3/23/2015

Medications Update – New Disclosures to Participants

and Emerging Therapies 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. WADE 2015 Annual Conference: Pathways to Positive Outcomes Sponsorship / Commercial Support: None.

Joshua J. Neumiller, PharmD, CDE, FASCP Non-Endorsement Of Products: Associate Professor Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR Department of Pharmacotherapy of any commercial products displayed in conjunction with this educational Washington State University 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 Pathophysiology of T2DM: The Ominous Octet 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.

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

SGLT-2 Inhibition

Small Intestine SGLT1

Blood Vessel SGLT1

Glucose Glomeruli

SGLT2

SGLT2 Inhibitor Urine

Inhibition of SGLT2 transporters in the proximal tubule blocks the reabsorption of filtered glucose = increased glucose excretion via urine.

ADA Standards of Medical Care in Diabetes – 2015. Diabetes Care. 2015. Idris I, et al. Diabetes Obes Metab. 2009.

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Empagliflozin Monotherapy: A1C Empagliflozin Monotherapy: Weight

Roden M, et al. Lancet Diabetes Endocrinol 2013;1:208-19. 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 Dapagliflozin vs. Glipizide as Add-on to Metformin to Metformin

*Dapagliflozin noninferior to glipizide

* *P<0.0001

Nauck MA et al. Diabetes Care. 2011. Nauck MA et al. Diabetes Care. 2011.

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Canagliflozin versus Glimepiride as add-on Canagliflozin versus Glimepiride as add-on to MET: A1C to MET: Weight

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

Canagliflozin and eGFR SGLT-2 Inhibitor Comparison/Contrast

Characteristic Canagliflozin Dapagliflozin Empagliflozin

Hypoglycemia Low Low Low Risk (monotherapy)

Dose 100 mg daily before 5 mg daily in the AM; 10 mg daily in the AM; breakfast, Increase to Increase to 10 mg Increase to 25 mg if 300 mg daily if daily if needed needed needed Weight Loss Loss Loss

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

SGLT-2 Inhibitors: Renal Dosing 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

Canagliflozin Prescribing Information. 2013. Dapagliflozin Prescribing Information. 2014. Empagliflozin Prescribing Information. 2014 Woo 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]

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Canagliflozin Efficacy 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

*Dual SGLT-1/SGLT-2 Inhibitor

Nauck MA. Drug Design, Development and Therapy 2014;8:1335-1380. Bays H. Diabetes Ther 2013;4:195-220. Woo V, et al. Poster presented at: The 73rd Scientific Session of the ADA, June 21-25, 2013, Chicago, IL. Misra M, et al. JPP 2013;65:317-327.

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

Technosphere Insulin- Kinetics Curve New and Emerging Insulin Products

Aspart, Lispro, Glulisine, (4–5 hr)

Regular (6–10 hr) NPH (10–20 hr)

Detemir once daily(~24 hr)

Glargine (~24 hr)

Levels Plasma Insulin Plasma

0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hr)

Rosenstock J. Clin Cornerstone. 2001;4:50-61. Technosphere Insulin Package Insert. 2014.

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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%)

Technosphere Insulin Package Insert. 2014.

Available Strengths

• Currently availabile in two dosage strengths

• Strengths are converted to injected Mankind Corporation, June 2014, [Afrezza® 4 unit cartidge], Retrieved from: SC insulin units http://www.mannkindcorp.com/collateral/documents/english-us/afrezza_medguide-ifu.pd • Supplied as cartridges in blister packs. • 4 Unit equivalent (Blue)

• 8 Unit equivalent (Green)

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

Packaging/Storage Technosphere Insulin- Device Use • 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.

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

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Technosphere Insulin- Device Use Technosphere Insulin- Device Use

Other Select Emerging Prandial Insulins U-300 Insulin Glargine • U200 Lispro – currently • When compared to U-100 glargine, similar efficacy with less risk of approved in Europe hypoglycemia • 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 Bolli GB, et al. EDITION 3. Diabetes, Obesity and Metabolism. 2015;17:386-394.

U300 Insulin Glargine U-300 Insulin Glargine: Determining Starting • Type 2 DM (EDITION 1) Dose • U300 Glargine vs. U100 Glargine in PM • Open label, 2 arm, parallel group over 1 year • End of Study • Available in SoloStar® Pen • U300- 1.03units/kg/day vs. U100- 0.9units/kg/day Outcome U300 U100 P value Prior Treatment: Start with: HbA1c (%) -0.86 -0.69 0.0074 FPG (mg/dl) -29.6 -26.0 NS Once-daily basal insulin 1:1 conversion Weight (kg) 1.17(0.8-1.5) 1.4 (1.1-1.8) NS Twice-daily NPH 80% of total daily NPH Hypoglycemia dose Severe 6.7% 7.5% --- Any* 74.8% 82.8% RR 0.9(0.84-0.97) No current basal insulin 0.2 units/kg Nocturnal** 44.6% 57.2% RR 0.78(0.68-0.89)

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

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Long-acting Basal Insulin Analogs in Degludec: Steady Release Occurs for Development More Than 24 Hours Following Injection Subcutaneous depot [Zn2+ ] • Insulin degludec

• Phase 3 Insulin degludec multihexamers • Pegylated insulin lispro

• Phase 3 Zinc diffuses slowly, causing individual hexamers to disassemble, releasing monomers.

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: Confirmed BEGIN Basal-Bolus Type 2: A1C Over Time Nocturnal Hypoglycemia

2.0 9.0 IDeg + IAsp (n = 744) IDeg + IAsp (n = 753) 25% risk IGlar + IAsp (n = 248) 1.8 IGlar + IAsp (n = 251) 8.5 reduction 1.6 RR: 0.75 [0.58; 0.99]

8.0 year) 1.4

- significant

) 1.2

%

( 7.5 1.0

C

1

A 7.0 0.8 Treatment difference: 0.6 6.5 noninferior

(Cumulative Number of of Number (Cumulative 0.4 Events per per Patient Events 6.00 0.2 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Confirmed Nocturnal Hypoglycemia Hypoglycemia Nocturnal Confirmed 0.0 Time (weeks) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (weeks) IDeg = insulin degludec; IGar = insulin glargine. Garber A et al. Lancet. 2012;379(9825):1498–1507. Garber A et al. Lancet. 2012;379(9825):1498–1507.

PEGylated Insulin Lispro vs Insulin Glargine in PEGylated Insulin Lispro vs Insulin Glargine in Patients With T2D: Glucose Control at Week 12 Patients With T2D: Nocturnal Hypoglycemia Insulin glargine • 12-week, randomized, open-label, Phase 2 study of 120 PEGylated insulin lispro patients with T2D (A1C ≤10.5%), taking metformin and/or sulfonylurea with once-daily basal insulin 80 PEGylated Lispro Insulin Glargine With comparable (n=195) (n=95) glucose control Change from Change from 40

baseline at baseline at (per 100 patients) 100 (per

12 weeks 12 weeks P Value Events Hypoglycemia Cumulative Nocturnal Nocturnal Cumulative FBG (SMBG [mg/dL]) –25.9 ± 2.5 –24.5 ± 3.8 0.388 0 A1C level (%) –0.7 ± 0.1 –0.7 ± 0.1 0.197 0 4 8 12 Week Since Randomization

FBG = fasting blood glucose. Bergenstal RM et al. Diabetes Care. 2012;35(11):2140–2147. Bergenstal RM et al. Diabetes Care. 2012;35(11):2140–2147.

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PEGylated Insulin Lispro vs Insulin Glargine in GLP-1: effects in humans Patients With T2D: Weight Change After food ingestion… Stimulates glucose- 0.4 Insulin glargine dependent insulin secretion 0.31 PEGylated insulin lispro Suppresses glucagon 0.2 0.17 secretion D = 0.84 0 Slows gastric emptying *P <0.05 vs GLP-1 is secreted from –0.2 Insulin glargine L-cells of the jejunum Leads to a reduction of and ileum food intake –0.4 –0.45

Mean Weight Δ (kg) Δ Weight Mean –0.58 –0.6 * That in turn…

–0.8 * Baseline 6 Weeks 12 Weeks Drucker. Curr Pharm Des 2001;7:1399-1412. Drucker. Mol Endocrinol 2003;17:161-171. D = treatment difference. Drucker DJ. Cell Metab. 2006;3:153-165. Bergenstal RM et al. Diabetes Care. 2012;35(11):2140–2147.

GLP-1 enhancement

GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life

Block DPP-4 to slow the Add GLP-1 analogues enzymatic degradation of with longer half-life: GLP-1: exenatide sitagliptin liraglutide saxagliptin exenatide LAR linagliptin albiglutide alogliptin dulaglutide

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

Comparison & Contrast of Exenatide Once Weekly-Pen Device Exenatide Products

Exenatide Once- Exenatide • Same dosing, just new device Weekly Twice Daily A1C reduction (%) 1.9a 1.5 At least 15 minutes at room temp. prior to mixing steps FPG reduction (mg/dL) 41b 25 Major Steps in preparation PPG reduction (mg/dL) 96 124c • Twist until mix diluent with microspheres (Audible Click Noted Upon Mixing) Achievement of A1C < 7% 77%d 61% • Gently move pen back and forth (oscillate) at least 80 times (about 1- 1 ½ minutes) Change in body weight (kg) -3.7 -3.6 • 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” A1C = hemoglobin A1c; FPG = fasting plasma glucose; PPG = postprandial glucose aP=0.0023; bP < 0.0001; cP=0.0124; dP = 0.0039 versus comparator • Attach needle → ready for injection

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

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Albiglutide Albiglutide Efficacy vs Liraglutide

• Albi 50mg weekly versus Lira 1.8mg daily • 97% homology to native GLP-1(7-36) • • 2 copies of a modified GLP-1 fused to human Albumin (C- At week 32 (n=422) terminus end of the modified GLP-1 sequence to the N- • A1C: Albi -0.78%, Lira -0.99% terminus of the human albumin) (difference 0.21%; 0.08—0.34; non-inferiority p • Resistant to DPP-4 metabolism- glycine replaces native GLP-1 alanine value=0.0846) • Half-life of 3.6-6.8 days • GI SE: Albi 36%, Lira 49% • Dosing • Injection site reactions: Albi 12.9%, Lira 5.4% • 30mg Weekly • May increase to 50mg weekly

Eperzan, EMA, Accessed 12-11-14: Pratley RE et al. Lancet Diabetes & Endo. 2014;2:289-297 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002735/WC500165119.pdf

Albiglutide- Device, Reconstitution, and Albiglutide-Injection Technique 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

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

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 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

Medication Guide, GSK 2014, accessed 7-9-14, http://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF#nameddest=MG American Diabetes Association 74th Scientific Sessions, San Francisco, LB-110, P-979, P-962

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Dulaglutide Efficacy vs. Dulaglutide Efficacy vs. Liraglutide Liraglutide

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

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.html http://pi.lilly.com/us/trulicity-lowdose-ai-ifu.pdf Henry RR et al. ADA 74th Scientific Sessions, San Franciso, 2014, LB-114

Thank you!

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