MTR-107 - Intradyalitic Hypotension
Hemodialysis (HD) is a procedure for removing metabolic waste products, excess fluid, and toxic substances from the bloodstream by means of a machine with a special filter called an artificial kidney or dialyzer. It is essential for the survival of End-Stage Renal Disease (ESRD) patients whose kidneys are not capable of processing waste, and it is administered when it is not possible to provide a kidney transplant or peritoneal dialysis. Most HD patients attend three dialysis sessions per week, each lasting 3-4 hours.
Intradialytic Hypotension (IDH) is the most common complication associated with HD, occurring in 10% to 30% of all HD treatments. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines defined IDH as a decrease in systolic blood pressure (SBP) by at least 20 mmHg or a decrease in mean arterial pressure (MAP) by at least 10 mmHg associated with symptoms that include: abdominal discomfort, yawning, sighing, nausea, vomiting, muscle cramps, restlessness, dizziness or fainting, and anxiety. Nevertheless, other, more recent and also widely accepted definitions exist, for instance, a drop of systolic blood pressure to below 90 mmHg.
IDH may occur in one of the three clinical patterns: (i) acute (episodic) hypotension defined as a sudden drop of systolic blood pressure to below 90 mmHg with accompanying clinical symptoms, (ii) recurrent – as detailed above but prevailing in a minimum 30% of dialysis sessions, and (iii) chronic, persistent hypotension in which interdialytic systolic blood pressure is maintained at less than 90–100 mmHg.[3,4,5]
IDH impairs the patient’s well-being, can induce cardiac arrhythmias, and predisposes patients to coronary and/or cerebral ischemic events.[2,6] It has been demonstrated that hemodialysis-associated hypotension increases mortality in the dialyzed population.[7,8] Evidence suggests that IDH causes myocardial stunning (acute reversible segmental myocardial hypoperfusion and contractile dysfunction), and that recurrent myocardial stunning can result in long-term loss of myocardial contractility, which is associated with increased mortality.[9,10] In addition, IDH, especially if recurrent, can damage other vital organs such as the brain and gut, contributing to mortality through stroke, and endotoxin translocation with associated inflammation and protein-energy wasting.
Recurrent IDH is a major source of morbidity and mortality for ESRD patients, and although a series of preventive strategies (like reassessment of target weight, avoidance of food intake during dialysis, withholding of antihypertensive agents prior to dialysis, limitation of interdialytic sodium intake, cardiac evaluation, use of cool dialysate, and increase in dialysis time and/or frequency) has been adopted during the last years, the condition still persists.[11,12]
Efficient treatment of IDH is still a great challenge to nephrologists and there is no FDA-approved treatment for IDH. The current acute treatment modalities produce unwanted side effects such as recurrent target weight misses and chronic volume overload, and they often require interrupting the hemodialysis session or increasing the time on it. Additionally, these interventions seldom address the symptoms associated with IDH.
- Perazella MA. Pharmacologic options available to treat symptomatic intradialytic hypotension. Am J Kidney Dis. 2001 Oct;38(4 Suppl 4):S26-36.
- National Kidney Foundation, Inc. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis. 2005 Apr;45(4 Suppl 3):S1-153.
- Sulowicz W, Radziszewski A. Pathogenesis and treatment of dialysis hypotension. Kidney International (2006) 70, S36–S39.
- Chou JA, Kalantar-Zadeh K, Mathew AT. A brief review of intradialytic hypotension with a focus on survival. Semin Dial. 2017 Nov;30(6):473-480.
- Flythe JE, Xue H, Lynch KE, et al. Association of mortality risk with various definitions of intradialytic hypotension. J Am Soc Nephrol. 2015 Mar;26(3):724-34.
- Chang TI, Paik J, Greene T, et al. Intradialytic hypotension and vascular access thrombosis. J Am Soc Nephrol. 2011 Aug;22(8):1526-33.
- Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients. Kidney Int. 2004 Sep;66(3):1212-20.
- Stefánsson BV, Brunelli SM, Cabrera C, et al. Intradialytic hypotension and risk of cardiovascular disease. Clin J Am Soc Nephrol. 2014 Dec 5;9(12):2124-32.
- Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis-induced cardiac injury: determinants and associated outcomes. Clin J Am Soc Nephrol. 2009a May;4(5):914-20.
- Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis-induced repetitive myocardial injury results in global and segmental reduction in systolic cardiac function. Clin J Am Soc Nephrol. 2009b Dec;4(12):1925-31.
- Assimon MM, Flythe JE. Intradialytic Blood Pressure Abnormalities: The Highs, The Lows and All That Lies Between. Am J Nephrol. 2015;42(5):337-50.
- Kotanko P, Henrich WL. Intradialytic hypotension in an otherwise stable patient. www.uptodate.com Accessed Jun 23 2017.
Intradialytic Hypotension has been recognized by the FDA as an "orphan disease", opening the way for increased funding and research possibilities.
2003:Phase IIa study in Moldova(Eastern Europe): Pharmacokinetic and Pharmacodynamic effect of MTR-107 in ESRD patients
2003 – IND Approval
With the consideration of the 1999-2000 Phase I clinical trial and a full summary of previous human experience gained through the clinical studies completed in Moldova (including Phase II clinical study n=36 open-heart surgery patients), the IND (number 66,505) was approved by the FDA in 2003.
At this moment, the IND covers two indications: MTR-105 for cardiac surgery related hypotension and MTR-107 for intradialytic hypotension. Both MTR-105 and MTR-107 are injectable forms of MTR-104. The IND document encompassed approximately 5,000 pages of detailed summaries and reports of toxicological and Phase I studies, as well as full documentation of the production of MTR-105 and MTR-107 for the clinical studies, done in compliance with cGMP.