The prospects for an oral insulin pill just got a boost from Harvard. New research out of the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) has shown that insulin, if combined with something called a deep eutectic, can get past the intestinal wall to the liver if delivered orally. This is the first major advancement reported on oral insulin since Oramed Pharmaceuticals (ORMP, Financial) began the first ever HbA1C blood glucose clinical study for oral insulin earlier this year.
First, what is a deep eutectic? Essentially, it’s a combination of acids that have dramatically reduced melting points than either compound alone. The deep eutectic that this team out of Harvard studied is a combination of choline, an essential nutrient, and geranate, also known as neric acid. Combined, it is known as CAGE, for choline and geranate.
The substance was studied back in June 2016 as a potential broad spectrum antiseptic, mostly directed at drug-resistant bacteria. Before Harvard scientists began testing it in diabetic applications, it was already known to be able to deliver insulin and other large molecules through the skin in research conducted by a team at UC Santa Barbara.
Preliminary results on rats were encouraging enough to get the mainstream media to report on the possibility of oral insulin, mentioning both Oramed’s and Harvard’s advancements. The Harvard team gave a 3-10 units per kilogram insulin dose with CAGE, in an enterically coated capsule, to six nondiabetic rats and the same dose in injections to three other rats. The oral arm registered a decrease in blood glucose of 45% over 10 hours, compared with 49% in one hour for the injections.
The technology is different from Oramed’s, but is it better? We don’t know yet because the data is very early and sparse, but there are two main things to consider here. First, the dosage. Oramed’s oral insulin pills contain about 200 units of insulin per pill. A typical daily dose of subcutaneous insulin can be up to 2 units per kilogram, depending on how advanced the disease is and how much insulin a patient needs. The dose required for Oramed’s oral insulin is much higher because much of it gets digested.
The dose required for insulin-CAGE seems closer to what an injection would require, at least in rats, whereas Oramed’s product mostly keeps blood sugar stable on higher insulin doses. (See page 26 for the data.)
But there’s another factor at play here, which is safety. I mentioned that CAGE was initially tested as a broad spectrum antibiotic/antiseptic, and that it appears to be highly effective at combating drug-resistant bacteria. That means it’s probably not specific to pathogenic bacteria and will kill bacteria across the board in the gut. So, it’s possible that taking CAGE every day as part of an insulin supplement could end up causing serious digestive problems by disturbing the microbiome in the gut, meaning the delicate balance between populations of microbes in the intestine. Taking a powerful antibiotic every day for the rest of your life certainly seems a bit dangerous.
Further, the fact that Oramed’s oral insulin product mostly keeps blood sugar stable is not a bad thing, nor does it make it inferior. A glucose stabilizing pill could be used, for example, as a pre-bedtime insulin supplement in order to keep nighttime glucose levels in range. Even for a diabetic on active insulin injections during the day, this is quite an advantage. So the fact that Oramed’s pill is does not have antibiotic properties could be crucial.
That, of course, and Oramed is much farther along. We will soon know if its oral insulin pill affects HbA1c levels in humans, which are average blood sugar levels over 90 days. Results are expected by May, and then it’s on to phase three trials. The insulin-CAGE team still has three to five years to go before it even enters the clinic.
Disclosure: No positions.
