Research Project
9546839
Three ultrasound contrast agents (Definity®, Optison® and Lumason®) are FDA approved for echocardiography in the U.S. Definity currently has over 75% market share. Definity?s dominance in the market is due to its ease of administration via IV infusion and robust ultrasound contrast. Definity® has shelf-life of 2 years and must be stored under refrigerated conditions. Definity has an unpleasant side effect of back pain in about 2% of patients. In some groups, e.g. patients with sickle cell disease, the rate of side effects is much higher, e.g. about 20%. The most likely etiology of the back pain is complement activation. Definity is stabilized by three phospholipids one of which is dipalmitoylphosphatidic acid (DPPA). The investigators in this proposal have shown that DPPA shortens the storage life of Definity and likely causes the side effect of the back pain. Microvascular Therapeutics (MVT) has discovered that not only is DPPA the most rapidly hydrolyzed lipid in the Definity formulation but that DPPA also accelerates the hydrolysis of the other lipids. When DPPA hydrolyzes it forms lyso-PA - a potent stimulating molecule causing inflammation likely responsible for the adverse side effects. MVT has invented a stable, neutral MB (MVT-100). Compared to Definity, MVT-100 is four times more resistant to hydrolysis. In a model of complement-mediated renal retention MVT-100 had fewer bioeffects than Definity ? which should translate into significantly less adverse events. Echocardiography in pigs shows that MVT-100 is comparable, if not superior to Definity, in providing LV opacification and myocardial perfusion contrast. MVT has received guidance from the FDA that MVT-100 can be developed via the 505(b)(2) pathway, no additional animal studies are required;? an accelerated clinical program can be used to lead to approval. MVT-100 will serve as a platform for development of theranostics. Specific Aims: 1. GMP manufacture MVT-100, file IND. 2. Dose ranging study in 32 volunteers (bolus and infusion, Definity vs MVT-100)3. Pivotal study in 61 patients with suboptimal echocardiograms;? significant improvement in LV border delineation in > 85% of subjects. 4. File NDA Rationale: MVT-100 is an improved product. Perfluoropropane is the API and the lipids are excipients in the product. The 505(b)(2) pathway allows for an accelerated approval pathway for such products. Upon NDA submission, typical 11-month review period by the FDA before approval. The development pathway will yield identical label claims as those for Definity. Additional label claims can be pursued later or in parallel. Expected outcomes of research: Development of an FDA approved improved perflutren product, MVT-100 with longer shelf-life (potential for room temperature storage and terminal sterilization ? increasing safety of the product) and decreased adverse side effects. Since the product is electrostatically neutral, MVT-100 will also serve as a robust platform for development of molecular imaging targeted ultrasound contrast agents and theranostic agents.
