Welcome to BioMarketing Insight's monthly newsletter.

We all know that obesity is growing at a rapid rate in the US and around the world and that obesity leads to diabetes.  November 14th was the Annual World Diabetes Day and Eli Lilly chairman, president and CEO John C. Lechleiter writes about the paradox of diabetes research.  This month's newsletter will cover this topic.

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 January 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

How to Avoid Over Indulgence During the Holidays

With the holiday parties upon us, I tend to over eat and have too many sweets in celebrating the holidays and it's ironic that my newsletter topic is on diabetes.  It's ok to indulge a little at this time, but when one over indulges or continues to over indulge that causes so many to eventually become obese and develop Type 2 diabetes. 

Figure 1. Diabetic Diet

The best way to avoid over indulgence is to change one's eating habits.  I don't mean a diet where one starves oneself, it's what one eats and the quantity.  A number of years ago when I wanted to lose weight, a physician recommended a diabetic diet where I lost weight, didn't feel hungry and was healthy.  The diabetic diet is outlined in Figure 1.

This diet is all about proportions and does not denying oneself of any foods.  As shown in the pyramid, the diet recommends more serving of grain, beans and starchy vegetable and less of milk and meats.  Fats, sweets and alcohol are allowed but in small quantities, so you can have a little bit of wine or a little bit of dessert to satisfy your palette.  My holiday and New Year's resolution is to get back on this diabetic diet.

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Is the Diabetes Research We Are Doing Today Enough?

Image: Wikepedia.

November 14th marks the Annual World Diabetes Day in honoring the birthday of Frederick Banting, who teamed with Charles Best in the discovery of insulin in 1922.  The discovery of insulin was truly an innovation.

John Lechleiter, CEO of Eli Lilly, a company that first sold insulin, said "Before insulin, a diabetes diagnosis was often a death sentence; today, our company regularly recognizes people who have lived for 75 years and more with Type 1 diabetes.  And yet, amid a growing worldwide epidemic of Type 2 diabetes and obesity, new breakthroughs are needed as urgently today as they were 90 years ago."

When I last wrote on the topic of diabetes in July of 2011, there were many companies that were working on a drug for both Type 1 and Type 2 diabetes and most of the trials did not meet primary end point, prove superior to what's already on the market, or had safety issues.

Diabetes, like personalized medicine, is different for each individual and according to Lechleiter "Research in diabetes is moving towards targeted interventions for patients in different stages of the disease and for its various complications.  And improved delivery systems - such as better injection devices or less frequent injections - can make it easier for people with diabetes to comply with their doctor's orders."

For Type 1 diabetes, the move toward a personalized closed loop system is where the trend is moving or devices that move away for daily injections.  For Type 2 diabetes, BMS and AZ have developed the promise of a new class drug, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, Forxiga (dapagliflozin) that work independently of insulin secretion by promoting excretion of sugar through the kidneys.  Clinical trials have shown that Forxiga improves blood glucose control either alone or in combination with other diabetes drugs, and its effect is sustained up to 102 weeks.

However, dapagliflozin did not fairing well with the FDA Advisory Committee and FDA due to the incidence of liver toxicity and breast and bladder cancer risk resulting in the FDA asking for more data and possibly more clinical trials.

The European Medicine Agency however, has endorsed dapagliflozin weighing the benefits against the risk and the fact that there is a need for new treatments options.  The EMA said it will maintain "close observation" of these risks, following a planned study of the drug's cardiovascular side-effects.  It was requested that the companies carry out an epidemiological study of Forxiga.  A number of companies also working on SGLT 2 inhibitors are watching BMS/AZ's progress very closely.

"Given the complexity of diabetes and the diversity of people it touches, what's needed is nothing less than a vast new wave of innovation.  This will require multiple paths of research that lead us to new and better options for managing diabetes in every stage of life," said Lechleiter.

The recently updated guidelines recommend that doctors take a patient-centered focus rather than targeting everyone's blood sugar to a standard targeted level.  The goal of a very low blood-sugar level might be appropriate for a younger person but older patients might do better with a less aggressive approach according to guidelines published in the journal Diabetes Care.

Blood sugar is typically defined as being under control for diabetic patients when it is below 7%, using a measure known as hemoglobin A1c, or HbA1c, according to the American Diabetes Association (ADA).  Under the new guidelines, this level is still desirable.  But younger, newly diagnosed, and well-motivated patients with a long life expectancy may want to aim for even lower levels, closer to 6%, according to the recommendations.  This aggressive therapy is expected to keep the disease from progressing further.

For older patients vulnerable to severe hypoglycemia, or those who may already have advanced cardiovascular disease, less stringent targets of up to 8% or even a little higher would be sufficient, the guidelines say (See Figure 1).  This also could reduce the burden of side effects from medications.

Figure 1. Guidelines - Diabetes Care

"We need to be less dogmatic about what matters and be open to different approaches and give patients a voice" in treatment decisions, says Victor Montori a diabetes specialist at Mayo Clinic, in Rochester, Minn., who wasn't involved with writing the guidelines, but supports the new direction.

There is a controversy among experts today as to whether the benefits of gradually stepping up the intensity of drug therapy is still true although the latest guidelines still advocate this approach.  The aim of the current guidelines is to maintain a patient's blood-sugar level while keeping up with the progressive nature of the disease.  But researchers at University of Texas (UT) Southwestern Medical Center in Dallas argue that it's more beneficial to hit the disease early and hard as demonstrated in a small trial.

The progression of diabetes is usually managed through three or four treatment tiers and finally insulin injections are added to help control their blood sugar.  Researchers at UT Southwestern Medical Center argue that this current treatment strategy does little to change the disease progression when the patients' own insulin-producing beta cells are still exposed to high blood sugar and the goal should be to preserve the function of the beta cells.

At the 2012 annual meeting of the ADA, UT Southwestern researcher presented their data on this theory.  Ildiko Lingvay said "two types of more aggressive treatments using insulin and drugs started when patients were initially diagnosed effectively preserved the function of beta cells in a study of 58 patients followed for three years.  The regimen included three months of insulin injections combined with metformin for all patients.  Then patients were randomly assigned to either the same treatment or a combination of three oral drugs, which continued for more than three years.  The study had important limitations, including the small number of patients and the lack of a control group that was followed with standard therapy to compare benefits and side effects."

"At our institution we treat patients intensively from the time of diagnosis," Dr. Lingvay says.  "We have no question this pays off in the long term."

Other research efforts to treat patients early with insulin have had mixed results.  In the UT Southwestern trials, patients on both regimens gained weight.

Gordon Weir, a researcher at Harvard-affiliated Joslin Diabetes Center, Boston, believes a strategy using short-term insulin treatment-a couple of weeks or months-to drive blood sugar back to safer levels, may eventually prove effective and become a treatment strategy.

While innovators have learned that treating diabetes early and aggressively is beneficial long-term, reimbursement policies by the insurance companies may stifle patient-centric and aggressive treatment strategies due to cost issues.  Lechleiter commented that "Unfortunately, too often today, the policies that dictate prescribing and reimbursement for diabetes treatments stifle this kind of innovation.  Rules that force population-based standardization ignore the individuality of this disease and instead result in treatment choices that are both too broad and too limited."

If we are ever going to get closer to personalized medicine, acceptance of higher costs upfront to achieve cost-saving long term will have to be advocated and supported in finding the best treatment for diabetics as individual by phenotype.  For insurance companies, unless these new aggressive treatment strategies show better outcomes and cost-saving, they will stick to the current guidelines and treat with cheaper medications first.  Who is going to support these studies?  One can't expect the industry to run trials, since the outcomes studies are not proving that a new drug will work; it's a paradigm shift in the management or treatment of diabetics with the same drugs.

In order to show better outcomes and cost-savings, physicians must be able to freely treat patients in a way they feel is best and neither physician nor patient should be penalized (physician and patient not getting reimbursed) for doing things outside of the current guidelines.

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Despite the lack of success for many companies in bringing new diabetic drugs to market, researchers, drug and device companies are still pursuing this area.

1) Intarcia Therapeutics Inc. recently raised $210 million in preferred stock and private debt placements for their Phase III trials with ITCA-650 for type 2 diabetes.  The privately held drug-device company's ITCA-650 uses a matchstick-size osmotic pump, initially developed by Johnson & Johnson's Alza Corp. that is inserted under the skin to provide a continuous and consistent flow of exenatide for a year treatment.  Exenatide is an approved drug that uses a glucagon-like peptide-1, or GLP-1, receptor agonist to treat Type 2 diabetes.  Today, GLP-1 is used as a twice-a-day, self-injection therapy.  The product is being touted to offer better glucose control, superior weight loss, and better compliance.

2) Australian scientists Dr. Ilia Banakh and Professor Len Harrison at the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria have "identified and isolated stem cells from the adult pancreas, and then developed a way to coax them into insulin-producing cells that can secrete insulin in response to glucose."

Harrison explains that there have been previous successes at generating insulin-producing cells in the adult pancreas from cells with "stem-like" features.  What excites him about this find is what Banakh pinpointed as "the cell of origin of the insulin-producing cells and shown that the number of these cells and their ability to turn into insulin-producing cells increases in response to pancreas injury".

These findings mean that we all have the potential to regenerate insulin-producing cells, even as adults, says Harrison, a clinician scientist whose work was awarded the Outstanding Contribution to Diabetes Award by Diabetes Australia at the Annual World Diabetes Day on November 14, 2012.

3) Researchers have found a protein biomarker that could predict Type 2 diabetes years in advance, according to a study published in the journal Cell Metabolism.  The researchers compared the protein levels of SFRP4 (secreted frizzled-related protein 4) in the blood of non-diabetics three times at three-year intervals, and found that those with above-average levels of the protein were 5 times more likely to develop diabetes in the next few years than those with below-average levels.

"This makes it a strong risk marker that is present several years before diagnosis.  We have also identified the mechanism for how SFRP4 impairs the secretion of insulin.  The marker therefore reflects not only an increased risk, but also an ongoing disease process," says Anders Rosengren of the Lund University Diabetes Centre (LUDC).

4)  CeQur Ltd, a Switzerland based company received CE mark for their CeQur device for continuous subcutaneous delivery of rapid acting insulin up to 3 days in the management of Type 2 diabetes mellitus and replacing daily injections.  It is designed to keeps basal insulin consistently balanced in the blood.

The CeQur insulin infuser includes a disposable insulin reservoir that attaches to a reusable electronic messenger.  The device easily attaches to the patient's abdominal area with a safe and secure adhesive backing.  Once in place, insulin is delivered subcutaneously through a fine, soft tube or cannula from the reservoir that is changed by the patient every few days. 

The CeQur insulin delivery device is designed to use just one type of insulin for both basal and bolus dosing, and will be available in multiple basal rates.

5) Boehringer/Eli Lilly, J&J/Mitsubishi Tanabe Pharma, Astella Pharma, Lexicon Pharma, Taisho Pharma, Chugai Pharma and Pfizer are all developing drugs with a similar pathway to dapagliflozin (BMS/AZ as discussed above) for Type 2 diabetes.

6) Catabasis - has a proprietary new chemical entity (NCE) made from conjugating two compounds docosahexaenoic acid (DHA) and salicylate that are active in the NF-κB pathway.  By delivering DHA and salicylate inside the cell, CAT-1004 acts synergistically to blunt the expression of pro-inflammatory cytokines (proteins that act as intracellular mediators) within the NF-κB pathway, and to activate the expression of anti-inflammatory modulators, resulting in a potent anti-inflammatory effect.  CAT-1004 improves glucose tolerance and blunts the expression of pro-inflammatory cytokines in Type 2 diabetic mice.

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Fifteen Medical Device and Twenty 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...     

Mergers & Acquisitions continue to be made for both medical device (20) and pharma/biotech (9).

This month, large medical device firms such as Boston Scientific, GE Healthcare, Baxter, Smith & Nephew and Baush+Lomb continue to acquire smaller firms to strengthen their product lines.  

PerkinElmer and Charles River Labs have purchased Shanghai Haoyuan Biotech and Vital River respectively to gain a larger presence in the China market.

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

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