By Grant Zeng, CFA
In addition to AIS, DiaMedica (TSX:DMA.V) (OTC:DMCAF) is also developing DM199 for the treatment of diabetic kidney disease (DKD).
Background on Diabetic Kidney Disease
Diabetic kidney disease (DKD) or Diabetic nephropathy (DN) is one of the most common complications of late stage diabetes.
DKD is a form of chronic kidney disease (CKD) characterized by a gradual loss of kidney function. Diabetes & high blood pressure are main causes. Clinically, DKD causes a progressive increase in urine albumin/albuminuria and a decrease in glomerular filtration rate (GFR) or hyperfiltration. In the healthy individual, the kidney has millions of capillaries with tiny pores that act as filters located in the glomerular basement membrane. Waste products pass through these filters and become urine while useful products, such as proteins and red blood cells, are too large to filter and stay in the blood stream. In DKD impaired glomerular membrane filtration leads to the abnormal release of protein into the tubules and urine (proteinuria). In normal healthy kidneys only a tiny amount of albumin is found in the urine. A raised level of albumin in the urine is the typical first sign that the kidneys have become damaged by diabetes.
Diabetic kidney disease is divided into two main categories, depending on how much albumin is lost through the kidneys:
Microalbuminuria: in this condition, the amount of albumin that leaks into the urine is between 30 and 300 mg per day. It is sometimes called incipient nephropathy.
Proteinuria: in this condition the amount of albumin that leaks into the urine is more than 300 mg per day. It is sometimes called macroalbuminuria or overt nephropathy.
At the final stages of DKD, the kidneys completely fail and dialysis or a kidney transplant is needed.
Treatment Options for DKD
There are no formally approved treatment strategies for DKD in the US and other Western countries. Current treatment strategies for DKD include the strict control of high blood pressure and high blood sugar.
Blood pressure medications including angiotensin converting enzyme inhibitors (ACEi: Ramipril®) and/or angiotensin receptor blockers (ARBs: Banicar®) are widely used and are considered the standard of care for DKD.
Both ACEi and ARBs work primarily in the renin-angiotensin system (RAS) of the kidney through the angiotensin receptors 1 (AT1) and 2 (AT2). These therapies act predominantly by blocking both receptor subtypes and thus suppressing aldosterone, and improve blood flow within the capillaries thereby decreasing kidney pressure.
However, both ACEi and ARBs can lead to increased level of blood potassium (hyperkalemia). The primary factor regulating potassium in the renal system is aldosterone, which modulates the potassium transport across the nephron. However, as the aldosterone systems fails or AT-receptors are blocked (i.e. ACEi and ARBs), high potassium levels can lead to cardiac complications including rapid decreases in resting membrane potential, increased cardiac depolarization and muscle excitability. KLK1 protects against hyperkalemia after consumption of potassium.
Studies have shown that people diagnosed with chronic kidney disease, regardless of treatment status, are more likely to develop hyperkalemia. This risk of hyperkalemia in DKD can result in suboptimal dosing of ACEi and ARBs. In fact, it is estimated that 42% of people with DKD are not receiving optimal dose regimens and 33% are not treated because they cannot tolerate the regimens.
A component of ACEi efficacy appears to involve increasing bradykinin levels by blocking bradykinin breakdown. Thus ACEi’s increase bradykinin in an unregulated, global fashion and will have less benefit if bradykinin production is already insufficient. Importantly, ACEi appear to lose efficacy in animals that lack a functional KLK1 enzyme. DM199 restores healthy levels of KLK1, which is the primary enzyme that produces bradykinin, likely focusing on cells and organs where bradykinin is needed to maintain normal function. This suggests that DM199 treatment can improve kidney function beyond what can be achieved with ACEi drugs.
Another complication that can arise from ACEi and ARB treatment is angioedema. Angioedema (AE) is a nonpitting edema (swelling) of the dermis and subcutaneous layers. ACEi block the degradation of kinins, which leads to a significant increase in plasma and tissue BK and substance P. The increase in BKB2 receptor activation leads to increased vascular permeability at the post capillary venules which causes the edema. DM199 could potentially be combined with an ARB with significantly lower risk of hyperkalemia and angioedema.
Another Huge Market of DKD for DM199
Diabetes is a worldwide heath issue for millions of people with billions of dollars spent for dealing with this epidemic. According to the World Health Organization (WHO) the number of people diagnosed with diabetes worldwide has risen to 422 million in 2014. The prevalence of diabetes mellitus has grown significantly, primarily due to the increased incidence of Type 2 diabetes.
Diabetic kidney disease (DKD) is one of the most common complications of both Type 1 and Type 2 diabetes occurring in 20-40% of all patients diagnosed with Type 2 diabetes. Additionally, people with hypertension or a familial history of DKD are at an even greater risk. DKD is the leading cause of end-stage renal disease (ESRD) accounting for approximately 50% of cases in the developed world.
In the United States, there are approximately 11 million people diagnosed with DKD currently and among them 2.5 million with both DKD and hyperkalemia. The cost of caring for DKD patients accounts for 90% of the direct and indirect costs of diabetes care. In China, approximately 119.5 million people are diagnosed with DKD with an overall prevalence of 10.8%. With these demographics, there is a potential $11.7 billion market for treatments of chronic kidney disease.
DKD Products in Development
In the clinic, along with DM199, there are approximately five other drugs in development to treat DKD, all with aldosterone-independent mechanisms of action. Most of these drugs are being developed to be combined with an ACEi or ARB.
Finerenone (BAY94-8862) is a non-steroidal mineralocorticoid receptor antagonist (MRA) currently in an active Phase III clinical trial. In a Phase II trial, Finerenone reduced urine albumin-to-creatinine ratio (UACR) at day 90 post treatment in a dose-dependent manner when combined with a low dose ACEi. However, approximately 1.8% of patients were discontinued from the study because of hyperkalemia.
Pentoxifylline, Atrasentan, Canagliflozin, and Liraglutide, marketed drugs that are used to treat other complications of diabetes, also are being tested for efficacy in DKD. For all these drugs, long-term efficacy and safety data is needed to completely elucidate the effects on DKD and the prevalence of side effects or serious adverse reactions.
DM199 Advantages for DKD
As we discussed above, blood pressure medications including angiotensin converting enzyme inhibitors (ACEi: Ramipril®) and/or angiotensin receptor blockers (ARBs: Banicar®) are widely used and are considered the standard of care for DKD. However, both ACEi and ARBs can lead to hyperkalemia and angioedema, which can cause severe cardiac complications.
DM199 is a recombinant human tissue kallikrien (KLK1), which has demonstrated excellent safety profile in animal models and in human studies. DM199 is in development as a replacement therapy for DKD patients to restore KLK1 levels to natural levels. Due to its unique mechanism of action, DM199 is believed to improve kidney function without risk of hyperkalemia and other side effects of compounds like ACEi. DM199 could potentially be combined with ARB or new treatments such as Finerenone if approved to further improve kidney function.
Kallidinogenase (porcine KLK1), a similar product of DM199 have been approved in Asia for the treatment of acute ischemic stroke (AIS), DKD and hypertension. We believe DM199 has a high probability to get approved by health authorities once its efficacy and safety have been established in clinical trials.
Worldwide peak sales of DM199 for DKD could potentially also surpass $1 billion. With combined sales from AIS, DM199 could become a blockbuster for DiaMedica.
Clinical Evidence of DM199 for the Treatment of DKD
Studies have shown that lower KLK1 level is associated with worsening kidney function.
The most compelling evidence for developing DM199 as an effective treatment for DKD lies in the therapeutic effect of porcine derived KLK1 in DKD patients in China. Porcine KLK1 (kallidinogenase) has been approved in China for the treatment DKD and hypertension.
In a 2015 study, 200 patients with diabetes were treated for 60 days with porcine KLK1 or dipyridamole (blood thinner) tables. The urinary albuminuria excretion of the KLK1 group decreased significantly from baseline and from the control group. When the treatment group was divided into participants that displayed microalbuminuria (UAE 30-300mg/24hrs) or clinical albuminuria (UAE >300mg/24hrs), participants with microalbuminuria showed more robust treatment effects of porcine KLK1 than the clinical albuminuria group. This suggests that during early stages of DKD (microalbuminuria) kidney damage is more easily reversed. However, as DKD evolves into clinical albuminuria, the disease might enter into an irreversible stage.
There have been several studies that have investigated the effects of ARBs and ARB + KLK1 in patients with DKD. Notably, studies have shown lasting effects of KLK1 plus ARB significantly reducing urinary albumin excretion (UAE) rate after 1, 3 and 6 months of dosing.
In a study of 68 patients with early DKD treated with either an ARB alone or an ARB + KLK1, after one month of treatment participants receiving the combination of ARBs and KLK1 had significantly lower levels of urinary albumin excretion rate (UAER) from baseline before treatment, and from participants who were treated with just an ARB alone (Left Panel).
In another study following 58 participants with daily dosing of ARB or ARB + KLK1 showed a significant reduction in UAER in the combination group. Levels were significantly lower than their own baseline and from the ARB alone treated group after 3 months of treatment (Middle Panel).
Similar effects were seen in participants treated for 6 months with either an ARB alone or a combination of ARB + KLK1 (Right Panel). Again, participants who were treated with a combination of medications showed significantly lower UAER (84.3% reduction) and β2-microglobulin (β2-MG; 56.9% reduction), a marker of reduced glomerular filtration rate, compared to their own baseline and to the placebo group and ARB alone group after 6 months of treatment. Notably, after 6 months of daily dosing, the KLK1 + ARB group UAER levels were brought from 129 mg/24 hr to 21 mg/24hr, which is lower than the clinical diagnosis for DKD (urine albumin >30 mg/24hrs).
Porcine KLK1 (Kallidinogenase) Treatment for DKD
Similar clinical studies have investigated the effects of KLK1 with ACEi in DKD patients. These studies have shown that participants treated with the combination therapy showed significantly lower urinary protein excretion and lower UAER compared to treatment with ACEi alone. Additionally, the combination treatment group showed decreased whole blood and plasma viscosity, decreased hematocrit and decreased fibrinogen. Each of these hemorheology measurements are correlated with cardiovascular disease, which can be comorbid with diabetes.
All these data from the clinical studies suggest that KLK1 treatment could greatly compliment the use of ARBs or ACEi in the treatment of DKD. Although a great deal of work has been published, it is worth noting that several clinical studies in China are not well-controlled and additional properly controlled trials designed according to Western standards are needed to confirm the Chinese publications.
Development Plan for DM199 for the treatment of DKD
As we discussed above, DiaMedica is conducting a Phase I bridge clinical trial to determine the safety, optimal dose & delivery. The trial has completed the first part of IV dosing and has identified a IV dose comparable to approved KLK1 products. The subcutaneous dosing is continuing.
The company plans to use the results of this study to guide the upcoming Phase II clinical trial. The planned Phase II clinical trial intends to enroll about 60 patients with stage 3-4 DKD disease. The primary endpoints include safety, tolerability, PK & PD profile. Secondary endpoints will include change in urinary albumin excretion (UAE) rate, cysteine protease inhibitor (Cys C), Beta-2 microglobulin (B2M), glomerular filtration rate (eGFR) & others. The patients will be treated and followed up for 3 months.
We expect the Phase II trial to begin in 2017 and that data from the trial will be available in 2018.
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