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.