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LIFESCI ADVISORS October 26, 2010

CorMedix Inc. Initiation of Coverage

We are initiating coverage on CorMedix Inc. Our research Andrew I. McDonald, Ph.D.
describes CorMedix’s two lead pipeline candidates, Neutrolin (415) 205-0591
(CRMD003) for the prevention of Catheter-Related Blood andrew@lifesciadvisors.com
stream Infections slated to enter a Pivotal trial in 1H11 and Shiri Wallach, Ph.D.
shiri@lifesciadvisors.com
Deferiprone (CRMD001) for the prevention of Contrast
Tyler Van Buren, M. Sc.
Induced Nephropathy, currently in a phase II trial initiated in tyler@lifesciadvisors.com
2Q10 and Phase III DEFEND-AKI trial projected to
commence in 2H2011.

Neutrolin (CRMD003) Pivotal Phase III Trial. CorMedix Ticker CRMD


is planning to initiate a Pivotal trial evaluating Neutrolin as a Price $1.43
catheter lock solution for the prevention of Catheter-Related
Bloodstream Infections (CRBIs) in approximately 400 End- Market Cap (M) $16
Stage Renal Disease (ESRD) patients. The study will consist EV (M) $6
of randomized 1:1 patients receiving Neutrolin vs. the active
Shares Outstanding (M) 11.4
comparator heparin as a lock solution. The primary endpoints
are freedom from CRBI and maintenance of useable catheter Avg. Daily Vol. 7,283
life. The Neutrolin program is expected to be expedited due 52-week Range: $0.40-$4.00
to the upcoming submission of an Investigational Device
Exemption (IDE) application and potential approval from the Cash (M) $10.6
Food and Drug Administration (FDA) expected by the end of Net Cash/Share $0.93
1Q2011.
Debt (M) $0.0
Neutrolin Proof of Concept Data. A feasibility study Annualized Cash Burn (M) $6.0
evaluating Neutrolin (n=20) (1.35% Taurolidine plus 4% Years of Cash Left 1.8
citrate) versus 5000u/ml heparin (n=30) in patients
demonstrated a very low incidence of CRBIs in the Neutrolin Short Interest (M) 6.42
arm when used for a 90 day time period. The study protocol Short Interest (% of NA
evaluated two main endpoints: the primary endpoint was the Float)
occurrence of CRBIs and the secondary endpoint included
the need for tPA instillation and/or catheter exchange to FY Dec 2009A 2010
restore catheter patency. The study demonstrated that CRBI-
free survival at 90 days was significantly higher among EPS: Q1 ($1.37)A ($6.40)A
patients who received Neutrolin when compared to control (GAAP) Q2 ($1.42)A ($0.10)A
patients who received Heparin (94% vs. 47%; p<0.001).
Q3 NA NA
Neutrolin Market Opportunity. CRBI rates are generally Q4 NA NA
reported to be approximately 2.5 to 5.5 cases/1,000 catheter-
days or roughly 0.9 to 2.0 events/patient-year. On an FY NA NA

annualized basis, the previous statistics translate into 67,500

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previous statistics translate into 67,500 to 150,000 cases of CRBIs. Of these cases, approximately
10% (7,000 to 15,000) of the patients will require hospitalization with serious complications
including severe sepsis or metastatic infections. 1 The overall cost for treating CRBIs was estimated
by Allon in 2008 to be $777MM comprised of $466MM and $311MM for inpatient and outpatient
treatments, respectively.2

Deferiprone (CRMD001) Phase II. Deferiprone is an iron chelator being developed for the
prevention of Contrast-Induced Nephropathy (CIN) in patients with Chronic Kidney Disease.
Deferiprone is currently approved for sale in 50 countries worldwide (excluding the U.S.) for the
treatment of iron overload in patients with Thalassemia Major. The Company is currently
conducting a phase II trial (started in 2Q2010). The phase II data is expected to be completed prior
to the initiation of the phase III trial in 2H2011. The double-blind, randomized, placebo-controlled
study is estimated to include approximately 60 patients and the primary endpoint is biomarker
evidence of Acute Kidney Injury (AKI) to assess Deferiprone’s efficacy compared to placebo after 8
days of treatment.3

Deferiprone (CRMD001) DEFEND-AKI Phase III trial. The phase III trial of Deferiprone is
anticipated to start in 2H2011 and will include up to 800 patients for the assessment of Deferiprone
in CIN. The study will consist of patients randomized 1:1 to Deferiprone vs. placebo and will only
include subjects with moderate-severe CKD and other risk factors for CIN. The procedure and the
composite endpoints will be evaluated during a 90-day period.

Financial Outlook. CorMedix is currently conducting a Phase II clinical trial for CRMD001 and
expects to initiate a pivotal Phase III clinical trial for CRMD003 in 1H011 and does not anticipate
revenues in the near future. CorMedix believes its currently available cash and cash equivalents will
be sufficient to meet its planned clinical development and operating requirements through the end
of the first quarter of 2012.

2Q10 Financials. For the six months ended 6/30/10, CorMedix reported no revenue and $4.9MM
in operating expenses, of which, $3.7MM was for R&D related expenses. In the comparable period
in 2009, CorMedix also generated no revenues and $1.3MM of operating expenses (R&D expense
of $0.5MM). The Company generated a net loss of $8.0MM in the first half of 2010 compared to a
net loss of $2.3MM in the comparable period in 2009.

2009 Financials. In FY 2009 CorMedix reported no revenue and operating expenses of $6.1 MM,
comprised of $4.9MM of R&D expenses and $1.2MM of general and administrative expenses. In
July 2006, CorMedix was granted from Shiva an exclusive, worldwide license agreement for a patent
estate covering proprietary formulations of Deferiprone and a biomarker diagnostic test for
measuring levels of labile iron. Pursuant to this agreement, the Company expensed $3.2MM in 2009.

Cash Position. As of June 30, 2010 CorMedix had $10.6MM of cash and cash equivalents and no
long-term debt. Cash increased $9.1MM in the first half of 2010 to $10.6MM, primarily reflecting
proceeds from the public equity offering in March 2010. Specifically, the Company’s IPO resulted in
the sale of 1.9 MM units (consisting of two shares of common stock and a warrant to purchase one

1 Am J Kidney Dis 2004;44:779-91


2  AmJ Kidney Dis 2008;51:165-8
3 clinicaltrials.gov, study NCT01146925

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share of common stock) at $6.50/unit, or $3.125 per share and $0.25/warrant. In conjunction with
the IPO, all of CorMedix’s outstanding convertible notes were converted into equity.

Expected Upcoming Milestones


Neutrolin (CRMD003) Milestones

• 4Q 2010: Investigational Device Exemption (IDE) application submission


• 1H 2011: CE (CE means European Conformity) marketing in Europe (EU)
• 1H 2011: Initiation of Pivotal trial for prevention of Catheter-Related Bloodstream
Infection (CRBI) in hemodialysis patients
• 2H 2011: Potential product launching in Europe
• 1H 2012: Release of preliminary data from Pivotal Phase III clinical trial
• 2H 2012: File Premarket Approval (PMA) application in the U.S
• 1H 2013: FDA approval of Neutrolin (CRMD003)

Deferiprone (CRMD001) Milestones

√ 2Q 2010: Deferiprone Phase II: proof-of-concept trial initiated


• 1H 2011: Phase II data from Deferiprone study
• 2H 2011: Phase III DEFEND-AKI clinical trial (prevention of Contrast-Induced
Nephropathy in patients with Chronic Kidney Disease) – Expected to begin
• 2H 2012: Release of data from Phase III DEFEND-AKI trial
• 4Q 2012: File for New Drug Application (NDA) for Deferiprone (CRMD001)
• 2H 2013: FDA approval of Deferiprone (CRMD001)

Company Description

CorMedix Inc. (“CorMedix,” “CRMD,” or the “Company”) was incorporated on July 28, 2006 in the
State of Delaware. In 2007, the Company established its corporate headquarters in Summit, New
Jersey. CorMedix is a pharmaceutical company that seeks to develop significant medical therapies for
unmet cardiorenal medical needs. CorMedix products target the overlap market of kidney (renal)
and cardiac diseases. The Company’s two leading products are:

1. Neutrolin (also referred to as “CRMD003”), which is a drug/device combination


product candidate, that serves as a catheter lock solution for the prevention of Catheter-
Related Bloodstream Infection (CRBI) and catheter dysfunction.
2. Deferiprone (also referred to as “CRMD001”), which is a pharmaceutical drug
candidate, used to reduce morbidity and mortality associated with Contrast-Induced
Nephropathy (CIN) in high-risk Chronic Kidney Disease (CKD) patients undergoing
invasive cardiac procedures (including the injection of iodinated contrast agents).

The Company has a number of products in the pipeline, including CRMD004 and CRMD002.
CRMD004, a thixotropic gel, may be used for the prevention of CRBI and maintenance of catheter
function in hemodialysis patients. CRMD002, another product developed by CorMedix, is a
biomarker assay for “toxic labile iron” in urine samples. Both product candidates are in preclinical
research stages. This report focuses on the two lead programs, CRMD001 and CRMD003. These
two products are being developed for the nephrology and cardiovascular markets, and aim to assist
in the prevention of CRBI and prevention of CIN and its associated morbidity and mortality.

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Neutrolin (CRMD003): A New Catheter Lock Solution
Neutrolin, one of CorMedix’s core product candidates, is being designed as a drug/device for
hemodialysis patients with Central Venous Catheters (CVCs). It has completed pilot clinical studies
and is expected to enter a Pivotal trial in 1H11. Neutrolin is designed to be used as the standard of
care in hemodialysis patients who require CVCs. CVCs are permanently implanted in the patients’
central veins allowing vascular access to enable rapid in-flow and out-flow of blood from the patient
through a dialysis machine in order to filter the blood from harmful wastes, salts and fluids.
Approximately 82% of patients initiating hemodialysis treatment in the U.S. in 2006 started using a
CVC as the functioning access4 . Another vascular access for hemodialysis used regularly is an
arteriovenous fistula (AV fistula). AV fistula is the connection of a vein and an artery, usually in the
forearm, to allow access to the vascular system for hemodialysis. Although most hemodialysis
patients start with CVCs, over 50% will go through the surgical procedure to connect a vein and
artery to obtain an AV fistula as their vascular access5 . The hemodialysis process is typically initiated
when the patients’ kidneys are functioning at 10-15% capacity. In this therapy, the patients’ blood is
drawn out of the body into a dialysis machine and filtered prior to returning it back into the body.
This therapy requires a lifelong commitment of visiting dialysis centers and hospitals (some patients
have a home dialysis machine), on average 3 times a week for 4 hours per session6 .

Unmet Medical Need: Prevention of CRBIs. The use of CVCs in hemodialysis patients may
result in two severe complications: Catheter-Related Bloodstream Infection (CRBI) and low blood
flow, due to blood clots within the tubing of the catheter. Approximately 250,000 CVC-associated
CRBIs occur in hospitals each year in the United States according to the Center for Disease Control
and Prevention (CDC), of which approximately 160,000 are hemodialysis related. The mean rate of
CVC-related CRBIs in dialysis patients is reported to be 5.0/1,000 catheter days7 . CRBI increases
morbidity and mortality among hemodialysis patients. These mortality and morbidity rates can reach
2,400-20,000 deaths per year with estimated hospitalization costs of $296 million to $2.3 billion for
CRBI in general8. Hemodialysis-related CRBIs’ mortality rate is estimated to be 6,000 deaths per
year9. Due to the aforementioned statistics and the increasing number of CVCs used in hospitals,
there is a critical need for the development of preventative strategies to reduce the rate of CRBIs.

Neutrolin Catheter Lock Solution for Prevention of CRBIs. The two main complications
associated with CVCs are CRBIs and thrombotic events. Neutrolin was developed as a catheter lock
solution to address these major complications by preventing CRBIs and blood clotting within the
catheter. The solution has to be inserted into the two lumens of a CVC at the end of the
hemodialysis session in order to reduce the risk for CRBI and catheter thrombosis10 . By reducing the
infection risk, the solution can prolong catheter life, as well as reduce the need for local or systemic
antibiotic regimens. The Neutrolin solution acts against strains of Methicillin-Resistant
Staphylococcus Aureus (MRSA), Methicillin-Resistant Staphylococcus Epidermidis (MRSE) and
Vancomycin-Resistant Enterococcus (VRE). These infections are common in healthcare facilities
(e.g. dialysis centers) due to the compromised immune system of the involved patients. Moreover,

4 Kidney Int 2009;76:1040-8


5 Encyclopedia of Surgery
6 The American Association of Kidney Patients (AAKP)
7 Infez Med 2010;18:79-85
8 Emerg Infect Dis 2001;7:197-9
9 CorMedix’s Presentation
10Clin Infect Dis 2003;36:1539-44

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the Neutrolin catheter lock solution contains an antimicrobial agent, not an antibiotic, which reduces
the risk of promoting bacterial resistance to the commonly used antibiotics.

Currently, physicians insert more than five million CVCs every year to patients beyond those
receiving hemodialysis. Other Neutrolin-related applications and secondary markets would likely
include chemotherapy, chronic antibiotic therapy, total parenteral nutrition and intensive care. The
estimated cost for CRBI treatment is $18,000 per episode as it requires approximately 12 days of
hospitalization.

Mechanism of Action (MOA): Antimicrobial and Anticoagulant Activity. The key


components of Neutrolin include: 1.35% Taurolidine (the antimicrobial and antifungal agent), 3.5%
citrate and 1000u/ml Heparin (the anticoagulant agent).

The antimicrobial Taurolidine (Chemical Abstracts Service (CAS) number 19388-87-5was


synthesized in the 1970s by Geistlich-Pharma, Inc. Early studies revealed the broad range of
antibacterial and fungal activity that taurolidine possesses. Taurolidine has been used to treat patients
with peritonitis and systemic inflammatory response syndrome due to its anti-endotoxin properties.
Additionally, Taurolidine demonstrates potential anti-tumor properties for the treatment of cancer.
It is currently manufactured and approved for use in Europe as an antimicrobial lock solution
(Taurolock) which contains Taurolidine (1.35%) for the prevention of CRBIs. The compound
becomes active when the molecule breaks into active methylol groups during a chemical reaction,
which is secondary to the decomposition of the parent molecule as demonstrated in (Figure 1).
These methylol groups contain moieties that react with and damage bacterial cell wall components
preventing adhesion of the affected microorganism to biological surfaces (such as CVC). 11 In
addition to this direct effect on bacterial cell wall components, Taurolidine has been reported to
prevent biofilm formation on catheters. 12

Figure 1: Chemical Structure of Taurolidine and its Major Breakdown Products

Source: Cancer Res 2001;61:6816-21

11 Cancer Res 2001;61:6816-21


12 J Pediatr Gastroenterol Nutr 2008;47:179-86

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CVCs are vital life sustaining devices used in many complex medical situations, including
hemodialysis. Infections remain the most problematic complication associated with CVC devices.
CRBI can be caused via different pathways; including the device itself, skin insertion or from a
distant septic location.

Studies report that an average of 4-6 infections occur in hemodialysis patients per 1000 catheter
days. 13 Since blood clotting provides a risk to hemodialysis patients, the Taurolidine is supplemented
with 3.5% citrate solution and 1,000 u/mL heparin. In addition to the anticoagulant activity, citrate
improves Taurolidine’s solubility and anti-microbial activity. The current standard of care catheter
lock solution is heparin at a concentration of 1000 u/mL. The concentration of heparin has been
significantly reduced in the past eight years due to a high incidence of bleeding that occurs with
higher concentrations of heparin. The US Food and Drug Administration (FDA) now recommends
a citrate concentration of 5% or less following the death of a patient inadvertently given 43% citrate
solution.

Pre-clinical Data. One of the mechanisms in which Neutrolin reduces CRBIs is by preventing
biofilm formation. Biofilms are complex structures containing matrix proteins, extracellular DNA,
and polysaccharides synthesized by bacteria that attach to the surface of hydrated polymeric
matrixes such as CVCs. The presence of biofilm on the surface of CVC creates a potential entryway
for bacteria to penetrate the patients’ bloodstream. The formation of these attached bacterial
communities and their inherent resistance to antimicrobial agents promotes many persistent and
chronic bacterial infections, particularly CRBIs. Neutrolin is highly effective in reducing biofilm
formation; which in turn lowers the incidence of CRBIs. As one can see in Figure 2, Neutrolin
blocks very efficiently the growth of biofilm on catheter surfaces when compared to untreated or
heparin treated surfaces. 14

Figure 2: Scanning Electron Microcopy Images of Biofilm Formation on Catheter Surfaces


Using Different Treatment Methods

Source: Blood Purif 2002;20:87-92and Company Reports

13 J Pediatr Gastroenterol Nutr 2008;47:179-86


14 Blood Purif 2002;20:87-92

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Neutrolin and Deferiprone, CorMedix’s two main product candidates, have untapped potential to
penetrate the cardiorenal disease space, particularly patients suffering from Chronic or End Stage
Kidney Disease. Chronic Kidney Disease (CKD) is characterized by the loss of kidney function that
can deteriorate into a severe condition called End-Stage Renal Disease (ESRD) in which either
hemodialysis or kidney transplantation is required. ESRD patients are at high risk for CRBIs, while
CKD patients are at high risk of Contrast Induced Nephropathy (CIN) and its complications.
CorMedix’s product candidates are being designed to address unmet medical needs and help patients
avoid these severe and debilitating complications.

CHRONIC KIDNEY DISEASE BACKGROUND


Chronic Kidney Disease (CKD) is a growing heath concern due to the rise in prevalence of the
disease. According to the National Kidney Foundation, 26 million adults have CKD and millions of
others are at increased risk. Early detection and prompt treatment can help prevent disease
progression and kidney failure. Heart disease is the major cause of death for CKD patients. CKD is
characterized by damage to the kidneys, which are organs that act as a natural blood filter, remove
waste such as urea and ammonium as well as controlling fluid balance by removal of salt and water.
CKD is defined as a persistent reduction in glomerular filtration rate (GFR) to <60mL/min/1.73m
or the presence of kidney damage, such as proteinuria or chronic glomerulonephritis. The disease
has been classified into 5 stages of increasing severity (Figure 3). Disease classifications assist in
evaluating screening recommendations and treatment.

Figure 3: CKD Disease Classification

Stage Associated GFR (ml/minute/1.73m2)

1 >90 with persistent kidney damage*

2 60-80 with persistent kidney damage*

3 30-59

4 15-29

5 <15
*Kidney damage includes both functional damage (proteinuria,
glomerulonephritis) and structural damage (polycystic kidneys).
GFR, glomerular filtration rate
Source: Am Board Fam Med 2010; 23:542-50

Disease Causes & Risk Factors. The two main causes for CKD are diabetes mellitus and high
blood pressure. These are responsible for two-thirds of disease cases. In addition to these high-risk
co-morbidities, CKD can intrinsically be caused by renal diseases, such as polycystic kidney disease
or glomerulonephritis (a condition that causes inflammation and damage to the kidney’s filtration
units). Approximately 33% of CKD cases are caused by diabetes in which type 2 is increasingly
prevalent. The disease is highly correlated with the onset of diabetic retinopathy due to both
diseases’ close correlations to microvascular disease. The second most common cause of CKD is
vascular diseases, particularly hypertension (about 21% of CKD cases). The long period of poorly
controlled hypertension can cause many organs to fail. Other CKD causes include nephrotoxic

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medication, systemic lupus and genetic syndromes (see Figure 4 for more details). In addition to
these causes, some non-modifiable risk factors are associated with disease progression, which
include age, African-American race and male sex.

Figure 4: Potential Causes of CKD


Diagnosis Clinical Indicators
Classical clinical course of microoalbuminuria, followed by clinical proteinuria,
Diabetes mellitus
hypertension and then declining GFR
Usually characterized by severely elevated blood pressure readings over a long
Hypertension
period with associated end-organ damage in the addition to kidney disease
Nephrotoxic Review prescribed and over-the-counter medications as well as intravenous contrast
medications dye or gadolinium exposure
Systemic lupus Evaluate for photosensitivity, malar/discoid rashes, oral ulcers, arthritis, serositis,
erythematosus neurological symptoms, hematological findings, ANA/dsDNA positive
HIV nephropathy Signs and symptoms of immunodeficiency; HIV positive on testing
Signs and symptoms of heart failure present. Because fluid overload is common in
Congestive heart
chronic kidney disease, diagnosis is made through echocardiogram to evaluate
failure
systolic and diastolic heart function
Genetic syndrome Evaluation of family history is suggestive
History of evidence of cirrhosis with resultant portal hypertension, ascites, and
Hepatorenal syndrome
renal vasoconstriction. Classically lack significant proteinuria
Evaluate for history of hematuria and symptoms of renal colic. Long standing
Nephrolithiasis
obstruction can cause permanent renal impairment
Benign prostatic Evaluate male patients for hesitancy, straining, or weak flow during urination and
hypertrophy nocturia, confirm with prostate exam
Broad category of disease including postinfectious (streptococcal) as well as various
Glomerulonephritis
vasculitisdisease. Urinalysis suggestive with presence of red blood cell casts
GFR, glomerular filtration rate, ANA, antinuclear antibodies; dsDNA, double stranded deoxyribonucleic acid; HIV,
human immunodeficiency virus
Source: Am Board Fam Med 2010;23:542-50

CKD Symptoms and Treatment. Symptoms might not appear in the early stages of the disease;
however some may experience weakness and exhaustion, trouble concentrating and sleeping, muscle
cramping and swollen feet and ankle and frequent urination. Treatment for CKD focuses on slowing
the progression of the kidney damage, usually by controlling the underlying cause. In order to halt
disease progression, the following modifiable risks should be under close monitoring: higher levels
of proteinuria, lower serum albumin levels, high blood pressure, poor glycemic control and smoking.

Proteinuria detection and control is crucial for slowing disease progression and kidney damage;
therefore, screening random samples of urine for quantification of the ratio of protein-creatinine
used in the identification of proteinuria, is essential. In the case of proteinuria, Angiotensin
Converting Enzyme (ACE) inhibitors should be applied as first line medication. Angiotensin
Receptor Blocker (ARB) is another medication used in combination or as an alternative for ACE.15

Blood pressure control is important in the care of CKD patients. ACE inhibitors and ARB are also
used as a medication for hypertension. However, in most cases, additional medications such as
diuretics are needed as well. The National Kidney Foundation suggests a blood pressure goal of <
125/75 mm Hg. Other controls include glycemic level monitoring, which is essential for halting

15 Am Board Fam Med 2010;23:542-50

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disease progression. The targeted glycated hemoglobin level is <7.0 for all diabetic and CKD
patients.

Hemodialysis and End-Stage Renal Disease (ESRD). CKD can progress to end-stage kidney
disease, which is fatal without artificial filtering (dialysis) or a kidney transplant. The most severe
stage of CKD patients (Stage 5) is called End-Stage Renal Disease (ESRD), in which patients
require kidney transplantation or dialysis. The incidence of ESRD patients increased to 527,283 in
2007 (according to Kidney and Urologic Diseases Statistics for the United States reported by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)) and it is on the rise.
There are two main types of dialysis: hemodialysis and peritoneal dialysis. Both types filter the blood
to free the body from harmful waste, extra fluid and salts. Hemodialysis uses an external
hemodialysis machine (or an artificial kidney) to filter the blood, while peritoneal dialysis uses the
lining of a patient’s abdomen, called the peritoneal cavity, to filter the blood inside the body.

Central Vein Catheters (CVC) and Therapeutic Options. Hemodialysis treatment requires
vascular access. Approximately 75,000 (25% out of 300,000 hemodialysis patients in the U.S)
patients undergoing dialysis treatment using Central Vein Catheters (CVC)16 while waiting for
alternatives such as AV fistula or graft which are more permanent vascular access devices that
require surgical procedures (Figure 5). CVCs can be placed into large veins in the neck (internal
jugular vein), chest (subclavian vein) or groin (femoral vein) to allow vascular access for
hemodialysis. Catheter-related bloodstream infections (CRBIs) and associated complications are
common and increase the morbidity and mortality rate in CKD patients undergoing chronic
hemodialysis treatments.

Figure 5: Types of Vascular Access for Hemodialysis

Source: Company Report and the U.S Food and Drug Administration (FDA) and National Kidney and Urologic
Disease Information Clearinghouse

Limitations of CVCs due to Catheter-Related Bloodstream Infections. CVCs, originally


introduced as a vascular access for short-term dialysis, have become an acceptable and frequently
used form of permanent vascular access. The different types of intravascular catheters currently

16 Am J Kidney Dis 2008;51:165-8

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being used are summarized in Figure 6. The main two factors limiting the long-term use of
hemodialysis catheters are poor flow and Catheter-Related Bloodstream Infections (CRBIs). CRBIs
are most often related to the development of a bacterial biofilm that forms in the catheter lumen.
These Biofilms are hard to treat with systemic antibiotics and require catheter removal in some
cases, which in turn reduces catheter patency and terminates one of the very few vascular access
points for hemodialysis patients.

Figure 6: Type of Intravascular Devices and Summary of Their Use


Type of
Intravascular Comment
Device
Peripheral venous Usually inserted into the veins of the forearm or the hand; the most commonly
catheter used short-term intravascular device.
For short-term use; commonly used to monitor hemodyanamic status and to
Peripheral arterial
determine blood gas levels of critically ill patients; risk of bloodstream
catheter
infection may approach that of CVCs
Peripheral catheter (size, 7.6–20.3 cm) is inserted via the antecubital fossa into
Midline catheter the proximal basilic or cephalic veins, but it does not enter central veins; it is
associated with lower rates of infection, compared with CVCs
Most commonly used CVC; accounts for the majority of all catheter-related
Short-­‐term CVC
bloodstream infections (in the general patient population)
Pulmonary artery Inserted through a teflon introducer and typically remains in place for an
catheter average duration of only 3 days
Pressure-monitoring Used in conjunction with arterial catheter; associated with both epidemic and
system endemic nosocomial bloodstream infections
Provides an alternative to subclavian or jugular vein catheterization; is inserted
Peripherally inserted via the peripheral vein into the superior vena cava, usually by way of cephalic
central catheter and basilar veins; similar risk of infection as CVCs in patients hospitalized in
intensive care units
Surgically implanted CVC (e.g., Hickman, Broviac, or Groshong catheter) with
the tunneled portion exiting the skin and a dacron cuff just inside the exit site;
Long-­‐term CVC
used to provide vascular access to patients who require prolonged
chemotherapy, home-infusion therapy of hemodialysis
A subcutaneous port or reservoir with self-sealing sptum is tunneled beneath
Totally implantable
the skin and is acessed by a needle through intact skin; associated with low rates
device
of infection
*CVC, central venous
catheter
Source: Clin Infect Dis 2009;49:1-45

Substantial efforts have been made to prevent CRBIs. These preventative approaches include several
modalities including: tunneling of CVC, cuffing of the catheter, topical antibiotics or antimicrobial
agents (povidone iodine, mupirocin, and bacitracin zinc and polymyxin B sulfate ointments) and
instilling an antimicrobial solution into catheters’ lumen [Antimicrobial Lock Solution (ALS)] have
been assessed as a means to prevent CRBIs (Figure 7). Some of the topical approaches, particularly
silver coating of tunneled catheters, cannot prevent biofilm formation and thus are not effective in

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reducing CRBIs. 17 Additionally, antibiotic resistance can be induced by a repeatable administration of
antibiotic-based catheter lock solutions into the patients system, which is not an optimal method for
preventing CRBIs.

Figure 7: Studies for the Prevention of CRBIs in Hemodialysis Patients


Study Design/ No. of Experimental/
Intervention Control Infection rate (1,000 d) Red (%)
Source control
Ointment Control Int  

R, OL Johnson, Mupirocin No 85 #
27/23 10.5 1.6
2002 ointment ointment
p<0.01

R, DB Polysporin Placebo 76 #
86/83 4.1 1
ointment ointment
Lok, 2003 p<0.0001
Silver-coated catheter
R, OL Silver-coated Standard
47/44 1.1 1.8 0
Trerotola, 1998 catheter catheter
Lock Solutions
R, DB Dogra, 93 #
Gentamicin/citrate Heparin 53/55 4.2 0.3
2002
P=0.002
NR 89 #
Taurolidine/citrate Heparin 20/30 536 0.6
Allon, 2003 p<0.001
R,OL 100
Taurolidine/citrate Heparin 37/39 2.1 0
Betjes, 2004 p=0.047
Subcutaneous device
R, 0L Schwab, Tesio
Clorpactin 36/34 3.3 3.4 0
2002 catheter
NR 62
Isopropyl alcohol Clorpactir 34/34 3.4 1.3
Schwab, 2002 P<0.05
*Analysis is restricted to tunneled dialysis catheters
**Abbreviations: R, randomized; OL, open label; DB, double blinded
# Statistical significant from the control
NR, nonrandomized; Int, intervention; Red, Reduction.
Source: Am J Kidney Dis 2004;44:779-91

The majority of antibiotic lock solutions are comprised of either a single antibiotic or a
combination, including Gentamicin, Minocycline/EDTA, Cefotaxime, Cefazolin, and Vancomycin.
These antibiotic agents are frequently combined with Heparin or citrate for anticoagulant purposes.
Although all appeared to lower the risk for CRBI, clinicians and the Centers for Disease Control are
concerned with the use of routine antibiotics for CRBI prophylaxis due to microbial resistance and

17 Clin Infect Dis 2008;47:83-93

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loss of drug efficacy over time. Other concerns include systemic absorption and subsequent adverse
events due to the high dosages of antibiotics.

Other antimicrobial lock solutions include sodium citrate (citrate) and Taurolidine, which are
antimicrobial but not antibiotic agents. Taurolidine is an antimicrobial agent with a wide range of
activities against Gram-positive and Gram-negative organisms, anaerobes, and fungi. Studies
evaluating the use of Taurolidine citrate lock solution (taurolidine 1.35%, citrate 4%) have shown a
significant decrease in CRBI incidence. 18

The instillation of an antimicrobial solution into the catheters’ lumen at the end of each
hemodialysis session assists in the prevention of intra-luminal bacterial colonization and biofilm
formation19. Labriola et al., reported a meta-analysis of prospective, randomized controlled trials to
measure the efficacy of Antimicrobial Lock Solution (ALS) for the prevention of CRBIs compared
with standard Heparin lock solution. The analysis concluded that the risk of CRBIs was reduced by
a factor of 3 when ALS was used in hemodialysis patients (Figure 8). Other meta-analysis
documented similar findings, which emphasizes the potential associated with the implementation of
ALS into routine hemodialysis clinical practice20 . Antibacterial/antimicrobial lock solutions have
been extensively investigated as preventive measures for CRBIs. CRBI remains a significant
challenge due to the increasing number of CVCs in use and the morbidity and mortality associated
with CRBIs.

Figure 8: Incidence of CRBIs Included in the Meta-Analysis


CRBIs (episodes per 1000 catheter-days)  
ALS Control RR (95% CI) Source
0(0.5) 2.65 0.058 (0.01-0.46) Dogra, 2002
0.308 4.049 0.076 (0.01-0.42) McIntyre, 2004
0(0.5) 2.122 0.155 (0.02-1.35) Betjes, 2004
0(0.5) 0.472 0.453 (0.04-5.69) Bleyer, 2005
1.067 4.066 0.263 (0.13-0.54) Weijmer, 2005
1.672 3.607 0.463 (0.31-0.69) Saxena, 2006
0(0.5) (a) 4.037 0.062 (0.01-0.5)
Nori, 2006
0.408 (b) 4.037 0.101 (0.02-0.58)
0.44 3.119 0.141 (0.02-0.81) Kim, 2005
Source: Nephrol Dial Transplant 2008;23:1666-72

18 Clin Infect Dis 2003;36:1539-44


19 Nephrol Dial Transplant 2008;23:1666-72
20 Clin Infect Dis 2008;47:83-93

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CRBI BACKGROUND
Infection is the second most common cause of death in hemodialysis patients. The relative risk of
CRBI-related morbidity and mortality is 2 to 3 fold higher among catheter-dependent hemodialysis
patients compared with those using fistulas or grafts.21 Due to repetitive infections and the current
treatment with antibiotics, some microorganisms associated with dialysis related infections are
becoming more resistant to antibiotics. Most catheter related bloodstream infections emanate from
the insertion site, hub, or both. In addition to the risks associated with the bloodstream infection,
infections reduce catheter patency, which requires additional access sites for hemodialysis.

CRBI rates are estimated at 5 episodes per 1,000 catheter days in non-tunneled catheters and
approximately 3.5 episodes per 1,000 catheter days in tunneled catheters. Non-tunneled catheters
have a higher CRBI event rate but are not used for chronic access in hemodialysis. Tunneled
catheters are used frequently in hemodialysis and have a cuff that stimulates tissue growth and
assists in holding the catheter in place. Additionally, these tunneled dialysis catheters have 2 ports,
which translates to 12 connections and disconnections weekly (based on 3 hemodialysis sessions per
week). Each connection is vulnerable to contamination and subsequent CRBIs. According to Allon,
infection rates are estimated at approximately 2.5 to 5.5 cases/1,000 catheter-days or 0.9 to 2.0
cases/patient-year. These translate into 67,500 to 150,000 annual cases of CRBIs. Approximately
10% (7,000 to 15,000) of these patients will be hospitalized with serious complications, including
severe sepsis or a metastatic infection (Figure 9). 22

Figure 9: Frequencies and Complications of CRBIs in Hemodialysis Patients


Frequency of Metastatic Infection Severe Sepsis Source
Bacteremia
(1,000 patient-days) (%) (%)
3.9 22 NA Marr et al, 1997
5.5 3.5 5.8 Saad, 1999
3.4 3.2 NA Beathard, 1999
NA 8.7 10.1 Tanriover et al, 2000
2.5 - - Mokrzycki et al, 2000
5.4 9.7 8.1 Krishnasami et al, 2002
2.4 - - Stevenson et all, 2002
2.5 - - Schwab et al, 2002
2.7 - - Dogra et al, 2002
2.5 - - Lok et al, 2003
4.6 4.4 2.9 Poole et al, 2004
*NA = Not available
**Frequency of Bacteremia = Total # of Catheter-related Bacteremia Episodes/ Total Catheter Days
Source: Am J Kidney Dis 2004;44:779-91

Even more significantly, more than 150 million intravascular devices are purchased each year by
hospitals and clinics in the U.S as reported by the Infectious Disease Society of America. These

21 Am J Kidney Dis 2004;44:779-91


22 Am J Kidney Dis 2004;44:779-91

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devices are used extensively for the administration of intravenous fluids, medication, blood
transfusions and parenteral nutrition. Additionally, statistics from the Center for Disease Control
and Prevention (CDC) indicate that approximately 250,000 CVC-associated CRBIs occur in
hospitals each year in the United States alone. Femoral catheters have the highest infection rates
when compared with jugular or subclavian catheters. 23

Bacterial biofilm, which is a major source of CRBIs, can form rapidly in central venous catheters.
The prevention of biofilm formation might assist in reducing CRBIs. Bacteria within biofilm are
relatively resistant to antibiotics, but are generally susceptible to high concentration of antibiotics
(100-fold higher than plasma antibiotics levels) and other antimicrobial agents such as taurolidine,
30% citrate and 70% ethanol24. Neutrolin uses both taurolidine and citrate in its formulation to
prevent bacterial biofilm from forming in CVCs.

Infections can be identified based on the microorganisms causing them. The most common causes
of CRBI are Gram-positive cocci, aerobic Gram-negative bacilli and Candida albicans. CRBIs are
not infrequently associated with more severe complications including endocarditis, osteomyelitis,
septic arthritis and septic pulmonary embolism. These complications significantly increase the
morbidity and mortality rates in this patient population.25

Symptoms. Exit site infections might be a cause of CRBI. Symptoms of catheter exit site infection
can be pain as well as erythema and purulent drainage. On the other hand, CRBI will manifest
systemic symptoms (primarily fever and rigors in hemodialysis patients) and might advance into
more severe complications and metastatic infections as noted above (Figure 10).

Figure 10: List of CRBI Symptoms


Local Infection Systemic Infection
Fever
Local inflammation
Rigors when the line is used
Discharge around the line
Erythema Tachycardia
Metastatic infection
Pain
Source: The British Society of Antimicrobial Chemotherapy

Diagnosis. According to Clinical Practice Guidelines for the diagnosis and management of
intravascular catheter-related infection: 2009 Update published by the Infectious Diseases Society of
America, the diagnosis of CRBI generally requires cultures from both the catheter as well as
peripheral blood. The samples will be paired and analyzed for accurate diagnosis prior to
antimicrobial treatment (Figure 11).

23 Infez Med 2010;18:79-85


24 Am J Kidney Dis 2008;51:165-8
25 Infez Med 2010;18:79-85

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Figure 11: Methods for the Diagnosis of Suspected CRBI (CFU, Colony-Forming Units)

Source: Clin Infect Dis 2009;49:1-45

Infection Treatment. The Infectious Disease Society of America (IDSA) issued guidelines for the
treatment of CRBIs in multiple patient populations; including patients undergoing hemodialysis
(Figure 13). The treatment for CRBIs includes parenteral antibiotics and removal of infected
hemodialysis catheters under specific clinical situations (see Figure 12 for suggested indication for
catheter removal). 26 Despite achieving adequate plasma therapeutic levels, systemic antibiotics have
low salvage rates in hemodialysis catheters. Systemic antibiotics fail to diffuse in sufficient
concentrations inside the catheter lumen where bacterial seeding might originate. Subsequently,
removal of the catheter in these cases is unavoidable.

26 Clin Infect Dis 2009;49:1-45

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Figure 12: Suggested Indication for Hemodialysis Catheter Removal
Persistence of fever and positive blood cultures while being on appropriate antibiotics for
36–48 hours.
Recurrence of fever and bacteraemia despite adequate dosage and duration of systemic
antibiotic administration.
Exit site infections extending to catheter tunnel with severe sepsis.
CRBI associated with hypotension or signs of cerebral hypoperfusion.
Septic thrombosis of great veins as determined by a Doppler flow study.
Infective endocarditis and systemic septic embolisation.
* Based upon NKF-DOQI Clinical Practice Guidelines for vascular access-update, 2000,
National Kidney Foundation, New York.
Source: Swiss Med Wkly. 2005;135(9-10):127-38

Treatment guidelines are dependent upon specific microbial identification and antibiotic sensitivity.
However, empirical antibiotics should be based on anticipated cause of infection and local
microbiologic surveillance cultures and sensitivities, which will assist in treatment determinations.

Figure 13: Guidelines for Treatment of Catheter-Related Bloodstream Infection

Source:Clin Infect Dis 2009;49:1-45

Suitable regimens of antimicrobial treatments for common causes of CRBIs are specified in Figure
14. Additionally, in the case of Staphylococcus aureus infections there is a need for immediate and
sufficient duration of antibiotic therapy. The therapy needs to be adequate enough to prevent
relapse or possible metastatic complications.

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Figure 14: Antimicrobial Treatment Regimens
Antimicrobial Strain Treatment Recommended
Methicillin-resistant Staphylococcus A glycopeptide such as vancomycin, with or without
aureus (MRSA) another anti-staphylococcal antibiotic
Methicillin-sensitive Anti-staphylococcal penicillin, such as flucloxacillin
Staphylococcusspp
Suitable agents include antipseudomonal cephalosporins,
Gram-negative organisms
aminoglycosides, or carbapenems
Source: The British Society of Antimicrobial Chemotherapy

CRBIs may be caused by a broad spectrum of bacteria including both Gram-positive and Gram-
negative. According to the treatment guidelines for dialysis catheter–related bacteremia, a substantial
proportion of staphylococcal infections in dialysis patients are methicillin-resistant. Initial antibiotic
treatment should include Vancomycin for Gram-positive bacteria and an aminoglycoside or third-
generation cephalosporin for treating Gram-negative bacteria. 27 However, when culture results
confirm the infecting organism, antibiotic therapy should be modified accordingly. The
recommended doses are shown in Figure 15. Antibiotic-based catheter lock solutions are a potential
strategy for improving catheter salvage following CRBI and preventing the reoccurrence of CRBIs.
The antibiotic lock technique improves the rate of catheter salvage following CRBI caused by some
types of infecting organisms.
.
Figure 15: Antibiotic Dosages for Hemodialysis Patients
Systemic Antibiotic Dosing Regimen
20-mg/kg loading dose infused during the last hour of the
Vancomycin dialysis session, then 500 mg during the last 30 min of
each subsequent dialysis session
Gentamicin (or tobramycin) 1 mg/kg, not to exceed 100 mg, after each dialysis session
Ceftazidime 1 g IV after each dialysis session
Cefazolin 20 mg/kg IV after each dialysis session
Daptomycin 6 mg/kg after each dialysis session
Antibiotic Lock
Volume of Solution (mL)
Type of Lock Solution
*Vancomycin Ceftazidime† Cefazolin† Heparin‡
Vancomycin/ceftazidime 1 0.5 — 0.5
Vancomycin 1 — — 1
Ceftazidime — 1 — 1
Cefazolin — — 1 1
*Vancomycin, 5 mg/mL (in normal saline solution).
†Ceftazidime and cefazolin, 10 mg/mL (in normal saline solution).
‡Heparin, 1000U/ml.
Source: Am J Kidney Dis 2009;54:13-7

27 Am J Kidney Dis 2009;54:13-7

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CRBI/CVC MARKET

Currently on the market are a few new devices to help fight CRBI including improved catheters such
as EverFlow Dolphin Protect and Centros. Since these products were launched in 2010, there is no
sales data publicly available. EverFlow Dolphin Protect, launched by Gambro in June 2010, is a
catheter combined with a new surface coating technology, antibacterial Bismuth additive, which
reduces the risk of CRBIs without the active release of antibiotics or other agents. EverFlow
Dolphin Protect is currently only available within the EEA (European Economic Area) and not in
U.S. Additionally, Ash Access Technology, Inc. partnered with AngioDynamics to launch Centros in
2010, which is an improved Central Venous Catheter (CVC) device for hemodialysis applications.
The company claims that the new device enhances blood flow catheter functionality due to new
technology and a unique configuration that allows centering of the catheter in the vein. The device
is approved for use in the U.S.

Although improved catheter devices are already on the market in the U.S, the two catheter lock
solutions are currently only approved in the EEA and not in the U.S. TauroLock and TauroSept are
both Taurolidine based catheter lock solutions. TauroSept is a catheter lock solution that is
comprised of 2% Taurolidine and has been on the market in Europe since 2006. TauroSept is
manufactured by Geistlich Pharma. The company initiated the patent for TauroSept in October
2004 for the expected duration of 10 years. This patent is not applicable in the U.S. TauroLock was
first introduced to the European market by TauroPharm GmbH as an antimicrobial lock solution
(Taurolidine and 4% citrate without Heparin). Recently, TauroLock formulations with heparin were
launched in Europe for patency and anticoagulant purposes.

There is a critical need in the U.S. for a locking solution that can prevent Catheter-Related
Bloodstream Infections (CRBIs) without promoting antimicrobial resistance or inducing an adverse
effect if infused systemically. Development of such an ideal solution would have a significant impact
on more than 75,000 catheter dependent hemodialysis patients in the U.S. The estimated current US
and global CVC market is presented in Figure 16.

Figure 16: The Estimated Current CVC Market


CVC Market Components
Estimated Number of CVCs Inserted in the Dialysis Setting in the US (2002)1 300,000
Estimated US CVC Sales in Dialysis Setting ($160/catheter and 300,000 $48 MM
insertions)2
Number of CVC Insertions in the General Setting in the US3 5 MM
Estimated US CVC Sales in General Setting in US ($160/catheter and 5MM $800 MM
insertions)
Total US Sales of CVCs (Dialysis and General Setting, estimated) $848 MM
ROW Sales (estimated) $1000 MM
Estimated Global CVC Market $1,848 MM
1 http://www.ashaccess.com/resources/cvcds.html

2 http://www.allegromedical.com/browse/browseProducts.do?searchPhrase=Central+Venous++catheter

3N Engl J Med 2003;348:1123-33


Source: LifeSci Advisors Estimates

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The economic impact of treating CRBIs in the dialysis population in the US has been estimated to
be $777MM, of which, ~$466MM is attributed to inpatient treatment and ~$311MM is attributed to
outpatient treatment. This calculation assumes a CVC dialysis population of 81,000 (~27%
hemodialysis patients use catheters), an infection rate of 2 episodes per patient per year, that 20% of
infections require hospitalization at a cost of $14,448 per patient, and that 80% of infections can be
treated in an outpatient setting at a cost of $2,414 per patient.28 Using these somewhat dated
estimations adjusted for the recent and expected growth of the hemodialysis population, the cost of
treating CRBIs is depicted in Figure 17. In our model, we assumed 15% growth in the dialysis
population and that approximately 93k dialysis patients will receive a CVC each year. We also assume
an infection rate of 2 episodes per patient per year and the total cost (inpatient and outpatient) of
treating this group is estimated to be $1.0B annually. A significant reduction of the overall healthcare
cost could be realized if an antimicrobial lock solution reduced CRBI occurrence by 50%, for
example. Our estimated market opportunity for Neutrolin is represented in Figure 17. With
approximately 93k dialysis patients receiving a CVC during 3 dialysis sessions per week, the total
number of sessions eligible for Neutrolin is 14.5MM annually in the US. Assuming an average cost
of $30.00 per session, Neutrolin faces a $436MM market opportunity in the US. If Neutrolin can
reduce the rate of CRBIs by greater than 50%, the price of therapy should be offset by the overall
cost savings to the system.

Figure 17: Neutrolin Market Opportunity


Estimated Cost of Treating CRBIs  
Estimated Number of Dialysis Patients 345,000
No. of Dialysis Patients with CVC (27% of Dialysis Patients) 93,150
CRBI Rate Per Patient Per Year 2
Inpatient Treatment Cost (20% of infections at $16.6k/patient) $619MM
Outpatient Treatment Cost (80% of infections at $2.8k/patient) $413MM
Total Treatment Cost Associated with CRBIs (estimated) $1,032MM

Estimated Neutrolin Market Opportunity (US)


No. of Dialysis Patients with CVC (27% of Dialysis Patients) 93,150
No. of HD Sessions (3 times per week) per Year 14.5MM
Estimated Neutrolin Price per Session $30.00
Estimated US Market for Neutrolin $436MM
Source: LifeSci Advisors Estimates

PRODUCTS MARKETED FOR CRBIs

Unlike Neutrolin that is a catheter lock solution used to fill the catheter lumen, other product/device
uses an antimicrobial built in the catheter. These devices (catheter with/out antibiotics) are marketed
for short term catheter use and can have potential safety concerns such as low tolerance for high
flow rates, leakage of antibiotic/antimicrobial solutions into the systemic circulation, long term
prophylactic antibiotic exposure that in turn can promote antibiotic-resistant infections.

28 Am J Kidney Dis 2008;51:165-8

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Centros (Ash Access) is a long term CVC for hemodialysis that is designed to reduce frequent flow
failure, recirculation and clotting. The catheter is manufactured by Ash Access Technologies, but
AngioDynamics holds the exclusive license for this product. In June 2007, the FDA granted 510(k)
clearance for Centros.

EverFlow Dolphin Protect (Gambro). It is a hemodialysis catheter that made from a reactive
copolymer coating technology that mimics the natural surface of cells or proteins. The designed
polymer surface and coating reduces blood activation, helps prevent the catheter’s biodegradation
and provides higher blood flow rates. The technology integrates the antibacterial Bismuth additive
into the surface coating of the catheter. This reduces the risk of catheter-related infections and
other associated complications and increases catheter patency. Although the product is
manufactured by Gambro, which is a global medical technology company, it is approved for use only
within the European Economic Area (EEA). Gambaro has many leading products and therapies for
kidney and liver dialysis, myeloma kidney therapy, and other extracorporeal therapies for Chronic
and Acute patients.

TauroSept (Geistlich Pharma AG). It is a Taurolidine (2%)-based catheter lock solution used in
the prevention of catheter sepsis. TauroSept prevents bacterial and fungal growth and biofilm
formation in the catheter lumen, as well as maintaining catheter function. It is marketed for both
home and in-center dialysis use and has broad antimicrobial activities. It is designed to be
administrated before and after dialysis sessions. TauroSept was initially marketed by Gambro, but
due to an unexpected occurrence of catheter malfunction, they decided to stop distribution of the
product. TauroSept is currently manufactured by Geistlich PharmaAG which is made up of three
business units: Geistlich Biomaterials (dental), Geistlich Surgery (orthopedics) and Geistlich Medical
(pharmaceuticals, OTC, hydrogels). TauroSept is available for sale in Europe only and not in U.S.

TauroLock (TauroPharm) is a lock solution (Taurolidine and 4% citrate without Heparin)


launched by TauroPharm GmbH in Europe and Middle East. It has been used as a catheter lock
solution in hemodialysis patients, in intensive care patients and in oncology patients receiving
chemotherapy. Several small studies using TauroLock have reported promising results relative to the
reduction of CRBI, although an increase in catheter malfunction was noted in some centers. In
November 2007, TauroPharm launched two new products called TauroLock Heparin 500 and
TauroLock Heparin 100 to address the issue of catheter dysfunction.

CorMedix holds a License Agreement with NDP (ND Partners LLC) for Neutrolin solution and a
Polaschegg License Agreement since January 2008. Currently, CorMedix is sponsor of the
Neutrolin® Investigational Device Exemption (which is the formulation used in TauroLock) in the
U.S.

Although no other catheter lock solutions are presently on the market, companies such as Ash
Access and Great Lakes Pharmaceuticals are in developmental stages for competitive products.

Neutrolin Clinical Data Discussion: Prevention of Catheter-Related


Bloodstream Infections
Neutrolin was initially under development by Biolink Corp. who conducted the initial preclinical
testing and the feasibility clinical trial. The results of the preclinical data demonstrated an acceptable
effectiveness and safety profile. The company applied for an Investigational Device Exemption
(IDE) request from the Food and Drug Administration (FDA) in 2003. The FDA approved the

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IDE, however the company filed for bankruptcy and the Neutrolin development was put on hold.
Biolink launched Neutrolin in the European Union (EU) under a CE mark (CE means European
Conformity). After Biolink's bankruptcy in 2003, TauroPharm reintroduced the product, initially in
Europe and the Middle East. CorMedix investigated the composition of TauroPharm and added
1000u/ml Heparin to the initial composition of 1.35% Taurolidine and 3.5% citrate solution. The
final solution includes Heparin as an anticoagulant, which would easily be anticipated to maintain
catheter patency.

The results of seven randomized clinical trials evaluating different antimicrobial agents indicated a
reduction in infection frequency by 50-100% when compared to patients receiving standard Heparin
locks (Figure 18)29. Other formulations of lock solutions contain antibiotics, which can result in
antibiotic-resistant infections if used long-term. Additionally, systemic toxicity is possible due to the
high antibiotic dosages used in some of these products and possible solution leaks from the catheter
to the bloodstream. Finally, some of the formulations do not include anticoagulant agents and thus
will not prevent thrombotic events within the catheter. The new formulation of Neutrolin (with
1000 u/mL heparin) addresses all of the major concerns associated with antibiotic lock solutions
and introduces a breakthrough product with antimicrobial and anticoagulant activity and without
antibiotics complications.

Figure 18: Summary of Frequency of Infections when Antimicrobial Lock Solutions Were
Used vs. Heparin Standard Locks.

Source: Am J Kidney Dis 2008;51:165-8

A proof of concept study with Neutrolin demonstrated a significant reduction in the rate of CRBI
when Neutrolin was placed into both limbs of a CVC at the end of each hemodialysis session.
Neutrolin reduced CRBI by approximately 90% in some of the studies used as a proof of concept
for Neutrolin. Examples of Neutrolin studies are summarized in Figure 19. Infection was defined
as a positive blood culture, which was the studies’ main endpoint.

29 Am J Kidney Dis 2008;51:165-8

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Figure 19: Studies with Neutrolin and its Efficacy in CRBI Prevention
CRBIs per 1000 Neutrolin:
Average
No. of catheter duration Catheter Days Control % of Catheter Source
(No. of patients) (days) (Neutrolin vs. Group Infection Dysfunction
control) Free

Catheter
Heparin removal: 2 Betjes,
76 (58) 158 0 vs. 2.1 (p=0.047) 5000u/ml 100 Heparin, 1 2004
Neutrolin
Sodemann
76 (76) 250 0.2 None 96 N/A poster,
2001
Unassisted
catheter
20/30 Neutrolin/ 0.6 vs. 5.6 (p<0.001) Heparin patency: 32% Allon,
85 94
Heparin 5000u/ml Neutrolin 2003
76% Heparin
(p<0.001)

Heparin Taylor,
~20/month 180 0.6 vs. 5.2 89 N/A
5000u/ml 2008

Source: CorMedix Company Report

Upcoming Neutrolin Pivotal Phase III Clinical Trial

CorMedix is in the process of submitting an Investigational Device Exemption (IDE) 30 application


to the Food and Drug Administration (FDA) for Neutrolin by the end of 2010. An approved IDE is
required before the company can start its clinical studies. The company is planning on launching a
Pivotal, double-blind, randomized, parallel arm, active comparator clinical study against Heparin
following approval of the IDE. This study is being designed to demonstrate the safety and
effectiveness of Neutrolin in preventing catheter-related blood stream infections (CRBIs) in addition
to maintaining catheter function and patency, in End-Stage Renal Disease (ESRD) patients.

Study Design. CorMedix is planning on conducting a Pivotal, prospective, multicenter, double-


blind, randomized, active comparator controlled study of approximately 400 ESRD patients to
demonstrate the safety and effectiveness of CorMedix Neutrolin (1.35% taurolidine, 4% citrate and
heparin 1000 u/mL) in preventing CRBIs and maintaining catheter function in patients receiving
hemodialysis therapy as treatment for ESRD. These patients receive an average of three sessions a
week. The study will utilize a tunneled silicone or polyurethane hemodialysis catheter that has
demonstrated an ability to deliver sufficient blood flow necessary for successful hemodialysis.
Patients can be enrolled with either incident catheters (catheters placed less than 14 days prior to
entry) or prevalent catheters. It is anticipated that the study will take approximately 15 months to

30http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/

InvestigationalDeviceExemptionIDE/default.htm

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complete (9 months recruitment, 6 months follow-up), with an expected product launch 12 to 15
months following the completion of the trial.

Phase III Anticipated Results/ Planned Endpoints. The study was designed and the sample size
calculated based on the assumption that Neutrolin will reduce the rate of CRBIs by 60%. The
planned study duration is 180 days, both for freedom from CRBI and useable catheter life, which are
the Co-primary endpoints for the study. Additional secondary efficacy endpoints include mortality,
infection rate per 1000 catheter days, patency rate and catheter removal rate per 1000 catheter days,
frequency of using thrombotic therapy (tPA) to restore catheter bloodstream access, freedom from
thrombotic therapy at 90 and 180 days and prevention of catheter blood flow and sufficient dialysis
treatment. The total study is estimated to cost $8MM.

ADDITIONAL STUDY DATA

The initial feasibility study was conducted by Michael Allon, who compared Neutrolin (1.35%
Taurolidine plus 4% citrate) in 20 hemodialysis (HD) patients with CVCs to a similar cohort of 30
HD patients using heparin (5000u/mL). This study recruited patients receiving long-term
hemodialysis using a tunneled CVC. There were two main endpoints: the primary endpoint was the
occurrence of CBSIs and the secondary endpoint included the need for tPA instillation and the
catheter exchange to restore catheter patency. The study results indicated that CRBIs-free survival at
90 days was significantly higher among patients who received Catheter Lock Solution (CLS) when
compared to control patients who received Heparin (95% vs. 47%; p<0.001). 16 out of 30 patients
in the heparin arm developed CRBI over the course of 90 days of follow up (compared with 1 out
of 20 in the CLS group). The results are shown in Figure 20.31

Figure 20: Effect of Catheter Lock Solution on Infection Free Survival

Citrate- Taurolidine Group- solid line


Heparin group- broken line

Source: Clin Infect Dis 2003;36:1539-44

The same study also evaluated catheter patency. An increased requirement for tPA was required in
the Neutrolin group to main catheter function, (32% vs. 76%; p<0.001), although there were not
more catheters removed due to catheter dysfunction32 (Figure 21).

31 Clin Infect Dis 2003;36:1539-44


32 Clin Infect Dis 2003;36:1539-44

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Figure 21: Effect of Catheter Lock Solution on Catheter Patency

Citrate- Taurolidine Group- solid line


Heparin group- broken line

Source: Clin Infect Dis 2003;36:1539-44

Another randomized prospective trial in which patients with dialysis catheters were administered
either heparin (n=39) or a Taurolidine/citrate (n=37) as a CLS was completed. Blood cultures were
drawn from the catheter lumen routinely every 2 weeks, at the time of suspected CRBI and at the
end of the trial. The primary end-point was CRBI, which was defined by a positive bacterial blood
culture results, and a second endpoint, which was defined by a positive bacterial colonization. The
results indicate a total of four CRBIs in the heparin control group in which three infections were
caused by Staphylococcus aureus and one by S. epidermidis. Infection rate for the heparin group was 2.1
per 1000 catheter days compared to no CRBIs reported for the citrate Taurolidine group (P = 0.047;
Figure 22).33
Figure 22: Prevention of CRBIs with Citrate Taurolidine Lock Solution

Citrate- Taurolidine Group- solid line


Heparin group- broken line

Source: Nephrol Dial Transplant 2004 ;19:1546-51

33 Nephrol Dial Transplant 2004 ;19:1546-51

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CRBI Drugs in Development and Competitive Landscape
Zuragen by Ash Access: (AAT-023) is comprised of 0.05% methylene blue, 7% sodium citrate at
pH 6.2, and parabens and is manufactured by Ash Access Technology. It is an antimicrobial (non-
antibiotic) and anticoagulant solution designed to prevent CRBI by reducing and eliminating biofilm
formation and maintaining catheter patency. Zuragen has completed a Pivotal clinical trial using
multiple centers and 415-patients.

Study Design: the Pivotal randomized multicenter study evaluated the effectiveness and safety of
Zuragen in reducing CRBIs in tunneled CVCs used for hemodialysis compared to the Heparin
group. The study endpoints include superiority over the Heparin group for CRBI and non-
inferiority for catheter function.

Study Method: Patients with End Stage Renal Disease (ESRD) received either randomized catheter
lock solution or the active comparator (heparin 5000 units/mL). The trial could not be blinded due
to the intense blue color of the Catheter Lock Solution (CLS). The primary endpoint was the
occurrence of CRBI, defined as concordant bacteria found in both the catheter and peripheral
blood combined with infection symptoms including temperature above 38 degrees Celsius34.

Results: The study was completed in 2008 with 407 participating patients; however study results are
not yet public. The Premarket Approval Application (PMA) was accepted by the FDA in May, 2009.
There may be issues related to infection rate and Methylene blue usage.

B-Lock by Great Lake Pharmaceuticals: This drug has antimicrobial and anticoagulant activity. It
is comprised of Minocycline, EDTA, and ethanol, and is in the early stages of development by
Great Lake Pharmaceuticals, Inc. Clinical trials were set to start in 2009. The company recently
received $2.4 million equity financing for the research and development of B-lock. Additionally in
July 2010 Great Lake Pharmaceuticals announced that they are planning on submitting an
Investigational Device Exemption (IDE) to the FDA and if approved, clinical trials will follow. The
main issue with this formulation is the use of Minocycline, which is an antibiotic agent that can
promote bacterial resistance with long term use.

34  clinicaltrials.gov, study NCT00628680

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Figure 23: Competitive Landscape for Neutrolin (CRMD003)
Product Company Mechanism Estimated Launch Comments
Currently the closest product for
Antimicrobial and
the prevention of CBSIs under
anticoagulant 2011/2012 but might
FDA review. Pivotal/phase III
Zuragen Ash Access Methylene blue + be delayed due to the
trials complited. There may be
parabens +citrate need for more studies
issues related to infection rate and
7%
Methylene blue usage.
The company discuss
pre Investigational
Minocycline + Device Exemption
Great Lakes
B-Lock EDTA + Ethanol (IDE) with the FDA. Contains an antibiotics
Pharmaceuticals
combination Clinical trials will
follow the submission
of IDE
This gel was under
phase III investigation
but did not exhibit
Omigananpenta-
Cadence superiority of Phase III Failed the product
Omigard hydrochloride 1%
Pharmaceuticals Omigard compared to development is discontinued
topical gel
povidone-iodine for
the prevention of local
catheter-site infections
Source: CorMedix Company Report and LifeSci Advisors

Omigard by Migenex par tner with Cadence Phar maceuticals. Omigard


(omigananpentahydrochloride (MBI 226) 1% topical gel) was developed for the prevention of
catheter related infections. Omiganan, a bactericidal and fungicidal cationic peptide was developed as
a topical gel for prevention of catheter-associated infections. This gel was under phase III (CLIRS)
investigation by Cadence Pharmaceuticals when it failed. The study’s original purpose was to
determine whether treatment with a topical Omiganan is more effective in the prevention of local
catheter infection/colonization in patients with Central Venous Catheters when compared to topical
providone-iodine therapy. The study was a randomized, double blinded multicenter with an
enrollment of 1,859 patients. The study endpoints include local site infection as the primary
endpoint and bacterial colonization as a secondary endpoint at 28 days time point 35.

Results: The Company’s results demonstrated a positive trend; however the study did not meet its
primary objective, which was to exhibit superiority of Omigard compared to povidone-iodine for
the prevention of local catheter-site infections. Therefore, Cadence has decided to discontinue the
development of Omigard. The results of the Omigard study are summarized in Figure 24. 36

35 clinicaltrials.gov, study NCT00231153


36 http://cadx.client.shareholder.com/releasedetail.cfm?ReleaseID=370462

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Figure 24: Omigard Study
Study Description Omigard phase III multicenter, double blinded, randomized sponsored
by Cadence Pharmaceuticals
Number of
1859
Patients
Control Povidone-iodine 10%
Primary efficacy endpoint was the incidence of local site infections in
Study Design/
Outcome Measure comparison to 10% providone-iodine. Secondary endpoint include
microbiologically confirmed local site infection and catheter colonization
Duration 28 days
Infection incidence was 6.3% for Omigard compared to 8.6% for patients
treated with providone-iodine (p=0.08). Microbiologically confirmed
local infection site measurements demonstrated 3.9% for Omigard
Results
compared to 7.6% for providone-iodine (p<0.01). Positive catheter
cultures incidence was 43.7% for Omigard compared to 55.1% for
providone-iodine (p<0.01)
Source: clinicaltrials.gov, study NCT00231153 & Cadence Pharmaceuticals

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Deferiprone (CRMD001): A Proven Oral Iron Chelator
Deferiprone (which is also referred to as CRMD001) is a well characterized oral iron chelator used
to reduce tissue-damaging oxidative stress caused by labile iron in the body. It is currently available
in over 50 countries around the world, excluding the U.S., as Ferriprox from ApoPharma Inc.
Ferriprox is indicated for the treatment of iron overload in patients with thalassaemia major when
deferoxamine (another iron chelator drug) therapy is contraindicated or inadequate.

Deferiprone’s initial proposed indication is to prevent Contrast-Induced Nephropathy (CIN).


Radiocontrast media is a well-known cause of acute kidney injury, and development of CIN is
associated with both renal and cardiovascular adverse events in high-risk patients with CKD. Since
many CKD patients have cardiovascular disease, the use of contrast agents in cardiac angiographic
procedures represents a high risk for these patients. Contrast exposure can cause severe damage to
the kidney, and CIN appears to increase the morbidity and mortality associated with heart attacks
and strokes. CIN has been reported in publications to be the third leading cause for hospital-
acquired renal failure.

CorMedix Deferiprone tablets are 900 mg doses and are formulated as separate immediate release
and extended release tablets. The intended dosage is one immediate release tablet and two extended
release tablets, twice a day for eight days, starting on the day of contrast exposure (angiographies).
The unique combination of one immediate release tablet and two extended release tablets resulted in
lower peak drug concentration (Cmax), reduced nausea, while allowing extended iron trapping for 12
hours.

Mechanism of Action (MOA): Deferiprone (DFP) (1,2-dimethyl-3-hydroxypyridin-4-one) is an


oral iron chelator that forms a stable 1:3 iron chelator complex that can be excreted from the body
in urine. DFP has a molecular weight of 139. After oral ingestion, DFP is quickly absorbed, with
peak plasma levels at 45–60 min. DFP is metabolized by glucuronidation37. Its affinity for iron is
greater than copper, aluminum, zinc, indium, gallium and uranium and other metals at physiological
(pH 7.4). It is also known to be a hydrophilic chelator, which means it forms more hydrophilic iron
complexes at physiological pH, more easily penetrates cells and subcellular organelles, and ensures
its rapid excretion with no accumulation in lipids.

Chelators are small molecules that bind very tightly to metal ions. These organic compounds, which
possess at least two ligands with electron donor atoms such as N, O and S, have an affinity for
binding metal ions (See Figure 25). The complex formed between the chelator and the metal ion is
very specific to the chelator used; since different chelators have different affinities to varying metal
ions. In addition, they also have specific physicochemical, pharmacological and toxicological
properties. The key role of chelators is to detoxify metal ions by binding to it. For instance, EDTA
is used to treat patients with extreme, life-threatening hypercalcemia. The iron chelator,
desferrioxamine, is used to remove excess iron that accumulates with chronic blood transfusions.

37Ann N Y Acad Sci 2010;1202:75-8

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Figure 25: Structure of Deferiprone and Deferiprone-Iron Complex

Deferiprone Deferiprone-iron Complex

Source: AntimicrobAgents Chemother2002; 46(6): 1741–1745 and TherClin Risk Manag 2007;3:795-805

The primary mechanisms leading to kidney injury, following contrast agent administration, include
both direct toxic effects of the dye and blood vessel spasms that lead to a reduction in tissue
oxygenation. The latter reaction can be thought of as a “mild heart attack” occurring in the kidney.
The secondary mechanism, leading to CIN, is the direct toxic effect of contrast agents on renal cells
and endothelial cells. Labile iron causes cellular injury, oxidative stress and mitochondrial
dysfunction. Using iron chelators, such as Deferiprone, reduces the concentration of labile iron and
oxidative stress, which in turn improves mitochondrial and endothelial function.

The most important side effect of DFP therapy is agranulocytosis, which is a failure of the bone
marrow to produce neutrophils, which can cause infection. Other side effects include arthropathy,
gastrointestinal symptoms and weight gain. Studies report 0.5%-3.6% incidences of agranulocytosis
post DFP treatment. Additionally, some cases report agranulocytosis and neutropenia, which are
reversible upon discontinuation of the drug (some patients needed stimulating factors treatment). 38
Agranulocytosis has not been reported with less than 14 days of dosing.

DFP’s role in reducing iron toxicity has been shown to provide heart protection. Studies have
demonstrated that patients on long-term treatment with Deferiprone have a better myocardial
magnetic resonance imaging pattern and less chance to develop or worsen cardiac disease. These
study results required a confirmation from randomized controlled trials, due to their case specific
retrospective observation.39

Many chelators are used in chemistry and industry. However, only a few chelators are approved for
clinical use since most have dangerous side-effects. Currently, there are no drugs approved by the
FDA to treat CIN specifically. However, there are three iron chelators on the market for other
treatment indications (only two in the U.S.). The current standard of care for prevention of CIN
includes hydration with saline or bicarbonate solutions. Other potential therapeutics include

38 Ann N Y Acad Sci 2010;1202:75-8


39 Ann N Y Acad Sci 2005;1054:169-74

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antioxidants and free radical scavengers, such as vitamin C and N-acetylcysteine, as well as
Prostaglandin E1, Theophylline and statins.

Pre-Clinical Data. The discovery of Deferiprone (DFP), a potentially effective oral iron chelator in
1985, led to the initiation of preclinical studies initially in animals and then humans with the first
publication of the use of DFP in 1987.

Multiple studies have shown that iron excretion was found to be about 25 mg per day in transfusion-
dependent patients. In these patients, the standard dose used was 75 mg/kg/day. 404142 Agarwal et al.
measured urinary iron excretion in thalassemia patients receiving various doses of DFP, ranging
from 25 to 100 mg/kg/day, and demonstrated an increasing amount of total iron excretion as the
dose increased (Figure 26).

Figure 26: Urinary Iron Excretion for Different Doses of Deferiprone

Source: TherClin Risk Manag 2007;3:795-805

Serum ferritin levels, detected by immunoassay technique, are another method to assess iron
overload after chelation therapy. Ferritins are a family of iron storage and detoxification proteins,
which play a critical role in cellular iron homeostasis in humans, animals, plants and microbes43. The
results of a multicenter safety study indicated that patients with high serum ferritin concentrations
before starting DFP treatment experienced the greatest decline in serum ferritin levels; while
patients that had lower serum ferritin levels prior to DFP levels generally experienced a stabilization
of values44 . These results indicate that DFP therapy can be monitored and doses can be tailored
based on serum ferritin levels in order to maintain concentrations below those associated with iron-
induced CIN and heart disease. Studies evaluating either urinary excretion and/or serum ferritin
concentration demonstrate DFP’s effectiveness as an oral iron chelator in maintaining a safe body
iron levels.

40 Br J Haematol 1990;76:295-300
41 Br J Haematol 1992;82:460-466
42 Blood 1992;80:593-9
43 Blood 1974;43:581-90
44 Br J Haematol 2000;108:305-12

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Safety and Efficacy. Assessment of the efficacy of an iron chelator can be determined by
measuring the amount of iron eliminated during use of the chelator via urine measurements. In the
case of DFP, urine measurements were taken and compared to the amount of iron input. Efficacy
assessments can be more complicated since some chelators may be tissue specific and thus remove
iron more effectively from certain tissues than others. Therefore, organ-specific iron removal is
another key factor in the assessment of DFP efficacy.

The safety and efficacy of Deferiprone has been studied extensively throughout the past 10 years.
The most frequent DFP related adverse drug reactions (ADR) include: transient gastrointestinal
symptoms (GI) (such as nausea, vomiting and abdominal pain), joint symptoms (pain and/or
swelling) and fluctuating serum alanine aminotransferase (ALT). According to Cohen et al. in a long-
term, four-year prospective study, 33% of 187 patients with thalassemia major developed GI
symptoms in the first year45 (Figure 27). In most of these patients, the GI events were mild to
moderate in intensity. The symptom prevalence decreased to 3% in subsequent years and did not
require discontinuation of DFP therapy.

Figure 27: Timeline to First Occurrence of Adverse Events

Source: Blood 2003;102:1583-7

Joint symptoms are another major ADR accounting for 3.9-20% of patients undergoing DFP
therapy for iron overload. These symptoms were mild to moderate in intensity in most patients;
however, approximately 2% of the patients suffering from severe joint pain discontinued DFP
treatment. Joint symptoms and problems associated with DFP treatment can appear even a few
years post treatment. Elevated ALT levels have been reported in a small subset of patients very early
following treatment (first months of DFP treatment in approximately 7% of the patients). Dose
reduction or DFP treatment discontinuation needs to be considered in these cases 46.

The most severe adverse effect of DFP treatment is agranulocytosis, defined as a confirmed
absolute neutrophil count (ANC) less than 0.5 ×109/L. In the study reported by Cohen et al., out of
187 patients followed for 4 years, agranulocytosis occurred in 0.5% of the patients (0.2 episodes per

45 Blood 2003;102:1583-7
46 Br J Haematol 1995;89:403-8

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100 patient-years)47. Another study reported by Ceci et al. indicated similar results on a larger scale.
In this study, out of 532 patients monitored, 1% of the patients (0.3 episodes per 100 patient-years)
experienced agranulocytosis symptoms48 . This extreme adverse effect normally resolved with the
discontinuation of the DFP therapy. Neutropenia, which is a milder adverse effect and defined by
ANC between 0.5 and 1.5 ×109/L, has been reported in 3.6%–8.5% of the patients undergoing
DFP therapy49 . Like agranulocytosis, it requires discontinuation of treatment. Currently, there are no
explanations for the reduced neutrophil count during DFP treatment.

The extensive evaluation of DFP safety over the last 10 years using multicenter studies with
relatively large number of patients and extended periods of follow-up provides a detailed long-term
safety profile. Thanks to the reported studies, DFP associated ADR are known and its risks are
manageable with careful monitoring of the patients.

Deferiprone to Prevent Contrast-Induced Nephropathy (CIN)


CIN BACKGROUND

CIN is contrast-induced Acute Kidney Injury (AKI) which is a severe complication caused by the
use of contrast media. The incidence of AKI varies depending on the patient population, baseline
risk factors and the criteria by which it is defined. AKI is typically defined as an increase in serum
creatinine (SCr) within 24 hours to five days from contrast exposure (approximately SCr increase
greater than 25% or 0.5mg/dl from baseline) 50. The overall frequency of AKI has decreased in the
past decade from 15% to 7% due to better awareness of the disease, prevention measures and
improved contrast agent media. However, high-risk patients with CKD and other risk factors may
have an incidence of CIN as high as 50%. The numerical incidence of AKI is still high due to the
increasing number of patients requiring contrast procedures.

AKI is associated with high mortality rates during the index hospitalization. In a study reported by
Levy et al., out of 16,248 hospitalized patients undergoing contrast agent procedures, 183 patients
developed AKI. Of these subjects, 34% died during their hospitalization51 . AKI is also associated
with other severe complications including cardiovascular events such as myocardial infarction (MI).

Pathogenesis. The most important risk factor for AKI is Chronic Kidney Disease (CKD). In
particular, reduced nephron numbers and renal vasoconstriction result in a 50% decline in renal
blood flow. The impaired blood flow allows for the maintenance of concentrated contrast agents in
the renal tubules and collecting ducts. The lingering exposure to the contrast agent causes
cytotoxicity and cellular death among the renal tubular cells. Additionally, the sustained reduction of
renal blood flow to the renal medulla leads to medullary hypoxia, ischemic conditions and apoptosis
of the renal tubular cells (See Figure 28). Other complications such as bleeding and use of intra-
aortic balloon counterpulsation might amplify the renal injury52 .

47 Blood 2003;102:1583-7
48 Br J Haematol 2002;118:330-6
49 Br J Haematol 2002;118:330-6, Blood 2003;102:1583-7
50 Clin J Am Soc Nephrol 2008;3:1242-3
51 JAMA 1996;275:1489-94
52 J Am Coll Cardiol 2008;51:1419-28

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Figure 28: Pathophysiology of AKI

Source: J Am CollCardiol 2008;51:1419-28

Diagnosis and Screening. Major AKI risk factors include abnormal baseline creatinine (SCr), low
glomerular filtration rate (GFR) or CKD. It is crucial to assess renal function and CKD classification
before the administration of contrast agents in order to make sure that all measurements and
appropriate steps are taken to reduce the risk of AKI. Additionally, patients at risk of AKI should
have follow up daily hospital visits including the monitoring of SCr and electrolyte levels between
24-96 hours, post discharge (Figure 30). Other screening methods are in developmental stages and
include biomarkers such as Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C that
can be detected in the bloodstream and can serve as measurements for kidney function and AKI
risk.

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Figure 30: Protocol for Screening for AKI Risks and Treatment

Source: Mayo Clin Proc 2009 Feb;84:170-9

Treatment Guidelines. Current guidelines attempt to reduce the risk of AKI by identifying major
risk factors and minimizing them by using strategies such as: reduced volume of contrast agents,
withholding of nephrotoxic drugs, volume expansion, dialysis and hemofiltration. High osmolar
contrast agents have been clearly demonstrated to be more nephrotoxic than low or isoosmolar
agents, although there is no convincing evidence of differences between the latter two classes of
agents (with the possible exception of iohexol or ioxyglate).

The only therapy proven to reduce the incidence of CIN is aggressive hydration. Hemofiltration
after contrast administration may play a role in reducing the risks of AKI in patients with very
advanced CKD. Although there are no approved pharmacologic agents for the prevention of AKI,

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drugs such as ascorbic acid and N-acetylcysteine, statins, aminophylline/theophylline and
prostaglandin E1 have been used clinically, although there is no definitive data demonstrating their
efficacy.

According to a study by Nash et al. radiographic contrast media was the third most common cause
of hospital-required renal failure and it accounted for 11% of renal failure cases (after decrease renal
perfusion and usage of nephrotoxic medications) 53.

MARKETED IRON-OVERLOAD DRUGS

Desferal (Deferoxamine) by Novartis. Desferal can be used to treat iron overload in cases such as
blood transfusions, acute iron poisoning in small children and hemochromatosis, which is a disease
of iron accumulation that can be either genetic or acquired. The drug has iron specificity which
allows it to bind with iron over other metal ions such as calcium. Additionally, it is a large molecule
which makes cellular penetration more difficult when compared to Deferiprone. The drug is
presently administrated parenterally while Deferiprone is administrated orally. Development of the
oral version of Desferal is currently ongoing. The drug is manufactured by Novartis Pharmaceutical
Corporation and is generic.

EXJADE (Deferasirox) by Novartis. It is another iron chelator formulation that is manufactured


by Novartis Pharmaceutical Corporation. Exjade is used to treat chronic iron overload due to blood
transfusions in patients two years of age and older. The drug is administrated orally. It is currently
under study for long term benefits and risks. Studies have revealed renal adverse events including
proteinuria and elevated creatinine levels; some cases of kidney failure requiring dialysis have been
reported.

Ferriprox (deferiprone) by Apotex. It is the brand name of deferiprone which is marketed as 500
mg immediate release tablets and thus has very different pharmacokinetics than the CorMedix
formulation. Ferriprox is sold and manufactured in Europe and Asia by Apotex, and it is
administrated orally three times a day for iron overload disorders. Ferriprox is a generic drug, is not
available in the U.S. and has never been evaluated for prevention of CIN or other forms of acute
kidney injury.
Figure 31: Comparison of Deferiprone with Marketed Iron Chelators
Deferiprone Deferiprone Deferoxamine
Desferasirox
CRMD001 Ferriprox Desferal
Exjade (Novartis)
(CorMedix) (Apotex) (Novartis)
Route Oral IR/ER (b.i.d) Oral IR (t.i.d) Oral daily I.V/S.C
Renal toxicity No No Yes No
Active drug in urine Yes Yes No Yes
Method of use patents in Yes No No No
cardiorenal disease
Effective at redistributing Yes Yes Yes No
iron/membrane permeable
Launch date N/A 2000 EU 2006 1970s
Source: Company Reports

53 Am J Kidney Dis 2002;39:930-6

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CIN EPIDEMIOLOGY
Approximately six million people suffer from cardiorenal diseases that require treatment and
challenging procedures including Percutaneous Coronary Intervention (PCI) and Cat Scans (CT)
(source: International Urology and Nephrology 2005). Contrast Induced Nephropathy (CIN) has
increased in prevalence due to an increase in procedures requiring radiocontrast such as PCI,
peripheral angiography and CT. CIN occurs immediately after contrast media exposure and might
result in acute renal failure which is associated with high morbidity and mortality rates. PCI, which
refers to the placement of an angioplasty guide wire, balloon, or other device such as stent or
thrombectomy catheter into a native coronary artery in order to mechanically induce
revascularization, are invasive procedures requiring contrast agent preformed over 1.3 million
procedure a year in cardiovascular related interventions54. About 11% of patients suffering from
renal insufficiency and undergoing diverse procedures requiring radiocontrast might develop CIN55.
This number is estimated to be around 150,000 patients annually56. The mortality rate of patients
suffering from CIN is estimated to be 34%57. CIN epidemiology statistics is summarized in Figure
32.
Figure 32: CIN Statistics
CIN Epidemiology Statistics
Cardiovascular disease no. of patients 81.0MM
Chronic Kidney Disease 26.0MM
Cardiorenal disease no. of patients 6.0MM
Cardiovascular related interventions/year 1.3MM
Number of CIN patients 150,000
Annual mortality rate for CIN 34%
Death from CIN/year 51000
Source: Circulation 2010;121:948-54; Int Urol Nephrol 2005;37:1755

There are no therapeutic interventions on the market for the prevention of CIN and there are no
approved preventative treatments. The current treatment includes hydration with saline or
bicarbonate in order to increase contrast agent secretion to maintain kidney function.

DISEASE MARKET INFORMATION

There are approximately 26 million American adults who currently suffer from chronic kidney
disease (CKD) 58. More than 30% of these patients are over the age of 60 and suffer from some
degree of kidney insufficiency59. Patients with CKD have a high burden of cardiovascular disease
and many more patients with CKD die from cardiovascular disease than develop ESRD. Due to this
high burden of cardiovascular disease, many CKD patients require cardiac procedures with contrast
agents including cardiac catheterization and CTs. According to America Heart Disease and Stroke
Statistics, there were approximately 1.3 million Percutaneous Coronary Intervention (PCI)

54 America Heart Disease and Stroke Statistics 2006 update


55 Clin J Am Soc Nephrol 2010;5:4-9
56 Nephrol Nurs J 2007;34:417-21
57 AJR Am J Roentgenol 2004;183:1673-89
58 The National Kidney Foundation
59 Arch Intern Med 2001;161:1207-16

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procedures performed in 2006. 50 million CT procedures are performed annually with
approximately 50% of them using a contrast agent.

There are an estimated 150,000 CIN cases per year in the United States (not including CT related
CIN, since the number of incidences from CT studies are not clear). It is the third most common
cause of hospital acquired renal insufficiency (11% of cases) and is associated with increased
mortality, cardiovascular complications (myocardial infarction, stroke, heart failure, etc.). A recent
economic analysis of the direct costs associated with contrast-induced nephropathy (CIN) indicated
that the average increase in additional hospital stay costs was approximately $10,345 and the one
year cost of treating a patient with CIN is $11,812 60. This increase in costs is related to increased
hospital days (from 5 to 10 days) and an increase in use of dialysis facilities. All CIN patients
required prolonged hospitalization with an estimated medical care of approximately $148 million
annually. Additionally, at least 1% of CIN patients will require a prolonged dialysis and
hospitalization with an estimated cost of $32MM annually61.

Exjade is another iron chelator used to treat chronic iron overload due to blood transfusions. While
it is an effective iron chelator that might be considered a potential therapeutic to prevent CIN,
Exjade has well recognized renal toxicity that precludes its use for this indication. Exjade is currently
available on the market and is manufactured by Novartis. For comparative purposes, Exjade sales
were $652MM, $531MM, and $357 in 2009, 2008, and 2007. Exjade’s patent is set to expire on April
5th, 2019.

The actual revenue that CorMedix might anticipate for this indication will depend on the level of
efficacy demonstrated in the DEFEND-AKI trial (phase III), its associated health economics, and
the chosen sales price.

Deferiprone Clinical Data Discussion


The background for the biologic plausibility for Deferiprone relies on an extensive body of in-vitro,
animal and human data supporting the role for catalytic iron and its attendant oxidative stress on
cardiovascular and renal disease. Proof of concept for Deferiprone was established based on two
pilot studies in CKD patients with two different types of kidney disease (diabetes nephropathy and
glomerulonephritis) (See Figure 33 for details).

Figure 33: Proof of Concept Studies Using Deferiprone


Study Disease Patients Dose Results
Diabetes 38 patients 50mg/kg The study time frame was nine months in
nephropathy received administrated orally which Deferiprone’s safety and efficacy was
Deferiprone evaluated. The mean albumin-to-creatinine
daily ratios declined and kidney function did not
decline. No safety issues were reported.
Glomerulonephritis 14 patients 50mg/kg Six months safety study revealed that
administrated orally patient’s total urinary protein level declined
Source: Company Report

60 Am J Kidney Dis 2002;39:930-6


61 Crit Care Clin 2005;21:261-80

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The first proof of concept study evaluated 38 patients with early Diabetic Nephropathy. The drug
demonstrated an excellent safety profile (with the exception of iron deficiency anemia in some
patients) and mean albumin-to-creatinine ratios decreased during the study. The second proof of
concept study evaluated 14 glomerulonephritis patients resistant to conventional therapy in which
Deferiprone was administrated at a dose of 50mg/kg/day for a period of six months. There was
also a significant reduction in proteinuria noted in these subjects.

Contrast agent exposure is associated with an increase in catalytic iron levels, even in normal
subjects. Both catalytic iron and oxidative stress are considered main contributors to the cause of
CIN, therefore reduction in catalytic iron levels might reasonably be expected to prevent CIN. The
data shown below documents that contrast media exposure increases urinary catalytic iron, even in
normal subjects receiving either an intravenous pyelogram or renal angiography (Figure 34).

Figure 34: Urinary Catalytic Iron Control vs. Treatment Group

Source: Cormedix Presentation

The Investigational New Drug application (IND) to the FDA has been approved and CorMedix is
currently conduction a Phase II proof of concept study using Deferiprone for prevention of CIN
in high-risk subjects with CKD and other risk factors.

Phase II Proof of Concept Trial

The primary objective of this trial is to assess the efficacy and safety of Deferiprone for prevention
of contrast-induced Acute Kidney Injury (AKI) in CKD patients undergoing coronary angiography
and PCI. The study is currently recruiting patients for a phase II, randomized, double blind, and
placebo-controlled trial.

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Study Design. Two primary study measurements are designed: novel biomarker evidence of acute
kidney injury and the incidence of acute kidney injury as defined by an increase in serum creatinine
or Cystatin C following contrast exposure. See Figure 35 for more details62 .

Figure 35: Deferiprone Phase II Proof of Concept Trial


Deferiprone for the Prevention of Contrast-Induced Acute Kidney Injury
No. of patients 60
Study Description A Phase II, randomized, double-blind, placebo-controlled trial
Primary outcome measures Biomarker evidence of Acute Kidney Injury (AKI) through 8
days
Secondary outcome measures Incidence of AKI using standard definitions based upon changes
in serum creatinine or cystatin C
Experimental group Subjects will be given one (900 mg) immediate release and two
(900 mg) extended release tablets 1-3 hours prior to angiography
and then every 12 hours for a total of 8 days
Placebo-control group 3 placebo tablets will be given every 12 hours for a total of 8
days, beginning 1-3 hours prior to angiography
Start date Jun-10
Estimated completion date Feb-11
Source: clinicaltrials.gov

Phase III DEFEND-AKI Trial

The phase III trial of Deferiprone (DEFEND-AKI) was previously designed and part of a Special
Protocol Assessment agreed upon with the FDA. Based upon the original agreement, this trial might
include as many as 800 patients for the assessment of Deferiprone to prevent morbidity and
mortality associated with CIN.

Study Design. The originally planned trial was a randomized, double blind, placebo-controlled,
parallel-arm, multicenter trial including patients with moderate-severe CKD and other risk factors
for CIN. The patients will receive the same dosing protocol currently being used in the Phase II
study.

The entry criteria for the trial includes the requirement of moderate to severe CKD as determined
by an eGFR<60 mL/min, and at least one additional risk factor (diabetes, age greater than or equal
to 75 years or heart failure). The patients may receive either low or iso-osmolar radiocontrast dye for
a cardiac interventional procedure. The subjects will otherwise receive standard of care treatment
for prevention of CIN which includes the avoidance of nephrotoxic medications, limiting contrast
volume as much as clinically possible and hydration both before and after the procedure.

Results/Outcomes. Patients will be evaluated and monitored for 90 days. The primary endpoint is
a composite of any of the following clinical events: death, myocardial infarction, dialysis, stroke/
TIA, heart failure or re-hospitalization.

62 clinicaltrials.gov, study NCT01146925

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NEW DRUGS IN DEVELOPMENT

Intravascular Temperature Management (IVTM™) by Zoll biomedical, who purchased the


technology from Radiant Medical, Inc., in 2007. IVTM technology provides a variety of catheter
options suited for body temperature adjustments depending on the application needed. Some of the
applications include temperature management of fever, intracranial pressure control and induced
hypothermia. The original product called Retrieve Endovascular Temperature Therapy developed by
Radiant Medical, Inc., focused on the research and development of endovascular therapeutic
hypothermia, for the treatment patients undergoing cardiac catheterization who are at risk of
developing contrast induced nephropathy (CIN). The produce allowed very rapid, precise cooling,
maintenance, and rewarming of the patient's core body temperature. The system works by inserting
a catheter into the femoral vein and positioning it in the inferior vena cava. As cool sterile saline is
circulated within the catheter, blood flowing past the catheter is cooled or warmed depending if the
body temperature needs to be cooled or warmed. The blood then reduces or increases the body
temperature. The CIN application is not indicated in the IVTM product description.

Benephit CV Infusion System. Benphit was developed by AngioDynamics, a company that


focuses on catheters for targeted renal therapy of physician-specified agents directly into the kidneys
via the renal arteries. The catheter system can be used for number of applications including
peripheral and coronary diagnostic and interventional procedures, and cardiovascular surgery. This
system can be combined with CIN preventive medications for CIN-related applications however the
system itself is not sufficient without a drug combination. Given there are no approved therapeutics
for CIN prevention and the invasive nature of the Benephit CV infusion system procedure, it would
appear to be little risk as a competitive product.

RenalGuard Therapy. RenalGuard Therapy is designed by PLC Medical System, Inc. to reduce the
toxic effects of contrast media on the kidneys in order to reduce the incidence of CIN. The
technology is promoting a high urine output that allows rapid elimination of contrast agents and
thus reducing its toxic effects. The combination of physician-prescribed loop diuretic for high urine
output and the RenalGuard System which is designed to measure urine output and replaces it in real-
time with an equal volume of sterile saline will assist in minimizing the risk of over- or under-
hydration that is correlated to increased patient risks and CIN. RenalGuard is currently in clinical
trials to assess the safety and effectiveness of the RenalGuard Therapy in reducing the incidence of
biomarker-defined CIN, not clinically relevant events. The company has received FDA conditional
approval for an Investigational Device Exemption (IDE) to begin the pivotal trial for RenalGuard
Therapy. The trial is designed as a multi-center, prospective, randomized study to evaluate the
effectiveness and safety of RenalGuard for the prevention of CIN during angiographies. Unlike the
Deferiprone approach that includes oral tablets for one week after the procedure, the RenalGuard
trial will include oral and IV N-acetylcysteine and saline hydration for only 1 day before and on the
day of the procedure.

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Intellectual Property & Licensing
The Neutrolin (CRMD003) patents were licensed from ND Partners LLC, and CorMedix holds an
exclusive worldwide license with ND Partners to develop Neutrolin for the prevention of CRBI.
Likewise Deferiprone (CRMD001) patents were licensed by Shiva Biomedical, LLC. Shiva
contribution agreement which was established on July 2006 has granted CorMedix an exclusive,
worldwide license to intellectual property for proprietary formulations of Deferiprone and a
biomarker diagnostic test for measuring levels of labile iron. This IP serve as the basis for the
Deferiprone (CRMD001) and CRMD002 programs.

Deferiprone (CRMD001)

Since the original patent for Deferiprone composition of matter has expired, Shiva Biomedical, LLC
filed for method of use patents and the new Deferiprone formulation utilized by CorMedix. The
new family of patents was filed originally in 2000 both in the U.S and Europe and it expires in 2020.
The patents are focused on:

1. Iron chelator use in cardiorenal disease (covering any iron chelators including deferoxamine
and desferasirox)
2. Diagnosis and treatment of CKD based on measurement of urinary catalytic iron
3. Treatment for kidney disease including all forms of glomerulonephritis and other
nephropathies

The second patent family was filed in August 2005 and is anticipated to expire in 2025. These
patents are focused on the prevention of acute renal failure associated with iodinated radiocontrast
dyes (CIN). The second patent family includes:

1. Application of iron chelators for the treatment of CIN filed in other major markets such as
Japan, Europe, Australia and Canada
2. Seven CKD diagnosis and treatment related patents were filed in the U.S (6,933,104;
6,906,052; 6,908,733; 6,995,152; 6,998,396; 7,045,282; 7,037,643)
3. Additional 14 patents applications in the CIN space

The third family of patents is focused on the application of iron chelators in erythropoietin
‘resistance’, a condition that is sometimes encountered in dialysis settings.

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Figure 36: Summary of CorMedix Intellectual Property
Jurisdiction Patent No. Expiration Date Related Product Candidate
U.S 6,166,007 May 10, 2019 CRMD003
U.S. 6,350,251 January 18, 2020 CRMD003
U.S 6,423,706 May 10, 2019 CRMD003
U.S. 6,451,003 August 16, 2020 CRMD003
U.S 6,498,157 May 10, 2019 CRMD003
U.S. 6,569,852 May 10, 2019 CRMD003
U.S 6,575,945 August 16, 2020 CRMD003
U.S. 6,803,363 March 31, 2020 CRMD003
U.S 6,908,733 April 20, 2020 CRMD001/CRMD002 *
U.S. 6,399,104 April 20, 2020 CRMD001/CRMD002 *
U.S 6,995,152 April 20, 2020 CRMD001/CRMD002 *
U.S. 6,998,396 April 20, 2020 CRMD001/CRMD002 *
U.S 7,037,643 April 20, 2020 CRMD001/CRMD002 *
U.S. 7,045,282 April 20, 2020 CRMD001/CRMD002 *
U.S 7,235,542 April 20, 2020 CRMD001/CRMD002 *
U.S. 7,696,182 May 16, 2025 CRMD003
Australia 2,004,201,714 April 20, 2020 CRMD001/CRMD002
China ZL 02108774.1 May 10, 2019 CRMD003
China ZL 02108777.6 August 16, 2020 CRMD003
Europe 1089738 May 28, 2019 CRMD003
Europe 1173757 ** April 21, 2020 CRMD001/CRMD002
Europe 1442753 February 3, 2023 CRMD004
Hong Kong HK 1059535 May 20, 2019 CRMD003
Hong Kong HK 1059746 16-Aug-20 CRMD003
*Referred to as the CKD patents.
**Issues by the European Patent Office and validated in Austria, Belgium, Switzerland, Cyprus, Germany, Denmark,
Spain, Finland, France, Great Britain, Ireland, Italy, Luxemburg, the Netherlands, Monaco, Portugal, and Sweden.
Source: Company Report

Neutrolin (CRMD003)

License and Assignment Agreement with NDP was initiated on January 30, 2008. NDP granted
CorMedix worldwide licenses for certain antimicrobial catheter lock solutions using biocidal solution
with Taurolidine used for the treatment and prevention of infections. NDP agreement with Dr.
Hans-Dietrich Polaschegg, Dr. Klaus Sodemann, and Dr. Johannes Reinmueller allowed for the
exclusive rights to use and display trademarks related to the technology. In the process, NDP
received an initial licensing fee of $325,000 and equity in the company in the form of shares.
Further payments will be take effect depending on future regulatory and sales milestones.

In addition to the catheter lock solution in January 30, 2008, exclusive rights to a gel lock invention
and Taurolidine treatment was granted in the U.S and serves as the base for CRMX004 product. As
part of the agreement, Dr. Polaschegg receives royalty payments ranging from 1-3% of net sales.

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Worldwide rights to the following patents were granted through both NDP licenses and the
Polaschegg License Agreement:

1. Four issued U.S. patents and three issued foreign patents for the Neutrolin composition of
antimicrobial catheter lock solution comprising Taurolidine, citric acid and sodium citrate
2. One issued U.S. patent application and four pending foreign patent applications including
antimicrobial catheter lock solution comprising Taurolidine and low concentration heparin
3. One pending U.S. patent application and one issued foreign patent linked to antimicrobial
catheter lock solution comprising a thixotropic gel incorporating Taurolidine
4. One issued U.S. patent and one pending foreign patent application including biocidal lock
system providing an infection-free fluid connection to the vascular system of a patient
5. Two issued U.S. patents, one issued foreign patent and two pending foreign patent
applications in connection with using an antimicrobial substance such as Taurolidine in the
procedure of disinfecting the space between an implanted device and encapsulating tissue
6. One issued U.S. patent and four pending foreign patent applications including an
antimicrobial peritoneal dialysis solution for preventing infection within the abdomen
7. One pending U.S. patent application and one pending foreign patent application for
processes and treatments of antimicrobial substances such as taurolidine for a wide range of
treatments for specific infections and prophylaxis

Financial Discussion
The Company has not generated any revenue since their inception in 2006. Prior to the IPO in 2010,
all of the Company’s operations and research and development expenses were funded through debt
financings. The Company received gross proceeds of $12.5MM from its IPO whose proceeds are
available for future expenses and operations.

The research and development expenses are the largest expense at approximately $16.2MM (as of
June 30, 2010 since inception, July 2006) and include costs associated with clinical trials, third party
costs such as manufacturers and consultants, manufacturing costs technology and intellectual
property licensing costs.

Other expenses of the Company are primarily comprised of salaries and related costs such as stock-
based compensation and other general and administrative expenses (accounting and legal services).
The Company also incurred a number of expenses associated with taking the Company public.

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Management Team
John C. Houghton BSc. President/CEO

John is a rare business executive, whose 20 years of experience has spanned global strategic and
affiliate tactical roles covering the full product life-cycle from research through generics, including
drugs, biologicals and devices. Before joining CorMedix, John established the global sales and
marketing infrastructure for the Biotech division of Stryker. Highlights include:
• Building EU and US sales and marketing infrastructure
• Managing the development and launch of OP-1® (BMP7) in >30 countries
• Leading the global launch of Calstrux®
• Directing a global team

Prior to Stryker Biotech, John worked for Aventis (and predecessor companies) for more than 14
years. Highlights include:
• Leading the global launch of Nasacort® ($100M+ brand)
• Serving as commercial lead on the Aventis-Millennium inflammation collaboration
• Serving as Global New Products Commercialization Head for Respiratory, Inflammation,
Cardiovascular and Metabolism
• Leading the commercial business development outside of core therapeutic areas

Mark T. Houser, M.D., MBA. Chief Medical Officer

As an experienced academic and clinical Nephrologist, with a strong clinical research, basic science,
and management background, Mark has a unique skill set that well suits CorMedix's cardiorenal
aspirations.
During his tenure at Johnson & Johnson (OrthoBiotech) Mark had diverse responsibilities including:
• Leading clinical development projects in oncology and critical care
• Leading business development projects primarily focused on cardiorenal projects; 50+
projects accessed
• Internal nephrology consultant to the J&J family of companies including OCD, OBI,
Cordis, Ethicon, Veridex, Centocor, J&J PRD
• Regional medical affairs management for Procrit

As a clinical and academic Nephrologist, his achievements include:


• Clinical Medical Director of a large dialysis network
• Basic research in the areas of oxidative stress in acute and chronic renal injury

He recently completed an MBA, majoring in marketing and management

Brian Lenz, CPA, MBA. Chief Financial Officer

Brian has over 15 years of financial and operational experience in addition to significant capital
raising, merger and acquisition and other strategic activities. Prior to joining CorMedix, Brian was
the Chief Financial Officer and Treasurer at Arno Therapeutics and prior to that served the same
roles at VioQuest Pharmaceuticals, Inc.

Prior to VioQuest, Brian was the controller of Smiths Detection Group where he was responsible
for corporate and operational financial reporting and consolidation of its international operations, in

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addition to being responsible for the information technology and human resources functions. Brian
started his career as a senior auditor with KPMG, LLP. Brian is a certified public accountant licensed
in the state of New Jersey, and a member of the CFO advisory committee of BIONJ.

Risk to an Investment
The outcomes of pivotal clinical trials for both Neutrolin and Deferiprone would affect
CRMD shareholders. Both Neutrolin and Deferiprone are going through major clinical trials that
are inherently risky and hard to predict their outcomes. The near-term major value proposition of
CRMD shareholders is the continued success of Neutrolin in Phase III clinical studies for catheter-
related bacterial infection and Deferiprone in Phase II and Phase III clinical studies for CIN.
Operating expenses over the next several years require capital for research, development, pre-clinical
testing and clinical trial that can impact shareholder value.

Lack of finance could impede corporate development. As the Company is currently not
generating revenues, there is a need for sufficient financial support from either the financial market
or non-dilutive sources in order to maintain development of the pipeline products. As a result of
limited operating history of CorMedix and net deficit due to early development stage Shareholder
value could be impaired. In addition, future equity offerings could dilute the value of existing
shareholders. The company incurred significant operating and capital expenditures in the past few
years and anticipates an increase in expenditures due to expensive clinical trials in the foreseeable
future.

The company did not apply for sales regulatory approvals for the CorMedix products. New
Drug Application (NDA) was submitted and approved recently for Deferiprone however approval is
needed for both products before they can be placed on the market. Approval or delays can dilute
shareholder value. Additionally, sales potential can be impaired by competitors.

Successful commercialization can be impaired by competitive disadvantages. Although there


are currently no approved products as catheter lock solution on the market, multiple companies are
in stages of developing catheter blocks solution for the prevention of blood stream infections. It is
hard to predict the sale value of the product or its competitors and whether the company can
properly market the products to obtain revenues.

After commercialization risks include physicians, hospital and patients usage of the new
products. Even if the FDA approves one or more of the company product candidates, physicians,
hospitals and even patients themselves might not accept and use the product. The prediction of how
the product will do on the market are hard and dependent on many components including
physicians familiarity and choice to use the new product, cost effectiveness of the product relative to
its competitor on the market, reimbursement from the government and healthcare payers and
effectiveness of the company in marketing the new product.

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DISCLOSURES
The material presented in this report is provided for information purposes only and is not to be used or considered as a
recommendation to buy, hold or sell any securities or other financial instruments. Information contained herein has been
compiled by LifeSci Advisors and prepared from various public and industry sources that we believe to be reliable, but
no representation or warranty, expressed or implied is made by LifeSci Advisors, its affiliates or any other person as to
the accuracy or completeness of the information. Such information is provided with the expectation that it will be read
as part of a broader analysis and should not be relied upon on a stand-alone basis. Past performance should not be taken
as an indication or guarantee of future performance, and we make no representation or warranty regarding future
performance. The opinions expressed in this report reflect the judgment of LifeSci Advisors as of the date of this
report and are subject to change without notice. This report is not an offer to sell or a solicitation of an offer to buy any
securities. The offer and sale of securities are regulated generally in various jurisdictions, particularly the manner in
which securities may be offered and sold to residents of a particular country or jurisdiction. Securities discussed in this
report may not be eligible for sale in some jurisdictions. To the full extent provided by law, neither LifeSci Advisors nor
any of its affiliates, nor any other person accepts any liability whatsoever for any direct or consequential loss arising from
any use of this report or the information contained herein. No LifeSci Advisors directors, officers or employees are on
the Board of Directors of a covered company and no one at a covered company is on the Board of Directors of LifeSci
Advisors. Neither the analyst who authored this report nor any of LifeSci Advisors’ directors, officers, employees invest
in the securities of the company that is the subject of this report. LifeSci Advisors has been compensated by the
company that is the subject of this report for this and future research reports, investor relations services, and general
consulting services.

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Page 47
CorMedix, Inc.
10/20/10
(in 000's)
1Q09A 2Q09A 1H09A 1Q10A 2Q10A 1H10A
OPERATING EXPENSES
Research and Development 233 291 524 3,097 560 3,657
General and administrative 405 341 747 646 618 1,265
Total Operating Expenses $ 638 $ 632 $ 1,271 $ 3,743 $ 1,178 $ 4,922
LOSS FROM OPERATIONS $ (638) $ (632) $ (1,271) $ (3,743) $ (1,178) $ (4,922)
OTHER INCOME (EXPENSE)
Interest Income 1 1 2 - 6 6
Interest expense, including amortization and write-off (513) (562) (1,076) (3,094) (3,094)
deferred financing costs and debt discounts
NET LOSS $ (1,150) $ (1,193) $ (2,345) $ (6,837) $ (1,172) $ (8,010)
LifeSci Advisors

NET LOSS PER SHARE- BASIC AND DILUTED $ (1.37) $ (1.42) $ (2.78) $ (6.40) $ (0.10) $ (1.20)
WEIGHTED AVERAGE SHARES OUTSTANDING- 842 842 842 1,067 11,408 6,677
BASIC AND DILUTED

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