Shiloh
Editor, Senior Moderator
Source: https://www.cidrap.umn.edu/news-per...bacter-infections-shows-promise-phase-3-trial
New drug for Acinetobacter infections shows promise in phase 3 trial
Filed Under:
Antimicrobial Stewardship
Chris Dall | News Reporter | CIDRAP News
| Oct 19, 2021
Pharmaceutical company Entasis Therapeutics yesterday announced positive topline results from a phase 3 trial of sulbactam-durlobactam (SUL-DUR), the company's investigational drug targeting infections caused by Acinetobacter baumannii.
The results from the ATTACK trial, which were announced in a press release and have not yet been peer-reviewed, showed that SUL-DUR demonstrated statistical non-inferiority versus colistin for the primary end point of 28-day all-cause mortality in patients with carbapenem-resistant A baumannii infections.
SUL-DUR also performed better than colistin for clinical cure rates, and caused less kidney damage, the company said.
A baumannii is commonly multidrug-resistant, causes severe, life-threatening infections in hospital patients, and has limited treatment options aside from colistin, a last-resort antibiotic that can be toxic to the kidneys. With mortality rates close to 50%, it is considered a critical priority pathogen by the World Health Organization and an urgent antibiotic-resistant threat by the US Centers for Disease Control and Prevention.
SUL-DUR, which combines a beta-lactam antibiotic (sulbactam) with a novel, broad-spectrum beta-lactamase inhibitor (durlobactam), specifically targets A baumanii. Sulbactam alone was once effective against Acinetobacter, but has been rendered ineffective by beta-lactamase–mediated resistance.
"Acinetobacter infections are clearly a significant unmet medical need, and the data we are announcing today shows SUL-DUR to potentially be an important advancement in the treatment of these patients," Entasis CEO Manos Perros, PhD, said during an investor conference call this morning.
Lower mortality, higher clinical cure rates
The ATTACK trial, conducted at 95 sites in 17 countries, enrolled 207 patients with documented hospital-acquired and ventilator-associated bacterial pneumonia, ventilated pneumonia, or bacteremia caused by A baumannii. Approximately 95% of the baseline A baumannii isolates were carbapenem-resistant. Part A of the two-part trial randomly assigned patients to receive either SUL-DUR with imipenem or colistin with imipenem.
Among the 125 patients with carbapenem-resistant A baumannii infections included in the modified intention-to-treat (mITT) population, mortality was 19% (12 of 63 patients) in the SUL-DUR arm, compared with 32.3% (20 of 62) in the colistin arm (treatment difference, –13.2%; 95% confidence interval [CI], –30.0% to 3.5%). The non-inferiority margin was 20%.
"This is a significant finding," said Entasis Chief Medical Officer David Altarac, MD, MPA. "This is the first time that efficacy has been demonstrated in a well-controlled clinical trial of carbapenem-resistant Acinetobacter-infected patients."
Similar trends were observed in 28- and 14-day all-cause mortality in trial subgroups. Clinical cure at test of cure (7 days after the last day of treatment) was observed in 61.9% of patients in the SUL-DUR arm compared with 40.3% in the colistin arm (treatment difference, 21.6%; 95% CI, 2.9% to 40.3%).
In part B of the trial, in which patients who had colistin-resistant A baumannii infections, or had known intolerance to colistin, were treated with SUL-DUR, the all-cause 28-day mortality rate was 17.9%.
SUL-DUR also met the primary safety end point of a statistically significant reduction in nephrotoxicity—meaning it caused less damage to the kidneys—with a nephrotoxicity rate of 13.2% versus 37.6% in the colistin arm.
"The difference in nephrotoxicity for SUL-DUR, relative to current treatment options for this high-medical-need and critically ill population, is a key differentiator," Altarac said.
Adverse events were similar in the two treatment arms (87.9% in the SUL-DUR arm vs 94.2% in the colistin arm), but drug-related adverse events were lower in patients treated with SUL-DUR (12.1% vs 30.2%).
SUL-DUR has been designated a Qualified Infectious Disease Product by the US Food and Drug Administration (FDA), a designation that aims to spur development of new antibiotics for difficult-to-treat infections. Entasis says it plans to file a new drug application with the FDA in mid-2022.
New drug for Acinetobacter infections shows promise in phase 3 trial
Filed Under:
Antimicrobial Stewardship
Chris Dall | News Reporter | CIDRAP News
| Oct 19, 2021
Pharmaceutical company Entasis Therapeutics yesterday announced positive topline results from a phase 3 trial of sulbactam-durlobactam (SUL-DUR), the company's investigational drug targeting infections caused by Acinetobacter baumannii.
The results from the ATTACK trial, which were announced in a press release and have not yet been peer-reviewed, showed that SUL-DUR demonstrated statistical non-inferiority versus colistin for the primary end point of 28-day all-cause mortality in patients with carbapenem-resistant A baumannii infections.
SUL-DUR also performed better than colistin for clinical cure rates, and caused less kidney damage, the company said.
A baumannii is commonly multidrug-resistant, causes severe, life-threatening infections in hospital patients, and has limited treatment options aside from colistin, a last-resort antibiotic that can be toxic to the kidneys. With mortality rates close to 50%, it is considered a critical priority pathogen by the World Health Organization and an urgent antibiotic-resistant threat by the US Centers for Disease Control and Prevention.
SUL-DUR, which combines a beta-lactam antibiotic (sulbactam) with a novel, broad-spectrum beta-lactamase inhibitor (durlobactam), specifically targets A baumanii. Sulbactam alone was once effective against Acinetobacter, but has been rendered ineffective by beta-lactamase–mediated resistance.
"Acinetobacter infections are clearly a significant unmet medical need, and the data we are announcing today shows SUL-DUR to potentially be an important advancement in the treatment of these patients," Entasis CEO Manos Perros, PhD, said during an investor conference call this morning.
Lower mortality, higher clinical cure rates
The ATTACK trial, conducted at 95 sites in 17 countries, enrolled 207 patients with documented hospital-acquired and ventilator-associated bacterial pneumonia, ventilated pneumonia, or bacteremia caused by A baumannii. Approximately 95% of the baseline A baumannii isolates were carbapenem-resistant. Part A of the two-part trial randomly assigned patients to receive either SUL-DUR with imipenem or colistin with imipenem.
Among the 125 patients with carbapenem-resistant A baumannii infections included in the modified intention-to-treat (mITT) population, mortality was 19% (12 of 63 patients) in the SUL-DUR arm, compared with 32.3% (20 of 62) in the colistin arm (treatment difference, –13.2%; 95% confidence interval [CI], –30.0% to 3.5%). The non-inferiority margin was 20%.
"This is a significant finding," said Entasis Chief Medical Officer David Altarac, MD, MPA. "This is the first time that efficacy has been demonstrated in a well-controlled clinical trial of carbapenem-resistant Acinetobacter-infected patients."
Similar trends were observed in 28- and 14-day all-cause mortality in trial subgroups. Clinical cure at test of cure (7 days after the last day of treatment) was observed in 61.9% of patients in the SUL-DUR arm compared with 40.3% in the colistin arm (treatment difference, 21.6%; 95% CI, 2.9% to 40.3%).
In part B of the trial, in which patients who had colistin-resistant A baumannii infections, or had known intolerance to colistin, were treated with SUL-DUR, the all-cause 28-day mortality rate was 17.9%.
SUL-DUR also met the primary safety end point of a statistically significant reduction in nephrotoxicity—meaning it caused less damage to the kidneys—with a nephrotoxicity rate of 13.2% versus 37.6% in the colistin arm.
"The difference in nephrotoxicity for SUL-DUR, relative to current treatment options for this high-medical-need and critically ill population, is a key differentiator," Altarac said.
Adverse events were similar in the two treatment arms (87.9% in the SUL-DUR arm vs 94.2% in the colistin arm), but drug-related adverse events were lower in patients treated with SUL-DUR (12.1% vs 30.2%).
SUL-DUR has been designated a Qualified Infectious Disease Product by the US Food and Drug Administration (FDA), a designation that aims to spur development of new antibiotics for difficult-to-treat infections. Entasis says it plans to file a new drug application with the FDA in mid-2022.