Safety and Efficacy Study of Pyridorin in Patients With Nephropathy Due to Type 2 Diabetes

Diabetic kidney disease afflicts about 20% of all diabetics and is the major cause of
end-stage renal disease (ESRD). There are an estimated 1.2 million diabetic overt
nephropathy patients in the US, and approximately 5.1 million diabetic patients exhibiting
signs of developing kidney disease.

Hyperglycemia-induced microvascular disease is the fundamental cause of diabetic kidney
disease. More specifically, hyperglycemia perturbs metabolic pathways, particularly in
tissues that do not regulate intracellular glucose levels. This favors a broad range of
pathogenic oxidative chemistries including the formation of advanced glycation end-products
(AGEs), toxic carbonyls, and reactive oxygen species (ROS) that are considered to be the
principal causative factors in the development of diabetic microvascular disease.

Pyridorin™ has been shown to inhibit AGE formation and to scavenge ROS and toxic carbonyl
compounds in extensive in vitro studies. The therapeutic potential of Pyridorin™ has been
demonstrated in vivo by extensive preclinical studies that have been carried out in a number
of independent laboratories by prominent investigators. In addition, Pyridorin™ has
demonstrated a significant treatment effect in slowing the progression of diabetic
nephropathy in two Phase 2 clinical trials. Thus, a solid scientific rationale and clinical
evidence exists for the application of Pyridorin™ therapy to slow the progression of
diabetic kidney disease.

NephroGenex is initiating a new Phase 2b clinical trial (PYR-210) that is evaluating the
safety and efficacy of Pyridorin™ in slowing the progression of overt nephropathy in
patients with type 2 diabetes. This trial incorporates the latest discussion with the FDA
regarding the use of an approvable surrogate marker that would be subsequently confirmed
with hard clinical endpoints.

In this double-blind, placebo-controlled study, eligible type 2 diabetic patients with overt
nephropathy will be treated for one year with bid doses of either Pyridorin™ 150 mg,
Pyridorin™ 300 mg, or placebo. The primary endpoint in the study is the change in serum
creatinine (SCr) from baseline after 1 year of therapy. Secondary 1-year endpoints include
the slope of SCr, the change in protein/creatinine ratio (PCR) derived from 24-hour urine
collections, and the change from baseline and slope of serum cystatin C.

The patient population studied will be type 2 diabetics with overt nephropathy defined as
having a SCr between 1.3 and 3.3 mg/dl in females and between 1.5 and 3.5 mg/dl in males,
accompanied by proteinuria in the macroalbuminuric range (PCR at least 1200 mg/g). In order
to reduce confounding variables, careful control of blood pressure (BP) will be required. If
not yet controlled, each patient's BP will brought to a level that the investigator believes
is appropriate for the patient prior to randomization, and this will remain the target BP
for that patient for the remainder of the study. Also, patients will be permitted to be on
only one ACE inhibitor or angiotensin receptor blocker (ARB) and no other drugs that inhibit
the renin-angiotensin-aldosterone axis throughout the study. A run-in period will be
required in some patients to achieve the BP and ACEi/ARB requirements.

This study will be conducted with the leadership of the Collaborative Study Group.

INCLUSION CRITERIA:

1. Patients who have given voluntary written consent to participate in this study prior
to conducting Screening Visit procedures;

2. Male and female patients 25 years of age or older with a diagnosis of type 2
diabetes; • If a woman is of childbearing potential (WOCBP) she must agree to use
appropriate birth control (double barrier methods, hormonal contraceptives, or
intrauterine device)for the duration of the study (WOCBP is defined as all women who
are not surgically sterile or are not at least 1 year post-menopausal). All WOCBP
must have a negative serum pregnancy test at the Screening Visit;

3. At the Screening Visit, ALL patients must have a history of overt diabetic
nephropathy, as defined by the following:

- A SCr measurement of 1.3 mg/dL to 3.3 mg/dL (women) or 1.5 mg/dL to 3.5 mg/dL
(men) inclusive, and

- A 24-hour urine collection PCR ≥1200 mg/g;

4. Patients must be receiving an ACE-I or an ARB, for at least 3 months prior to the
Qualifying Visit (Screening Visit for those patients not entering into the Optional
Run-in Period), where the dose of the ACE-I or the ARB is considered appropriate for
that patient and has been stable for at least 2 months;

5. Patients must be on stable blood pressure medications for 2 months prior to the
Qualifying Visit (Screening Visit for those patients not entering into the Optional
Run-in Period), with a seated blood pressure at the Qualifying Visit of ≤160/90 mmHg;

6. At the Qualifying Visit (only applies to those patients who enter into the Optional
Run-in Period), the following eligibility parameters must be met in order to be
randomized:

- A SCr measurement within 25% of the SCr measurement at the Screening Visit; and

- A 24-hour urine collection PCR ≥600 mg/g.

EXCLUSION CRITERIA:

1. Patients with type 1 diabetes;

2. Patients with a diagnosis of chronic renal disease other than diabetic renal disease
with or without hypertensive renal disease;

3. Patients receiving a renin inhibitor or an aldosterone antagonist or a combination of
an ACE-I and an ARB within 2 months of the Qualifying Visit (Screening Visit for
those patients not entering into the Optional Run-in Period);

4. Patients with a history of solid organ transplantation;

5. Patients with a history of myocardial infarction, coronary re-vascularization
procedures (including percutaneous transluminal coronary angioplasty),
cerebrovascular accident ortransient ischemic attack within 1 month prior to the
Screening Visit;

6. Patients with a diagnosis of Class III or IV congestive heart failure at any time (as
defined by the New York Heart Association);

7. Patients with a history of neoplastic disease (except basal or squamous cell
carcinoma of the skin) within 5 years prior to the Screening Visit;

8. Patients with any history of dialysis within 2 years prior to the Screening Visit;

9. Patients in whom dialysis or renal transplantation is anticipated by their physician
within 1 year after the Screening Visit;

10. Patients who used SCr altering drugs within 1 month prior to the Screening Visit;

11. Patients who require systemic immunosuppression therapy for >2 weeks (except for
inhalant steroids);

12. Patients with clinically significant liver disease or transaminase (alanine
aminotransferase and aspartate aminotransferase) levels >2.5 x upper limit of normal
measured at the Screening Visit;

13. Patients with bilirubin levels >1.5 x upper limit of normal measured at the Screening
Visit;

14. Patients with a history of allergic or other adverse response to vitamin B
preparations;

15. Patients who require >50 mg of vitamin B6 daily;

16. Patients who have a history of dysphasia and swallowing disorders;

17. Patients with a history of hypersensitivity to Pyridorin or any of the excipients in
the Pyridorin formulation;

18. Patients who have taken pyridoxamine or any other investigational drug within 30 days
prior to the Screening Visit, or have participated in a previous Pyridorin trial or
another clinical trial within 30 days prior to the Screening Visit;

19. Patients with a current history of drug or alcohol abuse;

20. Patients unlikely to comply with the study protocol (e.g., an inability and
unwillingness to participate in adequate training, an uncooperative attitude,
inability to return for follow-up visits, or unlikelihood of completing the study);

21. Women who are lactating, pregnant or intend to become pregnant during the course of
the study; and

22. Patients who are employees of NephroGenex or its representatives.