MG

Albiglutide- Injection Technique

Medication Guide, GSK 2014, accessed 7-9-14, http://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF#nameddest=MG

Dulaglutide

• Recombinant GLP-1 Fc fusion protein linking GLP-1 analog to a human IgG4 Fc fragment

• Results in:• Prolonged t1/2: ~5 days• Once weekly dosing • Important difference: A solution- No reconstitution

needed

American Diabetes Association 74th Scientific Sessions, San Francisco, LB-110, P-979, P-962

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Dulaglutide Efficacy vs. Liraglutide

Dungan KM, et al. Lancet 2014;384:1349-1357.

Dulaglutide Efficacy vs. Liraglutide

Dungan KM, et al. Lancet 2014;384:1349-1357.

http://pi.lilly.com/us/trulicity-lowdose-ai-ifu.pdf

Potential Future Options:

• Combinations:• Insulin Degludec and Liraglutide

• Insulin Degludec and insulin aspart

• Insulin Glargine and Lixisenatide

• Oral GLP-1 RA

• GLP-1 RA via patch

• Implantable osmotic pump• 6 month data with exenatide

http://www.zosanopharma.com/index.php/20091103117/Research/Research-General/Technology-Platform.htmlHenry RR et al. ADA 74th Scientific Sessions, San Franciso, 2014, LB-114

Thank you!