Insulin Buccal Spray (Oral-Lyn) efficacy in Type 1 Diabetes
Zohreh Annabestani1, Sasan Sharghi1, Samimeh Shahbazi1, Seyed Sajad Mohseni Salehi Monfared1, Farzaneh Karimi1, Eghbal Taheri1,
Ramin Heshmat1, Bagher Larijani1
1-Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Iran
Background: To determine efficacy and side effects of oral insulin spray (Oral-Lyn) in comparison to subcutaneously injected regular human insulin.
Methods: Fifteen patients with type 1 diabetes entered in this open-label single arm study with historical control of the same patients for 8 weeks conducted at the Endocrine and Metabolism Research Institute (EMRI). Some biochemical and hormonal lab tests were taken before and at the end of the study. All patients used Oral-Lyn spray instead of regular insulin in dinner time and peripheral glucose measurements were self-monitored by them via similar type glucometer in four different times included fasting, two hours after breakfast, before dinner and two hours post dinner time blood glucose measures.
Results: This study demonstrated that buccal spray had not serious complications and had the same effects on blood glucose control in comparison with regular insulin injections. Also, the rate of hypoglycemia was decreased to 33.3% at the end of the study from 50% at the beginning. Hemoglobin A1C (HbA1c) values did not show any significant changes throughout the study.
Conclusion: Oral-Lyn provides similar postprandial glucose control and caused lower hypoglycemic episodes when compared to regular insulin injections.
Introduction
Conventional injection insulin therapy is recognized to be inconvenient due to multiple daily injections. As we know, insulin is a large peptide molecule that might be absorbed from gastrointestinal tract, but it rapidly degraded in acidic gastric condition. Many efforts have been performed to deliver insulin via oral roots. So, a rapid-acting, orally administrated recombinant human insulin formulation (Oral-Lyn, Generex Biotechnology, Toronto, ON, Canada) has been identified to improve absorption properties in compare with subcutaneous injection of human regular insulin, but with an earlier maximum effect and a shorter duration of action (1, 2).
In the present study, buccal spray insulin was administrated to patients with type 1 diabetes to determine its efficacy in lowering blood glucose levels and evaluation of possible side effects in compare with subcutaneous regular insulin at mealtime.
Methods
This was an open-label single-arm study with historical control of the same patients for eight weeks since May to November 2009 which involved 15 patients with type 1 diabetes (12 males and 3 females). All the participants received information about the purpose of the study, procedures, and possible side effects of buccal spray, in detail. Screening evaluations included physical examinations and clinical and laboratory tests before study recruitment. Also, we questioned about the history of previous hypoglycemic episodes.
Inclusion criteria were at least 1-year history of type 1 diabetes mellitus, which is currently managed with daily insulin injections totaling 0.3 to 0.8 IU/kg of body weight. Their HbA1c should be greater than 6.5 % and less than or equal to 9.5%. Exclusion criteria were oral lesions and/or disease involving the oral cavity. They should not have history of severe hypoglycemia with seizure or coma within the past 6 months. All the participants underwent training about how to use an identical placebo spray device to avoid improper using of the device. Moreover, all the patients were given a certain glucometer device to check their blood glucose at different 4 times included fasting blood sugar (FBS), 2 hours post breakfast (2hpp), and specially before dinner and 2 hours after throughout the study period. We assigned a visit session one week before the recruitment for adjusting the dose of regular insulin injection and Oral-Lyn spray puffs. Each puff was considered as one unit insulin. Oral-Lyn was considered in divided doses with 50% of the dose before the meal and the rest after the meal as recommended. We just substituted regular insulin in dinner time with Oral-Lyn and regular insulin in the morning and lunch times were unchanged. We assigned some visits to collect information about any new problem or side effect and results of self-monitored blood glucose values recorded by the patients. Before start and at the end of the study, the participants were evaluated for some laboratory tests included: cell blood count (CBC), HbA1c, lipid profile, liver enzymes, blood urea nitrogen (BUN) and serum Creatinine (Cr), 24 hours urine protein and microalbumin values. The study protocol was approved by the Ethics Committee of Endocrine and Metabolism Research Institute of Tehran University of Medical Sciences and all the participants signed informed consent.
Results
Insulin which administered via the buccal root was well-tolerated in all the patients. No serious complication was observed among the patients; nonetheless just one patient had bleeding gum that was in case of dropouts. Two patients had mouth numbness and one of them reported vertigo which lasted no longer and had no serious sequel (Table 1). More than 50% of the patients at the beginning of the study reported hypoglycemia episodes and this rate decreased to 33.3% at the end of the study (Table 2).
Mean glucose values before dinner and 2 hours after the dinner at start and at the end of the study has shown in Table 2. Also, this Table shows that the mean values of patients' weight were not changed throughout the study. Mean values of HbA1c did not significantly change throughout the study period. There were no changes in hormonal and biochemical lab test values except Creatinine which was raised in patients at the end of the study (Table 3).
Discussion
Our study showed that Oral-Lyn provided similar postprandial glucose control in patients with type 1 diabetes comparing with regular insulin. Also, it caused lower hypoglycemic episodes when compared to regular insulin injections. Hypoglycemia rates decreased from 54% to 33% as evidenced by our results which suggest that lesser risk of hypoglycemia is expected by using this root of insulin delivery; although it was not statistically significant due to low sample size, it seems clinically meaningful. As we know, the pharmacokinetic properties of Oral-Lyn have been found to be similar to that of rapid-acting regular insulin in patients with type 1 and type 2diabetes (1-4). The Oral-Lyn peptide has some advantages such as rapid absorption, no need for injection, and decrease postprandial hyperglycemia. Also, this formulation causes no major complication or discomfort in the mouth as we observed in our study and is rapidly absorbed within 5-10 min which is faster than subcutaneous injected regular insulin. Although, our results derived from a small number of patients, which considered our study limitation, it was revealed that insulin delivered via oral root at mealtime could be considered as an acceptable substitute for regular insulin injections.
Acknowledgements
This project was financially supported by Sinamode Pars organization. The link for the above study can be found here.
This Is Generex Biotechnology Pipeline Review
Antigen Express
Antigen Express is the fully owned life science subsidiary of Generex Biotechnology. Antigen Express is a platform and product-based company developing proprietary vaccine formulations for large, unmet medical needs. Their focus is on stimulating critical members of the immune response, known as T helper cells. The technology allows for antigen-specific stimulation or suppression of a T-helper response to virtually any antigen of known pathogenic potential. Antigen Express is building a deep pipeline of therapeutics aimed at a variety of major diseases, including cancer, infectious diseases and autoimmune-based syndromes.
Early efficacy analysis of the AE37 vaccine in a Phase II study
Click the logo to see the results for AE37 that were presented at the 2012 ASCO Breast Cancer Symposium
Peptide Vaccine Stimulates Immune Response in Patients With Breast Cancer
Click the logo to read about the results for AE37 that were presented at AACR 2012
Antigen Express President Dr Eric von Hofe
The President of Antigen Express is Dr Eric von Hofe, who has been impressive with advancing Antigen Express' pipeline and entering into smart collaborations. Dr. von Hofe joined Antigen Express in November of 2003. Prior to this time he held two positions at Millennium Pharmaceuticals; first as Program Director for Target Validation, where he presided over technology development efforts for Aventis and Cereon, and second as Director of Programs and Operations, Discovery Research. He received his Ph.D. from the University of Southern California and was a postdoctoral fellow at the University Hospital of Zurich and Harvard. From 1989 to 1992 he was Assistant Professor of Pharmacology at the University of Massachusetts Medical School. Click on the image of Dr von Hofe to read the abstract for his latest peer review article regarding cancer vaccines.
The AE37 Ii-Key synthetic peptide vaccine
Click on image to enlarge. Harvard scientists, who founded and lead Antigen Express, have pioneered and patented technology that modify MHC class II epitope peptides with a fragment of the MHC class II-associated invariant chain. Antigen Express recently reported interim results from a Phase II trial of the AE37 HER2/neu Ii-Key modified peptide vaccine for patients treated for breast cancer who are at high risk of relapse. While there was a 7% relapse rate in the control arm, there were no relapses in the Ii-Key peptide arm (AE37) when analyzed at the 13-month time point. A review article co-authored by Dr. Eric von Hofe, Ph.D., President of Antigen Express, entitled "A New Era in Anticancer Peptide Vaccines", will appear in an early 2010 edition of the journal Cancer, the International Interdisciplinary Journal published by the American Cancer Society. An advantage of using the type of active immunotherapy offered by AE37, as opposed to passive immunotherapy such as treatment with Herceptin, is that activated immune cells can detect and destroy cancer cells expressing much lower levels of HER-2/neu than is needed for recognition by Herceptin.
San Antonio Breast Cancer Symposium December 2009
Positive AE37 Phase II Interim results were reported at the San Antonio Breast Cancer Symposium in December 2009. Click the SABCS logo to view the poster presentation for AE37's Interim Phase II results, while the abstract text will be provided below.
Antigen Express' Ii-Key Peptide Vaccine Platform Technology
Click on the image for Antigen Express' pipeline to enlarge. AE37 is a novel peptide vaccine that is the product of a proprietary technology platform established at Antigen Express designed to increase the antigen-specific stimulation of CD4+ T helper cells. AE37 is capable of eliciting HER2/neu-specific immune responses, even without the use of an adjuvant. AE37 is the first peptide-based cancer vaccine to show potency in the absence of an immunoadjuvant.
Mary Crowely Cancer Research Center is Fully Funding the AE37 Combo Vaccine Study
Click on the Mary Crowley logo, provided above, to see the clinical trial listing for the AE37 Combo Vaccine
About Me
- Rich Steffens
- Rich Steffens has grown up in New Jersey, is a successful businessman, and studies social media trends amongst life science and biotech companies. His family is deeply influenced by the ill effects of diabetes. I am not qualified to offer investment or medical advice, and make no claims that I am an expert in these areas. I seek to share and learn.
The Future of Insulin Treatment
Dr Gerald Bernstein, Generex VP and former Pres of the ADA, was featured in an online video at the Doctor's Channel in a segment titled "Diabetes & Endocrinology Oral Insulin Delivery with Oral-Lyn". With many new insulin based drugs on the horizon, Dr Bernstein explains both the history of insulin treatment and what he believes to be the best future option- Oral-lyn. Click on the image of the current new insulin based drugs in development to view the video.
Oral-lyn's time profile; insulin only when a diabetic needs it, bringing less risk of hypoglycemia
This image, which you can click to enlarge, illustrates that with its very fast onset and offset of action, Oral-lyn buccal insulin spray may offer less risk of postprandial hypoglycemia as compared to conventional injected insulin therapy. Hypoglycemia is a life-threatening risk, and along with injections is the most important obstacle towards achieving good metabolic control. With each spray of the RapidMist device one unit of meal time Oral-lyn buccal insulin is said to be rapidly delivered into the bloodstream. The amount of sprays given is determined by the amount of insulin each unique diabetic requires to cover a meal. The company informs that the insulin only remains in the bloodstream during the time period the diabetic needs it, promising a safer and simpler approach.
The extended action of injectables may lead to hypoglycemia; the insulin often lingers too long
In this graph, which you can click to enlarge, we can see the long tail of both meal time analogues and regular insulin. Analogue prandial insulin is dosed approx 15 minutes before a meal, peaks in an hour, and with a duration of effect of 4 hours. Regular insulin is dosed 30 minutes before a meal, peaks in 2 hours and lingers up to 6 hours in the bloodstream. This slow acting tail activity often causes low blood sugar levels to occur after the glucose spike provided by the meal starts to decline. Generex states that Oral-lyn is taken right before the first bite of the meal, immediately begins to be absorbed in the inner lining of the mouth, peaks in 30 minutes, and blood sugar levels cleanly return to baseline within two hours. Generex finds there is no tail of activity with Oral-lyn as there is with all other forms of injectable insulin, so they believe the risk of postprandial hypoglycemia is greatly minimized. If blood levels are back at baseline after the meal, there is no reason to gorge on post meal snacks to offset any lingering insulin, which helps avoid unhealthy weight gain. The unique time action profile for Oral-lyn, if proven in the Phase III study, may provide greater flexibility in usage, as well as the ability to take small dose sprays before a snack when that tasty treat simply can not be resisted. Another main advantage for Oral-lyn may be its ability to mimic the first-phase insulin response seen in a healthy person. This first-phase insulin release is one of the first functions that people with diabetes lose. In healthy people our bodies release insulin within 10 minutes after eating.
Oral-lyn Buccal Insulin X-RAY imagery proves no deposition into the lungs
Unlike Mannkind's Afrezza, in which a powder insulin formulation is inhaled into and absorbed by the lungs, Oral-lyn is delivered as a fine spray to the buccal cavity by the RapidMist delivery system. Generex states the result is rapid insulin absorption through the buccal mucosal lining of the mouth without pulmonary (lung) exposure. The lungs, like all other vital organs in the body, are already a target of diabetes leading to lower lung function over time. The lungs are meant to process gasses, and not proteins. I think that Generex, via Oral-lyn buccal insulin, avoids potential pulmonary complications in a simpler and safer approach. Click on the provided X-Ray image to learn more.
Prandial insulin dosing is now as simple as a spray
Oral-lyn is available in a US FDA approved Treatment IND as well as in Phase III trials as a 1 UNIT per spray dose. For Oral-lyn, the delivery devise appears built to provide fine tuning post meal dosing. It appears as simple as taking another quick spray. In my opinion, as the safety concerns swirl around prospects for inhalable insulin, the Oral-lyn buccal insulin Treatment IND sounds like a great marketing advantage, since more and more diabetics and physicians will learn of buccal insulin as Generex works towards full approval.
Generex Oral-lyn Buccal Insulin
"Patients who are needle averse face a serious barrier to their recommended treatment," warns Generex "Generex Oral-lyn promises a pain-free alternative to injectable insulin, which is good news especially for older patients and children who find needles uncomfortable." Click on the image provided above to learn more about aversion to injections and diabetes.
Dr Gerald Bernstein, VP Medical Affairs Generex, former President of American Diabetes Association
Click on the photo of Dr Bernstein to view his interview on FOX Health. Dr Bernstein recently commented further on the unique safety profile for Oral-lyn: "It’s extremely safe by all the studies that have been done so far, including two years in animal tests. We haven’t seen allergic reaction. The lining of the mouth hasn’t shown any abnormalities. The buccal mucosa is an extra-tough and resilient tissue, it’s beaten up all the time. People bite themselves or burn themselves. Whatever doesn’t get absorbed is going to go to the stomach. Now the insulin molecule is unprotected and therefore it will be denatured by the acid and then broken down. There are no side effects." Dr Bernstein is an attending physician at Beth Israel Medical Center, and physician emeritus at Lenox Hill Hospital and Montefiore Medical Center, all in New York. He was formerly Director of the Beth Israel Health Care Systems Diabetes Management Program. Dr. Bernstein was president of the American Diabetes Association in 1998-99 and was for many years a member of the ADA's Board of Directors and its Executive Committee. He received the ADA's Banting Medal for Service in 1999. Dr. Bernstein presently serves on several ADA committees and on the Board of Directors of the American Diabetes Association Research Foundation.
Buccal Absorbtion
RapidMist Buccal Drug Delivery Device
