BBI Contributing Editor

PITTSBURGH About 45 medical device companies gathered at the Convergence: Drug/Device Summit here in March to make presentations or participate in panels that focused on their initiatives at combining drugs with their devices. This subject has gained great popularity by the success of the drug-eluting stents marketed by Boston Scientific (Natick Massachusetts) and the Cordis (Miami Lakes, Florida) subsidiary of Johnson & Johnson (New Brunswick, New Jersey). A diverse range of medical devices are being considered for the combination with drugs. These include cardiovascular, orthopedic, ophthalmic and general surgical implants. Also participating were companies that employ external energy sources acoustical, electrical (iontophoresis and electroporation) and thermal to deliver drugs. Drugs needed for drug-eluting medical devices usually are intended for reducing the incidence of thrombosis, inflammation and infection.

There are major differences between the pharma and med-tech industries, which present formidable challenges for device companies seeking to add a drug to their products. These differences include the technical skill sets, regulatory processes, cost and duration of development, and the size of the commercial opportunities. There are only a few billion-dollar medical devices, as contrasted with many in the drug sector, but the risk is lower, the approval process is typically much faster and the development cost much lower for devices. A technical hurdle is achieving a uniform application of a drug to a device when scaled up to full production. Analysts and bankers have a dilemma in how to value companies that are developing combination products. It was noted during the conference sponsored by the Advanced Medical Technology Association (Washington), Biotechnology Industry Association (also Washington), Pittsburgh Life Sciences Greenhouse and Windhover Information (Norwalk, Connecticut) that these combination products should not be viewed simply as drug delivery systems but that the therapeutic value of the medical device also needs to be considered.

Paul LaViolette, chief operating officer of Boston Scientific, provided an overview of the development program for the Taxus drug-eluting stent. He gave a sobering account of the cost and effort needed to develop drug/device combination products, estimating the cost for developing the Taxus stent at $750 million, compared to $20 million to $50 million for developing a bare stent. A typical cost range for developing a medical device was placed at $3 million to $10 million, compared to developing a drug, which was projected at $1.1 billion.

Cardiovascular combination products

Afmedica (Kalamazoo, Michigan) is in pre-clinical trials with a sirolimus-impregnated bioresorbable polymer for use in a drug-eluting wrap that is placed around the outside of a blood vessel or graft to prevent excess scarring during the healing process and allow normal blood flow inside the vessel or graft. The polymer, known as PEA, is a polyamino acid that is currently used as an adjuvant in vaccines. It adheres to blood vessels due to its thermoplastic property. It is licensed from MediVas (San Diego, California).

Potential applications for this technology include prolonging patency in patients undergoing peripheral vascular surgery and in vascular access sites in patients requiring hemodialysis for end-stage renal disease, reducing stenosis following coronary artery bypass grafting surgery and endarterectomy procedures, and preventing adhesion formation after surgical procedures.

ImaRx Therapeutics (Tucson, Arizona) uses nanobubble technology to diagnose and treat cardiovascular disease, cancer and diseases of the central nervous system. The company's presentation focused on the convergence of its nanobubbles and ultrasound, called SonoLysis, for the "NanoInvasive" treatment of thrombosis. Its lead product, MRX-815, comprised of perfluoropropane gas-filled nanobubbles, is entering a Phase II trial to dissolve clots in patients with acute ischemic stroke. SonoLysis uses acoustic activation to extend the current treatment window for these patients from three hours to up to nine hours following the onset of stroke.

Additional applications planned by ImaRx for this technology are for the prevention of stroke by treating vulnerable plaque, opening the blood-brain barrier, and delivering drugs and genes to treat cancer. ImaRx is collaborating with several academic institutions and companies, including Guerbet in France, in developing a targeted magnetic resonance contrast agent.

X-Cell Medical (Monmouth Junction, New Jersey) is developing a drug-eluting stent (DES) using the Bravo drug delivery polymer matrix from SurModics (Eden Prairie, Minnesota) that is used in the Cypher DES from Cordis. The polymer is coated on the R stent from Orbus Medical Technologies (Fort Lauderdale, Florida). The company is in a Phase I trial with a stent that is coated with a polymer impregnated with 17beta-estradiol, which promotes endothelialization and is used commercially for post-menopausal hormone therapy.

Preclinical studies also are under way with a polymer-coated stent containing a new chemical entity, PDGF receptor kinase inhibitor.

NOvoVascular (Walnut Creek, California) develops technologies for coating the surfaces of medical devices to help prevent blood clot formation, tissue growth and infection. The company is developing a DES for the treatment of peripheral vascular disease. Sodium nitroprusside is incorporated into a polymer matrix for use as a generator of nitric oxide. The polymer is coated onto the aSpire stent and controlled expansion delivery system that is licensed from Vascular Architects (San Jose, California). Nitric oxide occurs naturally in the body in a gaseous state and is known to exhibit anti-platelet, anti-proliferative and anti-inflammatory properties.

Angiotech Pharmaceuticals (Vancouver, British Columbia) is a leader in the drug/device arena with its development of the paclitaxel-releasing Taxus stent sold by Boston Scientific. The Taxus stent has been implanted in more than 1 million patients worldwide and is claimed to be the most successfully launched medical product of all time.

Paclitaxel also is being used in clinical trial programs for peripheral vessels in a co-exclusive licensing agreement with Cook (Bloomington, Indiana) and Boston Scientific, and in a vascular wrap. Proof-of-concept work is underway in drug/device combinations for use in preventing surgical adhesions (using pegylated drugs) and in a non-vascular stent.

Angiotech reported at the conference an exclusive license with CABG Medical (Minneapolis) for use of its technology to treat restenosis and proliferative disease through the local delivery of paclitaxel. CABG Medical is developing the Holly Graft System, which is designed to eliminate the need during a coronary artery bypass procedure to perform a second surgery to harvest vessels from the chest, legs or arms. The Holly Graft System consists of a thin-walled and flexible vascular graft made of expanded Teflon (polytetrafluoroethylene) that is attached to coronary arteries using one or more vessel connectors and a titanium flow limiter to control flow and pressure. The vessel connector will use a drug combination that includes paclitaxel.

Polymer-containing drugs for coating implants

SurModics described its Bravo non-biodegradable drug delivery matrix as a blend of two polymers with mechanical properties that can be controlled by adjusting the polymer ratio. Earlier this year, the company acquired InnoRx (Mobile, Alabama), which has an ophthalmic drug delivery system for treating ocular diseases. Its lead product is an intravitreal implant that releases triamcinolone acetonide over a two-year period into the posterior chamber of the eye for treating age-related macular degeneration and diabetic macular edema. An investigational new drug application has been filed for this product, and authorization is awaited for initiating clinical trials. SurModics offers seven families of polymers that are available for use in site-specific delivery of drugs to the eye.

TyRx Pharma (Monmouth Junction, New Jersey) is in collaboration with Boston Scientific to develop a biodegradable coating for its Taxus drug-eluting stent. TyRx's core technology is its tyrosine-based resorbable polymer licensed from Rutgers University (New Brunswick, New Jersey). The company is developing surgical products, such as a mesh for inguinal hernia repair, containing an antimicrobial agent for preventing post-implant infection, and general surgery drug-eluting analgesic/anesthetic products to provide post-implant pain management.

Interface Biologics (Toronto) described its capabilities in programming devices to utilize body mechanisms and to harness these mechanisms to turn on and off drug release, making it possible for a device to respond to specific events in vivo. The company seeks to commercialize two novel biomaterials. Epidel is a biodegradable polymer that incorporates drug monomer components into its backbone, allowing for surface erosion over an extended period. The components can be designed to allow for release of drug by the host in response to a clinical event. The company is using this systematic bioresponsive approach to customize its materials for exit site infection applications by using different quinolone drugs.

Kinesyx is a low-molecular-weight block copolymer comprising fluorinated tails that bloom to the first 10 nanometers of the surface of the base polymer in admixture. This technology is being developed for use in peripheral stent applications. The molecule can act as a bioactive agent for the delivery of peptides, oligonucleotides and other cell initiators. The molecule becomes part of the base biomaterial and, unlike coatings, is not prone to delamination.

Polymerix (Piscataway, New Jersey) is developing PolymerDrug technology in which up to 90% of a drug by weight is contained within the backbone of a polymer. The rate and duration of drug release is controlled by varying the linker, bond types and/or the size and shape of the product. A family of PolyNSAIDs has been created from salicylic acid and other FDA-approved nonsteroidal anti-inflammatory drugs (NSAIDs) and have been found to be highly durable, flexible and adhesive to metals used in medical implants. PolyNSAID microspheres are being developed for sustained local relief of inflammatory pain from arthritis and for treating post-operative pain.

Orthopedic drug/device application

pSivida (Perth, Australia) has developed BioSilicon, a nanostructured drug delivery system that is based on elemental silicon (the same material that is used on microchips). BioSilicon allows drug molecules to be held in nanosized pockets that release tiny pulses of drugs as the BioSilicon dissolves. The rate of dissolution can be "tuned" so that delivery can be achieved over days or months.

The company's subsidiary, pSiMedica (Worcestershire, England), is collaborating with Dr. Susan Anderson at the University of Nottingham (Nottingham, UK) on the use of BioSilicon composites for constructing biodegradable orthopedic devices such as screws, pins and plates. Studies have shown that the addition of low levels of BioSilicon can encourage bone to grow (osteoinduction) by inducing the growth of calcium phosphate and enhance collagen production by osteoblasts.

Energy-driven drug delivery systems

Ichor Medical Systems (San Diego) has developed the TriGrid delivery system for use in administering DNA drugs. The promise of DNA drugs has not been realized due to inadequate delivery technologies. The TriGrid system is a hand-held device that uses pulsed electric fields (electroporation). Using pushbutton activation, the delivery takes less than five seconds, and it has been shown in animal studies to greatly increase the uptake of DNA into targeted cells.

The company plans to investigate the use of its delivery system for DNA vaccines to treat infectious diseases (e.g., anthrax), for cancer therapy (melanoma, breast and prostate cancers), and for delivering DNA encoded with a therapeutic protein (IFN-beta) to treat multiple sclerosis.

Light Sciences (Snoqualmie, Washington) is using Light Infusion Technology (Litx) that comprises a light-emitting diode (LED) and a proprietary photoreactive agent, LS11, that is activated with non-coherent light at 644 nm. The target for Litx is small poorly formed blood vessels that support the development of abnormal tissues in proliferative diseases.

The company has operating units in three therapeutic categories and plans to spin each of them off as a separate company. Light Sciences Oncology has completed enrollment for a Phase II clinical trial for treating refractory, stage 3 and 4 solid tumors using a percutaneous approach. The LED is placed inside the tumor and creates singlet oxygen, which is the active agent that attacks the neovasculature. Visient Therapeutics is in a Phase I/II trial using targeted light to induce rapid neovessel closure for treating wet age-related macular degeneration. Vascular Reconditioning is focused on interventional cardiology and is targeting atherosclerosis and vulnerable plaque.

Transport Pharmaceuticals (Framingham, Massachusetts), a virtual company under the management of neXusTherapeutics (also Framingham), is developing a system that utilizes iontophoretic technology for delivery of topical drugs. The initial application is for delivering high doses of acyclovir for treating herpes labialis (cold sores) and is licensed to GlaxoSmithKline (London).

The technology is applicable to multiple dermatological diseases by delivering medication locally through the skin. The system consists of a reusable, hand-held control unit and a small, disposable hand-held device and a single-use pre-filled cartridge that allows patients to self-administer topical drugs.

Nanomagnetic particles for drug delivery

Biophan Technologies (West Henrietta, New York) recently established a subsidiary, Nanolution, to leverage its patented discoveries in nanotechnology and nanomaterials for drug delivery and drug elution from the surfaces of medical devices. The first application being developed by Nanolution is targeted drug delivery based upon nanomagnetic particle technology. This technology was originally developed by Biophan for addressing problems of MRI visibility and compatibility of medical devices. The individual particles can be tuned to provide a uniquely identifiable signal under MRI, which is the basis for Biophan's NanoView contrast agent that is currently being developed.

The drug also can be bound to nanomagnetic particles that can be activated by the application of energy at specific wavelengths for selective drug delivery. Particles can be targeted to a site by employing an external magnetic field. It is envisioned that a drug-eluting device can be reloaded in situ by using a controlled electromagnetic field. Nanomagnetic particles are being investigated for use as medical device coatings and for administration in guided drug delivery.

Pulmonary drug delivery systems

Alexza Molecular Delivery (Palo Alto, California), co-founded by Dr. Alejandro Zaffaroni, has developed a patented thermal method for delivering drugs systemically through the lungs using a pulsatile mechanism, referred to as Staccato technology, and yields pharmacokinetic properties similar to intravenous delivery. The rapid onset of action provided by Staccato technology is due to the almost instantaneous absorption of the pure drug that is inhaled. It is possible to deliver water insoluble compounds without the need for formulation excipients. The system employs rapid heating (300 milliseconds to 400 milliseconds) of a drug that is coated on a metal substrate to generate drug vapor which quickly cools and condenses to form a drug aerosol with particle sizes (1 micron to 3 microns) appropriate for systemic delivery via inhalation. The company has completed a Phase 1 trial of AZ-001 for the treatment of migraine headaches.

Aerogen (Mountain View, California) featured its OnQ aerosol generator technology for aerosolizing liquids, its Aeroneb nebulizer, and an aerosolized antibiotic product is in a Phase II clinical trial for treating ventilator-associated pneumonia.

Aradigm (Hayward, California) reviewed its AERx pulmonary hand-held device for delivering liquid aerosols through the lungs for both respiratory and systemic applications. The AERx system consists of a disposable pre-filled strip with an integral nozzle from which a drug is aerosolized upon activation. Initial products being developed are for treating pain and diabetes, and for pulmonary diagnostics.

Aradigm also presented its Intraject pre-filled, needle-free delivery device for administering liquid formulations. The actuator consists of a nitrogen gas-powered ram and piston for pushing the drug through the skin and into the subcutaneous tissue.

MAP Pharmaceuticals (Mountain View, California) is developing the Tempo inhaler, described as the next-generation pressurized metered dose inhaler, designed for the pulmonary delivery of respiratory and systemic drug therapies. The device incorporates a synchronized trigger and flow control chamber that enhances patient compliance by reducing sub-optimal dosing and providing more reliable dose-to-dose consistency. The initial product is for delivering budesonide, which is in a Phase II trial in asthmatic patients.