BB&T Contributing Writer

There are more than 21 million diabetics in the U.S. today. While the majority can control their disease with careful management, more than 3 million of them fall into the serious Type 1 category requiring insulin.

These patients in the Type 1 category can stave off the complications of this disease through tight glucose control via intensive therapy requiring frequent subcutaneous insulin infusion as was shown in two major studies, the Diabetes Complications and Control Trial, and the UK Prospective Diabetes Study.

The intensive approach, however, thus far requires methods that factor heavily against compliance: the daily “fingersticks” required to measure glucose and the delivery of insulin via injections. Thus, the major efforts at innovation in this field have focused on carrying out these activities non-invasively and more discretely to offer better compliance and self-management.

Finding alternatives to "fingersticking" has been extremely frustrating. The newest alternatives involving insertion of sensors beneath the skin — less invasive, but still requiring puncture of the skin and potential infection.

Greater progress over the past year has been seen in the realization of alternatives to insulin injections — with hopeful developments being explored for the near-term future.

On the drug side, Exubera, the first inhaled insulin was FDA-approved in early 2006, a joint development of Pfizer (New York) and Nektar Therapeutics (San Carlos, California), adapting the drug to the inhaler device.

Other companies in Phase III clinical trials of inhaled forms of insulin are: Eli Lilly (Indianapolis) together with Alkermes (Cambridge, Massachusetts), Novo Nordisk (Bagsvaerd, Denmark) together with Aradigm (Hayward, California), and Mannkind (Valencia, California).

Other technologies and development programs being explored for alternative insulin delivery include the transdermal, oral, nasal and buccal.

They want to 'pump' diabetics up

Needle injection remains the most common form of insulin delivery, but the most advanced system with the most common use today is the pump. And a majority of clinicians in the field believe that insulin pumps offer the advantages of automatic compliance and thus far better control, as demonstrated in a host of studies.

Ambulatory pumps offer great convenience to insulin-dependent patients. The market for these pumps is growing, which has led to acquisitions of MiniMed (Northridge, California) by Medtronic (Minneapolis) and Animas by Johnson & Johnson (New Brunswick, New Jesey). Also competing in this market are Smiths Medical (St. Paul, Minnesota), a unit of Smiths Group (London), and Disetronic Medical Systems (Burgdorf, Switzerland/St. Paul, Minnesota) which plans to enter the U.S. market sometime this year.

Following are some other companies pushing advances in pump technology:

• Insulet (Bedford, Massachusetts) markets the OmniPod pump for continuous subcutaneous insulin delivery. It is a small, lightweight (1.2 ounces) self-adhesive device that is filled with insulin by the patient and adheres directly to the body for up to three days. This feature makes it more discrete than most insulin pumps that clip to a belt or fit in a pocket.

The OmniPod delivers precise, personalized doses of insulin based on instructions programmed into the Personal Diabetes Manager (PDM), a wireless handheld device that incorporates a FreeStyle blood glucose monitor from Abbott Laboratories (North Chicago, Illinois). Thus, patients can both control insulin delivery and check blood glucose levels. The OmniPod Insulin Management System received 510(k) approval in January 2005.

The OmniPod pump received a code from the Centers for Medicare and Medicaid Services for billing as durable medical equipment and is working with Medicare to establish a pricing model for the OmniPod which is being marketed in the northeast region of the U.S.

The OmniPod is sold directly to patients by Insulet's own sales force. A startup kit costs $800 and includes a PDM remote controller, two OmniPods and training information. The manufacturer's list price is $32.50 per OmniPod which is packaged 10 to a box.

The company is vertically integrated from manufacturing through sales. Insulet claims that the cost of its pump is comparable to non-disposable pumps based on their four-year warranties, after which a replacement pump would be purchased.

Insulet has raised $120 million to date and is now pursuing an initial public offering.

• M2 Medical (Hellerup, Denmark/Sunnyvale, California) is developing an insulin pump. The company has kept a low profile. Its product is believed to be a syringe pump that contains a prefilled insulin cartridge. A principal advantage is its ease of use because it is prefilled. Senior management comes from MiniMed. The company has completed several rounds of venture capital financing. Insulin is M2 Medical's initial drug of interest; however, the device is intended to ultimately be used for delivery of other peptides and proteins.

• SreadyMed is a development-stage incubator within the Profile Group of Companies (Toronto). It has completed a feasibility study of the concept for its pump and has a working model, with initial focus on delivery of a drug, such as morphine, for pain control. It can also be adapted to insulin delivery and can hold 3 cc's of insulin, sufficient for three days.

The pump is designed in three layers — a polymer laminated foil pouch containing the drug above which is a disposable battery which is topped by a plastic cover having a button in the middle. It weighs only 22 grams when empty. A needle for subcutaneous administration is on the bottom of the pump. The pump can be worn anywhere on the body, and it can be designed with a tube extending out of the side that can be connected for intravenous delivery. The company says it will offer a separately colored pump for each drug.

It plans to file a 510(k) with the FDA and is seeking a corporate partner to assist in initiating clinical trials.

Pumping with disposability, discretion

Insulin pumps recently have entered a newer generation with the addition of disposable components being developed by several companies. They are all seeking capital, whether from angels, venture capital firms or by an equity offering to the public.

• TheraFuse (Carlsbad, California) is developing a disposable pump that employs a unique non-contact optical flow sensor for precisely measuring fluid flow rates with better than 3% accuracy. The technology uses a pair of miniature lasers to detect flow in a small tube. Flow rate changes are controlled by sizing the cross-sectional geometry of the flow tube, allowing precise delivery over the range from 30 nanoliters (.003 Units of insulin) to 100 microliters (10 Units of insulin).

The pump has three main components: a disposable insulin-containing dose-pad, a reusable dose-chip that mates with the dose-pad at the time of use to control the delivery of the insulin, and a handheld programmer for both bolus and basal dosing.

TheraFuse also has technology for interstitial fluid analyte monitoring for potential use as a combination therapy product for glucose monitoring and insulin delivery. Although the company's primary program is for insulin delivery, the disposable pump has application for use in pain management.

The principal advantages of TheraFuse's product are claimed to be improved safety and accuracy, improved convenience and better economics. The improved safety is in its detection of occlusion in seconds (pumps take up to eight hours) and improved air in-line detection (not available on marketed pumps). The improved convenience is in the form of a much smaller, thinner product (about 8 mm thick) and a vacation mode which allows the user to remove the product for up to two hours once per day for athletics, intimacy, etc. Better economics is achieved by putting the more costly components in the reusable part and disposing of the reservoir and the associated plastic housing.

Therafuse was awarded a Phase I Small Business Innovative Research (SBIR) contract in December 2005 from the U.S. Department of Defense for a project entitled "Miniature Disposable Drug Infusion Pumps with Improved Safety Features and Embedded Computer Control." More recent funding came from a venture capital firm, and the company is seeking to raise additional capital.

• Valeritas (Shrewsbury, Massachusetts), a spin-off from BioValve Technologies (Parsippany, New Jersey) has received FDA 510(k) clearance for its h-Patch, a fully disposable micro-infusion system that can deliver insulin either as a basal only (continuous) rate for 24 hours or as a basal combined with patient controlled bolus. It is targeted for Type 2 diabetics. The h-Patch fills the gap between multiple daily injections and intensive therapy using complicated pumps. The company anticipates the launch of its h-Patch before the end of this year. It claims to have multiple partnerships with global pharmaceutical companies, although they are not disclosed. In 2008, it plans to pursue reimbursement for a prefilled insulin h-Patch and to explore the use of its h-Patch to deliver other drugs.

In August 2006, Valeritas reported plans to become a public company by merging into a Special Purpose Acquisition (SPAC), titled Paramount Acquisition Corp. This transaction was not consummated, however.

• Debiotech (Lausanne, Switzerland) has developed the NanoPump for the hospital market, but it has not been commercialized. Animas had previously acquired rights to Debiotech's NanoPump for insulin delivery, but these rights have been returned and Debiotech is still seeking to outlicense the product.

The NanoPump employs Micro Electro Mechanical Systems (MEMS) technology for control of the pumping mechanism. Each pump actuation injects 200 nanoliters of drug with 2% reproducibility. The pump can detect occlusion and air bubbles within a few actuations.

Its safety features include a closed fluidic path at rest, an anti-free-flow system, permanent functional monitoring and a ventilated reservoir. The NanoPump is semi-disposable. The cartridge (reservoir with 3 ml capacity) and the pumping mechanism are disposable, but the electronics are reused. The company has started the process of transferring the MEMS technology for mass production which will take several months. FDA approval is possible in the second half of 2007 or in 2008.

From 'pumping' to 'patching'

Patches have been used for some time in drug delivery. And a patch for the delivery of insulin provides even more disposability and discretion than the pump, and so is one of the newest applications being explored in this sector.

• Starbridge Systems (Swansea, UK), on the southern coast of Wales, is developing the disposable Starlet patch which combines a micro-pump and drug reservoir that can be used for three to nine days and a reusable power source for seven days duration. The device uses proprietary miniature mechanical drives that provide accurate liquid flow rate control and can be filled at the point-of-use.

Starbridge says it plans to file for a 510(k) with the FDA and for CE marking in Europe for its Starlet patch and is planning European launch in mid-2007, U.S. launch in 2008. Although insulin delivery is the primary focus of Starbridge's development program, fertility drugs represent another potential application of its Starlet patch.

Most of the company's funding came from angel investors, but it has also received funds from the National Endowment for Science, Technology and the Arts. It is seeking additional capital.

• Encapsulation Systems (Broomall, Pennsylvania) is developing the U-Strip, a disposable drug delivery patch that is activated using ultrasound. It can be used to deliver large molecules and the first application being pursued is for daily insulin delivery.

The U-Strip is comprised of four components: disposable patch cap that contains the drug in an absorbent pad, ultrasonic transducer couple which dilates the skin's pores and pushes the drug through, sonic applicator that controls the device which is the size of an iPod and fits on the patient's arm or waist, and 9-volt battery. It is portable and can provide basal and bolus insulin. The U-Strip contains 100 units of insulin.

Encapsulation Systems is conducting pilot Phase I trials on 25 Type 2 diabetic patients and plans to enter a 250-patient Phase II trial in 5 geographic areas. It estimates that it is 18 months away from a 510(k) FDA submission.

The company claims that ultrasound causes no damage to the skin or drug and is safer than electroporation which causes the insulin to boil and iontophoresis which denatures insulin. The U-Strip can be used to deliver drugs that cannot be delivered through conventional transdermal pouches.

• Medingo Medical Solutions (Yoqneam Illit, Israel) is developing the Solo miniature insulin dispensing patch that uses no tubes. This device allows simple disconnection, saves insulin, and is safe to use. The Medingo insulin dispensing patch is a discreet and lightweight insulin dispenser that is easy to maintain. It adheres to the skin underneath clothing at any desired location on the body, without cumbersome tubing or connections, allowing patients to perform daily activities without interruption. As an added safety feature, the device has an occlusion sensor which alerts the patient a few minutes after occlusion.

The Solo system comes in two parts, a miniature dispensing patch unit and a separate remote control unit which allows the patient to program the system and deliver insulin remotely. The remote control includes an integrated blood glucose monitor which avoids carrying another glucometer device.

The Solo insulin dispensing patch should be reimbursable because it meets current Medicare-allowable payments and codes.

Leading Israeli companies are shareholders of Medingo Medical Solutions. They are Given Imaging (Yoqneam), Elron Electronic Industries (Tel Aviv) and Rafael Development Corporation (Yoqneam Illit). The company is seeking additional funds via a public offering.

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