Faculty Disclosures Optimizing Healing of Diabetic Foot ... · PDF filePMN influx →...

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Supported by an educational grant from Smith & Nephew, Inc

Optimizing Healing of Diabetic Foot Ulcers:

An Updated Look at Growth Factors

Faculty

Larry Lavery, DPM, MPH Professor, Department of Plastic Surgery

University of Texas Southwestern Medical Center Dallas, Texas

Jeffrey D. Lehrman, DPM, FASPS, FACFAS, AAPWCA

Foot & Ankle Specialists of Delaware County Center for Wound Healing and Hyperbaric Medicine

Springfield, Pennsylvania Twitter: @DrLehrman

Susie Seaman, NP, MSN, CWOCN Nurse Practitioner/Wound Specialist

Sharp Rees-Stealy Wound Clinic San Diego, California

[email protected]

Disclosures

Dr. Lavery: Grant/Research – Osiris, Macrocure, ThermoTek, Integra LifeSciences, GlaxoSmithKline, KCI; Consultant – KCI, Innovative Therapies Inc (ITI), PamLabs; Promotional Speakers’ Bureau – KCI, ITI, PamLabs, Smith & Nephew, Inc; Stock Shareholder – Prizm Medical

Dr. Lehrman: Consultant – Musculoskeletal Transplant Foundation; Promotional Speakers’ Bureau – Smith & Nephew, Inc; BSN Medical

Ms. Seaman: Scientific advisor – Smith & Nephew, Inc; Promotional Speakers’ Bureau – Smith & Nephew, Inc

Disclaimer

This continuing medical education activity includes device brand names for participant clarity purposes only due to the presence of different branded versions of the same device. No product promotion or recommendation should be inferred.

Learning Objectives

•  Review the physiology and pathophysiology of wound healing in diabetes

•  Examine the role of growth factor therapy as an evidence-based biologic therapy for treating diabetic foot ulcers

•  Translate the science of growth factor therapy into clinical relevance as an adjunct to proper wound care

•  Summarize late-breaking safety data on adjunctive therapy based on PDGF to diabetic foot ulcer healing

PDGF = platelet-derived growth factor.

Physiology and Pathophysiology of Wound Healing in Diabetes

The Role of Growth Factor Therapy as an Evidence-Based Biologic Therapy for Treating Diabetic Foot Ulcers

Susie Seaman, NP, MSN, CWOCN Nurse Practitioner/Wound Specialist

Sharp Rees-Stealy Wound Clinic San Diego, California

[email protected]

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Hemostasis Inflammation Proliferation Remodeling

Acute Wound Healing vs Chronic Wound Healing

Mast BA, et al. Wound Rep Regen. 1996;4(4):411-420. Acosta JB, et al. Int Wound J. 2008;5(4):530-539. Demidova-Rice TN, et al. Adv Skin Wound Care. 2012;25(7):304-314.

Repetitive trauma Ischemia Bacteria

Healed wound Chronic wound

Chronic inflammation

Normal phases of wound healing

Acute wound

Acute Wounds

PMN = polymorphonuclear leukocyte. Mast BA, et al. Wound Rep Regen. 1996;4(4):411-420. Acosta JB, et al. Int Wound J. 2008;5(4):530-539. Demidova-Rice TN, et al. Adv Skin Wound Care. 2012;25(7):304-314.

One-time injury ↓

Bleeding/platelet activation/growth factor release ↓

PMN influx → Secretion of pro-inflammatory cytokines → Bacterial kill/debridement

↓ PMNs recede

Macrophage/fibroblast influx ↓

Inflammatory phase ends/Proliferative phase begins

Acute-Wound Fluid

•  High mitogenic activity

•  High levels of growth factors

•  Appropriate levels of pro-inflammatory cytokines (TNFα, IL-1β, etc)

•  Balance between MMPs and TIMPs

TNFα = tumor necrosis factor alpha; IL-1β = interleukin-1β; MMP = matrix metalloproteinase; TIMP = tissue inhibitors of metalloproteinase. Lobmann R, et al. Diabetologia. 2002;45(7):1011-1016. Trengrove NJ, et al. Wound Rep Regen. 1999;7(6):442-452.

Chronic Wounds

ECM = extracellular matrix. Mast BA, et al. Wound Rep Regen. 1996;4(4):411-420. Acosta JB, et al. Int Wound J. 2008;5(4):530-539. Demidova-Rice TN, et al. Adv Skin Wound Care. 2012;25(7):304-314. Gould L, et al. J Am Geriatr Soc. 2015;63(3):427-438.

Repetitive trauma, ischemia, bacteria ↓

Prolonged PMN influx and secretion of pro-inflammatory cytokines (TNFα, IL-1β, etc)

Macrophages fail to switch from pro-inflammatory phenotype to reparative phenotype

↓ Increased MMP/decreased TIMP activity

↓ Degradation of growth factors and target cell receptors

Degradation of ECM Decreased cell proliferation and migration

Cellular senescence ↓

Impaired healing

Chronic-Wound Fluid

•  Low mitogenic activity

•  Decreased levels of growth factors

•  Increased levels of pro-inflammatory cytokines

•  Increased MMP/decreased TIMP levels

Rayment EA, et al. Br J Dermatol. 2008;158(5):951-961. Gohel MS, et al. J Vasc Surg. 2008;48(5):1272- 1277. Acosta JB, et al. Int Wound J. 2008;5(4):530-539. Trengrove NJ, et al. Wound Rep Regen. 2000;8:13-25.

Factors Interfering with DFU Healing

•  Altered microenvironment

•  Inflammation: Bacterial burden/infection, tissue necrosis

•  Tissue ischemia (PAD and/or impaired vasodilation)

•  Repetitive trauma (pressure)

•  Edema

•  Systemic conditions (eg, smoking, glycemic control, medications)

DFU = diabetic foot ulcer; PAD = peripheral artery disease. EWMA. Position Document: Hard to heal wounds: a holistic approach. London: MEP Ltd, 2008. Game FL, et al. Diabetes Metab Res Rev. 2012;28(suppl 1):119-141. Alavi A, et al. J Am Acad Dermatol. 2014 Jan;70(1):1.e1-18.

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Holistic Care of the Patient with a Chronic Wound

NPWT = negative pressure wound therapy. Adapted from Schultz GS, et al. Wound Rep Regen. 2003;11(suppl 1):S1-S28.

Treat the Cause

Patient-centered Concerns

Debridement Inflammation and Infection Control

Moisture Management

Epithelial Edge Advancement

•  Perfusion •  Edema control •  Pressure relief

•  Pain •  Quality of life

•  Sharp •  Autolytic •  Enzymatic •  Mechanical •  Biologic

•  Protease inhibitors •  Topical

anti-microbials •  Systemic antibiotics

•  Dressings •  NPWT •  Edema control

•  Growth factors •  Cell- or tissue-

based products •  Other

Prepare Wound Bed

Chronic Wound

What Are Growth Factors?

Complex proteins, released by cells, that stimulate:

•  Cell migration (chemotaxis)

•  Cell proliferation (mitosis)

•  Angiogenesis

•  Production and degradation of ECM

•  Growth factor production by other cells

Growth Factor Activity

www.scidiv.bellevuecollege.edu.

EXTRACELLULAR FLUID

Receptor

Growth factor

Relay molecules in a signal transduction pathway

Plasma membrane CYTOPLASM

• Change in cellular activity

• Protein synthesis

• Cell proliferation

1. Reception 2. Transduction 3. Response

Growth Factors Are Key: They Mediate Many Biologic Steps in Wound Healing

EGF = epidermal growth factor; TGF = transforming growth factor; BMP = bone morphogenetic protein; VEC = vascular endothelial cell; TIMPs = tissue inhibitors of metalloproteinase; IGF = insulin-like growth factor; SMC = smooth muscle cell; CTGF = connective tissue growth factor. Behm B, et al. J Eur Acad Dermatol Venereol. 2012;26:812-820. Barrientos S, et al. Wound Repair Reg. 2008;16:585-601.

Family Cell Source Biologic Action

EGF EGF, TGFα, HB-EGF

Platelets, epidermal cells, macrophages, fibroblasts

↑ Epidermal cell proliferation, migration, angiogenesis

TGFβ TGFβs, BMPs, activin/inhibin osteogenin

Platelets, macrophages, fibroblasts, epidermal cells, VECs

↑ECM synthesis, ↓MMPs, ↑TIMPs ↑chemotaxis inflammatory cells and fibroblasts, ↑bone synthesis, ↑wound contraction, ↓epithelial cell

FGF aFGF, bFGF, KGF

Platelets, epidermal cells, fibroblasts, VEC

↑Proliferation of fibroblasts ↑ECM synthesis, ↑angiogenesis

PDGF PDGF-AB, PDGF-BB, VEGF

Platelets, smooth muscle cells, fibroblasts, VEC

↑Proliferation of fibroblasts ↑ECM synthesis, ↑angiogenesis

IGF IGF-I, IGF-II

Platelets, skeletal muscle cells, macrophages, neutrophils

↑Proliferation of SMC, epidermal cells, fibroblasts, ↑angiogenesis

CCN family CTGF

Fibroblasts, epidermal cells, VEC

↑Proliferation of fibroblasts mediates actions of TGFβ on ECM synthesis, chemotaxis, and bone

PDGF Plays Key Roles in Each Phase of Wound Healing

•  Hemostasis –  Released from platelets

•  Inflammation –  Chemotactic for PMNs, macrophages

•  Proliferation –  Chemotactic and mitogenic for fibroblasts, vascular smooth muscle cells, pericytes –  Stimulates fibroblasts to synthesize collagen –  Stimulates cell synthesis of angiogenic factors, VEGF and bFGF –  Stimulates endothelial cells to form new blood vessels (angiogenesis) –  Recruits bone marrow-derived stem cells (endothelial progenitor cells) to wound –  Stimulates transformation of fibroblasts into myofibroblasts

•  Remodeling –  Chemotactic, mitogenic, and stimulation of fibroblasts to remodel scar

PMN = polymorphonuclear leukocyte; VEGF = vascular endothelial growth factor; bFGF = basic fibroblast growth factor. Deuel TF, et al. J Clin Invest. 1982;69(4):1046-1049. Seppa H, et al. J Cell Biol. 1982;92(2):584-588. Massberg S, et al. Thromb Res. 2003;110(4):187-194. D’Amore PA, et al. Growth Factors. 1993;8(1):61-75. Sato N, et al. Am J Pathol. 1993;142(4):1119-1130. Pierce GF, et al. J Exp Med. 1988;167(3):974-987. Oh SJ, et al. Histochem Cell Biol. 1998;109(4):349-357.

Becaplermin Gel

•  rhPDGF-BB in CMC topical gel

•  Biologic activity similar to endogenous PDGF-BB

•  The only approved prescription drug indicated for treatment of full-thickness lower-extremity diabetic neuropathic ulcers with adequate blood supply

rhPDGF = recombinant human platelet-derived growth factor; BB = becaplermin; CMC = carboxymethyl cellulose. Steed DL. J Vasc Surg. 1995;21(1):71-81. Wieman TJ, et al. Diabetes Care. 1998;21(5):822-827. d'Hemecourt PA, et al. Wounds. 1998;10(3):69-75. Margolis DJ, et al. Wound Repair Regen. 2005;13(6):531-536.

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Phase 3 Trial of Becaplermin Gel in the Treatment of DFUs

Objective •  Study the efficacy and safety of becaplermin gel

Design •  Multicenter, double-blind, placebo-controlled trial •  Healing rates including complete wound closure over a maximum duration of

20 weeks were assessed

Patient population –  382 patients with type 1 or type 2 diabetes mellitus with at least 1 full-thickness

neuropathic ulcer of the lower extremity ≥8 weeks’ duration

–  Ulcer size 1 cm2 to 40 cm2 post-debridement

–  TcPO2 ≥30 mm Hg on affected limb

Treatment regimen •  After sharp debridement of the ulcer, patients were randomized to receive:

–  Becaplermin gel + good ulcer care

–  Placebo gel + good ulcer care

TcPO2 = transcutaneous partial pressure of oxygen. Wieman TJ, et al. Diabetes Care. 1998;21(5):822-827.

Results: Wound Closure at 20 Weeks

2 6

40

30

60

50

20

10

0 0 10 14 20

Patie

nts

Ach

ievi

ng C

ompl

ete

Wou

nd C

losu

re (%

)

Weeks of Treatment 8 12 4 16 18

Placebo Becaplermin (rhPDGF)

50% P=.007

35%

Compared to placebo gel, becaplermin gel significantly increased the incidence of complete wound closure by 43% (P=.007)

Wieman TJ, et al. Diabetes Care. 1998;21(5):822-827.

Results: Wound Closure Rates

Wieman TJ, et al. Diabetes Care. 1998;21(5):822-827.

2 6 0 10 14 20

Good Ulcer Care + Becaplermin Gel

Average Healing Time (weeks) 8 12 4 16 18

Becaplermin gel, along with good ulcer care, reduced healing time by 32%, nearly 6 weeks faster, compared with patients receiving placebo gel

(86 vs 127 days, P=.013)

Good Ulcer Care + Placebo Gel

Summary

•  Chronic wounds, including DFUs, do not follow expected sequence of repair

•  Recognize and address issues leading to impaired healing

•  Growth factors are crucial in wound-healing process

•  Becaplermin gel (PDGF) has been shown to speed healing in patients with DFUs

Translating the Science of Growth Factor Therapy into

Clinical Relevance

Jeffrey D. Lehrman, DPM, FASPS, FACFAS, AAPWCA

Foot & Ankle Specialists of Delaware County Center for Wound Healing and Hyperbaric Medicine

Springfield, Pennsylvania Twitter: @DrLehrman

Every 30 Seconds

International Working Group on the Diabetic Foot. Diabetes and the foot. http://iwgdf.org/. Accessed March 21, 2016.

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5-Year Mortality Rates

Moulik PK, et al. Diabetes Care. 2003;26(2):491-494. Armstrong DG, et al. Int Wound J. 2007;4(4):286- 287. American Cancer Society. Cancer Facts & Figures 2014.

100

0

5-Ye

ar M

orta

lity

Rat

e (%

) 90

Lung

Leuke

mia

Ovaria

n

Ischem

ic

Ulcer (

DFU)

Prosta

te

Pancre

atic

Neuro

pathic

Ulcer (

DFU)

70

60

50

40

30

20

10

Colon

Melanoma

Urinary

Blad

der

Non-Hodgkin

’s

Lymphoma

Breast

83 80

94

1 9 11

22

29 35

41 45

56 56

Healing of DFUs after 4 Weeks

Sheehan P, et al. Diabetes Care. 2001;25.

Wounds achieving <53% closure at week 4 have minimal chance of healing with conventional therapy

Percentage of Patients in Whom the Ulcer Healed during the 12-Week Period

30

40

70

50

20

0

Patie

nts

(%)

<53% Area Reduction

at Week 4

>53% Area Reduction

at Week 4

10

60

9%

Good Ulcer Care

•  Instituting a structured diabetic foot program can yield a major reduction in amputation rates and a large reduction in in-patient mortality

Weck M, et al. Cardiovasc Diabetol. 2013;12:45-53.

Good Ulcer Care: Debridement

Good Ulcer Care: Infection Control

Good Ulcer Care: Moisture Balance

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Good Ulcer Care: Offloading Advanced Wound Healing

•  Early adoption of advanced or appropriate care may be more cost-effective than traditional standard practices for decreasing the incidence of lower-extremity amputation and may speed healing

Kirsner RS. The Standard of Care for Evaluation and Treatment of Diabetic Foot Ulcers. http://www. barry.edu/includes/docs/continuing-medical-education/diabetic.pdf.

Case Study: Left Lateral Foot

Patient description

•  60-year-old woman with:

–  Uncontrolled type 2 diabetes mellitus (HbA1c, 12%)

–  Peripheral neuropathy

–  Peripheral artery disease

•  Left foot ulcer that she thought developed as “insect bite”

•  Fully ambulatory in postoperative shoe

•  Intermittent sharp pain in left foot

HbA1c = hemoglobin A1c.

Wound Presentation

•  3.2 cm x 3.2 cm x 1.7 cm

•  Vascular examination showed left femoral bruit

•  Non-palpable pedal pulses

•  Angiogram showed: –  40% focal stenosis of left popliteal

artery

–  Left anterior tibial artery occluded

–  Left dorsalis pedis filled via collaterals

–  Extensive plaque and diffuse narrowing in left peroneal artery and left post-tibial artery

Regranex Gel Case Studies. Regranex (becaplermin) Gel 0.01%. http://www.regranex.com/case-studies-1.php. Accessed March 22, 2016.

Wound Presentation (cont)

•  Day 16: Revascularization

•  Day 23: NPWT

•  Day 58: Split-thickness skin graft


Day 75


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Day 110: Start PDGF


After 2 Weeks of PDGF










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Late-Breaking Data on Safety of PDGF-Based Therapies

Larry Lavery, DPM, MPH Professor, Department of Plastic Surgery

University of Texas Southwestern Medical Center Dallas, Texas

Objectives

•  To discuss Boxed Warning Label for PDGF

•  To discuss animal research and the risk of cancer

•  To discuss epidemiologic studies

…increase in the risk of death from cancer…was five times higher than in those patients who did not use Regranex

However, the risk of getting new cancers…was not increased… The duration of follow-up of patients in this study

was not long enough to detect new cancers

Becaplermin Boxed Warning Label 2008

•  FDA has received information regarding a study that was performed to investigate the possibility of an increased risk of cancer in patients with diabetes mellitus

•  This study was done using a health insurance plan database

•  Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January 1998 through June 2003

•  Deaths from all types of cancer combined were observed

FDA = US Food and Drug Administration. Update of Safety Review: Follow-up to the March 27, 2008, Communication about the Ongoing Safety Review of Regranex (becaplermin) June 6, 2008.

Becaplermin Boxed Warning Label 2008 (cont)

•  Following publication of an abstract suggesting use of multiple tubes (3+) associated with cancer mortality, but not increased cancer incidence

•  Resulted in decline in use

•  Restricted-use guidance in certain institutions

•  FDA required another postmarketing study

Regranex (becaplermin) Gel 0.01% [product insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, March 1999. FDA.gov. Accessed April 23, 2013.

WARNING: INCREASED RATE OF MORTALITY SECONDARY TO MALIGNANCY An increased rate of mortality secondary to malignancy was observed in patients with 3 or more tubes of REGRANEX® Gel in a postmarketing retrospective cohort study. REGRANEX Gel should only be used when the benefits can be expected to outweigh the risks. REGRANEX Gel should be used with caution in patients with known malignancy. [See Warnings and Precautions (5.1)].

Becaplermin and Safety

•  Long-standing theoretical concern for growth factor and cancer promotion

–  PDGF is overexpressed by some tumor cells

–  Some types of cancer exhibit upregulated PDGF signaling

–  Very limited clinical evidence of any association with therapy

–  Stimulates tumor-infiltrating fibroblasts in melanoma

–  Activation of PDGF signaling is growth promoting in certain gliomas, sarcomas, and leukemias

Mantur M, et al. Adv Med Sci. 2008;53:37-41. Yu J, et al. J Biochem Mol Biol. 2003;36:49-59. Fang RC, et al. Biologics. 2008 Mar;2(1):1112. Poeschla EM, et al. Principles and Practice of Oncology. 6th ed. New York, NY: Lippincott Williams & Wilkins; 2001.

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Cancer Studies: J&J Study

•  Premarket follow-up of two European trials of sterile becaplermin gel vs placebo gel

•  Follow-up for 20 months with cancer monitoring

–  291 exposed → 9 cases (2.7%)

–  200 placebo → 2 cases (1.0%)

–  Rate ratio = 2.8 (0.6-12.8); not statistically significant

–  Various types of cancer; no skin cancer; no cancer deaths

J&J = Johnson & Johnson. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00740922?term=NCT00740922&rank=1. Accessed March 21, 2016.

Nonclinical Safety Studies

β-TCP = beta-tricalcium phosphate; Cmax = maximum concentration observed; Tmax = time point at which the maximum concentration was observed; CL = clearance. Solchaga LA, et al. J Tissue Eng. 2012;3(1):2041731412453577. Augment® Bone Graft SSED. Franklin, TN: Wright Medical Technology, Inc. BioMimetic Therapeutics, LLC. Summary of Safety and Effectiveness Data (SSED). Pages 1-22.

Study Results

Pharmacokinetics Rat 10x maximum clinical dose

Pharmacokinetics of rhPDGF-BB in Sprague-Dawley rats following intravenous administration

Cmax: 6161.2 ng/mL Tmax: 1.0 min CL: 17.5 mL/min/kg

Pharmacokinetics Dog 23x maximum clinical dose

Pharmacokinetics study in male beagle dogs following single intravenous administration of rhPDGF-BB

Cmax: 14,603.8 ng/mL Tmax: 1.0 min CL: 423.3 mL/min/kg

Reproductive and developmental toxicity 210x maximum clinical dose

rhPDGF-BB: an intravenous injection teratology study in the rats

No maternal toxicity No fetal toxicity

Carcinogenicity and chronic toxicity 4x maximum clinical dose

Evaluation of the chronic toxicity and carcinogenicity of rhPDGF-BB mixed with β-TCP (Augment® Bone Graft) implanted in a rat model

No carcinogenicity No toxicity Transient local reaction to implanted material observed in both groups

Safety of PDGF-Based Therapies •  Because of its biologic activity, altered expression of

PDGF-BB has been associated with concerns of potential tumor promotion

•  Emerging data appear to provide reassurance about the safety of rhPDGF-BB

–  Animal data

–  Bone grafts with rhPDGF-BB

–  DFU epidemiologic studies

Mantur M, et al. AdvMed Sci. 2008; 53:37-41. Yu J, et al. J Biochem Mol Biol. 2003;36:49-59.

Safety of PDGF-Based Therapies

•  Reported adverse events and cancers in clinical trials using rhPDGF-BB/β-TCP combination products

•  Augment® Bone Graft

–  Resorbable synthetic bone substitute made of pure beta-tricalcium phosphate (β-TCP) (1000-2000 µm)

–  rhPDGF-BB solution (0.3 mg/mL)

•  Approved in 2009 for foot and ankle fusions

Solchaga LA, et al. J Tissue Eng. 2012;3:2041731412453577.

Reported Adverse Events and Cancers in Clinical Trials Using rhPDGF-BB/β-TCP Combination Products

Solchaga LA, et al. J Tissue Eng. 2012;3:2041731412453577.

Indication No. of Subjects (rhPDGF-BB + β-TCP/control)

Country Patients with Device-Related Adverse Events

Reported Cancers Comments

Periodontal defects 180 (121/59) USA 18 (10.0%) [13 (10.7%)/5 (8.5%)] 1

rhPDGF-BB + β-TCP: 0 (0.0%) β-TCP alone: 1 (1.7%) 1. Basal cell carcinoma

Distal radius fracture 40 (20/20) Sweden 0 (0%) 0 (0%)/0 (0%) 0 ‒

Foot and ankle arthrodesis 60 (60/0) Canada 4 (6.7%)

[4 (6.7%)/‒ (‒)] 1 Augment: 1 (1.7%) 1. Colon cancer

Foot and ankle arthrodesis 10 (10/0) Canada 0 (0%)

[0 (0%)/‒ (‒)] 0 ‒

Hindfoot and ankle arthrodesis 20 (14/6) USA 0 (0%)

[0 (0%)/0 (0%)] 0 ‒

Hindfoot and ankle arthrodesis (submitted to J Bone Joint Surg)

414 (272/142) USA Canada

12 (2.9%) [6 (2.2%)/6 (4.2%)] 5

Augment: 3 (1.1%) 1. Prostate cancer 2. Prostate cancer 3. Infiltrating lobular carcinoma Autograft: 2 (1.4%) 1. Renal carcinoma 2. Endometrial cancer

Foot and ankle arthrodesis 108 (108/0)

Netherlands Belgium Austria France

6 (5.6%) [6 (5.6%)/‒ (‒)] 0 ‒

Total 832 (605/227) 40 (4.8%) [29 (4.8%)/11 (4.8%)] 7 rhPDGF-BB + β-TCP: 4 (0.7%)

Control: 3 (1.3%)

Cancer Studies: i3 Study •  Postmarketing follow-up (cohort) study

–  1622 becaplermin users and 2809 nonusers in yearly propensity score matches from Ingenix (Optum360® Coding) Research Data Mart (1998-2003)

–  Followed for an average of 20 months with cases confirmed by medical charts and cancer deaths from National Death Index

–  1622 PDGF group: 28 confirmed cancers and 9 cancer deaths

–  2809 control group: 43 confirmed cancers and 16 cancer deaths

ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00518102. Accessed April 22, 2014. Seeger JD, et al. Pharm Drug Safety. 2007;16:S167‐S168. Ziyadeh N, et al. Adv Skin Wound Care. 2011;24:31-39. Optum360Coding.com. https://www.optum.com/life-sciences/technology/clinformatics-data-mart.html. Accessed March 29, 2016. Centers for Disease Control and Prevention. Data Access. National Death Index. http://www.cdc.gov/nchs/ndi.htm. Accessed March 29, 2016.

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Cancer Studies: i3 Study (cont)

•  Postmarketing follow-up (cohort) study –  1622 becaplermin users and 2809 nonusers in yearly propensity

score matches from Ingenix (Optum360® Coding) Research Data Mart (1998-2003)

–  Followed for an average of 20 months with cases confirmed by medical charts and cancer deaths from National Death Index

NMS = non-melanoma skin; RR = relative risk; CI = confidence interval. ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00518102. Accessed April 22, 2014. Seeger JD, et al. Pharm Drug Safety. 2007;16:S167‐S168. Ziyadeh N, et al. Adv Skin Wound Care. 2011;24:31-39. Optum360Coding.com. https://www.optum.com/life-sciences/technology/clinformatics-data-mart.html. Accessed March 29, 2016. Centers for Disease Control and Prevention. Data Access. National Death Index. http://www.cdc.gov/nchs/ndi.htm. Accessed March 29, 2016.

Becaplermin Users Comparators Adjusted RR

No. /1000 No. /1000 RR 95% CI All cancers 28 10.5 43 9.2 1.2 0.7-1.9 NMS cancer 19 7.1 43 9.3 0.8 0.5-1.4 Cancer deaths 8 3.0 8 1.7 0.9 0.7-1.3

No increased risk of incident cancer or cancer death overall

Extension of i3 Study

•  Continued follow-up of original study sample for cancer deaths for up to 9 years

Ziyadeh N, et al. Adv Skin Wound Care. 2011;24:31-39.

Cancer Becaplermin Users Comparators Adjusted RR

Deaths No. /1000 No. /1000 RR 95% CI

Any 9 1.0 16 1.0 1.1 0.5-2.4

3+ tubes dispensed 4 2.0 16 1.0 2.4 0.8-7.4

Risk estimate for cancer death decreased and was no longer statistically significant

VA Study

•  Observational, retrospective, cohort study of patients with diabetes mellitus who were eligible for care through the VA system

–  DEpiC includes >2 million patients (1998-2012)

–  Included VA patients from 1999-2007 with DFUs and no prior cancer

–  Becaplermin users and becaplermin nonusers followed up to 11 years

•  Primary outcome: Number and rate of cases of incident cancers in patients who have used becaplermin vs patients who have not used becaplermin

–  Grouped as NMS cancer, all other invasive cancers combined, and site-specific cancers

•  Secondary outcome: Number of becaplermin doses associated with risk of incident cancer and/or cancer death

VA = veterans affairs; DEpiC = Diabetes Epidemiology Cohorts database. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01235260.

VA Study: Becaplermin and Cancer

•  Study sample consisted of 6429 becaplermin users and an equal number of matched unexposed control subjects (N=12,858)

•  This sample was used for evaluating the risk of cancer death

Per personal correspondence with Donald Miller.

VA Study Design

•  Follow-up study of veterans in VA care from 1999-2007

–  Limited to those with foot ulcers and no prior cancer

–  Followed through 2009 (up to 11 years)

•  Becaplermin initiators compared with matched comparators

–  Random sample of other patients in VA care on initiation day, matched on survey participation, sex, age, prior amputation, treatment of diabetes mellitus, and frequency of VA and Medicare visits

•  Identified in follow-up

–  Incident cancer: Confirmed in reviews of charts and pathology reports by trained nurse abstractors

–  Cancer deaths: Identified in National Death Index searches ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01235260. Centers for Disease Control and Prevention. Data Access. National Death Index. http://www.cdc.gov/nchs/ndi.htm. Accessed March 29, 2016.

VA Study: Incident Cancer Risks

•  Multivariable Cox regression with adjustment for demographics, healthcare use, cancer screening, physical examination and laboratory tests, comorbidities, medications, other foot ulcer treatment, as well as survey data on the duration of diabetes mellitus, tobacco and alcohol use, diet, physical activity, military exposures, education, and employment

HR = hazard ratio. Per personal correspondence with Donald Miller.

Survey Sample

Becaplermin Comparison Cox Regression Models 1507 1507 Unadjusted Fully Adjusted

Person- years Cases Person-

years Cases HR 95% CI HR 95% CI

NMS cancer 7045 65 7077 62 1.05 0.74-1.49 1.02 0.64-1.61

Other malignancies 6929 163 6976 161 1.02 0.82-1.26 1.06 0.83-1.36

Risk estimates are close to 1.0 with narrow CIs for risk of incident skin cancer and other cancers

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VA Study: Incident Cancer Risks

NMS=non-melanoma skin Per personal correspondence with Donald Miller.

Survey Sample Cancer Type

Becaplermin Comparison Cox Regression Models

1507 1507 Fully Adjusted

Person-years Cases Person-

years Cases HR 95% CI

NMS 7045 65 7077 62 1.02 0.64-1.61

All cancer, except NMS 6929 163 6976 161 1.06 0.83-1.36

Malignant melanoma 7285 2 7268 5 – –

Lip, oral, or pharynx 7276 6 7278 8 0.58 0.11-3.09

Digestive organs 7215 40 7199 47 1.00 0.62-1.62

Respiratory 7255 44 7244 32 1.53 0.92-2.54

Genitourinary organs 7109 52 7159 49 1.13 0.73-1.75

Lymphatic/hematopoietic 7246 15 7266 11 1.07 0.20-5.74

No increased risk of incident cancer at any specific site

Results: Incident Cancers Malignancies Other Than NMS Cancer


Inci

dent

Can

cer

1.00

0.95

0.90

0.85

0.75

0.80

0 1000 2000 3000 4000 5000

Kaplan-Meier Curves

Time from Baseline (days)

VA Study: Study Sample

No significant difference

in cancer incidence between groups

Becaplermin Initiators Comparison Patients

Results: Incident Cancers NMS Cancer (Basal Cell, Squamous Cell)




VA Study: Study Sample


Inci

dent

Can

cer

1.000

0.975

0.950

0.925

0.900 0 1000 2000 3000 4000 5000

Kaplan-Meier Curves


Results: Cancer Deaths


VA Study: Total Sample




Can

cer D

eath

1.000

0.975

0.950

0.925

0.900 0 1000 2000 3000 4000 5000

Kaplan-Meier Curves


VA Study: Cancer Death Risks


No increased risk for cancer death, overall, and at any specific site

Total Sample Cancer type

Becaplermin Comparison Cox Regression Models

6429 6429 Fully Adjusted



All cancer, except NMS 29,798 197 29,232 206 0.94 0.76-1.18

Malignant melanoma 29,799 1 29,233 1 – –

Lip, oral, or pharynx 29,799 8 29,233 3 – –

Digestive organs 29,799 56 29,233 69 0.77 0.51-1.15

Respiratory 29,799 74 29,233 78 1.04 0.73-1.48

Genitourinary organs 29,799 22 29,233 12 1.79 0.79-4.04

Lymphatic/hematopoietic 29,799 16 29,233 12 1.13 0.47-2.71

VA Study: Cancer Death Risks by Dose


Compare i3 study signal of 5.2 (1.7-17.6) with

No evidence for increased risk in any pre-specified subgroup or with higher becaplermin dose

Total Sample Subgroups All malignancies (except NMS)

Becaplermin Comparison Fully Adjusted Cox Models



Subgroups Peripheral neuropathy 17,116 104 13,087 87 0.92 0.67-1.27 Prior amputation 7422 54 7052 57 1.26 0.79-2.00 Insulin treatment 17,379 88 15,278 92 0.96 0.69-1.34 No Medicare use 17,322 99 17,043 107 0.87 0.64-1.18

Person-years Cases Cases/1000

Person-years HR 95% CI

Becaplermin Dose None (Comparison) 27,455 182 6.6 1.00 – 1 tube 11,852 58 4.9 0.73 0.50-1.05 2 tubes 6912 48 6.9 1.05 0.71-1.55 3 or more tubes 9285 67 7.2 1.04 0.73-1.48

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Safety of PDGF-Based Therapies •  Because of its biologic activity, altered expression of

PDGF-BB has been associated with concerns of potential tumor promotion

•  Emerging data appear to provide reassurance about the safety of rhPDGF-BB

–  Animal data

–  Bone grafts with rhPDGF-BB

–  DFU epidemiologic studies

Mantur M, et al. AdvMed Sci. 2008; 53:37-41. Yu J, et al. J Biochem Mol Biol. 2003;36:49-59.

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