MTR-107 - Intradyalitic Hypotension

Intradialytic Hypotension MTR-107

Dialysis is required when the kidneys can no longer fulfill their role of removing waste (diffusion) and unwanted water (ultrafiltration) from the blood, a condition known as End Stage Renal Disease (ESRD). Hemodialysis is a clinical procedure which substitutes for the normal function of the kidneys, removing waste products, excess fluid and toxic substances from the bloodstream. This process is essential for the survival of ESRD patients whose kidneys are no longer able to perform their crucial function.

Intradialytic hypotension (IDH) is defined as a decrease in systolic blood pressure or in mean arterial pressure, a common adverse event that occurs in 10-30% of all dialysis treatments. Dialysis hypotension usually presents in one of two ways: either episodic hypotension or chronic, persistent hypotension. The latter condition is more commonly recognized in patients who have been on dialysis for a number of years. Both conditions present therapeutic challenges, as ultrafiltration requirements are difficult to achieve within the context of hemodynamic instability.

Intradialytic hypotension is a major source of morbidity for ESRD patients. Few pharmaceutical solutions have been provided to date for treatment of the condition. Current common options include:

  • Dialysate temperature adjustments (from 37 to 35°)
  • Dialysate calcium adjustments
  • Sodium modeling
  • Ultrafiltration modeling

These common treatment modalities can produce unwanted side effects, such as significant weight gain, and often require interrupting the hemodialysis treatment or increasing the dialysis time. Additionally, they seldom address the symptoms associated with intradialytic hypotension, which require a substantial amount of medical and nursing care before and during dialysis in order to control.

Chronic hypotension is characterized hemodynamically by generally preserved cardiac index, heart rate or stroke volume, juxtaposed with reduced total peripheral vascular resistances. Although its pathophysiology is not well defined, a reduced cardiovascular response to vasopressor agents (such as norepinephrine and angiotensin II), associated with a down-regulation of their receptors, as well as an increased production of vasodilators (such as nitric oxide or adrenomedullin), are possibly involved. The treatment of this complication is not well defined, and the measures recommended (contention in the lower limbs or the sympathomimetic agent Midodrine) are of limited benefit. [1] This is a clear indication of the unmet medical need in this market segment.

In a most promising development, intradialytic hypotension has recently been officially designated by the FDA as an "orphan disease", opening the way for increased funding and research possibilities.

1 Cases A. and Coll E. J Nephrol 2002 Jul-Aug;15(4):331-5    Division of Nephrology, IDIBAPS, University of Barcelona, Catalonia, Spain

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.