MINNEAPOLIS -- MGI PHARMA, INC., a biopharmaceutical company focused in oncology and acute care, announced the results of a successful pivotal phase 3 trial of Aquavan® (fospropofol disodium) Injection in patients undergoing colonoscopy. Primary and secondary efficacy endpoint results, as well as safety data, were presented at Digestive Disease Week 2007 in Washington, D.C., by Lawrence B. Cohen, MD, department of medicine/gastroenterology, Mount Sinai School of Medicine, New York.
Aquavan Injection is a proprietary water-soluble prodrug of propofol that is in clinical development for moderate sedation of patients undergoing therapeutic and diagnostic procedures.
Aquavan has not yet been approved for marketing by the U.S. Food and Drug Administration (FDA) or any other regulatory agencies.
"Aquavan has a favorable pharmacokinetic profile, making it possible to deliver a predictable concentration of sedative and achieve the desired level of sedation," said Cohen, a lead investigator of the trial.
Colonoscopy Results: Primary Endpoint of Sedation Success Achieved (Abstract W1451)
A randomized, double-blind, multi-center phase 3 pivotal trial was conducted to evaluate whether an Aquavan dosing regimen of 6.5 mg/kg would be safe and effective in providing moderate sedation in patients undergoing colonoscopy, compared to a 2.0 mg/kg Aquavan regimen. A total of 312 patients in 18 sites were pre-treated with fentanyl citrate (50 mg) and then received either Aquavan 2.0 mg/kg, Aquavan 6.5 mg/kg, or midazolam 0.02 mg/kg (2:3:1 ratio). Gastroenterologists administered the sedatives, as is consistent with a large percentage of routine colonoscopies. Patients were ages 18 and older and in varying states of health and sedation risk.
The results showed that 87 percent of patients who received an initial bolus dose of Aquavan 6.5 mg/kg achieved sedation success, which was defined by three consecutive Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scores of <4, plus completion of the procedure without the need for alternative sedative medications and manual or mechanical airway assistance. In comparison, 26 percent of patients who received Aquavan 2.0 mg/kg achieved sedation success (p<0.001), while 69 percent who received midazolam 0.02 mg/kg achieved sedation success. MOAA/S scores measure a patient’s sedation level.
Furthermore, 88 percent of patients in the Aquavan 6.5 mg/kg treatment arm achieved "treatment success," the secondary efficacy endpoint of the trial, meaning they completed their colonoscopy without requiring manual/mechanical ventilation and alternative sedative medication (non-study sedative[s] used because of inadequate sedation). By comparison, 28 percent of patients in the Aquavan 2.0 mg/kg treatment arm achieved treatment success (p<0.001). In addition, the 6.5 mg/kg dose of Aquavan was associated with a lower rate of supplemental analgesic use (55 percent of patients required additional analgesic medication, compared to 77 percent receiving the 2.0 mg/kg dose, p<0.001). The most common adverse reactions were paresthesias (abnormal neurological sensations, such as increased sensitivity, numbness, tingling, and burning) and pruritis (itching). These were generally mild in intensity, transient and self-limiting. Results from this pivotal phase 3 trial have been reported previously.
Physician/Patient Satisfaction (Abstract W1440) and Procedural Recovery (Abstract W1441) Analyzed
Additional endpoints of the phase 3 study were analyzed prospectively in two sub-analyses to assess physician- and patient-reported satisfaction as well as patients’ cognition during recovery. In the first sub-analysis, physicians used a 10-point scale (1 = low, 10 = high) to rate their experience with both Aquavan doses at the end of the sedation initiation phase (the period between the first administered dose and the start of the procedure, i.e., when the scope is inserted), and again at the end of the procedure (i.e., when the scope is removed). The results showed that physician satisfaction ratings were higher for Aquavan 6.5 mg/kg at the end of the procedure (median score 9, versus median score 4 for Aquavan 2.0 mg/kg, p<0.001). In addition, patients completed a six-question satisfaction survey prior to discharge. Fewer patients who received Aquavan 6.5 mg/kg remembered the scope being inserted (32 percent versus 45 percent of patients who received Aquavan 2.0 mg/kg, p<0.05).
In another sub-analysis, patients were given the Hopkins Verbal Learning Test-Revised (HVLT-R™), an instrument that measures verbal learning and memory retention. Measures of time to fully alert (TTFA) and time to discharge (TTD) were also analyzed, and showed that patients who received Aquavan 6.5 mg/kg achieved a TTFA of 6.7 minutes and a TTD of 8.7 minutes. Among patients who received at least one dose of study drug and no alternative sedative medication, patients in the Aquavan 6.5 mg/kg treatment arm demonstrated a higher mean retention score than those in the midazolam group (70 percent versus 41 percent, p <0.01).
Data from the phase 3 study, together with the results of another phase 3 trial in patients undergoing bronchoscopy and an open-label study in patients undergoing minor surgical procedures, will form the foundation of the Aquavan New Drug Application (NDA).
"There is a need for new agents for moderate sedation that offer an alternative to existing agents. Aquavan was designed to help fulfill this need," said Mary Lynne Hedley, PhD, executive vice president and chief scientific officer of MGI PHARMA. "We are very pleased with the outcome of this trial and remain on track to submit the Aquavan New Drug Application to the U.S. Food and Drug Administration in the third quarter of this year."
Source: MGI Pharma