Clinical Trials

Date: 2017-05-02

Type of information: Results

phase: 3

Announcement: results

Company: Melinta Therapeutics (USA - CT)

Product: Baxdela® (delafloxacin)

Action mechanism:

• antibiotic. Delafloxacin is an investigational anionic fluoroquinolone antibiotic currently in Phase 3 clinical development for hospital-treated skin infections, known as acute bacterial skin and skin structure infections (ABSSSI). In clinical trials, delafloxacin is being tested in both IV and oral formulations.

Disease: acute bacterial skin and skin structure infections (ABSSSI)

Therapeutic area: Infectious diseases

Country: Croatia, Israel, Latvia, Russian Federation, Spain, Ukraine (study 302) Argentina, Brazil, Bulgaria, Chile, Estonia, Georgia, Hungary, Republic of Korea, Latvia, Mexico, Republic of Moldova, Peru, Romania, Slovakia, Taiwan, USA (study 303)

Trial details:

• The PROCEED studies for ABSSSI (studies 302 and 303) are Phase 3, multicenter, randomized, double-blind, active-controlled studies to evaluate delafloxacin compared with vancomycin + aztreonam for the treatment of patients with ABSSSI. The studies’ primary endpoints are change in the area measurements of lesion erythema at the primary infection site at 48 to 72 hours. Secondary measures included the objective response using reduction of erythema of ?30% at 48-to-72 hours; and investigator-assessed response of signs and symptoms of infection at the day-28 follow-up visit in the overall study population.
• RX-3341-303 is a pivotal Phase 3 study, the second of a Phase 3 program. This  was a randomized, double-blind study of patients with ABSSSI conducted under FDA Special Protocol Assessment. Patients in the Baxdela arm received 300 mg of IV Baxdela every 12 hours for 6 doses followed by 450 mg oral Baxdela every 12 hours. The recommended vancomycin dose was 15 mg/kg of IV vancomycin every 12 hours based on actual body weight plus 1-2 g of IV aztreonam every 12 hours. Duration of treatment in either the Baxdela or active control arms was 5-14 days based on the physician’s judgment. All patients were asked to return for a follow-up visit on day 14 ± 1 and a Late Follow-Up visit on days 21 to 28.(NCT01811732 and NCT01984684)

Latest news:

•  • On May 2, 2017, Melinta Therapeutics announced an upcoming presentation of findings from the Baxdela™ (delafloxacin) Phase 3 clinical program. These findings suggest Baxdela may represent an important treatment option for patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI), particularly obese patients, diabetics, and the elderly, who typically provide challenges in antibiotic selection and dosing. In particular, obese patients, representing 42% of the Baxdela Phase 3 clinical program, were demonstrated to be aggregators of co-morbidities, with twice the rate of important co-morbidities when compared to non-obese patients.
• The Phase 3 patient population was diverse, enrolling individuals with diabetes (11%), renal impairment (16.2%) and obesity (42%). In addition, 13% of trial participants were over 65 years of age. Treatment with IV/oral Baxdela monotherapy yielded clinical outcomes that were comparable to the control combination of vancomycin/aztreonam in these patient subgroups. No increases in glucose or liver function test were observed in the Baxdela treatment arm compared to the vancomycin/aztreonam group. The most common adverse events were mild-to-moderate gastrointestinal complaints, which did not routinely lead to discontinuation.
• • On May 12, 2016, Melinta Therapeutics announced top-line results from the second Phase 3 study (RX-3341-303) of Baxdela® (delafloxacin) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Baxdela® met the primary endpoints required by the FDA as well as the European Medicines Agency (EMA) in this confirmatory pivotal study. In the intent-to-treat population (ITT), IV-to-oral Baxdela® met the FDA’s primary endpoint of statistical non-inferiority (10% non-inferiority margin) at the early clinical response at 48-72 hours after initiation of therapy (83.7%) compared to IV vancomycin combination therapy with aztreonam (80.6%). The 95% confidence interval for the treatment difference had lower and upper bounds of -2.0% and 8.3%, respectively.
• Baxdela® also met the EMA’s required endpoint of statistical non-inferiority (57.7%) compared to vancomycin plus aztreonam (59.7%) based on the investigator’s assessment of complete cure (resolution of all baseline signs and symptoms) at the follow-up visit in the ITT population. Lower and upper bounds of the 95% confidence interval for the treatment difference were -8.6% and 4.6%, respectively. In addition, Baxdela® was comparable to vancomycin plus aztreonam in achieving treatment success at Follow-Up (cure or improved, with no further antibiotics needed) with success rate of 87.2% vs 84.8%, respectively. IV/oral Baxdela® monotherapy successfully eradicated Gram-positive pathogens, including MRSA, and Gram-negative pathogens at rates comparable to IV vancomycin/aztreonam combination treatment.
• Both intravenous (IV) and oral Baxdela® were well tolerated in the study participants.
• Overall adverse event rates were similar between treatment arms. The most common treatment-emergent adverse events on Baxdela® were diarrhea and nausea, which were generally mild and did not lead to treatment discontinuation. The oral formulation of Baxdela® was well tolerated with no increase in GI events compared to the IV formulation. Only 1.2% of Baxdela®-treated patients discontinued due to treatment-related adverse events.
• In this study, obese patients (BMI? 30kg/m2) constituted 50% of the enrolled population and had a higher prevalence of co-morbidities such as diabetes and cardiovascular disease than non-obese patients. Co-morbidities present challenges to appropriate antibiotic selection due to factors such as pathogen coverage, underlying disease, concomitant medications, drug metabolism and other issues. • On October 9, 2015, Melinta Therapeutics announced complete results from the first of two Phase 3 studies (RX-3341-302) of delafloxacin in late-stage development for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Delafloxacin met the study’s primary endpoint, reduction in lesion size by at least 20% at 48-72 hours in the intent-to-treat (ITT) population without nonstudy antibiotics or major procedures, which was comparable to the response in the control arm receiving vancomycin plus aztreonam.
• Delafloxacin also was comparable to vancomycin+aztreonam in the study’s secondary endpoint of cure, defined as the complete resolution of signs and symptoms at the follow-up visit (Day 14). Delafloxacin-treated patients experienced fewer treatment-emergent adverse events, and fewer discontinuations due to adverse events than patients in the vancomycin+aztreonam arm. The most frequent adverse events in the delafloxacin arm were infection, infusion site extravasation, diarrhea, and nausea. • On January 7, 2015, Melinta Therapeutics announced positive top-line results from the first of two Phase 3 PROCEED studies (study RX-3341-302),  to evaluate delafloxacin, compared with vancomycin + aztreonam for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI).
• Delafloxacin met the study’s primary objective endpoint of a reduction in the measurement of lesion erythema at the primary infection site at 48-to-72 hours, the endpoint required by the FDA. It also was comparable to vancomycin in the study’s secondary endpoints, including investigator assessment of signs and symptoms of infection at the follow-up visit, a metric required by the European Medicines Agency.
• In this study, delafloxacin was shown to be well tolerated among study participants. Mild gastrointestinal symptoms were the most treatment-related adverse events reported for delafloxacin, and rarely led to study discontinuation.
• Enrollment continues in the second confirmatory Phase 3 PROCEED study (study RX-3341-303 ) in patients with ABSSSI. Melinta anticipates that top-line results from study 303 will be available in the second half of 2015. The two studies are designed to support a New Drug Application.

Is general: Yes