Dr. Miriam Kidron thinks injecting insulin is a lousy way to deal with diabetes, a point on which all Type 1 diabetics would agree. However, unlike those who dislike their shots but press on regardless, Kidron and her team of researchers are doing something about it. Three decades after research into creating an insulin pill began at Hadassah Medical Center in Jerusalem, Oramed, (www.oramed.com) a company built around Dr. Kidron’s and her colleagues’ work, appears to be within a few years of introducing an oral insulin capsule.
“When they initiated this project almost 30 years ago at Hadassah, trying to get insulin delivered orally looked almost impossible,” says Nadav Kidron, Miriam’s son and CEO of Oramed. “Today it’s just a matter of time until it’s on the market.” The company’s flagship product is ORMD-0801, a soft gel insulin capsule primarily focused on the Type 2 market, but potentially quite useful for Type 1s as well. Oramed filed an Investigational New Drug (IND) application with the FDA in December, 2012, and a follow-up IND in mid-April 2013, the latter a response to the agency’s request for a one-week single-center inpatient trial before a multi-center Phase II trial begins later in 2013.
The Harsh World of Digestion
Dr. Kidron and her colleagues aren’t insensitive to the sting of shots or the lifetime burden of looking for new injection sites to avoid the buildup of scar tissue that may reduce insulin’s effects. Rather, they know that introducing insulin directly into the bloodstream is a clumsy substitute for the body’s natural method of secreting insulin into the liver and then, through it, into blood cells. On that point, there is no disagreement from anyone in the professional diabetes community.
Developing an insulin pill, however, has been a daunting task. One of the big questions about oral delivery of insulin has been how to get a dose from mouth to the portal vein, and liver – a short but perilous journey through the harsh environment of the stomach and gastrointestinal tract. Our digestive system is marvelously effective at breaking food down into its molecular components. Getting a group of active insulin molecules through this mill and releasing insulin at just the right time and place is a breakthrough accomplishment.
Oral insulin can only spring into action following the natural delay between administration and its breakdown, and later absorption, across the small intestine. The key to success of Oramed’s therapy is that the ORMD-0801 capsule survives the harsh acidic environment of the stomach. It releases the insulin in the small intestine, where it then crosses the digestive lining, enters the portal vein, and is carried off to the liver, where normally secreted insulin is deposited.
The average time to full insulin release of ORMD-0801 in trial subjects has been 60 minutes. While this is much slower than the onset of naturally secreted insulin, directly delivering insulin into the liver, where it undergoes first-pass metabolism, clears about 80% of it from the system. Only the remaining 20% of the insulin reaches circulation and is absorbed into cells. By contrast, subcutaneously injected insulin delivers its entire dose of insulin directly into circulation, and this is what can cause hypoglycemia.
Oramed has a number of patents protecting its drug delivery technology, which might work not only for insulin, but also for other drugs and vaccines that have traditionally been delivered only by injection. Is a medical world without needles possible? Perhaps not, but we once thought that cancer was incurable, and that diabetes was a death sentence.
Early Adoption is the Goal
Clinical trials must focus on specific patient populations, and the IND for ORMD-0801 is for therapy in Type 2 patients. Since 90% of the world’s 371,000,000 people with diabetes are Type 2s, this seems like the obvious path to prosperity for the company. Oramed believes that an oral medication would persuade more doctors to introduce insulin therapy early in a Type 2’s treatment, rather than waiting until natural insulin secretion has slowed to a trickle or stopped completely. Likewise, removing the bogey of injections ought to make patients more compliant, and healthier. The purpose of early insulin intervention is maintaining at least part of the natural insulin secretion process as long as possible. This should reduce the chances of hypoglycemic events due to having too much injected insulin on board, and may reduce the risk of diabetes complications such as heart disease, renal failure, peripheral neuropathy, or blindness.
What’s the possible benefit for Type 1s? For those recently diagnosed, oral insulin might allow the remaining beta cells to rest, and regain strength, after surviving the initial immune system attack. As is the case with Type 2 patients, the longer that some portion of the natural insulin secretion process can be maintained, the better the long-term outcomes. ORMD-0801 has been shown to have a particularly marked effect on glucose profiles in Type 1 patients, when delivered before meals.
A Combo Drug Magic Bullet?
Oramed’s product pipeline doesn’t stop with ORMD-0801. An oral exenatide capsule, ORMD-0901, is also being tested. Exenatide is an analog to glucagon-like peptide-1 (GLP-1), an incretin, or gastrointestinal hormone, that stimulates secretion of insulin from the pancreas. A bonus side effect of exenatide is that it reduces appetite by making people who take it feel full and satisfied after eating smaller amounts of food.
There are other drugs available for Type 2s that also stimulate insulin secretion, but only GLP-1 analogs directly produce insulin in response to increased presence of glucose in the bloodstream. Right now, GLP-1 class therapy is only available through injections (Amylin’s Byetta, for example; some endocrinologists prescribe Byetta injections as a pre-cursor to beginning insulin therapy in Type 2 patients). A capsule delivery system might significantly increase adoption by both physicians and patients. Clinical trials of ORMD-0901 to date also have demonstrated greatly reduced episodes of nausea in response to the therapy. Frequent nausea among patients has been another reason many prescribing physicians have been slow to embrace GLP-1 injections.
Combining ORMD-0801 with ORMD-0901 controls glucose levels in two different ways, while simultaneously reducing appetite. It is a prospective win-win scenario. Early Phase II trials of ORMD-0901 are expected to begin by the middle of 2013. Trials of the two pills taken together are at an earlier stage. As always, both drugs, as well as the possibility of taking them in combination, must be cleared separately by the FDA. If no major roadblocks occur in the trials, ORMD-0801 might be commercially available in 2 to 3 years, with the others following suit 1 to 2 years later. A potential drawback at present is the FDA’s recent warnings about increased risk of pancreatitis in patients who use GLP-1 analogs, a development that may take years to resolve one way or the other.
The World Turned Upside Down
Oramed currently has 11 employees; only five or six are full-time. Successful proof of the ORMD-0801 product over the next 24 to 36 months inevitably raises the question of how a tiny company with a great technology will bring its product to market. Oramed is keeping its cards close to the chest so far, but acknowledges that partnership with a larger business that has worldwide production, distribution, and marketing capabilities will probably be necessary to take advantage of global opportunities.
In any event, the importance of Oramed’s insulin capsule, like the possible approval this year of Afrezza’s (http://www.mannkindcorp.com) inhalable product (see Inhalable Insulin: A Breathtaking Development), potentially turns the marketplace for insulin upside down. Most important, the chances seem good that insulin therapy will grow by leaps and bounds in the coming years, and hopefully reduce complications and allow Type 2 and Type 1 patients to achieve better control of their diabetes.
“We wanted to do more than just replace injections — we wanted to provide an alternative oral medication as an earlier treatment that can extend the second phase of diabetes and prevent patients from becoming insulin dependent,” says Nadav Kidron. “That’s the revolution.” Whatever the drug is called, it’s the benefits that matter.