He said that both studies also used drug formulations (putting the drug in glucose) that changed the osmotic pressure gradient. In order for the drug to work, it has to penetrate into the mucus, he said. By putting the drug into glucose, they reduced the osmolaric pressure gradient between the amphotericin B solution and the mucus, to the effect that lesser amphotericin B diffuses in.
Explore this issue:March 2008
Dr. Ebbens responded by pointing out a study by Kintzel et al. (Am J Hosp Pharm 1992;49:1156-64) that adding glucose instead of water to the solution reduced nasal irritation because of low osmolarity and has no effect on drug bioavailability. She also said that the addition of glucose is advised as diluent by the manufacturer. No proof exists that a pressure gradient is needed for treatment effect.
Also pointing out flaws in the Weschta and Ebbens studies was Francis E. O’Donnell Jr., MD, Chairman and Chief Executive Officer of Accentia BioPharmaceuticals, who said the limitation in the Weschta study is that he used a pump spray, not a lavage. And, he used a very high concentration of amphotericin B, 30 times the concentration that Mayo and we used in our clinical trials. He used 3 milligrams per cc and anything above 500 micrograms, or half a milligram per cc, is likely to be toxic to the epithelia.
Both Dr. Ponikau, who is not affiliated with Accentia, and Dr. O’Donnell also criticized Dr. Ebbens’s use of a gravity-fed drug delivery device that was designed to deliver 250 cc. However, in their trials, it was only filled with 25 cc-indicating that the pressure may have been too low to effectively administer the drug. Dr. O’Donnell noted that SinuNase, in contrast, is delivered with the equivalent of a bulb syringe so patients can apply sufficient pressure to deliver it throughout the nasal cavity.
Dr. O’Donnell was enthusiastic about his own company’s current Phase III clinical trials of SinuNase. He said that Accentia expects to present the unblinded Phase III clinical trial primary results in mid-March. These will include complete resolution of the cardinal symptoms of nasal congestion and sinus headache/facial pressure. The secondary endpoints, including endoscopy and CT scan results, will be available at a later point and presented at a scientific forum.
In January of this year, Dr. O’Donnell announced in a news release and letter to shareholders that we now have interim, blinded, intent-to-treat data on the primary endpoint (complete resolution of both cardinal symptoms) at the conclusion of the study for approximately 80% of the patients in the study. This interim blinded data shows that approximately 20% of all patients are achieving the primary endpoint of complete resolution of both cardinal symptoms and another 23% of patients are achieving complete resolution of one or the other cardinal symptom at 16 weeks. To put these results in perspective, it is important to remember that 50% of the patients received SinuNase and that 50% received a placebo control that had no antifungal activity.