Aankondiging • Jan 27
Aridis Pharmaceuticals, Inc. Announces Top-Line Results from the AR-301-002 Phase 3 Study
Aridis Pharmaceuticals, Inc. announced top-line results from the AR-301-002 Phase 3 study, which evaluated the superiority of adjunctive use of the investigational monoclonal antibody candidate AR-301 with standard of care (SOC) antibiotics versus SOC antibiotics alone, for the treatment of VAP caused by Gram-positive bacteria Staphylococcus aureus (S. aureus). AR-301-002, the first of two planned Phase 3 studies, enrolled 174 mechanically ventilated intensive care unit (ICU) patients who were likely to have pneumonia caused by S. aureus, with 120 of those patients ultimately meeting the criteria of S. aureus as the predominant cause of pneumonia (microbiologically evaluable Full Analysis Set [micro-FAS]), being evaluated for efficacy. The COVID-19 pandemic and the subsequent conflict in Eastern Europe limited patient enrollment from the original target sample size of 240. Key findings: Primary outcome measures of efficacy compared clinical cure of AR-301 + SOC vs. SOC alone at Day 21 post-treatment: An improvement in clinical cure rate (or absolute efficacy) of =10% (considered a clinically meaningful improvement by many key opinion leaders) was observed with adjunctive use of AR-301. However, with the limited sample size evaluated, statistical significance was not reached for the primary endpoint of clinical cure rate on Day 21 compared to antibiotics alone. Clinical cure at Day 21 was 68.9% (42/61 patients) for AR-301 + SOC versus 57.6% (34/59) for SOC alone, (efficacy difference or absolute efficacy: 11.3%, [p= 0.23]). In the prespecified older adult population of 65+ years, the absolute efficacy (improvement in clinical cure rate) on Day 21 was increased to 34% (p= 0.057), and to 38% on Day 28 (p= 0.025). The increase in absolute efficacy was driven primarily by the lower efficacy of SOC antibiotics in older adults 65+ years old compared to adults less than 65 years old (30% vs. 75%, respectively). In the methicillin resistant S. aureus (MRSA) patients, the absolute efficacy was 28% higher than SOC alone (p=0.774). The increase in absolute efficacy was also driven primarily by the lower efficacy of SOC antibiotics in MRSA patients compared to methicillin susceptible S. aureus (MSSA) patients (38% vs. 63%, respectively). Treatment with AR-301 was associated with reduction trends in key secondary outcomes measures of duration of hospitalization (median 19 vs. 28 days, difference: 9 days) time in ICU (median 13 vs. 20 days, difference: 7 days) and mechanical ventilation days (median 6 vs. 8 days, difference: 2 days). Consistent positive efficacy trends were observed in favor of AR-301 treatment in other key secondary efficacy outcomes (e.g. clinical cure at days 7, 14, 28). Primary outcome measures of safety and tolerability of AR-301 were achieved. AR-301 intravenous (IV) infusion was well tolerated. Adverse Events (AEs) and Serious Adverse Events (SAEs) reported over the 28-day study period for the single IV infusion were similar across the active and placebo treatment groups, with no SAEs deemed drug-related. None of the deaths in the study were deemed drug-related by the blinded investigators. The independent unblinded Data Safety Monitoring Board (DSMB) also did not express any safety concerns. The all-cause mortality rates in all patients were AR-301: 23.6% (21/89) vs. SOC: 18.8% (16/85) (p=0.367); these deaths were primarily associated with patients’ underlying conditions which brought the patient into the ICU. The all-cause mortality in the evaluable microFAS population were similar between the AR-301 23.0% (14/61) and placebo 23.7% (14/59) groups (p=0.830). The mortality due to pneumonia was: AR-301 1.6% (1/61) vs SOC 5.0% (3/59) groups among the population with confirmed S. aureus pneumonia (p=n.s.). AR-301-002 is the first of two planned Phase 3 studies evaluating the efficacy and safety of AR-301 for adjunctive treatment of pneumonia caused by S. aureus in mechanically ventilated hospitalized patients. Aridis plans to initiate a second Phase 3 study after discussing the current study results with regulatory authorities, including the US FDA and the European Medicines Agency (EMA). The company also plans to present the study findings at a future scientific conference. About AR-301-002 Phase 3 Study: AR-301-002 is the first of two planned Phase 3 studies evaluating the efficacy and safety of AR-301 for adjunctive treatment of VAP caused by S. aureus. The study is a randomized, double-blind, superiority trial with the primary efficacy endpoint clinical cure of pneumonia measured at Day 21 post-treatment. A total of 152 clinical sites in 20 countries participated in the study, with enrollment occurring in 45 clinical sites over 40 months. The COVID-19 pandemic and the subsequent conflict in Eastern Europe limited patient enrollment to 174 (original target was 240 enrolled patients), with 120 of those patients ultimately meeting the prespecified criteria of S. aureus pneumonia (microbiologically evaluable Full Analysis Set [micro-FAS]). Study subjects across the treatment arms were comparable in terms of baseline demographics, comorbidities, and baseline disease severity measures. About AR-301: AR-301 is a fully human IgG1 monoclonal antibody that specifically targets S. aureus alpha-toxin, an important virulence factor that is secreted by both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). AR-301 is designed to protect against alpha-toxin mediated destruction of host cells, preserving a functional host immune response. AR-301's mode of action is independent of the antibiotic resistance profile of S. aureus and it is active against infections caused by both MRSA and MSSA. Staphylococcus aureus Ventilator Associated Pneumonia (VAP): VAP poses serious challenges in the hospital setting, as standard of care antibiotics are becoming inadequate in treating infected patients. There are approximately 251,600 cases of hospital acquired pneumonia reported in the U.S. annually caused by S. aureus (Decision Resources Group 2016 data base). These patients are typically at high risk of mortality, which is compounded by other life-threatening co-morbidities and rise in antibiotic resistance. Epidemiology studies estimate that the probability of death attributed to S. aureus ranges from 29% to 55%. In addition, pneumonia infections can prolong patient stays in ICUs (intensive care units) and the use of mechanical ventilation, creating a major economic burden on patients, hospital systems and payors. For example, ICU cost of care for a ventilated pneumonia patient is approximately $10,000 per day, and the duration of ICU stay is typically twice that of a non-infected ICU patient (Infection Control and Hospital Epidemiology. 2010, vol. 31, pp. 509 515).