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IMPROVED ADVENTITIAL RAPAMYCIN THERAPY FOR PERIPHERAL ARTERY RESTENOSIS

PRECISELY SHAPED ACOUSTIC ABLATION OF TUMORS UNDER 3D ULTRASOUND IMAGE GUIDANCE

ULTRASOUND ABLATION ON BONE CANCER UNDER CT FLUOROSCOPY

IMAGE-GUIDED ULTRASOUND ABLATION FOR PRECISION TARGETING OF PROSTATE CANCER

PREVENTING POST-THROMBOTIC SYNDROME AFTER DEEP VEIN THROMBOSIS WITH PERIVASCULAR ANTI-INFLAMMATORY AGENT DELIVERY - PROJECT SUMMARY POST-THROMBOTIC SYNDROME (PTS) IS A CHRONIC DEBILITATING CONDITION CHARACTERIZED BY LIMB SWELLING, DISCOMFORT, HYPERPIGMENTATION, SKIN ULCERS, AND IMPAIRED QUALITY OF LIFE. WITHIN 2 YEARS OF DEEP VEIN THROMBOSIS (DVT) TREATMENT, 50-60% OF PATIENTS WITH ILIOFEMORAL THROMBOSIS AND 30-50% OF ALL DVT PATIENTS REGARDLESS OF THROMBOSIS LOCATION EXPERIENCE PTS (1). CATHETER-BASED THERAPIES TO REMOVE THE OBSTRUCTIVE THROMBUS HAVE FARED NO BETTER IN CLINICAL TRIALS (E.G. ATTRACT, CAVENT AND CAVA) THAN ANTI-COAGULANT THERAPY ALONE IN PREVENTING PTS ONSET. IN THE NHLBI/NIH-FUNDED ATTRACT RANDOMIZED TRIAL, FOR EXAMPLE, CATHETER-BASED THROMBOLYSIS WITH OR WITHOUT THROMBECTOMY DID NOT REDUCE THE INCIDENCE OF PTS VS. CONTROL ANTICOAGULATION ALONE. IN SUBGROUP ANALYSIS, CATHETER-BASED THROMBUS REMOVAL CONFERRED REDUCED MODERATE-TO-SEVERE PTS IN MORE PROXIMAL (ILIOFEMORAL) DVT (2,3), BUT NO BENEFIT IN EITHER ILIOFEMORAL VEINS WHEN TREATMENT WAS ADMINISTERED LATER THAN 8 DAYS POST-SYMPTOM ONSET (4) NOR IN MORE DISTAL (FEMOROPOPLITEAL) DISEASE REGARDLESS OF TIMING (5). THERE REMAINS A CLEAR UNMET NEED IN THE TREATMENT OF DVT, BECAUSE CATHETER TECHNOLOGIES THAT CLEAR THE THROMBUS BURDEN DO NOTHING TO TREAT THE UNDERLYING VASCULAR INFLAMMATION THAT (A) LED TO THE DVT FORMATION IN THE FIRST PLACE, AND (B) RESULTED FROM THE THROMBUS ORGANIZATION AND RESOLUTION PROCESS. LEFT UNTREATED, INFLAMMATION LAYS DOWN A THICK COLLAGEN LAYER CAUSING FIBROTIC VEIN WALL STIFFENING, DAMAGED VENOUS VALVES, REDUCED VENOUS COMPLIANCE, AND VENOUS INSUFFICIENCY (6,7). PREVENTING THIS SCAR-LIKE PROCESS FROM DAMAGING THE VEIN AND LEADING TO PTS IS THE CENTRAL GOAL OF THIS PROJECT. IN RESPONSE TO THE INFLAMMATORY HYPOTHESIS, A FIELD OF RESEARCH HAS EMERGED TO FIGHT VENOUS INFLAMMATION AND REVERSE THE COURSE OF DVT PROGRESSION TOWARD PTS (8-13), BUT SYSTEMIC DRUG THERAPIES AIMED AT SPECIFIC INFLAMMATORY TARGETS HAVE PROVEN INEFFECTIVE (14). IT HAS NOW BEEN SHOWN THROUGH THE PHASE I RESEARCH PHASE OF THIS PROJECT THAT LOCALLY DELIVERED ANTI-INFLAMMATORY (DEXAMETHASONE) THERAPY IS AN EFFECTIVE MEANS OF BLOCKING COLLAGEN DEPOSITION AND REDUCING THROMBUS BURDEN IN A MOUSE MODEL. IN TANDEM WITH THE PHASE I STTR PRECLINICAL RESEARCH, MERCATOR MEDSYSTEMS HAS LAUNCHED AN OPEN-LABEL CLINICAL TRIAL TO DETERMINE THE EFFECT OF LOCAL DEXAMETHASONE DELIVERY TO PERIVASCULAR TISSUES SURROUNDING VEINS UNDERGOING DVT RECANALIZATION, WITH POSITIVE RESULTS IN COMPARISON TO HISTORICAL DATA FROM THE ATTRACT TRIAL. BASED ON THE PHASE I PRECLINICAL RESEARCH AND THE CLINICAL DATA TO DATE, THE PHASE II AIMS ARE PROPOSED WITH CONFIDENCE. IN THIS PHASE II SBIR PROPOSAL, WE WILL ENROLL A 60-PATIENT, DUAL-BLINDED, RANDOMIZED CONTROLLED TRIAL (SPECIFIC AIM 1) AND FOLLOW PRIMARY AND SECONDARY SAFETY AND EFFICACY SIGNALS (SPECIFIC AIM 2) IN ACUTE DVT TO DETERMINE THE ABILITY FOR PERIVENOUS DEXAMETHASONE THERAPY TO IMPROVE OUTCOMES BETWEEN THE TWO GROUPS. SUBSEQUENT PHASE 3 CLINICAL TRIALS WILL BE POWERED BASED ON THE SIGNALS SEEN IN THIS PHASE 2 TRIAL.

IMAGE-GUIDED TRANSURETHRAL HIFU FOR GENITOURINARY THERAPY

BRONCHO-ADVENTITIAL DRUG DELIVERY: PACLITAXEL FOR BRONCHIAL CARCINOMA

MINIMALLY INVASIVE HIGH INTENSITY ULTRASOUND TREATMENT OF UTERINE FIBROIDS

IMAGE-GUIDED TRANSURETHRAL HIFU FOR GENITOURINARY THERAPY - ABSTRACT STRESS URINARY INCONTINENCE (SUI) IN WOMEN IS AN INCREASE OF PELVIC FLOOR COMPLIANCE WHICH RESULTS IN DECREASED URETHRAL PRESSURE, TYPICALLY THROUGH CHILDBIRTH, AND PRESENTS AS URINE LEAKAGE DURING ABDOMINAL STRAIN. SUI HAS SIGNIFICANT IMPACT ON WOMEN’S HEALTH, INCLUDING AN ASSOCIATION WITH INCREASED LEVELS OF DEPRESSION. CURATIVE OPTIONS ARE LIMITED TO THE INVASIVE SURGICAL INSERTION OF A TAPE IMPLANT WHICH LIMITS THE MOBILITY OF THE URETHRA. BULKING AGENTS INJECTED IN THE PERI-URETHRAL TISSUE ARE A LONGSTANDING EFFECTIVE BUT TEMPORARY TREATMENT. PHARMACEUTICALS ARE RELATIVELY NEW, PROHIBITIVELY EXPENSIVE, AND THERE IS NO TRACK RECORD OF LONG-TERM EFFICACY AND NEGATIVE SIDE EFFECTS CAN OCCUR. APPROXIMATELY 14 MILLION WOMEN ARE RELEGATED TO THE PALLIATIVE APPROACHES OF WEARING ABSORPTIVE PADS OR DIAPERS THROUGH THE DAY. A SUBSTANTIAL CLINICAL NEED EXISTS FOR A NONINVASIVE ALTERNATIVE TO TRADITIONAL SURGICAL APPROACHES WITH THE PROMISE OF LESS MORBIDITY AND RECOVERY TIME, FASTER PROCEDURE TIME, AND LOWER COST. RECENT CLINICAL INVESTIGATIONS OF MINIMALLY-INVASIVE THERMAL TECHNIQUES HAVE DEMONSTRATED TARGETED THERMAL MODIFICATION AND STIFFENING OF PELVIC TISSUE CAN REDUCE SYMPTOMS OF SUI. THESE TECHNIQUES HAVE SHOWN PROMISE, BUT ARE MORE INVASIVE THAN THE CURRENT SURGICAL OPTIONS AND ARE LESS EFFECTIVE. OUR PHASE II DEVELOPMENT STUDY SHOWED ENCOURAGING IN VIVO RESULTS SUGGESTING THAT OUR INNOVATIVE THERAPEUTIC ULTRASOUND CATHETER BASED NONINVASIVE TECHNOLOGY CAN EFFICIENTLY DELIVER THERMAL THERAPY AT THE TARGET TISSUE OF ENDOPELVIC FASCIA WITHOUT DAMAGING SURROUNDING TISSUE (VAGINAL AND URETHAL WALL), BASED ON HISTOPATHOLOGICAL ANALYSIS, WITH DEMONSTRATED CAPABILITIES TO PROVIDE DYNAMIC SPATIAL CONTROL OF SELECTIVE HEATING PATTERNS, WELL-CONTROLLED RADIAL THERMAL PENETRATION, AND FAST TREATMENT TIMES. IN COMPARISON TO EXISTING THERMAL APPROACHES, OUR PHASE II RESULTS CLEARLY DEMONSTRATE A SIGNIFICANT ADVANCE IN TECHNOLOGY AND APPROACH FOR TREATING SUI WITH THE PROMISE OF MORE ACCURATE AND THOROUGH TARGETING OF HEAT-INDUCED COLLAGEN REGENERATION, PROTECTION OF CRITICAL NON-TARGETED TISSUE (E.G., URETHRAL AND VAGINALMUCOSA), SHORT PROCEDURE TIMES, AND THEREBY INCREASING ACCESSIBILITY TO A LARGER NUMBER OF SUI PATIENTS. THE OBJECTIVE OF THIS PHASE IIB PLAN IS TO DESIGN-FREEZE OUR THERAPY APPLICATOR DESIGN AND THEN CONDUCT A GLP IN-VIVO STUDY WITH OUR ULTRASOUND SUI CATHETER AND FDA 510(K) CLEARED THERAVISION® SYSTEM FOR DATA TO SUPPORT A FOLLOW-ON CLINICAL STUDY UNDER FDA GUIDANCE AND TO FURTHER BUILD ADDITIONAL STRONG INTELLECTUAL PROPERTY AROUND THE TECHNOLOGY. MARKET ANALYSES WILL BE CONDUCTED TO DEVELOP STRATEGIES LEADING TO COMMERCIALIZATION. DEVICE DESIGN, BENCH EXPERIMENTS, BIOTHERMAL AND ACOUSTIC MODELING, TOGETHER WITH EXPERIMENTAL TESTING IN BOTH HUMAN FEMALE PELVIS CADAVERIC STUDIES AND AN IN-VIVO GLP COMPLIANT STUDY IN EWES GU TRACT, COMBINED WITH WORKFLOW STUDY WILL BE CONDUCTED TO FREEZE DEVICE DESIGN, EXTENSIVELY CHARACTERIZE DEVICE PERFORMANCE, AND APPLIED TO POTENTIAL TREATMENT APPROACHES IN PREPARATION FOR THE ULTIMATE GOAL OF PRODUCT FINALIZATION AND CLINICAL IMPLEMENTATION. DEVICES WILL BE MANUFACTURED UNDER OUR EXISTING ISO COMPLIANT QUALITY MANAGEMENT SYSTEM.

MINIMALLY INVASIVE IMAGE-GUIDED TUMOR ABLATION IN AN ONCOGENIC PIG MODEL

CRANIALPROGRAMMER: IMAGE-GUIDED DIRECTIONAL DEEP BRAIN STIMULATION PROGRAMMING USING LOCAL-FIELD POTENTIALS

PREVENTING POST-THROMBOTIC SYNDROME AFTER DEEP VEIN THROMBOSIS WITH PERIVASCULAR ANTI-INFLAMMATORY AGENT DELIVERY - PROJECT SUMMARY POST-THROMBOTIC SYNDROME (PTS) IS A CHRONIC DEBILITATING CONDITION CHARACTERIZED BY LIMB SWELLING AND DISCOMFORT, HYPERPIGMENTATION, SKIN ULCERS, AND IMPAIRED QUALITY OF LIFE. IT OCCURS WITHIN 2 YEARS OF DEEP VEIN THROMBOSIS (DVT) TREATMENT IN 50-60% OF PATIENTS WITH ILIOFEMORAL THROMBOSIS AND IN 30-50% OF ALL DVT PATIENTS REGARDLESS OF THROMBOSIS LOCATION (1). EVEN WITH PHARMACOLOGICAL CATHETER-DIRECTED THROMBOLYSIS (PCDT) OR CATHETER- DIRECTED THROMBECTOMY (CDT) AS USED IN THE MOST RECENT CLINICAL TRIALS (E.G. ATTRACT, CAVENT AND CAVA), THERE REMAINS A 40-50% RATE OF PTS. IN THE NHLBI/NIH-FUNDED ATTRACT RANDOMIZED TRIAL, FOR EXAMPLE, PCDT DID NOT REDUCE THE INCIDENCE OF PTS OVER 24 MONTHS, COMPARED TO CONTROL ANTICOAGULATION ALONE. IN SUBGROUP ANALYSIS, PCDT CONFERRED REDUCED MODERATE-TO-SEVERE PTS IN ILIOFEMORAL DVT (2,3), AND NO BENEFIT WHEN PCDT WAS ADMINISTERED AFTER 8 DAYS POST-SYMPTOM ONSET (4). OVERALL, THERE REMAINS A CLEAR UNMET NEED TO EXPAND THE ARMAMENTARIUM OF THERAPIES BEYOND SELECTIVE PCDT IN REDUCING THE CLINICAL AND ECONOMIC BURDEN OF PTS. POST-THROMBOTIC SYNDROME EVOLVES FROM AN INTERPLAY OF MULTIPLE FACTORS: FIBROTIC VEIN WALL STIFFENING LEADING TO DAMAGED VENOUS VALVES AND SUBSEQUENT VALVULAR REFLUX, AND CONTINUED OBSTRUCTION OF VENOUS OUTFLOW DUE TO THROMBUS PERSISTENCE, LEADING TO VENOUS HYPERTENSION. EACH OF THESE OUTCOMES CAN ARISE FROM VENOUS INFLAMMATION, WHICH IS NOW CONSIDERED A KEY IN THE PROCESS OF DETERIORATION TO PTS AFTER DVT TREATMENT (5,6). HYPOTHETICALLY, DRUGS WITH ANTI-INFLAMMATORY PROPERTIES MAY THEREFORE HAVE THE ABILITY TO PREVENT PTS (7-10). IT IS FURTHER PLAUSIBLE THAT ANTI-INFLAMMATORY THERAPY MAY BE MORE EFFICACIOUS IF DELIVERED LOCALLY, CONCOMITANTLY WITH CATHETER-DIRECTED CLEARANCE OF THROMBOSIS (E.G. PCDT/CDT). MERCATOR MEDSYSTEMS IS THE PIONEER IN LOCAL PERIVASCULAR DRUG DELIVERY, PARTICULARLY WITH ANTI-INFLAMMATORY AGENTS SUCH AS DEXAMETHASONE (A POWERFUL, INEXPENSIVE GLUCOCORTICOID). VIA THE BULLFROG® MICRO-INFUSION CATHETER PLATFORM (CURRENTLY AVAILABLE TO TREAT VESSELS OF 2-8 MM DIAMETER), MERCATOR IS DEVELOPING A DEVICE TO TREAT THE LARGER ILIOFEMORAL VEINS, WHICH WILL HAVE DIAMETER UP TO 20 MM. LOCALIZED ANTI-INFLAMMATORY AGENT DELIVERY IS PROPOSED AS A NOVEL THERAPY TO REDUCE THE PROGRESSION TO PTS AFTER DVT TREATMENT. IN THIS PHASE I STTR PROPOSAL, AIM 1 WILL INVESTIGATE THE ANTI-INFLAMMATORY CAPABILITY OF PERIVASCULAR DEXAMETHASONE DELIVERY IN A MOUSE MODEL OF DVT, AND AIM 2 WILL ENGINEER A LARGER BULLFROG® DEVICE FOR HUMAN USE IN UP TO 20 MM-DIAMETER VEINS. AFTER COMPLETION OF THIS PHASE I PROJECT, THE CENTRAL HYPOTHESIS OF LOCALLY DELIVERED ANTI-INFLAMMATORY TREATMENT OF THE VEIN WALL POST-DVT TREATMENT WILL BE INVESTIGATED IN LARGE ANIMALS AND HUMAN TRIALS IN PHASE II RESEARCH.

MINIMALLY-INVASIVE CATHETER-BASED ULTRASOUND FOR PRECISION TUMOR ABLATION IN LUNG

SOFT-FOCUSED HIFU TREATMENT OF COMMON PERONEAL NERVE INJURY

ROBOTIC SYSTEM WITH MULTIPLEXED DOF CONTROL FOR MINIMALLY INVASIVE INTERVENTIONS

BRONCHIO-ADVENTITIAL DRUG DELIVERY: PACLITAXEL FOR BRONCHIAL CARCINOMA

IMPROVED ADVENTITIAL SIROLIMUS THERAPY FOR PERIPHERAL ARTERY RESTENOSIS

ERC-SMALL BUSINESS: ULTRASOUND-GUIDED ROBOTIC BRACHYTHERAPY NEEDLE-INSERTION SYSTEM WITH INTRAOPERATIVE RE-OPTIMIZATION

INTEGRATED PHOTOACOUSTIC ULTRASOUND REAL-TIME IMAGING FOR BRACHYTHERAPY TREATMENT

IMAGE-GUIDED HIGH-INTENSITY INTERSTITIAL ULTRASOUND FOR THERMAL ABLATION OF UTERI