FDA News

FDA grants priority review to plazomicin for treatment of cUTIs, BSIs

Achaogen, Inc. recently announced that the FDA has accepted the company’s new drug application for plazomicin — an investigational treatment for complicated urinary tract infections, including pyelonephritis, and bloodstream infections caused by certain Enterobacteriaceae.

The FDA has granted priority review for plazomicin — a next-generation aminoglycoside — and established a target action date of June 25, according to a press release. In the acceptance letter, the FDA said it plans on holding an advisory committee meeting to discuss the application. Achaogen plans on submitting an application seeking marketing authorization of plazomicin in the European Union later this year, the release said.

The NDA is based on data from the EPIC and CARE trials, which assessed plazomicin in patients infected with gram-negative pathogens, including extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE).

EPIC trial

For the EPIC trial, researchers randomly assigned 609 patients with complicated urinary tract infections (cUTIs) and acute pyelonephritis (AP) to receive 15 mg/kg of plazomicin as a once-daily, 30-minute IV infusion or 1g of meropenem as a 30-minute IV infusion every 8 hours, according to the release. After 4 days of therapy, certain patients with improved outcomes were able to receive oral levofloxacin for the remainder of their 7- to 10-day treatment course.

An analysis investigating an FDA-specified endpoint of clinical cure and microbiological eradication in the microbiological modified intent-to-treat (mMITT) population showed that plazomicin was noninferior to meropenem at day 5 (88% vs. 91.4%; difference = –3.4%; 95% CI, –10 to 3.1) and superior to meropenem at the test-of-cure visit (81.7% vs. 70.1%; difference = 11.6%; 95% CI, 2.7-20.3).

A separate analysis investigating endpoints of microbiological eradication set by the European Medicines Agency at the test-of-cure visit showed that plazomicin was superior to meropenem in the mMITT population (87.4% vs. 72.1%; difference = 15.4%; 95% CI, 7.5-23.2) and the microbiologically evaluable population (90.5% vs. 76.6%; difference = 13.9%; 95% CI, 6.3-21.7).

Plazomicin was well-tolerated, according to the release. Less than 4% of patients in the plazomicin arm and 1.3% of patients in the meropenem arm reported treatment-emergent adverse events related to renal function. One patient in each treatment group also reported cochlear or vestibular function adverse events, but both were mild and resolved completely, the release said.

CARE trial

For the CARE trial, researchers examined the safety and efficacy of plazomicin in two cohorts. According to data presented at ASM Microbe, the first cohort included patients with bloodstream infections (BSIs) or hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) who were randomly assigned to plazomicin (n = 18) or colistin (n = 21). The second, single-arm cohort included patients with BSI and HABP/VABP who were ineligible for enrollment in cohort one due to low APACHE II scores (< 15), known colistin-resistant CRE or polymicrobial infections involving additional, non-Enterobacteriaceae gram-negative pathogens, as well as patients with cUTIs or AP. All patients in the second cohort (n = 30) received plazomicin.

In the first cohort, in addition to adjunctive therapy, patients with BSI or HABP/VABP received either 15 mg/kg of once-daily IV plazomicin or a 300-mg loading dose of colistin, followed by 5 mg/kg divided every 12 or 8 hours for 7 to 14 days. Patients with cUTIs or AP received plazomicin monotherapy for 4 to 7 days, followed by optional oral therapy. The rate of 28-day all-cause mortality or significant disease-related complications (SDRCs) among the mMITT population was 23.5% in the plazomicin arm (n = 17) vs. 50% in the colistin arm (n = 20). When assessing for 28-day mortality alone, the rate was 11.8% in the plazomicin arm vs. 40% in the colistin arm. Overall, plazomicin was associated with a 53% relative reduction in all-cause mortality or SDRC and a 70.5% relative reduction in all-cause mortality alone.

Research presented at ASM Microbe also demonstrated a low 28-day all-cause mortality rate (14.3%) among patients with BSIs in cohort two, supporting the findings observed in cohort one.

According to the release, plazomicin has a favorable safety profile compared with colistin. Less than 17% of patients in the plazomicin arm and 38.1% of patients in the colistin arm reported treatment-emergent adverse events related to renal function.

“In the EPIC trial, the overall safety profile and the sustained microbiological effect of plazomicin suggests a favorable clinical benefit for patients with cUTIs and AP and limited alternative treatment options,” Kenneth Hillan, MB ChB, Achaogen's president, R&D, told Infectious Disease News. “In the CARE trial, plazomicin-based combination therapy demonstrated a substantial and sustained reduction in mortality in acutely ill patients with BSIs due to CRE, combined with important safety advantages over a colistin-based regimen.”– by Stephanie Viguers

Disclosure: Hillan is an employee of Achaogen.

References:

Achaogen. Achaogen Announces FDA Acceptance of New Drug Application with Priority Review for Plazomicin for Treatment of Complicated Urinary Tract Infections and Bloodstream Infections. http://investors.achaogen.com/releasedetail.cfm?ReleaseID=1053003. Accessed January 3, 2018.

Achoaogen. Achaogen Announces Positive Results in Phase 3 cUTI and CRE Clinical Trials of Plazomicin. http://investors.achaogen.com/releasedetail.cfm?ReleaseID=1003671. Accessed January 3, 2018.

Connolly LE, et al. Plazomicin (PLZ) associated with improved survival and safety compared to colistin (CST) in serious carbapenem-resistant Enterobacteriaceae (CRE) infections: Results of the CARE study. Presented at: ASM Microbe; June 1-5, 2017; New Orleans.

Achaogen, Inc. recently announced that the FDA has accepted the company’s new drug application for plazomicin — an investigational treatment for complicated urinary tract infections, including pyelonephritis, and bloodstream infections caused by certain Enterobacteriaceae.

The FDA has granted priority review for plazomicin — a next-generation aminoglycoside — and established a target action date of June 25, according to a press release. In the acceptance letter, the FDA said it plans on holding an advisory committee meeting to discuss the application. Achaogen plans on submitting an application seeking marketing authorization of plazomicin in the European Union later this year, the release said.

The NDA is based on data from the EPIC and CARE trials, which assessed plazomicin in patients infected with gram-negative pathogens, including extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE).

EPIC trial

For the EPIC trial, researchers randomly assigned 609 patients with complicated urinary tract infections (cUTIs) and acute pyelonephritis (AP) to receive 15 mg/kg of plazomicin as a once-daily, 30-minute IV infusion or 1g of meropenem as a 30-minute IV infusion every 8 hours, according to the release. After 4 days of therapy, certain patients with improved outcomes were able to receive oral levofloxacin for the remainder of their 7- to 10-day treatment course.

An analysis investigating an FDA-specified endpoint of clinical cure and microbiological eradication in the microbiological modified intent-to-treat (mMITT) population showed that plazomicin was noninferior to meropenem at day 5 (88% vs. 91.4%; difference = –3.4%; 95% CI, –10 to 3.1) and superior to meropenem at the test-of-cure visit (81.7% vs. 70.1%; difference = 11.6%; 95% CI, 2.7-20.3).

A separate analysis investigating endpoints of microbiological eradication set by the European Medicines Agency at the test-of-cure visit showed that plazomicin was superior to meropenem in the mMITT population (87.4% vs. 72.1%; difference = 15.4%; 95% CI, 7.5-23.2) and the microbiologically evaluable population (90.5% vs. 76.6%; difference = 13.9%; 95% CI, 6.3-21.7).

Plazomicin was well-tolerated, according to the release. Less than 4% of patients in the plazomicin arm and 1.3% of patients in the meropenem arm reported treatment-emergent adverse events related to renal function. One patient in each treatment group also reported cochlear or vestibular function adverse events, but both were mild and resolved completely, the release said.

CARE trial

For the CARE trial, researchers examined the safety and efficacy of plazomicin in two cohorts. According to data presented at ASM Microbe, the first cohort included patients with bloodstream infections (BSIs) or hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) who were randomly assigned to plazomicin (n = 18) or colistin (n = 21). The second, single-arm cohort included patients with BSI and HABP/VABP who were ineligible for enrollment in cohort one due to low APACHE II scores (< 15), known colistin-resistant CRE or polymicrobial infections involving additional, non-Enterobacteriaceae gram-negative pathogens, as well as patients with cUTIs or AP. All patients in the second cohort (n = 30) received plazomicin.

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In the first cohort, in addition to adjunctive therapy, patients with BSI or HABP/VABP received either 15 mg/kg of once-daily IV plazomicin or a 300-mg loading dose of colistin, followed by 5 mg/kg divided every 12 or 8 hours for 7 to 14 days. Patients with cUTIs or AP received plazomicin monotherapy for 4 to 7 days, followed by optional oral therapy. The rate of 28-day all-cause mortality or significant disease-related complications (SDRCs) among the mMITT population was 23.5% in the plazomicin arm (n = 17) vs. 50% in the colistin arm (n = 20). When assessing for 28-day mortality alone, the rate was 11.8% in the plazomicin arm vs. 40% in the colistin arm. Overall, plazomicin was associated with a 53% relative reduction in all-cause mortality or SDRC and a 70.5% relative reduction in all-cause mortality alone.

Research presented at ASM Microbe also demonstrated a low 28-day all-cause mortality rate (14.3%) among patients with BSIs in cohort two, supporting the findings observed in cohort one.

According to the release, plazomicin has a favorable safety profile compared with colistin. Less than 17% of patients in the plazomicin arm and 38.1% of patients in the colistin arm reported treatment-emergent adverse events related to renal function.

“In the EPIC trial, the overall safety profile and the sustained microbiological effect of plazomicin suggests a favorable clinical benefit for patients with cUTIs and AP and limited alternative treatment options,” Kenneth Hillan, MB ChB, Achaogen's president, R&D, told Infectious Disease News. “In the CARE trial, plazomicin-based combination therapy demonstrated a substantial and sustained reduction in mortality in acutely ill patients with BSIs due to CRE, combined with important safety advantages over a colistin-based regimen.”– by Stephanie Viguers

Disclosure: Hillan is an employee of Achaogen.

References:

Achaogen. Achaogen Announces FDA Acceptance of New Drug Application with Priority Review for Plazomicin for Treatment of Complicated Urinary Tract Infections and Bloodstream Infections. http://investors.achaogen.com/releasedetail.cfm?ReleaseID=1053003. Accessed January 3, 2018.

Achoaogen. Achaogen Announces Positive Results in Phase 3 cUTI and CRE Clinical Trials of Plazomicin. http://investors.achaogen.com/releasedetail.cfm?ReleaseID=1003671. Accessed January 3, 2018.

Connolly LE, et al. Plazomicin (PLZ) associated with improved survival and safety compared to colistin (CST) in serious carbapenem-resistant Enterobacteriaceae (CRE) infections: Results of the CARE study. Presented at: ASM Microbe; June 1-5, 2017; New Orleans.