Insulin Pumps: You’ve come a long way, baby!

In the Beginning

The first attempt at a “portable” insulin pump was made back in the 1960s by Dr. Arnold Kadish, a private doctor in Beverly Hills, CA. His backpack-sized contraption (pictured below) was in some ways years ahead of its time, ambitiously seeking to act as an artificial pancreas—which is still considered to be the holy grail of this field—through a closed-loop insulin delivery system consisting of an adapted lab Autoanalyser to measure blood glucose, a venous blood circuit and a servo-mechanism pump. While this represented an important proof-of-concept, the system’s size, complexity and its dependance on intravenous access made it impractical.

Kadish artificial pancreas from 1960s

Kadish artificial pancreas from 1960s

Things really began to take off in the 1970s, with major progress being made both in developing a practical, portable insulin pump and in validating its cinical use. Prof. John Pickup (King’s College, London) is regarded by many as the father of pump insulin pump therapy for his pioneering work as a research fellow at Guys Hospital, London, where he developing a simple, portable pump (159g—pictured below) for continuous subcutaneous insulin infusion (CSII), providing both basal therapy and a pre-set bolus dose.

Insulin pump from the 1970s developed by John Pickup at Guys Hospital, London, by John Pickup.  The button on the end was pressed to deliver the meal-time bolus, fixed at 8 times the basal rate for 15 min.  This pump is now in the Science Museum in London.

Insulin pump from the 1970s developed at Guys Hospital, London, by John Pickup. The button on the end was pressed to deliver the meal-time bolus, fixed at 8 times the basal rate for 15 min. This pump is now in the Science Museum in London.

Previous pumps had delivered insulin intravenously, which is not suitable for long-term therapy due to the risks of septicaemia and thrombosis. Pickup began clinical use of his device in 1976 and two years later the BMJ published his seminal paper describing CSII for achieving long-term diabetic control.

Around the same time, other groups were also active in this area, giving rise to a little trans-Atlantic rivalry. Perhaps most famously, US-based Dean Kamen (also the inventor of the Segway and the HomeChoice peritoneal dialysis system) developed his AutoSyringe portable drug infusion pump in the mid-1970s, which was initially used for chemotherapy and neonatology and later adapted for insulin therapy.

Insulin Pumps in T1D

Over the years, insulin pumps have continued to improve in terms of size/portability, ease of use, functionality and reliability. Today, pumps for CSII can fit in the palm-of-the-hand and are considered to be the gold standard therapy for type 1 diabetes (T1D) patients. Insulin pumps are a major medical device product segment generating $2.5 billion in annual global sales and growing at 15% per year—making this the second-fastest growth segment in diabetes products.

The benefits of pump therapy for T1D (ie, insulin dependent) patients are well established (eg, Cochrane Review and the DCCT trial). Due to the more physiologically compatible profile of insulin delivery compared with multiple daily injections (MDI), pump therapy leads to better glycemic control (A1C) and fewer hypoglycemic events (eg, NICE review) while offering greater accuracy and patient convenience.

In light of this, most countries offer pump therapy to eligible T1D patients, with utilization rates ranging from around 40% in the US (estimated to grow to 50% by 2018) to an average of 15% in Europe. Ironically, given its role in pioneering pump therapy, the UK is a notable laggard, currently at around only 7%. However, NHS primary care trusts have a statutory obligation to provide funding for insulin pumps and UK clinical guidelines provide clear eligibility criteria for T1D patients having (1) frequent hypos, causing “persistent anxiety” or (2) A1C levels above 8.5%. As awareness of this expands, helped in part by greater patient demand and advocacy by groups such as INPUTdiabetes, UK adoption rates are expected to converge with European norms.

Patch Pumps in T1D

For the past couple of decades, the MiniMed pump (Medtronic) has held a dominant market-share in insulin pumps based on a strong body of clinical evidence on the benefits of pump therapy and through leadership in integrating pumps with continuous glucose monitoring (CGM). However, more recently, traditional tubed pumps like the MiniMed Paradigm, Spirit (Roche) and Animas (J&J) have been severely challenged by smaller, more discreet body-worn “patch pumps”. The market pioneer in this category has been Insulet, which launched in 2005 its first generation patch pump, the OmniPod. A couple of years later, loss-making Insulet completed its IPO on NASDAQ, after reporting 2006 sales of $3.6m with a cost of goods sold of $15.6m (practically shipping dollars with every pump sold). The IPO raised nearly $120m in funds at a market cap of around $385m; on top of nearly $120m in venture funding that had already been invested.

Since its launch eight years ago, OmniPod—until now the only patch pump available for T1D—has captured a 10% share of the overall insulin pump market, with annual sales growth of over 30% in recent years. But this growth has come at a price, as historically Insulet has suffered from a high cost of goods in producing its 3-day disposable pump—which is why in the full year 2012 the company was still loss making (operating loss of around $36m) despite substantial annual sales of over $210m. Nonetheless, investors don’t seem to mind much, giving this loss-making company a current market cap of over $1.7 billion, which values the business at a hefty 8x historical sales. The company and its investors appear to be hopeful that, following the launch earlier this year of its smaller and cheaper (to produce) Gen2 OmniPod, light is finally visible at the end of the long tunnel to profitability.

One of the questions around patch pumps has been what, if any, clinical benefits these devices might provide, beyond mere convenience. Work by Dr Howard Zisser (Sansum Diabetes Research Institute, Santa Barbara, CA) suggests that patch pumps have the potential to offer improved glycemic control over conventional tubed pumps due to the fact that tubed pumps may have to be disconnected for activities such as swimming, bathing, participating in sports or intimate moments, whereas patch pumps are more suitable for such purposes—thereby avoiding the need to disconnect, which has been shown to result in a rise of 1 mg/dl in blood glucose for each minute that insulin delivery is interrupted.

Cellnovo

Competition in the patch pump space will soon heat up. Several new entrants—such as the Cellnovo system, the JewelPump from Debiotech and, possibly, the SOLO from Medingo/Roche—are expected to be launched over the next year or so.

Offering the world’s first mobile-connected diabetes pump system, Cellnovo (pictured below) has the potential to be a game-changer—which is why my fund NBGI Ventures has backed the company (where I’m also a board member). Cellnovo integrates a highly accurate, small patch pump; a proprietary color touch-screen controller having an integrated blood glucose test-strip reader and providing a platform for a range of diabetes managment apps; and mobile data connectivity and web-based remote monitoring.

The Cellnovo mobile diabetes management system

The Cellnovo mobile diabetes management system

An example of just one useful feature is the automated bolus calculator, which provides bolus dosing recommendations based on values obtained from its integrated blood glucose meter and its food journal app for counting and tracking carbs intake. This type of “automated bolus advisor” provides not only convenience, but has also been shown to improve glycemic control, as demonstrated by the ABACUS study.

Mobile connectivity will automate data collection around important parameters such as insulin dosing, blood glucose values, physical activity and food/carb intake. This will liberate patients from paper-based record-keeping while providing accurate and complete information to physicians and timely alerts to parents and carers.

With its minimalist sleek lines, discreet size, graphical touchscreen interface, and automated wireless connectivity—the Cellnovo system looks more like an aspirational high-end consumer electronic device than a clunky medical product. In a patient-centric world, intuitive usability and appealing aesthetics are important considerations for a device that will be worn and used 24/7.

A recent research report by the investment bank Canaccord Genuity noted that, with its CE marked system and an initial commercial launch expected later in 2013, “Cellnovo is the closest competitor to Insulet”. Of course, as ever, the market—and patients in particular—will be the ultimate arbiter. Meanwhile, we can all take satisfaction in seeing how much these devices have evolved since their early, awkward beginnings fifty years ago, bringing meaningful improvements to the lives of hundreds-of-thousands of patients. The future will surely deliver even greater gains, with promising work already underway in implantable pumps, improved CGM technologies integrated with closed-loop systems (more on these later), prefilled insulin cartridges/pumps, and enhanced integration across a range of wireless devices.

Diabetes: Game On

Afflicting nearly 350 million people worldwide, diabetes is a lifelong condition that can be effectively managed, but not yet cured. Prevalence is set to dramatically rise in developing countries, as greater numbers of people adopt a Western lifestyle, with all its attendant consequences. This will place an increasing burden on health systems everywhere, posing a major policy and delivery challenge. Research by the consultancy firm Booz Allen highlights the magnitude of this issue, noting that “diabetes is the most expensive disease cost-wise in the U.S.”, accounting for one-out-of-four of every health care dollar spent. The direct medical cost of treating diabetes is only the tip of the iceberg, with billions of dollars of additional indirect costs incurred due to lost productivity and social welfare support.

Diabetes is also big business. The global diabetes products market was estimated to be over $40 billion in 2010, and is expected to grow to nearly $120 billion by 2018. Blood glucose (BG) test strips alone accounted for $10 billion in annual sales—which is five times the size of the much ballyhooed molecular diagnostics market. But size isn’t everything and all is not rosy for the big manufacturers, as competition and price pressures have ruthlessly eroded margins to the point that some of the major players (eg, Roche, Bayer) are understood to be looking to exit the BG monitoring market.

A market this large facing uncertain headwinds is ripe for innovation and disruption. When a big problem meets a big business opportunity, innovators, investors and entrepreneurs take heed! Indeed, diabetes has inspired many start-ups dedicated to delivering better products and solutions. This is an exciting field, ripe with potential; and one where I’ve been active by leading an investment from NBGI Ventures in Cellnovo, which has developed a mobile diabetes management system (more about this in a subsequent post).

Role of Medical Devices in Patient-Centric Care

Innovation in medical devices—particularly in the areas of insulin delivery and BG monitoring—has played an important role in improving diabetes care by empowering patients and enabling self-care. Diabetes management is a leading area of patient-centric medicine, serving as a validation test bed and exemplar for solutions relevant to a range of other chronic diseases. The goals and methods of the patient-centric care model also align strongly with another powerful medtech trend: the emerging digital health movement that embraces the convergence of mobile connectivity, information technology and data analytics with medical devices and healthcare delivery. Therefore, it should come as no surprise that diabetes is a major focus area for advocates of digital health solutions, as reflected by the GSMA’s (the global industry alliance of mobile operators) prioritization of diabetes in its mHealth initiative for connected living.

The patient-centric care paradigm also respects the importance of product design, usability and patient choice in achieving better outcomes and improved quality of life. A good example of the commercial relevance of this is the rapid adoption of the discreet OmniPod patch pump by Insulet—driven largely by patient preference—at the expense of market share lost by traditional tubed insulin pumps such as the MiniMed by Medtronic.

Diabetes Pic2 Pumps

The appeal of incorporating “consumer electronics” design principles is also visually evident by comparing Sanofi’s iBG Star (a BG meter integrated with an iPhone) with the rather clunky design traditional BG meters:

Diabetes Pic1 BG Meters

Perspectives from the recent ADA

Of course, innovation goes far beyond just good product design. At the recent American Diabetes Association (ADA) congress in Chicago, a range of promising approaches were reported and discussed, including improved continuous glucose monitors (CGM), closed-loop pumps integrating CGM feedback (ie, an artificial pancreas), dual drug delivery systems, improved glucagon formulations and even wilder ideas such as engineered/regenerative pancreatic tissue, exercise mimetics and neuromodulation-based therapies.

Neuro-Modulation/Stimulation (NMS) is a particularly interesting field having a broad range of potential medical applications that are just now being explored more widely. A rather conventional application for NMS relates to pain management, which Neurometrix has developed with its SENSUS TENS device for treating diabetic neuropathy. SENSUS is a body-worn transcutaneous electrical nerve stimulator designed to provide symptomatic relief from pain through the excitation of nerve fibers to block transmission of pain signals to the brain (ie, exploiting “gate theory”). An even more novel NMS approach is being pursued by a Metacure with its DIAMOND (TANTALUS) “gastric pacing” implanted stimulation device for treating obesity and type 2 diabetes (T2D) by inducing satiety and, putatively, modulating signaling to the brain, affecting glucose and fatty acid metabolism. This echoes the bariatric approach being pursued by another device startup, GI Dynamics, which has recently raised almost $60m to further fund the development and commercialisation of its orally inserted intestinal liner EndoBarrier that prevents food absorbtion, mimicking the effects of a gastric bypass to treat obesity and T2D by affecting mechanisms broadly underlying metabolic syndrome.

For me, as a medtech investor, one of the most notable commercial developments at the ADA was the emergence of new players in the insulin pump space. Targeting the established market segment of tubed pumps for type 1 diabetes (T1D) patients, Tandem’s t:slim very much embraces the principles of attractive product design and usability. Meanwhile, the V-Go from Valeritas—targeting the nascent, but potentially much larger T2D market segment—is a “cheap and cheerful” disposable insulin delivery device seeking to capture market share from prefilled insulin pens.

Diabetes Pic3 Pumps.png

In an upcoming post, I will dig deeper into insulin pumps and CGM. For the time being, as a final note for anybody interested in following developments in diabetes, I’d just like to mention a few of the many excellent blogs being written by patients and physicians:

A Sweet Life: http://asweetlife.org/
Diabetes Mine: http://www.diabetesmine.com/
Diatribe: http://diatribe.us/
EndoGoddess: http://endogoddess.blogspot.co.uk/