Last week, we announced that our partner in India, Shreya Life Sciences, has completed it’s phase three trial of General Oral-lyn in patients with type II diabetes and submitted the results to the Indian government with a view to securing approval for the marketing of the product. I will now ask Dr. Anderson to comment on this positive development and it’s impact on our own plans for Generex Oral-lyn in the clinical and regulatory sphere. Dr. Anderson?
Dr. James Anderson:
Thank you, Mr. Fletcher. Good morning, I will address three topics today with regard to Generex Oral-lyn buccal insulin spray product program. First, a review of trial O84, part of which was discussed at a prior AGM, second, the completion and regulatory submission of the Oral-lyn phase three study in India and the partnership of Generex and Shreya Pharmaceutical to produce, distribute, market Oral-lyn in India, thirdly, the planned improvements in the Oral-lyn formulation for global registration will be discussed.
Previously, I’ve provided data on patients who had completed the O84 clinical trial, a six month trial with a six month extension comparing Oral-lyn to injected regular insulin in patients with type I diabetes. You will recall that in that patient segment of completers, as measured by hemoglobin A1C, the metabolic control achieved with Oral-lyn was equivalent to the control of patients randomized to injected regular insulin. For a number of significant reasons, the data from the O84 trial was re-examined, re-analyzed and the final report re-written.
While the positive data from the small group of completers did not change appreciably, the trial as a whole did not meet the primary objective of showing non-inferiority of Oral-lyn to injected regular insulin. Although the study did yield some useful information, why did the study fail to meet the primary objective? The major reason was that two-thirds of the subjects randomized to receive Oral-lyn failed to complete the study. The majority of those patients who dropped out did so during the first one to three weeks of therapy. While a few study sites were in the U.S. and Canada, the majority were in Eastern Europe, in the new republics of the former Soviet Union.
More than two-thirds of the patients enrolled in the study were given educational instructional materials not in their native languages. As importantly, two-thirds of the physicians and healthcare professionals did not have complete material in their native language. We believe that this was the flaw that resulted in a lack of understanding of how to use Oral-lyn correctly which produced an excessive dropout rate that led to not achieving the primary objective.
For this study, the pre-specified non-inferiority margin was 0.50 percent. The 90 percent confidence interval, which is that range of values to finding a difference between two parameters, was calculated to be 0.24 percent to 0.53 percent. Since the 0.50 non-inferiority margin is in between the upper and lower values of the confidence interval, the study was not able to show that Generex Oral-lyn was non-inferior, that is equal to, the injected human insulin. The extremely low number of patients completing that trial directly affected the values of the confidence interval, but even with that huge dropout, the upper limit of the 90 percent confidence interval was very close to the pre-specified non-inferiority margin of 0.50 percent. The study almost was successful.
In sharp contrast, the phase three trial conducted in India, a Shreya Life Sciences, was an excellent example of the way a trial should be conducted. This study, 12 week parallel controlled study comparing Oral-lyn to injected rapid insulin in patients with type II diabetes, was conducted at 14 sites in India with 209 patients put on drug. The educational materials and the informed consents were translated into nine different languages so that each individual participant and his or her representatives could read the information in a language in which they were conversant and comfortable. In this study, only 11 of the 209 subjects, five percent, dropped out of the trial.
While a manuscript of the full trial results has been submitted to an international journal of clinical diabetes and thus the detailed results are embargoed until publication, I can share that there was a statistically significant improvement in the hemoglobin A1C of those patients randomized to Oral-lyn compared to injected insulin and that the statistically significant improvement in metabolic control occurred much more rapidly in the Oral-lyn treated group than in the injected insulin group. Shreya Life Sciences and their investigator are excited about the results and so are we.
The results of that trial were also submitted to the drug controller general of India, the Indian regulatory authority, in December of 2012 as part of the dossier to gain final approval for marketing in India. We are extremely pleased to announce that Shreya anticipates approval for the sale of Oral Recosulin, which is their trademark for Oral-lyn in India, within mid 2013.
In the country of India, the International Diabetes Federation has estimated there are over 50 million people with diabetes mellitus. Generex is currently working with Shreya to transfer the technology to facilitate the local manufacturing of Oral-lyn to global standards to ensure continuous product availability. We are also working with Shreya in the planning and design of patient and professional educational materials, product launch materials and sales and marketing strategies.
Now I’d like to address the planned improvements in Generex Oral-lyn. A review was conducted last year with insulin formulation chemists, clinical diabetologists and diabetes sales and marketing leaders. The new techniques in protein chemistry and pharmaceutical formulation science suggested that with minimal changes in the production process and contents of the components, we could improve Oral-lyn less increasing the convenience, compliance and safety for patients by producing a more concentrated Oral-lyn formulation that would allow dosing in the average patient to be reduced to fewer sprays.
We have developed a clear and complete plan for identifying the modifications to the Oral-lyn formulation and rapid mist delivery device to ensure two to three international units of bio available insulin per spray. Our new program encompasses a pharmaco kinetic and gluco dynamic trial design and clinical study plan for conducting trials with appropriately validated methodology. These short studies will demonstrate the integrity and bio viability of the insulin formulation delivered by the device, assess the pharmaco kinetics using validated methodology and appropriately designed clinical models, confirm the bio availability of the delivery insulin and assess the gluco dynamic response in fasted, post meal and (inaudible) clinical models.
Our planned final phase three trial required by the USFDA for registration will examine the reproducibility and intrasubject variability both short term and over the duration of the study. We will also assess intrinsic and extrinsic factors that could affect absorption such as pharyngeal infections, smoking and vascular medications. These studies will also provide data demonstrating the ability of Oral-lyn to achieve metabolic results that are not possible with subcutaneous injected insulins, even with the rapid acting insulin analogs available today. This will allow our marketing partners to justify any potential price premium over injected insulin and help ensure a more rapid uptake of view in the medical community.
The obvious question that many of you may be asking right now is, “Why are you changing the formulation if the current formulation is good enough to sell in India?” I’m not going to immediately defer to the bandwagon of blaming all of our ill on Coca-Cola, McDonald’s and the Ford Motor Company, but an unpleasant reality of western civilization is that we are more obese than our Asian brethren. With our increased weight, our mealtime insulin doses are also higher, frequently in the range of double or more. So while the less obese and better exercised patients in India can easily use the current formulation of Oral-lyn, a stronger formulation is required for the average patient in North America. Since we anticipate that obesity will continue to become a more prevalent worldwide, we are already in discussions with our partner, Shreya, for future production and sales of the improved Oral-lyn formulation in India and other global markets as well.
In summary, we’re quite excited and pleased with the progress we have made with Generex Oral-lyn over the last six months. Conduct of correctly designed and well-implemented clinical studies continue to demonstrate the validity and efficacy of the Oral-lyn product and the platform. The anticipated approval, launch and sales of Oral-lyn in one of the largest populations of diabetes mellitus in the world signifies the new milestone in the successful reorganization of Generex Biotechnology. While the Oral-lyn reformulation, clinical study work and final FDA submission are dependent upon adequate and appropriately timed funding and partnering to meet timeline goals, we are confident that we are now moving forward in the right direction both for Generex and for its investors.
Thank you and I look forward to our next opportunity to inform you of the additional new programs in diabetes detection, diagnosis, therapy and prevention that are in development in the Generex pipeline.