On the Horizon in Diabetes Therapy: A Delivery System That Doesn't Rely on the Patient

Each year, diabetes complications send more than 10 million Americans to the emergency department,¹ cause nearly 50,000 cases of kidney failure, necessitate nearly 75,000 amputations, contribute to millions of heart attacks and strokes,² and cost nearly $100 billion.^3,4

The good news is that existing treatments control the disease well enough to prevent most of those problems and eliminate most of those costs. The bad news is that the majority of patients

fail to follow treatment plans with the precise diligence that would keep them healthier and the healthcare system solvent. In theory, a system that automatically gives patients just the right amount

of medication at just the right time could revolutionize diabetes treatment, and that’s why some researchers are so excited about an experimental product for type 2 diabetes mellitus (T2DM), ITCA 650. ITCA 650 can pack a full year’s worth of a medication called exenatide into a matchstick-sized tube, which sits under the skin and dispenses a continuous trickle of treatment.

Implantation takes only a few minutes and hurts little more than a single shot. Operation is automatic. Trial results are impressive. “I have been doing diabetes research for 47 years now, and this ranks among the most exciting things I’ve ever seen,” said Jay S. Skyler, MD, MACP, deputy director of the Diabetes Research Institute at the University of Miami’s Miller School of Medicine. “It has shown itself to be truly powerful in trials to date, reducing A1C (glycated hemoglobin) levels to a remarkable degree without any effort from patients."

The only way to consolidate a year’s worth of medication into an implantable device is to start with an incredibly potent medication, and it would be hard to find one more potent than exenatide. In

2005, the FDA approved the drug for use in T2DM patients at 2 tiny doses: 10 or 20 micrograms per day.5 Those doses equate to 3.65 or 7.3 mg per year. A single tablet of extra-strength acetaminophen, by comparison, contains 500 mg of medication. Of course, the medicine inside an implantable device must also be stable enough to remain at body temperature for months

on end without degrading. Exenatide, in its original formulation, failed miserably on this front. It was a synthetic hormone that degraded almost immediately under anything short of optimal

conditions. The notion of using it inside an implantable device only became possible when researchers at Intarcia Therapeutics, a Boston-based company, discovered a technique for stabilizing

proteins, peptides, and antibodies at very high temperatures. Intarcia’s executives quickly realized that this stabilization process would allow medications to remain potent for long periods inside the human body.

The only real obstacle was distribution. However, as they soon discovered, another company had already designed osmotic mini-pumps that could release a steady stream of medication into the body for years on end. Intarcia bought the rights to that technology and, shortly thereafter, began testing its lead product. The most recent information about ITCA 650’s performance came out in October, when Intarcia announced top-line results of 2 phase 3 trials of the formulation. The first of those trials randomized 460 patients with A1C levels between 7.5% and 10% evenly among placebo and 2 doses of ITCA 650, 40 mcg per day and 60 mcg per day. (Doses of Intarcia’s formulation are higher than approved doses of exenatide because earlier trials demonstrated 40 mcg and 60 mcg to be more effective than lower doses of the form of the drug and delivery system.)

Patients in the active arms started with 3-month devices that delivered an initial dose of 20 mcg per day, and then received 6 months of treatment at one of the 2 trial doses. Those who eventually received the lower trial dosage of 40 mcg saw their A1C levels drop an average of 1.4 percentage points, and those who received the higher dosage of 60 mcg saw their A1C levels drop an average of 1.7 percentage points. Both of those reductions significantly bested results for patients in the control arm of the trial.⁶

Intarcia announced these results, of the FREEDOM-1 and FREEDOM-1 high baseline phase 3 trials, in an October press release. The company said it was submitting full findings for presentation

at the 75th Annual Meeting of the American Diabetes Association, scheduled for June 2015 in Boston.⁶ The second set of results involved patients with A1C levels between 10% and 12%, and gave them 20 mcg per day for 3 months and 60 mcg per day for an additional 6 months. Patients in this second trial started with average A1C levels of 10.8% and ended, on average, 3.4 percentage points lower at 7.4%. These results, which were considered preliminary, were presented at the 50th meeting of the European Association for the Study of Diabetes in Vienna, Austria,

which took place September 15-19, 2014.⁷

Many of the patients in both of the trials were already using 1 or more oral treatments when their trial started. Such patients continued using those medications throughout the trial and, thus, used

ITCA 650 as part of a combination therapy. Some patients, however, particularly in the first trial, were not using medications when they enrolled and, thus, used ITCA 650 as monotherapy. The medication provided significant benefits in both cases. “I think this device has the potential to be a true game changer,” said Robert Henry, MD, a professor of medicine at the University of California at San Diego and the director of the Center for Metabolic Research at the VA Medical Center in San Diego. Henry, like Skyler, does consulting work for Intarcia, among other pharmaceutical companies, and he has participated in ITCA 650 trials.

“The medication reduces A1C levels in virtually everyone. Only 2 of 60 patients in a recent trial I led did not experience reductions of at least 0.5%. It also produces significant weight loss—3% of

body weight, on average—in most people. And it requires no effort from patients. The pump, to my knowledge, has never failed. It just works.”

Intarcia is currently undertaking 2 more phase 3 trials, and if they meet their goals, the company expects to submit ITCA 650 for FDA approval in early 2016. Doctors who have used the treatment

in trials are counting the days. “With continued success in the remaining phase 3 trials, we should have a real game-changing therapy available soon to help physicians to better manage this

serious disease,” Henry said. If ITCA 650 does win FDA approval, it will constitute a significant step on the road toward easier treatments for T2DM. Patients who had the disease in the early part of the last century had no option other than insulin injections. That changed in 1955 when drug makers introduced the first oral medications that stimulate the pancreas to make more insulin.⁸ In the early days, these oral medications were often used in addition to injections, rather than as a replacement, but as oral therapies have improved, more patients have stopped using any kind of injection. Nearly 57% of all Americans with diabetes now solely use oral medications to treat their condition.²

Still, many patients fail to follow the treatment plans prescribed by their doctors. According to a recent review of research on patient compliance, more than one-third of all patients eat things they should avoid, and more than 80% of them exercise too little. In fact, electronic monitoring of pill consumption found that adherence rates for oral medication ranged from 53% to 67%.⁹ Specialists say that even fewer patients with T2DM religiously follow instructions for using injectable medication. These failures trigger many of the complications that exact such a physical toll on people with

diabetes and such a financial toll on the American medical system. That toll has ballooned in recent years as America has grown older, fatter, and more racially diverse. The number of people diagnosed with T2DM grew from about 6 million in 1980 to more than 21 million in 2011,¹⁰ and the problem will likely get worse.

Another 86 million Americans 20 years and older had prediabetes as of 2012, and experts estimate that one-third of all Americans will eventually develop the condition.¹¹ Unless people with diabetes begin controlling their condition better than they have to date, such an increase in patient numbers will threaten the solvency of the healthcare system and ruin millions of lives.

Countless initiatives are already under way in nearly every corner of the healthcare system to help patients get a better handle on their disease: local governments are making restaurants put

calorie counts on menus, employers are subsidizing gym memberships, insurers are adjusting co-pays, doctors are joining accountable care organizations, and drug makers are spending billions on research.

Intarcia joined this widespread fight against diabetes in the mid-2000s, shortly after one of its experimental medications failed in phase 3 trials. The privately held company had focused on cancer

medications since it opened its doors in 1997, but its owners were considering all their options, including liquidation, when several Intarcia researchers discovered the technique for stabilizing proteins, peptides, and antibodies at high temperatures. “Their announcement came as a total surprise. No one else in the company even knew they’d been working on the project, but the importance of their discovery was immediately obvious,” said Intarcia CEO Kurt Graves. “These biological compounds are some of the best treatments we have for a wide range of diseases, but they’re totally unstable at room temperature, let alone body temperature. That makes them hard to manufacture and hard to store and hard to use, and that, in turn, limits their usage and makes them expensive. Finding a way to keep these medicines stable at body temperature for years on end was like finding the Holy Grail.”

Intarcia patented the technique, of course, but Graves still declines to explain it in anything but the broadest terms: Intarcia imbeds unstable medications in a suspension formula that keeps them fixed indefinitely. Company researchers have yet to determine how long its process can keep fragile medications in working order. They have kept some bottled samples at 105 degrees for more than 3 years now, and those samples show no sign of deterioration.

Still, it was quickly apparent that the process worked well enough to create something unprecedented in the treatment of chronic illnesses: once-a-year implants that delivered continuous edication. Intarcia, therefore, began looking for approved medications that were suitable candidates for its stabilization technique and the micro-pump technology that it acquired for product delivery. Many biological medications appeared insufficiently potent for long-term delivery. A year’s supply of a medication with a therapeutic dose of 500 mg per day would require an implant the size of a bread box, which, presumably, would not be very comfortable. Exenatide, however, looked about as promising as a candidate could look: a very effective treatment for a very common disease that was used by relatively few people because its fragile formulation could only be taken by injection. Despite the existing approval for exenatide, Intarcia put ITCA 650 through a full trial process and submitted a new drug application to the FDA in an attempt to prove that its stabilization process did not increase side effects or, conversely, stabilize the drug so much that it

provided no therapeutic value.

Trial results to date indicate that the stabilization process and continuous delivery affect both the medication’s efficacy and its side effect profile. Fortunately, they seem to increase the former and

decrease the latter. It is unclear whether the increased efficacy stems entirely from eliminating the dosing errors that took place when exenatide was tested as an injection or whether other factors,

such as continuous delivery, play a role. As for the reduction in side effects—especially the nausea that is common with exenatide injections—Intarcia’s scientists and some of the researchers who have worked on ITCA 650 trials generally credit the transition from concentrated injections to a small but steady stream of medication. Whatever the reason, Intarcia executives believe that the combination of effortless administration and negligible side effects might allow them, eventually, to get expanded approval for ITCA 650, approval that would allow them to use the product both as a treatment for T2DM and as a tool for preventing people with prediabetes from developing the disease.

“We haven’t announced pricing yet,” Graves said. “But the stability of our formulation of this medication greatly reduces manufacturing and handling costs, so we could price ITCA 650 far

closer to an oral therapy than a typical biologic injection….At that sort of price, it could certainly make sense to use it for prevention as well as treatment.”

References

1. Washington RE, Andrews RM, Mutter R. Emergency department visits for adults with diabetes, 2010 [statistical brief #167]. Rockville, MD: Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality; November 2013. www.hcup-us.ahrq.gov/reports/statbriefs/sb167.jsp. Accessed December 30, 2014.

2. Centers for Disease Control and Prevention. National Diabetes Statistics Report: estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: HHS; 2014.

3. National Association of Chronic Disease Directors. Addressing a major complication of diabetes to reduce health care costs. Society for Public Health Education website.http://www.sophe.org/

Sophe/PDF/NACDDDiabeteWhitePaper.pdf. Published February 2012. Accessed December 2014.

4. Li R, Bilik D, Brown MB, et al. Medical costs associated with type 2 diabetes complications and comorbidities. 2013;19(5):421-430.

5. FDA approval history for Byetta. Drugs.com website. www.drugs.com/history/byetta.html. Accessed December 30, 2014.

6. Intarcia announces two positive phase 3 trials for ITCA 650 in type 2 diabetes: FREEDOM-1 and FREEDOM-1 high baseline (HBL) study results [press release]. http://intarcia.com/media/pressreleases/2014-oct-1-phase-3.html. Boston, MA: Intarcia Therapeutics; October 1, 2014.

7. Henry RR, Rosenstock J, Baron MA. Efficacy and tolerability of ITCA 650 (continuous subcutaneous exenatide) in poorly controlled type 2 diabetes with base A1C >10%. Presented at: 50th Meeting of the European Association for the Study of Diabetes; September 19, 2014; Vienna, Austria. Abstract 242.

8. History of diabetes. American Diabetes Association website. http://www.diabetes.org/research-and-practice/student-resources/historyof-diabetes.html. Updated May 9, 2014. Accessed

December 30, 2014.

9. Delamater A. Improving patient adherence. 2006;24(2):71-77.

10. Katz MJ, Laughton F. Diabetes type 2 continuing education for health professionals. A-Train Education website. https://www.atrainceu.com/course-all/diabetes-type-2-090. Accessed December 30, 2014.

11. American Diabetes Association. Infographic: a snapshot of diabetes in America. http://www.diabetes.org/diabetes-basics/statistics/cdc-infographic.

html. Updated June 11, 2014. Accessed December 30, 2014.

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