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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.
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
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:
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.
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,
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.
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
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
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
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.
Source: Company Report and the U.S Food and Drug Administration (FDA) and National Kidney and Urologic
Disease Information Clearinghouse
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
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
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.
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
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
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).
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).
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.
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.
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.
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
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.
2 http://www.allegromedical.com/browse/browseProducts.do?searchPhrase=Central+Venous++catheter
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.
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.
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.
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.
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.
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
30http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
InvestigationalDeviceExemptionIDE/default.htm
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.
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
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).
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
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.
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
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.
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.
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
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).
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
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.
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
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.
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
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.
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,
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.
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.
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
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.
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)
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.
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).
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.
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.
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.
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.
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.
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.
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.
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
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
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
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.
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.
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