PLoS One. 2013 Apr 9;8(4):e59524.
Glucose-reducing effect of the ORMD-0801 oral insulin preparation in patients with uncontrolled type 1 diabetes: a pilot study.
Eldor R, Arbit E, Corcos A, Kidron M.
Diabetes Unit, Internal Medicine, Hadassah University Hospital, Jerusalem, Israel. firstname.lastname@example.org
The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5-10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1 ± 7.9% pretreatment vs. 45.4 ± 4.9% during ORMD-0801 treatment; p = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055 ± 5547 mg/dL/24 hours vs. 55060 ± 3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.
Unstable Type 1 diabetes
Severely unstable Type 1 diabetes is considered a rare complication of Type 1 diabetes mellitus (T1DM) and is characterized by frequent unpredictable episodes of drastic swings in blood glucose levels. Patients are irresponsive to standard treatment regimens designed to achieve glycemic control, and require recurrent and long hospital stays. The condition is associated with severe psychosocial disruption and places a considerable strain on hospital resources and family/work stability.
Precise assessment of the prevalence of this subtype of T1DM is complex, as no universally accepted diagnostic criteria exist, and verification of the condition can only be achieved under close, long-term medical supervision. Nevertheless, unstable diabetes patients are thought to make up approximately 1-3% of the world T1DM population. The condition is most common in the second or third decade of life and reportedly demonstrates a second peak of risk at ages 60-70, with a suggested higher frequency among females.
While the factors underlying unstable diabetes are still unclear, a number of studies have suggested that these patients feature an unusual absorption barrier below their skin, reflected by the significantly higher injected insulin doses they require when compared to stable diabetic individuals. Insulin requirements exceeding 2.0 units/kg/day is a common indication of brittle diabetes.
PODTM: and oral drug delivery platform
Currently, insulin-based therapies are only available in injectable forms, owing to the complexity of its oral delivery. However, at the same time, it has become increasingly evident that oral delivery of insulin better mimics the localized gradients obtained when it is naturally produced by the body. Moreover, oral insulin options are expected to result in fewer adverse events, which are highly common to injectable insulin. When administering protein-based drugs via the mouth, the active ingredient must traverse the gut, where it is exposed to harsh, degradative conditions, jeopardizing its integrity and effectiveness. In addition, it must then cross the barrier, typically limited to small particles only, between the small intestines and the blood circulation. Oramed Pharmaceutical has been actively pursuing development of a drug delivery platform supportive of oral delivery of protein-based drugs. Its PODTM technology provides the active ingredient with a protective environment as it travels through the gut. This is achieved by packaging the drug in a specially designed capsule which is resistant to the harsh conditions of the gut. Once it reaches the small intestine, the capsule disintegrates and releases the drug, along with specified protective proteins, which ward off locally acting enzymes that can potentially inactive the drug. At the same time, a highly effective absorption enhancer is released from the capsule, and assists the active ingredient in crossing the barrier between the small intestine and the nearby blood vessel. From there, the drug is carried off to the liver, where it is metabolized to the correct degree, allowing for final release of only a small proportion of the delivered drug to the general circulation. In this manner, the body is exposed to natural levels of active drug, in sharp contrast to the levels it is exposed to following injections made directly into the bloodstream.
ORMD-0801: oral insulin
ORMD-0801, the PODTM-based oral insulin capsule,has been tested in various clinical trials, and has consistently led to controlled blood glucose levels in T1DM patients, when taken just before meals. Following its crossing of the small intestine barrier, its high localized concentrations in the neighboring vein allow it to directly and effectively counteract postmeal glucose loads, leading to lower circulating glucose levels. In addition, it is then metabolized in the liver and released to the circulation at natural concentrations.
In this study, Oramed Pharmaceuticals sought to assess the stabilizing effect of ORMD-0801 on glucose levels of unstable T1DM patients. To this end, patients were asked to carry on with their regular insulin therapies, while concomitantly taking one ORMD-0801 capsule before the three main daily meals, over a period of ten days (treatment phase). Participants were continuously monitored with a glucose monitoring device (known as a continuous glucose monitor, CGM), whose recordings were only released at the end of the study. The typical blood glucose readings and fluctuations for each participant were determined by continuously monitoring their blood glucose levels for five consecutive days prior to the onset of ORMD-0801 treatment (pretreatment phase). At the end of the study, pretreatment and treatment phase glucose readings were compared. Treatment with oral insulin was associated with a significant decrease in drastically high blood glucose levels and seemed to have a greater effect during the early evening hours. In parallel, the number of normal glucose readings while on ORMD-0801 support quadrupled when compared to the number of such readings during the pretreatment phase. Overall, the premeal ORMD-0801 treatment was well tolerated by all participants and triggered a clinically significant reduction in the incidence of drastic glucose swings. This oral insulin support therapy still requires further evaluations, but presents great promise in achieving better control of blood glucose concentrations in diabetes patients in general and in patients with unstable T1DM, in particular.
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