In a placebo-controlled Phase II pharmacokinetic study in patients with type 1 diabetes, the 12 patients receiving Nasulin demonstrated more rapid onset of action than when they received either regular or fast-acting injectable insulins. In addition, blood sugar levels for two hours after eating in patients treated with Nasulin were similar to those who received both injectable insulin formulations. No adverse events were reported during this study.
Patients in the study were randomized to receive the following 4 regimens: intranasal doses of 25 IU Nasulin (approximately bioequivalent to 5 IU insulin SC), regular insulin (Humulin R(R) (5 IU)), rapid-acting insulin (Humalog(R) (5 IU)) and saline nasal spray (placebo). The primary objectives of the trial were to compare the pharmacokinetic and glucodynamic characteristics of Nasulin, as well as its bioavailability/bioequivalency, with injectable forms of insulin. Each regimen was given after an overnight insulin drip to maintain standard glucose levels. Each patient received a 450 calorie high-protein boost challenge after the study drug was administered.
Researchers also presented results from two additional Bentley-sponsored studies to determine if smoking had any effect on the absorption of Nasulin in normal male smokers and non-smokers and to determine if there were any absorption differences due to the normal nasal cycles that occur between nostrils (alternating levels of mild congestion). Nasulin was absorbed equally in a study of 18 smokers and 18 non-smokers, demonstrating more rapid onset of action than Humalog. When Nasulin was administered to different nostrils in 12 healthy male subjects, no significant differences in absorption were noted, although there was a slight trend in favor of the mildly congested nostril. However, researchers concluded this difference is unlikely to be clinically important, and noted if nostrils are totally blocked, they should be cleared with gentle nose-blowing before administration.
Adverse events reported in the smoking/non-smoking and dominant nostril studies included a total of four episodes of hypoglycemia in subjects receiving the investigational drug. In addition, some volunteers experienced transient, mild nasal irritation and/or watery eyes, which resolved rapidly. These transient findings were not consistently present with each dose, and were generally resolved within 15-20 minutes.
"These trials show favorable results for Nasulin intranasal insulin spray as being equivalent in several key clinical measures when compared to the leading formulations of injectable insulin," said John Sedor, president of Bentley. "For more than two decades, the medical community has been searching for a less painful and easier method for treating diabetes than insulin injections. Nasulin presents a significant opportunity of achieving this goal for many patients and has the potential for significantly better patient compliance than a routine of insulin injections. Nasulin does not require constant refrigeration for use, and the delivery device is small enough to be carried discretely in a pocket or purse. In addition, Nasulin does not enter the lungs, avoiding possible long-term effects on lung function and holding the potential for use in diabetes patients with COPD and asthma. We are excited by the prospects for Nasulin, and Bentley is committed to finding collaboration partners to help conduct the additional clinical studies necessary to make this potentially important diabetes tre atment commercially available to patients around the world."
Sherwyn L. Schwartz, M.D., of dgd Research Associates, Inc., principal investigator in the type 1 diabetes and smoking/non-smoking trials, said, "The encouraging results of these clinical studies demonstrate the positive pharmacokinetic, glucodynamic and bioavailability properties of Nasulin compared with injected insulin. Onset of action with Nasulin was favorable. In the type 1 diabetes study, patients' plasma insulin levels peaked sooner with Nasulin than with the very rapid acting Humalog and Humulin R (20 vs. 53 vs. 81 min.). Compared with Humalog, Nasulin resulted in a greater decrease in plasma glucose concentration (AUC) in the first hour, with Humalog being slightly better in the second hour."
"Bioavailability is a key consideration in assessing the efficacy of non-injected formulations of insulin, and Nasulin performed well in this area," said Schwartz. "When administered to type 1 diabetes patients, the relative bioavailability of Nasulin versus Humalog was 17.0 percent over one hour and 8.7 percent over two hours. The relative bioavailability of Nasulin versus Humalin R was 26.5 percent over two hours. In addition, it was encouraging to find that absorption of Nasulin was not affected by smoking in the study of normal male smokers and non-smokers."
As administered to patients in the type 1 diabetes study, Nasulin was formulated as a stable liquid emulsion containing 1 percent human recombinant insulin, 2 percent CPE-215(R)excipient, Bentley's patented permeation enhancer, and surfactants as emulsifiers. CPE-215, which has received GRAS status from the FDA as a direct food additive, has been shown to be non-irritating, stable and effective in gels, ointments, lotions and creams as well as intranasal spray formulations.
About dgd Research Associates, Inc.
The research arm of the Diabetes & Glandular Disease Clinic, founded in 1979 by Dr. Schwartz, dgd Resear ch Associates has a staff of more than 250 employees, and has conducted over 1,500 Phase I through III clinical trials, primarily in targeted endocrine populations. The Diabetes & Glandular Disease Clinic is the largest private endocrine clinic in the United States with more than 70,000 active patients; eight board certified endocrinologists, seven NPs/PAs and an ADA recognized diabetes education program. For more information visit www.dgdclinic.com and www.dgdresearch.com.
About Bentley Pharmaceuticals, Inc.
Bentley Pharmaceuticals is a specialty pharmaceutical company focused on advanced drug delivery technologies and generic pharmaceutical products. Bentley's proprietary drug delivery technologies enhance the absorption of pharmaceutical compounds across various membranes. Bentley manufactures and markets a growing portfolio of generic and branded generic pharmaceuticals in Europe for the treatment of cardiovascular, gastrointestinal, infectious and central nervous system diseases through its subsidiaries -- Laboratorios Belmac, Laboratorios Davur, Laboratorios Rimafar and Bentley Pharmaceuticals Ireland. Bentley also manufactures and markets active pharmaceutical ingredients through its subsidiary, Bentley API. Additional information regarding Bentley Pharmaceuticals may be obtained through Bentley's web site at www.bentleypharm.com.
Safe Harbor Statement under the Private Securities Litigation Reform Act of 1995: This press release contains forward looking statements, including without limitation, statements regarding Bentley's Nasulin intranasal insulin product candidate, its potential as a treatment for diabetes mellitus, and prospects for further clinical trials of Nasulin,. These forward-looking statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from future results expressed or implied by such statements. Factors that may cause such differences include, but are not limi ted to, risks associated with further `studies of the safety and efficacy of Bentley's intranasal insulin product candidate and its drug delivery technology, risks associated with international clinical trials and regulatory review of a pharmaceutical product, and other risks detailed under Item 1A "Risk Factors" in Bentley's most recent Annual Report on Form 10-K and its subsequent periodic reports filed with the Securities and Exchange Commission. Bentley cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this document, and Bentley undertakes no obligation to update or revise the statements, except as may be required by law.