Completed Clinical Trials
Dalbavancin has completed a total of fifteen Phase 3, Phase 2 and Phase 1 clinical trials, over approximately ten years, in which more than 1,000 patients have been dosed with dalbavancin. These clinical trials assessed more than 60,000 isolates, from over 390 centers worldwide, the majority of which were Staphylococci and Streptococci, in particular species that are relevant to abSSSI, including MRSA and multiple resistant isolates.
Ongoing Phase 3 Clinical Trials
Based on the draft guidance issued by the FDA in August 2010 regarding expectations from sponsors and clinical trials for abSSSI, Durata negotiated two SPAs with the FDA for the clinical development of dalbavancin. Based on these SPAs, the Company is currently enrolling patients in two global multicenter, double-blind, double-dummy, randomized, controlled pivotal Phase 3 clinical trials to compare the clinical efficacy of dalbavancin to vancomycin, with the option to switch to oral linezolid after three days of dosing, for the treatment of patients with suspected or proven Gram-positive abSSSI. The Company is using the same two dose regimen for dalbavancin in these trials that has been used in each Phase 3 clinical trial for dalbavancin conducted to date, with a 1,000 mg dose administered on day 1 and a 500 mg dose administered on day 8. All patients randomized to active dalbavancin also will receive placebos to mimic the comparator regimen, which includes placebo intravenous infusions to mimic vancomycin and oral placebos to mimic linezolid. Patients randomized to active vancomycin/linezolid also will receive placebo intravenous infusions on days 1 and 8 to mimic dalbavancin. Pharmacists at each trial site are unblinded to the dosing regimens while the clinical investigators and patients remain blinded.
The primary outcome measure will be a comparison of clinical response at 48 to 72 hours following initiation of treatment, based on the cessation of the spread of the lesion and body temperature. To achieve this primary outcome measure, Durata must demonstrate non-inferiority of dalbavancin compared to vancomycin based on a pre-determined non-inferiority margin. Non-inferiority comparisons of drugs are the standards for antibiotic drug development, and non-inferiority margins are used in the statistical analysis comparing two treatment arms in a study to distinguish the degree of potential difference between the antibiotics being evaluated. The pre-specified non-inferiority margin in our ongoing Phase 3 clinical trials is 10%.
The trial protocol provides for a secondary outcome measure of non-inferiority of clinical response at the end of treatment, which is 14 days following initiation of treatment, based on the investigator’s assessment of the resolution or improvement of all signs and symptoms of the infection. Based on input from the EMA during scientific advice discussions the Company expects that this secondary outcome measurement will serve as the primary measure of efficacy for our MAA submission to the EMA.
Patients enrolled in these two Phase 3 clinical trials are required to have at baseline a minimum abSSSI lesion size of 75 cm2 and at least one systemic manifestation of infection, based on fever or a minimum white blood cell count. The Company plans to enroll approximately 556 patients in each ongoing Phase 3 clinical trial and is conducting the two clinical trials simultaneously. The Company expects to conduct the first Phase 3 clinical trial at approximately 80 to 90 sites and the second Phase 3 clinical trial at approximately 120 to 150 sites, in each case, in North America, Europe, Asia and Africa. The Company expects to complete these ongoing Phase 3 clinical trials and have initial, top-line data available by the beginning of 2013 and, if these trials are successful, submit an NDA to the FDA in the first half of 2013 and an MAA to the EMA in the second half of 2013. Under the Prescription Drug User Fee Act, or PDUFA, commitments that will be in effect, FDA will have a goal of 12 months from the date of receipt of a standard non-priority NDA (for a new molecular entity) to review and act on the submission. For a priority review submission the goal will be 8 months. After the efficacy and safety profile of dalbavancin is further evaluated in the ongoing Phase 3 clinical trials of abSSSI, the Company also plans to submit a pediatric development plan to the FDA and EMA for review and comment.