The size of the diabetes treatment marketplace has been growing at a rapid pace, and is expected to reach $55.3 billion in 2017, from $35.6 billion in 2012. That growth is being fueled by an unfortunate trend---the increasing prevalence of diabetes worldwide. According to the International Diabetes Federation (IDF), there are 387 million people worldwide with diabetes, including 29.1 million people in the United States (U.S).
With prevalence hovering at the 9% mark, diabetes has become a major public health threat, with large-scale societal, financial and individual consequences, including a 1.8-fold increased risk of heart attack, a 2-fold risk of premature death and a significantly increased risk of neuropathies, blindness, end-stage renal disease and lower-limb amputations.
Enter Oramed’s oral insulin-in-development
Oramed, based in Israel, is currently one of three companies, including Biocon and Novo Nordisk, developing an oral insulin treatment option for diabetes. Oramed’s oral insulin (ORMD-0181) is moving into phase IIb after successful completion of phase IIa, in which a total of 196 patients received 2,063 doses of oral insulin, with positive safety, tolerability and efficacy outcomes.
According to Josh Hexter, chief operating officer of Oramed, “Our oral insulin is not a substitute for insulin injections, but rather a new, earlier treatment option.”
Based on current diabetes treatment algorithms, most physicians and patients opt to save insulin as a last resort. Patients are generally counseled to modify their lifestyles before physicians add on Metformin, sulfonylureas, thalzolidinediones, DPP-4 inhibitors and other oral antidiabetic treatments, before finally progressing to injectable insulin.
However, Hexter makes the point that diabetes clinical treatment guidelines suggest starting insulin therapy as early as possible in order to preserve beta-cell functioning. There’s a problem with this recommendation: Most patients do not want to use injectables and prefer to try other options before committing to insulin---most likely for the rest of their lives.
Why oral insulin is such a game-changer
It’s not just a question of changing the mode of delivery and getting the same outcomes. Barry Mennen, MD, a Washington, D.C.-based physician and diabetes expert, says, “ Oral insulin therapy has been the Holy Grail of diabetes therapy ever since insulin was developed as an injectable therapeutic for diabetes.”
He says, “Since better mealtime blood sugar control has been shown to be essential for better outcomes in diabetes, more injections have been needed for type 1 diabetes (T1DM) and about one-fifth of patients with type 2 diabetes (T2DM). A consistent orally-administered insulin would be a huge game changer for patients and the overall diabetes market.”
A more natural, truly physiologic MOA
Injectable insulin is not only inconvenient, but because it is administered into the peripheral blood stream, which does not mirror the way natural insulin is processed in the body, it is not as effective as it could be. Mennen explains, “From the clinical point of view, oral insulin is actually more physiologic than injectable since it is absorbed via the gut and therefore passes directly into the portal circulation (the same system that natural insulin is secreted into from the beta cells of the pancreas). This is important since the liver now gets the first flush of the insulin and can extract what it requires when the insulin couples with its receptor sites in this key target organ. Subcutaneous insulin gets to the liver only after passing through the systemic circulation. Mimicking physiology is usually a good thing.”
With insulin, which was first extracted from the pancreas of cows and pigs and injected into humans in the 1920’s, the goal has always been to enhance the mode of action (MOA) to give it a faster onset of action, while also slowing its release in order to provide the body with insulin over a longer period of time. Novo Nordisk and other companies have successfully developed long-lasting insulins, with various pharmacokinetic properties that have improved treatment outcomes, but many patients with diabetes are still poorly controlled.
Combating FBG overnight
Fasting blood glucose (FBG) is the major point of reference for determining short term glycemic control, while glycosolated hemoglobin, or A1C, is the go-to metric for gauging long-term control. Approximately 70% of patients with impaired FBG develop T2DM, while almost 80% of patients who already have T2DM fail to achieve control with Metformin and other oral hypoglycemic treatment options.
According to Hexter, the goal of using ORMD-0181 to treat patients with T2DM is to “reduce the excessive nocturnal glucose production from the liver” by going after a nighttime dosing indication for this population. As for patients with T1DM, the goal is to use oral insulin, in addition to injectable insulin, with the goal of decreasing the number of injections a patient needs on a daily basis.
He says, “By providing a dose of hepatically focused insulin to patients at the most challenging time you basically nip the problem of high morning FBG in the bud by addressing the problem while the patient sleeps.”
An innovative delivery system
According to Hexter, “The goal of Oramed’s delivery system is to deliver a therapeutic protein into the body and protect it from the digestive system, which is designed to rip apart proteins before they can ever exert a therapeutic effect. The system is also designed to enhance absorption.”
Towards that end, Oramed’s technology is comprised of three main proprietary components---a pH sensitive enteric coating that only degrades in the small intestine; protease inhibitors , which protect oral insulin from degradation by digestive proteases and absorption enhancers which assist with translocation of insulin across the intestinal membrane into the bloodstream.
Time and money
While Hexter did not provide specific financial projections, Oramed is strategically positioned with ORMD-0801, as well as an oral GLP-1 analog that it is developing (ORMD-0901), to move into phase III trials by 2017, with the goal of receiving quality feedback from the FDA and possibly an expedited approval pathway. Oramed is pursuing U.S. and ex-U.S. markets.
Market research shows that the global insulin market will reach roughly $47 billion by 2020, up from $20 billion in 2013. Assuming successful development and approval outcomes, Oramed and other companies that develop oral insulin treatments, can expect to become a core part of the diabetes treatment paradigm, to be used as monotherapy and as part of combination therapy.
Paradigm shift and a huge step forward for diabetes therapeutics
While many companies call their therapies “novel” or “first-in-class,” oral insulin will change the way patients and physicians handle the diabetes treatment timeline. Hexter says, “The earlier you can start insulin therapy, the better. You want to de-burden the pancreas and preserve beta-cell functioning. It completely changes long-term outcomes.”
The implication of exerting control over blood sugar as early as possible is not only about preserving beta-cell functioning, but ultimately preserving patients’ quality of life, staving off the worst consequences of diabetes, saving money and ultimately changing what it means to be diagnosed with diabetes.