MGI Pharma, Inc, a biopharmaceutical company focussed in oncology and acute care, announced that the New Drug Application (NDA) for Aquavan (fospropofol disodium) injection has been submitted to the US Food and Drug Administration (FDA) for review.
Aquavan is an investigational drug that is being studied as a sedative-hypnotic agent in patients undergoing brief surgical or diagnostic procedures, the company said in a press release
Data from phase II and phase III trials in patients undergoing colonoscopy, a phase III trial in patients undergoing bronchoscopy, and an open label study in patients undergoing a variety of minor surgical procedures form the foundation of the Aquavan NDA. In total, data from 21 clinical studies, including 1,611 subjects are included in the application. Consistent with standard medical practice, the four foundational trials were conducted without monitored anesthesia care (MAC) sedation, and study drugs were administered by medical personnel as dictated by local investigative site guidelines, the company said.
"We are pleased with the results of the Aquavan pivotal efficacy and safety trials. The submission of the Aquavan NDA marks the completion of a key milestone for MGI Pharma as we continue to expand our product portfolio," said, Mary Lynne Hedley, executive vice president and chief scientific officer, MGI Pharma.
A randomised, double blind, multi-centre, pivotal phase III trial of Aquavan Injection for sedation of patients undergoing bronchoscopy successfully met the primary endpoint of sedation success as well as all secondary endpoints. A total of 252 patients were randomised and received either a 6.5 mg/kg dose of Aquavan or a control dose of 2.0 mg/kg. Following administration of the initial bolus dose of the study drug, the design of this trial allowed a limited number of supplemental doses to be administered as required to initiate or maintain sedation during the procedure.
The primary endpoint of this trial was sedation success, defined as a patient having achieved three consecutive Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores of less than or equal to 4 after administration of sedative medication and completion of the bronchoscopy procedure without the use of alternative sedative medication and without manual or mechanical ventilation. The secondary endpoint of treatment success was defined as completion of the procedure without the use of alternative sedative medication and without manual or mechanical ventilation. Additional endpoints included measures of patient and physician satisfaction, the press release stated.
Among patients treated with an initial bolus dose of 6.5 mg/kg (n=150) of Aquavan, the sedation success rate was 88.7 per cent compared to 27.5 per cent of patients in the control arm (n=102) (p less than 0.001). The treatment success rate among patients treated with the initial bolus dose of 6.5 mg/kg Aquavan was 91.3 per cent compared to 41.2 per cent for control (p less than 0.001). Of those patients in the 6.5 mg/kg Aquavan arm, 94.6 per cent indicated that they would be willing to be treated again with the same sedative dose, compared to 78.2 per cent of those in the control arm (p less than 0.001). Additionally, 83.3 per cent of patients in the 6.5 mg/kg Aquavan arm reported that they did not recall being awake during the procedure, compared to 55.4 per cent for control (p less than 0.001).
The nature and frequency of sedation-related adverse events were similar between patients who received the Aquavan 6.5 mg/kg dose and those in the control arm, and were predictable for this patient population. Based upon the American Society of Anesthesiologists (ASA) Physical Status Classification System, 43 per cent of patients were classified as P3 (having severe systemic disease), or P4 (having systemic disease that is a constant threat to life), the company said.
The most frequently observed sedation-related adverse event in the two study arms was transient hypoxemia (defined as blood oxygen saturation levels less than or equal to 90 per cent for more than 30 seconds at any point, as measured by pulse oximetry), which was observed in 15 per cent of patients who received an initial bolus dose of 6.5 mg/kg of Aquavan compared to 13 per cent of patients who received control. Eight patients (5 per cent) who received 6.5 mg/kg Aquavan experienced hypotension. Summary results from this phase III trial have been previously reported.
A randomised, double-blind, multi-centre 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 control dose of 2.0 mg/kg. A total of 312 patients in 18 sites were pre-treated with fentanyl citrate (50 ug) 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 of 18 years and older and in varying states of health and sedation risk.
According to the company statement, the results showed that 87 per cent 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 greater than or equal to 4, plus completion of the procedure without the need for alternative sedative medications and manual or mechanical airway assistance. In comparison, 26 per cent of patients who received Aquavan 2.0 mg/kg achieved sedation success (p less than 0.001), while 69 per cent who received midazolam 0.02 mg/kg achieved sedation success.
Furthermore, 88 per cent 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 per cent of patients in the Aquavan 2.0 mg/kg control arm achieved treatment success (p less than 0.001). In addition, the 6.5-mg/kg dose of Aquavan was associated with a lower rate of supplemental analgesic use (55 per cent of patients required additional analgesic medication, compared to 77 per cent receiving the 2.0 mg/kg dose, p less than 0.001). The most common adverse reactions were paresthesias (tingling, and burning) and pruritus (itching). These were generally mild to moderate in intensity, transient and self-limiting.
A single arm, open label study was conducted in 123 patients undergoing a variety of minor surgical procedures to assess the safety and tolerability of Aquavan at a dose of 6.5 mg/kg in a variety of settings including arthroscopy, bunionectomy, dilation and curettage, endoscopy, hysteroscopy, lithroscopy, shunt placement and trans-esophageal echoes. The most frequently observed sedation-related adverse event in this study was transient hypotension (3 per cent). No adverse events led to procedure or study drug discontinuation, the company reported.