CD&D Contributing Editor

Israel has provided fertile soil for developing a broad range of medical technologies. The reasons are probably several-fold but two of them stand out: Israel is an inherently entrepreneurial culture, given the everyday risk-taking required to live there; and the country has a disproportionately high percentage of physicians, often with innovative ideas that can be turned into commercializable products.

Still another factor is that seed-stage firms in Israel can draw on a variety of incubators formed by the country’s universities, research institutes and government-funded organizations.

Several towns in Israel are home to medical technology companies, chief among them Yokneam and Caesarea. And there is an expanding network of venture capital firms in Israel that invest in high-tech medical products. This sector is beginning to draw increased attention from the venture capital community and corporations in the U.S.

Out of this med-tech hotbed of incubation has entrepreneurship has grown a particularly high number of cardiovascular companies and products, such as stents and other implanted devices, telemetry for heart monitoring, catheter-maneuvering systems, imaging technologies and vascular treatment products.

Peregrine Ventures (Or Yehuda) focuses on seed-stage investments and has financed three of the companies profiled in this article. And as these emerging companies grow, they represent acquisition candidates.

Years ago, Johnson & Johnson (New Brunswick, New Jersey) acquired Biosense (Tirat Ha’Carmel), which has since been renamed Biosense Webster Cordis. This past year, Edwards Lifesciences (Irvine, California) acquired Percutaneous Valve Technologies (Caesarea), and Guidant (Indianapolis) acquired X Technologies (Yavne). Guidant also has been an investor in several cardiovascular device companies.

Stents, other implanted devices

• B-Balloon (Ariel) is developing devices that will allow for quick and successful percutaneous interventions at ostial and coronary bifurcation lesions, two of the biggest unresolved challenges in percutaneous coronary intervention. Ostial lesion procedures account for roughly 5% of coronary interventions, and bifurcated lesions account for about 20% of coronary lesions.

B-Balloon’s devices may also be used in the carotid and renal arteries. They employ innovative delivery systems, including novel balloon designs that enhance the accuracy of stent implantation and reduce the dependence on fluoroscopic imaging. The company’s stents offer improved scaffolding of the treated area, provide support during the procedure and enable future access. Preclinical trials are underway and are showing promising results.

• Neovasc Medical (Or Yehuda) has developed a minimally invasive treatment for patients with ischemic heart disease that are not candidates for revascularization by existing medical procedures.

Neovasc’s Reducer is a stent-like device that is implanted percutaneously through the venous system. It increases the supply of oxygen to the heart muscle and improves cardiovascular function by slowing blood drainage and flow from arteries to the venous circulation. The Reducer is designed to establish a permanent and controlled narrowing of the coronary venous system. It can be implanted in the Cath Lab. Large animal studies have demonstrated elevated intramyocardial pressure, the formation of new blood vessels and increased blood flow in the hearts that were implanted with the device.

The company has received IRB approval, and eight patients have been treated with the Reducer without complication or adverse event. The Reducer has potential for reducing or eliminated chronic chest pain from angina. Guidant (Indianapolis, Indiana) is an investor in Neovasc.

• Elutex (Herzliya) specializes in surface modification of medical implants with current emphasis on cardiovascular stents. It has developed a novel approach to coating vascular stents using its proprietary electropolymerization process which forms an extremely thin (less than 2 microns), highly adherent and stable coating on the stent surface. This process can precisely control the thickness and homogeneity of the stent coating and enhances its drug loading ability. Several hundred stents can be produced under identical conditions.

Elutex is currently using Paclitaxel as the active agent for demonstrating its proof of concept. The company’s electropolymerization process is patent pending in the U.S. and in Europe.

Elutex — founded in Meytav Technological Enterprises Innovation Center — in February of 2007 raised NIS 24 million, the offering oversubscribed by 45%.

• CorAssist Cardiovascular (Yokneam) is developing products for treating diastolic heart failure. Its ImCardia is an elastic self-expanding device attached to the external left ventricular surface of the heart through an off-pump, closed-heart procedure. It applies an outward expansion force to the ventricular wall, thereby reducing the intraventricular filling pressures and improving the diastolic function. The ImCardia device does not require an external power source.

Initial preclinical trials have been completed, and these have demonstrated ventricular pressure reduction and an increase in left ventricular volume. The company is conducting long-term trials prior to initiating pilot clinical trials, expected to begin by the end of 2006.

CorAsst also has developed the Aurora, an elastic device implanted inside the left ventricle in a percutaneous procedure. The device applies direct internal expansion forces distributed on the left ventricle wall and the septum to improve diastolic function. The company in early 2007 reported completing “preliminary” proof of concept work for the Aurora.

• Rafael Medical Technologies (Caesarea Industrial Park) sells in several non-U.S. markets its SafeFlo retrievable vena cava filter that has a spiral design and utilizes shape memory alloys. Unlike other filters, it does not employ hooks or struts for anchoring within the vessel. Its placement is performed using the company’s Space Station fully retrievable intravascular platform that provides repositioning, full control of the delivery procedure, improved stability and reduced vessel trauma. Currently, there are no other retrievable intravascular platforms.

Rafael says that as its FDA-approved IDE clinical trial progresses in the U.S., it will be initiating market-focused studies in leading European medical centers for evaluating various features of the SafeFlo, including long-term retrievability.

The company’s VascuGrasp retrieval system is used for removal of the SafeFlo vena cava filter. Its multiple loop design minimizes the degree of manipulation needed for device retrieval. It can potentially be used as a stand-alone device for capture, retrieval and manipulation of a wide variety of devices and foreign bodies, with applications in the cardiovascular, neurosurgery and urology fields.

The SafeFlo filter and VascuGrasp are CE-marked and clinical trials are ongoing in Austria, Greece, Israel and the UK for the purpose of gaining FDA approval.

• HDH Medical (Migdal Ha’Emek) is developing a hermetic docking head (HDH) vascular device, delivery instruments (insertion tool and forceps) and a suture-less open surgical procedure capable of enhancing the existing treatment of aortic and peripheral aneurysms, arterial occlusions and blood vessel traumas.

The HDH device is used to connect any standard vascular graft to the blood vessels with a diameter greater than 5 mm. Suture-less, migration-free and leak-proof anastomosis can be performed in less than two minutes, even for major vessels, which shortens the cross-clamping time by an order of magnitude, and reduces the operative and post-operative complications.

The company has developed prototypes which have been tested in vitro and in vivo using vascular grafts of three leading graft manufacturers. These test results showed that the HDH device provides a permanent leak-proof anastomosis and fixation reliability.

HDH plans to soon begin trials in humans. The first target market segment is open abdominal aortic aneurysm repair, where there is a significant cost benefit from a shorter time in surgery, fewer operative and post-operative complications, shorter ICU and hospital stays, and fewer blood transfusions needed.

HDH also is targeting the laparoscopic vascular surgery market. It expects that laparoscopic repair using its devices will compete with complex and expensive endovascular procedures which cost from $8,000 to $18,000 and frequently require customization.

• Atria Medical (Caesarea) is developing an implantable device to improve the clinical symptoms and improve the quality of life of patients with congestive heart failure by preventing lung edema and shortness of breath.

The company’s product is an implantable device to reduce the left heart filling pressures, while providing adequate left ventricle function. The device is inserted percutaneously into the right atrium via the femoral vein. After causing an intentional atrial septum defect, the device is attached to the atrial septum opening, so that blood can flow from the left atrium into the right atrium, reducing the left heart filling pressure and implanted in the wall separating the two atria. It is currently in preclinical studies with clinical trials about a year away.

Implanted energy generators

• Sirius Implantable Systems (Mobile Post Hefer) is developing a microgenerator for harvesting the energy of the mechanical movement of the body and body organs and generating electrical energy, which it turn an be harnessed to activate an implanted device.

The company’s initial efforts are directed at using this technology in a cardiac pacemaker that will utilize a continuously regenerating energy source. The device will consist of a miniature energy producing system, a miniature energy storage system, an electronic activation system and integrated electrodes. The device should be activated by the energy derived from the heart itself.

• Impulse Dynamics (Tirat Carmel) is developing electrical therapies for the treatment of heart failure. Impluse R&D is focused on refining the principle and practice of modifying tissue properties and function through the predictable and reproducible delivery of electrical signals.

The company’s flagship product is the Optimizer III, an implantable pulse generator that delivers electrical pulses to the heart for treatment of moderate to severe heart failure. Impulse bills the Optimizer as having the potential to treat those under-served patients with Class III or Class IV heart failure who presently have no other options. The Optimizer delivers non-excitatory impulses to the heart during a period of time called the absolute refractory period. These signals do not initiate the heart to beat — as with a pacemaker — but are intended to modify heart cell function for the treatment of heart failure.

Impulse in June of 2007 reported completing patient enrollment for the FIX-HF-5 congestive heart failure (CHF) study. The FIX-HF-5 study is the company’s largest randomized clinical trial to date and is designed to evaluate the safety and efficacy of the Optimizer.

Cardiac monitoring and imaging

• Remon Medical Technologies (Caesarea) is developing “smart” miniature implants for non-invasive assessment and treatment of a wide variety of medical conditions. The company’s enabling technology utilizes wireless communications to exchange energy and data with miniature devices placed deep inside the body.

Remon is developing HeartLook, a non-invasive home-based monitor of a congestive heart patient’s hemodynamic status for the purpose of identifying high risk patients requiring therapy adjustments prior to hospitalization. Preclinical trials have been successful and it will soon enter human trials. Remon’s Impressure implanted device monitors intra-aneurism pressures following an endovascular graft procedure, allowing physicians to non-invasively conduct a post-surgery assessment of the risk of aneurismal rupture.

The Impressure device is attached to the endograft during graft manufacturing, eliminating the need for a separate implantation procedure. It has been implanted in 21 patients in an ongoing clinical trial in the U.S.

Boston Scientific in 2007 reported an agreement to acquire Remon.

• Biological Signal Processing (Tel Aviv) is a pioneer in the field of high frequency ECG. It recently received FDA clearance for marketing its HyperQ System, a PC-based ECG device that records, analyzes and displays both conventional and high frequency ECG for the detection of myocardial ischemia. The system uses proprietary signal acquisition and processing algorithms and offers a user-friendly interface, numeric readout of the results and graphs that demonstrate changes in the high frequency components of the QRS complex.

A 1,000-patient study showed that critical changes in certain high frequency components of the QRS complex are consistently present with acute myocardial ischemia and are reversed by reperfusion.

Other products under development by the company are the HyperQ rest monitor, a patient monitoring product for bedside and perioperative implementation, and the HyperQ check-up system, a periodic rest ECG check-up device.

• Paieon Medical (Rosh Ha’Ayin), the R&D center of Paieon (New York), works in the field of image processing for interventional cardiology procedures. Its initial product, the CardioOp-B System, is the first commercial 3D imaging system for real time use in cardiovascular procedures. It is a stand-alone, PC-based workstation that connects to the Cath Lab through a DICOM interface.

CardioOp-B allows the interventional cardiologist to use two standard 2D images to reconstruct the desired vessel segment into a 3D image, providing accurate quantitative information such as lesion length, stenosis cross-section area and diameter. CardioOp-B is FDA and CE-mark certified. It is sold worldwide and has formed OEM agreements with Siemens Medical Solutions (Malvern, Pennsylvania) and Stereotaxis (St. Louis, Missouri).

Under development by the company are: CardioOp Guidance which will enable interventionalists to localize therapeutic devices within vessels in real time using the 3D reconstruction as a guide; CardioOp Flow which presents information on the flow of blood across a vessel segment as a means and may be used to assess the significance of a stenosis severity, as well as to evaluate the outcome of treatment; and EP, a 3D reconstruction of coronary veins in bi-ventricular pacing to facilitate the bi-ventricular lead navigation and localization.

• BioScan Technologies (Yokneam) combines laser and ultrasound technologies in one device for use in diagnosing and treating cardiovascular diseases. Its first product, Light-Wire, is a 0.3 mm imaging guidewire that is used as a regular coronary guidewire and provides reconstructed images of a vessel’s internal structure during cardiac catheterization intervention, atherectomy or stent placement. By using a laser to generate ultrasound within a fiber optic, BioScan reduces the size of its ultrasound probe to that of an optic fiber.

Light-Wire is used in coronary arteries to provide diagnostic information such as location, quantity and type of atherosclerotic plaque. Its uses in cardiovascular procedures include angioplasty and treatment of restenosis plaque. It can also be used to facilitate deployment of stents and assess treatment results.

Catheter, stent navigation and delivery

• NaviCath (Haifa) is developing NaviCor and NaviPer remote controlled catheterization systems for use on coronary and peripheral arteries, respectively, and NaviEP for electrophysiology procedures. They provide physicians with a radiation-free tool for navigating catheters and guidewires and offer improved accuracy for stent positioning. They minimize the exposure of the interventional cardiologists to X-ray radiation and the need to wear a heavy lead apron for long hours.

The system has so far been tested in animal trials and in pilot clinical experiments and shown to be feasible for accurate percutaneous coronary intervention with stent implantation.

• F.D. Cardio (Tel Aviv) is developing a novel catheter technology for advancing and maneuvering catheters and stent delivery systems from their front distal therapeutic part for use in interventional cardiology, neurology and other medical interventional procedures. Currently, pushing force is applied by the physician to the rear end of the catheter which is outside the patient’s body.

Using the company’s Front Drive (F.D.) catheters, the physician can apply force to the distal part of the catheter and by so doing advance and steer the catheter to reach and treat blood vessel lesions and sites that are currently unreachable. The front drive mechanism allows for the use of very flexible catheters that can pass through small diameter and curved blood vessels.

Non-invasive vascular treatment

• FlowMedic (Caesarea) is developing a family of medical and consumer devices for the non-invasive treatment of various circulatory disorders of the lower limbs, such as deep vein thrombosis, peripheral arterial disease and related clinical conditions such as critical limb ischemia and intermittent claudication. The products are cauterized by their light weight, portability and ease-of-use for treatment both at home and in the hospital.This proprietary technology increases circulation in the lower extremities by rapidly applying and releasing pressure to the lower limbs, resulting in more effective blood flow to the limbs. Clinical studies are currently being conducted to quantify the efficacy of this therapy.

• NeuroSonix (Or Yehuda) is engaged in the development and commercialization of non-invasive embolic protection technology and devices to be used in surgical and catheter-based cardiovascular procedures.

The company’s first product is the EmBlocker intended to provide embolic protection during cardiovascular surgical procedures, such as coronary bypass grafts, valves and congenital procedures. Clinical studies with the EmBlocker are due to start in mid-2005.

The company in 2007 received the Techno-College Innovation Award from the European Association of Cardio-Thoracic Surgery Techno-College Innovation Award for the EmBlocker, the award established to honor technological breakthroughs in areas related to thoracic and cardiovascular research.

Vascular closure

• CardioDex (Tirat Ha’Carmel) is the developer of disposable vascular closure devices, the Epiclose and Epiclose Plus, that do not use any glue, collagen, suturing or other foreign materials, thus leaving no residual material in the patient’s body.

The EpiClose vascular closure devices are designed for rapid closure of punctures in the femoral artery following catheterization procedures. It is introduced into the vessel through an interventional 6 Fr introducer sheath and employs a balloon inflation/deflation technique that is commonly used in invasive cardiology and radiology. The device has the CE Mark

The Epiclose devices are designed to expedite arterial closure through hemostasis. The process relies on familiar balloon inflation/deflation techniques, which apply selective pressure precisely over the puncture site. The products do not require exchange of the introducer sheath.