Welcome to BioMarketing Insight's monthly newsletter.  

Last month I covered health monitoring devices that incorporate wireless technology and wearable devices with mobile applications. I mentioned that the largest growth area where health monitoring devices would be used is in monitoring chronic diseases. In this month's newsletter, we'll look at the Closed Loop System or Artificial Pancreas for Type 1 diabetes.  

Read on to learn more about this topic and other current news. On the right are quick links to the topics covered in this month's newsletter. The next newsletter will be published on October 15th.                                                                                                     

We encourage you to share this newsletter with your colleagues by using the social media icons at the top left or by simply forwarding the newsletter via email.

Please email me, Regina Au, if you have any questions, comments, or suggestions.

Sincerely,

Regina Au

Principal, Strategic Marketing Consultant

BioMarketing Insight 

I've been asked by a number of people who were not able to attend my breakout session "Using Systems Biology to "Fast Track" Development and Approval of Novel Therapeutics and Diagnostics," if the presentation would be available online for them to view.  The entire presentation is now available on my website.

For those who haven't had the opportunity to view the interviews of my speakers by BIO, you can view all the interviews on my website.

Enjoy the presentation and interviews.    

Type 1 diabetes occurs when the pancreas does not produce enough insulin to properly control glucose (blood sugar) levels. Type 1 diabetes, sometimes called juvenile or insulin-dependent diabetes because it was most often diagnosed in children, adolescents, or young adults, but it can occur at any age.

Insulin, a hormone produced by beta cells in the pancreas, is needed to move glucose into cells, where it is stored and later used for energy. In type 1 diabetes, these cells produce little or no insulin. Without enough insulin, glucose builds up in the bloodstream instead of going into the cells and the body is unable to use this glucose for energy. When this happens, symptoms of type 1 diabetes occur.

Within 5 - 10 years, the insulin-producing beta cells of the pancreas are completely destroyed and the body can no longer produce much - needed insulin. The exact cause of this phenomenon is unknown, but is hypothesized that a viral or environmental trigger for those who are genetically predisposed causes an immune reaction. The body's white blood cells mistakenly attack the insulin-producing pancreatic beta cells.

Type 1 diabetes is a chronic disease that requires constant monitoring of glucose and injection or infusion of insulin. People with type 1 diabetes usually have to prick their finger 5 times a day to monitor their glucose, determine the amount of insulin needed, and inject themselves, usually before every meal and again at bedtime.

This is an extremely difficult daily regiment to maintain, but maintaining this regiment is extremely vital to the survival of a diabetic. If a diabetic becomes hypoglycemic, which results in insufficient insulin being available to the brain, the person can faint, or even go into a coma and subsequently die.

If a diabetic is hyperglycemic, over time this can have serious long-term effects, including kidney failure and blindness. This fear of hyper- or hypoglycemia can affect the quality of life and psychological well being to the extent that many diabetics may over compensate by overeating or taking less insulin. Compliance is a significant barrier to getting people to manage their diabetes.

A number of medical companies have developed continuous glucose monitoring systems (CGMS) to eliminate the finger pricks and/or an insulin pump to eliminate the injections and help overcome these compliance issues. Medtronic and DexCom currently offer CGMS devices and earlier this month, Bayer announced the launch of its CONTOUR NEXT LINK wireless device used to measure glucose levels.  

Medtronic, Roche Diagnostics, Animas, Insulet, and Sooil are currently offering an insulin pump.  Bayer's wireless device will be incorporated with all Medtronic's insulin pumps. At least three other companies, Tandem Diabetes Care, Asante Solutions, and Cellnovo, also plan to introduce insulin pumps. CGMS devices and insulin pumps are separate devices and they do not communicate with each other. For this reason, the two entities are considered to be part of an Open Loop System.

The next step is to combine the CGMS with the insulin pump to form a Closed Loop System, or artificial pancreas. There are a number of challenges to overcome in developing a Closed Loop System and I will address them in the next section.

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The goal of the Closed Loop System is to have it function like a normal pancreas where there is no intervention from the diabetic and the insulin dosing is accurate in order to maintain a normal life. The Closed Loop System is comprised of three parts: 1) the glucose sensor, 2) an algorithm program to determine how much insulin to give and 3) the insulin pump to administer the insulin.

Closed Loop System.

Sounds simple, right? There are three critical issues to factor in when developing an artificial pancreas, particularly when it comes to determining the level of insulin needed:

1) Physical activity after meals has a profound impact on blood sugar levels for people with type 1 diabetes. "You would expect this result, but we wanted to know to what extent this phenomena would happen in people with type 1 diabetes, (since this has not been examined before)" says Dr. Yogish Kudva from the Mayo Clinic in Rochester, Minnesota developing an artificial pancreas. 

Diabetics who engaged in low-grade physical activity after eating had blood sugar levels close to those of people with fully functioning pancreases. Those who remained sedentary after their meal, however, had elevated blood sugars.

"Physical activity enhances insulin action, hence lowering blood glucose concentration," Dr. Kudva says. "Real-time detection of physical activity -- and modeling of its effect on glucose dynamics -- is vital to design an automatic insulin delivery system."

2) Calculating the correct dose of insulin is difficult due to two things: 1) the lag time that occurs between tissue and bloodstream in getting an accurate glucose reading and 2) the lag time for the uptake of insulin delivered from the bloodstream to the tissue for a second accurate glucose reading.

"For instance, current glucose monitors measure levels in the surface layer of skin, which may not reflect blood glucose accurately since there is an inherent delay between the two measures of about 5 to 10 minutes," says Dr. Michael Rickels , an endocrinologist at the Hospital of the University of Pennsylvania. The same goes for the lag in insulin delivery, which could prove dangerous for someone whose blood sugar has risen rapidly. One solution that William Tamborlane of the Yale School of Medicine has started to explore is heating up the skin directly under the insulin infusion area to speed up blood flow, and hence, insulin travel time.

3) Nocturnal hypoglycemia which occurs during sleep is the most common type of hypoglycemia. It is particularly dangerous because patients are unlikely to recognize symptoms or awaken during an episode. Progress has been made to minimize the risk for nocturnal hypoglycemia for insulin-dependent patients with continuous subcutaneous insulin infusion (CSII) pumps and the introduction of long-acting [basal] analogs, insulin detemir and insulin glargine.  Both analogs have relatively flat and predictable time-action profiles.

Patient education is critical in preventing nocturnal hypoglycemia. Patients are encouraged to plan meals and exercise, adhere to dosing guidelines for diabetes therapy, moderate their alcohol intake, carefully and consistently perform bedtime self monitoring blood glucose (SMBG), eat a bedtime snack and made aware that a simple change in routine (i.e., change in time zone, holidays, vacation) may increase their risk for nocturnal hypoglycemia. The CGMS with an alarm would be extremely helpful, but the person still has to determine and administer his/her insulin. This is yet another reason that the Closed Loop System would be so important to develop.

Juvenile Diabetes Research Foundation (JDRF)

In January 2010, the JDRF announced a non-exclusive partnership with Animas Corporation to develop an automated, partially Closed-Loop System to help control blood sugars, the first step toward a fully automated artificial pancreas. 

The system will integrate an insulin pump from Animas, a Johnson & Johnson company, with technology from DexCom, a leading manufacturer of continuous glucose monitors, said Aaron Kowalski, Ph.D., Assistant Vice President of Glucose Control at JDRF and Research Director of the JDRF. This system is called a partial Closed-Loop System because the diabetic still has to determine the correct dose of insulin to administer and take into consideration such things as exercise, food, and stress.

However, "in times of impending low blood sugar or high blood sugar, the system (through its software algorithm) will have the ability to automatically intervene. We call this a 'treat to range' approach, meaning that the system is trying to minimize exposure to glucose levels above and below a certain number. The range is probably going to be below 70 mg/dl on the low end, and around 180 mg/dl on the high end," said Kowalski.

"The goal would be for the system to automatically bring you back within the target. The reason we're taking this approach now is that we want the system to be as safe as possible...a very clinically important step. The systems use complex algorithms that are much, much more sophisticated than what is in our continuous glucometers now, and they are able to say with far better accuracy when you're going to be low or high," continues Kowalski.

The JDRF and leading clinical organizations such as the American Association of Clinical Endocrinologists, American Association of Diabetes Educators, American Diabetes Association, and the Endocrine Society have been lobbying the FDA to obtain written guidance for the approval of an artificial pancreas and in December 2011, the FDA released draft guidance on the artificial pancreas. For updates on the progress of the artificial pancreas project, click here.   

"The key component of the artificial pancreas is the control algorithm, which directs insulin delivery according to glucose levels while accounting for inherent measurement errors and kinetic delays. Various algorithms have been developed, but two main categories are the most relevant: the proportional-integral-derivative control (PID) and the model-predictive control (MPC)," are according to a review article on Closed Loop Systems in BMC Medicine.

"PID algorithms adjust insulin delivery by considering deviations from a target glucose level (proportional component), the area under the curve between the measured and the target glucose level (integral component), and the rate of change in the measured glucose levels (derivative component)."

"MPC algorithms, by contrast, employ a mathematical model of human glucose regulation to link insulin delivery and glucose excursions as described in numerous theoretical, animal, and computer-simulation studies. Insulin delivery is calculated by minimizing the difference between forecast glucose concentrations and the target glucose levels over a prediction window of 1.5 to 3 hours, or longer."

Mayo Clinic, Rochester Minnesota

In continuing to pursue the Closed Loop System, Mayo Clinic researchers Yogish C. Kudva, M.B.B.S., an endocrinologist and lead researcher along with Dr. Ananda Basu, are also developing a Closed Loop System with the goal of personalized medicine in mind.

"There is tremendous variability in blood sugar levels day to day in a person with type 1 diabetes. This is why type 1 diabetes is notoriously difficult to manage," Dr. Basu says. He notes that within a single day, the blood sugar level of a person with type 1 diabetes can swing from 30 to 300 milligrams per deciliter (the normal range is 70 to 100 mg/dL). "This has a huge impact on patients' quality of life."  

The complexity of developing a medical device is an immense challenge that took many years of research by Mayo scientists. Their research revealed that the physiology of metabolism is very important and needs to be factored into the artificial pancreas software algorithm.

One critical set of variables, "Physical activity plays an important role in insulin action," explains James A. Levine, M.D., Ph.D., a Mayo endocrinologist. "Insulin dosing must be adjusted based on the amount of physical activity a patient does."

Dr. Levine leads a laboratory team whose work involves gauging people's total daily activity - not just calories burned at the gym, but every fidget and sedentary moment. "We've worked hard over many years to develop a series of technologies to measure very precisely how active or chair-ridden an individual has been," Dr. Levine said.

The Mayo clinical trials, unlike other studies of insulin-delivery systems that use computer simulations to predict insulin needs will use real data from type 1 diabetics thus making each algorithmic program personalized to each patient, the goal of personalized medicine.

In the first phase, type 1 diabetics will spend 40 hours in Mayo's Clinical Research Unit in a controlled monitored environment where participants will be given precisely measured meals and regulated exercise on a treadmill. Participants will use the conventional methods to measure blood sugar and in consultation with Mayo physicians to determine the insulin dosage. Metabolic data from each study participant will be collected and fed into the artificial pancreas algorithm program.

A few weeks later in Phase II, participants return to the research unit and follow the same meal and exercise routine, but with an artificial pancreas programmed with his or her unique metabolic information. "We will see how well this personalized closed-loop system controls blood sugar levels compared to the first visit," Dr. Basu says. He and Dr. Kudva hope to progress to an outpatient trial in 2014.

Closing Thoughts

The Mayo Clinic's approach in tailoring the Closed Loop System to each individual patient is the ultimate goal for personalized medicine. However, because insulin metabolism is affected by the slightest change to a daily routine that includes exercise, stress, and meals, an algorithm is needed to respond instantaneous to these changes or anticipate these changes for a Closed Loop System to be truly self-sufficient.

There has been a lot of research done in diabetes, both in the pharma/biotech world for drugs and the medical device world in developing a Closed Loop System. Both drugs and devices have faced major challenges. Researchers are not willing to hazard a guess as to when a viable Closed Loop System will reach the market, but a few are predicting within the next 5 - 10 years.

On the plus side, the new business model for our industry is collaboration. Collaboration between academic and clinical institutions, device companies, software companies, clinical organizations, and advocate organizations have the potential to speed up the development of an ideal Closed Loop System. There are many institutions and device companies besides the ones mentioned above all working on the same goal. If we all work together, we may be able to reach the goal within 5 - 10 years.

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German scientists at the Fraunhofer Institute are working on a new technology: blood vessels created with specialized inkjet printers. Scientists are trying to create or "print" blood vessels to help direct blood flow to areas that need blood such as a Cardiac Bypass Surgery or organ transplant.

It works exactly like an inkjet printer. Organic ink is used as the basis for the blood transport structure. The printer sprays out a mist of the organic ink onto a plate in several layers and an artificial blood vessel is formed.

Click on the video for more information.

Blood vessels from an Inkjet Printer

To read the full story, click here 

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Twenty Medical Device and Fourteen Pharma/Biotech Funding Deals

To determine whether funding is picking up, I will be focusing on all types of funding that are $1 million or greater in seed investments and series A or B (or the valley of death) that are pre-IPO. Even though VCs are investing, they continue to invest in their existing portfolio companies and less in start-ups. Incubators, state funding, and business competitions are great for initial seed money but not enough to keep the company going long-term.  These are worldwide funding deals. 

Partnerships and licensing deals with upfront payments and milestones will not be included.

Funding deals are in chronological order by date.

$0 = No financial terms disclosed. For more information, read more ....

Funding deals are in chronological order by date.

$0 = No financial terms disclosed. For more information, read more...     

Acquisitions continue to be made for both medical device (13) and pharma/biotech (9).  

Teleflex Inc. has made another acquisition this month for LMA International.  Large medical device and pharma companies such as Siemens Healthcare, EMD Millipore, Becton Dickinson, Agilent Technologies, Quintiles, and Sunovion Pharmaceuticals continue their acquisition plan to enhance their product portfolio.     

Private Equity Firms BC Partners, Cinven and TPG bought Aenova, a German company, Mercury Pharma, a UK company and a finalized deal for Par Pharmaceuticals respectively.  

Acquisitions are in chronological order by date with Medical Device/Diagnostics followed by Pharma/Biotech.

$0 = No financial terms disclosed. For information on specific companies, read  more ....

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About BioMarketing Insight

We help companies de-risk their product development process by conducting the business due diligence to ensure that it is the right product for the right market and the market potential for the product meets the business goals of the company. We can then develop marketing strategies to drive adoption for the product.

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