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ProThelial™Driving down the cost of mucositis care

Ricky W. McCullough MD MSc
Medical Director, MMI

The Bottom Line By rapidly reversing mucositis in 2-3 days(1), or by preventing it(2) entirely, ProThelial™ reduces the cost of mucositis care by $6,928 - $29,418* per course of chemo-radiation therapy.

* Hard costs 2002 Medicare dollars

1. McCullough RW. Oncology Discovery Journal 2014. Review Polymerized Cross-linked Sucralfate Paste (ProThelial™) http://www.hoajonline.com/journals/pdf/2052-6199-1-7.pdf
2. Mucositis Registry Phase IV Post-Marketing Surveillance Trial. Center for Translational Medicine Research. Mueller Medical International LLC

http://www.hoajonline.com/journals/pdf/2052-6199-1-7.pdf

What is ProThelial™?FDA Indications

FDA Cleared Medical Device
510K 123904
UPC 33801-125-04

ProThelial™ Sucralfate Malate Paste forms a protective layer over the oral mucosa by adhering to the mucosal surface, which allows it to protect against further irritation and relieve pain. The paste may be used in the management of mouth lesions of all types including aphthous ulcers, stomatitis, and mucositis.

Therapeutic UsesUsed by Radiation Oncologists 
TO PREVENT both Oral and Esophageal Mucositis
Used by Medical Oncologists 
TO TREAT Oral & Esophageal Mucositis
TO TREAT Chemo-induced Diarrhea

! US Patent 5,447,918 US Patent 5,968,906 US Patent 7,795,239 Other Pending Patents

What is Mucositis?• A Toxic Side Effect of Chemo-radiation therapy for cancer affecting

400,000 patients annually

• An Epithelial breakdown in the lining of Oral & GI mucosa • Patients with many types of cancer contract mucositis but especially

• Myelosuppressed patients: 59.5% get oral mucositis, 18.9% get GI mucositis, 21.6% get both1

• Head/neck cancer patients: 91% get oral mucositis, 66% get grade 3-4 mucositis2

• Bone marrow transplant patients: 100% get oral mucositis, 89% get grade 3-4 mucositis3

5

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Symptoms None Oral soreness Painful ulcers and swellingAlmost

unbearable pain

Life-threatening consequences to airways and

esophagus

Signs None Redness, painless ulcers

Patchy ulcerations and

psuedo-membranes

Confluent ulcerations Tissue necrosis

Functions Can swallow Able to swallow solidsOnly swallow

soft solids and liquids

IV hydration and tube feeding

Feed tube dependent, IV hydration and TP required

What Does Mucositis Look Like?

When a cancer patient contracts oral mucositis, the cost of care** increases by

• $10,900/4 cycles – $16,350/6 cycles per episode of Grade 1 & 2 oral mucositis ($2,725 per cycle)

• $22,260/4 cycles – $33,390/6 cycles per episode of Grade 3 & 4 oral mucositis ($5,565 per cycle)


When a cancer treatment patient contracts gastrointestinal (GI) mucositis the cost of care doubles to

• $20,956/4 cycles – $31,434/6 cycles per episode of Grade 2-4 GI mucositis ($5,239 per cycle)

Mucositis Costs by the Numbers

**2002 Medicare dollars

0

25

50

75

100

April May June July

Current formulary options INCREASE costs while providing INFERIOR patient outcomes

MUGARD®, Episil®, Gelclair®, Caphasol®, Magic Mouthwash and Kepivance® drive UP the cost of care, while still unable to alter the 60-70 day5 course of mucositis.

0

25

50

75

100

April May June July

ProThelialTM Provides DECREASED Costs with SUPERIOR Patient Outcomes

ProThelial™ drives down or eliminates the cost of mucositis care, being associated with 2-3 day reversal or complete prevention of mucositis, thereby eliminating the 60-70 day** course of mucositis.

Other Mucositis Treatments Fall ShortKepivance® ($4,000) does not eliminate Grade 1, 2, 3 or 4 Mucositis • Reduce the occurrence of Grade 3 mucositis from 98% to 68% • Reduce the occurrence of Grade 4 mucositis from 68% to 20% • Cannot prevent or treat Grade 1, Grade 2 Mucositis • Cannot eliminate Grade 3, Grade 4 !

Other Remedies (Rinses) ($200-$500) per box-bottle • Only target the discomfort of ulceration • Reduce the discomfort by 30%, but cannot eliminate it • Do not target the mucositis process • Cannot treat or prevent Grade 1, Grade 2 Mucositis • Cannot treat or prevent Grade 3, Grade 4 Mucositis


Covering ProThelial™ ( $3,972) allows insurers to • eliminate the $10,900 - $33,390 of added cost which they now pay

to manage oral mucositis with their current formulary. !

Superior Patient Outcomes from its FDA Cleared Use • ProThelial™ is associated with the reversal of oral mucositis in 2-3

days • ProThelial™ is associated with complete prevention


Superior Patient Outcomes from an Off Label Therapeutic Action • ProThelial™ is associated with reversal of GI mucositis in 2-3 days

Savings Occur With ProThelial™ Because

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Standard Sucralfate IS NOT Polymerized Cross-Linked Sucralfate

Standard Potency Sucralfate Polymerized Sucralfate Polymerized Cross-Linked Sucralfate

Single Molecular Sucralfate Sucralfate sheets hydrogen bonded Sucralfate sheets are cross-linked

Hydrated and held apart by water By multi-dentated chelators Cross linking by chelatable cations

Remains mostly dissolved in solution with incomplete mucosal

coating

● Sheets of Sucralfate, less in solution ● More Sucralfate available for layering ● More complete Mucosal Coating

● Pi – Stacking3 (pancaking) Sheets of Sucralfate ● Fastening layer upon layer ● 3 Hour following dosing 


Seven-fold greater coating on normal lining; 23-fold greater coating on ulcerative lining

Technology in US Patents 5,447,918 ▪ 5,968,906 ▪ 7,795,239 ▪ other pending applications

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How Does ProThelial Work?Growth Factor Dependent Immuno-modulation

● High Affinity Binding of Growth Factor (GF) 5, 6,7
● Enhanced GF Receptor Expression 8
● GF Receptor Site Activation-Dependent Responses
 ● Rapid Cellular Regeneration (Healing) 9
 ● Secretion of PGE, Mucus, Bicarbonate 10 
 ● GF-Dependent de-excitation of IEL 11-14 
 ● Reversal of Mast Cell-activated Submucosal Neurons 15-17
 ● Down-regulation of neurogenic nausea, cramping, diarrhea 18, 20

Reverse Depolarization of Ion-Gated Receptors● Multi-layered Sucralfate Sheets Cause Smothering Micro-environments Around /Ion Voltage Gated Switches of

Receptors
Turning Off Receptor Switches, which 
Turns Off What the Switch is Responsible for in the GI Tract
● Acid Pain stops, Nausea Stops, Cramping stops 20-22

1. KASHIMURA K, OZAWA K. Sucralfate Preparations. US Patent 5,968,906. Oct 19, 1999. 
2. MCCULLOUGH RM. Saccharide Compositions and Method of Use. US Patent 7,795,239. Sept 14, 2010 3. MA JC, DOUGHERTY DA. The Cation-Pi stacking interaction (1997) Chem Rev 97:1303-1324. 4. GLASZIOU P, CHALMERS I, RAWLINS M, MCCULLOUCH P. When are randomized trials unnecessary? Picking signal from noise. BMJ Feb (2007) 334:349-351 
5. VOLKIN DB, VERTICELLI AM et al: Sucralfate and soluble sucrose octasulfate bind and stabilize acidic fibroblast growth factor. Biochimica et biophysica acta (1993) 1203(1): 18-26. 
6. JONES LS, YAZZIE B, MIDDAUGH CR: Polyanions and the proteome. Mol Cell Proteom (2004) 3:746-769. 7. ORNITZ DM, HERR AB NILSSON M, et al: FGF binding and FGF receptor activation by synthetic heparin-derived di- and tri-saccharides. Science (1995) 268:432-436. 
8. KONTUREK SJ, KONTUREK JW, BRZOZOWSKI T, BRONISLAWL, SLOMIANY BL, SLOMIANY A. Effects of Sucralfate on Growth factor availability. Chap 17. Pg 175-185. In Sucralfate: From Basic Science to the Bedside, edited by Hollander D, Tygart GNJ. Plenum Press, New York, 1995. 9. TARNAWSKI A, HOLLANDER D, STACHURA J et al: Effect of sucralfate on the normal human gastric mucosa. Endoscopic, histologic, and ultrastructural assessment. Scan J Gastroenterol (1987) 22 (suppl 127): 111-123. 10. HOLLANDER D, TARNAWSKI A, KRAUSE W et al: Protective effect of sucralfate against alcohol-induced gastric mucosal injury in the rat. Macroscopic, histologic, ultrastructural, and functional time sequence analysis. Gastroenterol (1985) 88(1Pt2): 366-374. 
11. SHANAHAN F: Intestinal lymphoepithelial communications.AdvExp Med Biol (1999) 473:1-9. 12. MCKAY DM, PERDUE MH: Intestinal epithelial function: the case for immunophysiological regulation. Implications for disease. Dig Dis Sci (1993) 38(9): 1735-45; 13. PERDUE MH, MCKAY DM: Integrative immunopathology in the intestinal mucosa Am J Physiol (1994) 267: G151-65. 
14. BERIN MC, MCKAY DM, PERDUE MH: Immune-epithelial interactions in host defense. Am J Trop Med Hyg (1994) 60(4Suppl): 16-25. 15 LEON A, BURIANI A, TOSO RD et al: Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci USA (1994) 91: 3739–3743 16. BAUER O, RAZIN E: Mast cell-nerve interactions. New Physiol Sci (2000) 15: 213-218. 
17. Barbara G, Stanghellini V, Degiorgio R. Neuro-immune interactions in the colonic mucosa of IBS patients. Gastroenterol 2000;118:A138. 18. HOLZER P, SCHICHO R, HOLZER-PETSCHE U, et al: The gut as a neurological organ. Wien Klin Wochenschr 113(17-18): 647-660, 2001. 
19. HOLZER P: Gastrointestinal pain in functional bowel disorders: sensory neurons as novel drug targets. Expert Opin Ther Targets (2004) 8(2): 107-123. 20. Yunjong Lee, Chang-Hun Lee, and Uhtaek Oh: Painful Channels in Sensory Neurons. Mol. Cells (2006) 20(3) : 315-324 
21. TEBROCK HE, Fisher MM: Nausea and vomiting: Evaluation of an orally administered phosphorylated carbohydrate solution. Med Times 82(4): 271-275, Apr 1954 22. SUGIURA T, DANG K, LAMB K et al: Acid-sensing properties in rat gastric sensory neurons from normal and ulcerated stomach. J Neurosci 25(10): 2617-2627, Mar 2005.

References