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Background Analysis: US FDA Advisory Committee to Review Achaogen’s Plazomicin for the Treatment of Complicated Urinary Tract Infections and Bloodstream Infections – May 2, 2018 (AMDAC)

Announcement

The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Wednesday, May 2, 2018 to discuss a new drug application (NDA) for plazomicin, sponsored by Achaogen, Inc. (Achaogen), for the proposed indications of the treatment of complicated urinary tract infections and bloodstream infections in adults.

Indication Background

Description of Indication

FDA Guidance defines complicated urinary tract infection (cUTI) as a clinical syndrome characterized by pyuria (pus in the urine) and a documented microbial pathogen on culture of urine or blood, accompanied by local and systemic signs and symptoms, including fever (i.e., oral or tympanic temperature greater than 38 degrees Celsius), chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness, that occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization. Patients with pyelonephritis (inflamed kidney), regardless of underlying abnormalities of the urinary tract, are considered a subset of patients with cUTI. Usually, one or more of the following conditions that increase the risk of developing a cUTI are present:

·      In-dwelling urinary catheter

·      100 milliliters (mL) or more of residual urine after voiding (neurogenic bladder)

·      Obstructive uropathy (nephrolithiasis, fibrosis)

·      Azotemia caused by intrinsic renal disease

·      Urinary retention, including retention caused by benign prostatic hypertrophy.

Bloodstream infections (BSI) are systemic infections of the bloodstream that can lead to secondary infection and sepsis.

Both cUTI and BSI can become life-threatening, especially when due to multi-drug resistant microbial pathogens.

Due to increasing antimicrobial resistance to currently available treatments, there is a significant unmet need for new and effective antibiotic treatments.

Product Background

Description of Product

Plazomicin is an investigational, next-generation aminoglycoside antibiotic that is designed to overcome aminoglycoside-modifying enzymes (AME) that inactivate existing aminoglycosides.  It is administered by intravenous (IV) injection.

Clinical Trials of Proposed Indication

According to Achaogen, the NDA includes data from two phase 3 clinical trials, named EPIC (Clinicaltrials.gov ID: NCT02486627) and CARE (Clinicaltrials.gov ID: NCT01970371). Both trials were completed in September 2016; however, results are not posted at ClinicalTrials.gov. The study designs, as presented at ClinicalTrials.gov, are summarized below, followed by a summary of the results, based on a presentation made by Achaogen in March, 2018.

EPIC

EPIC was a randomized, multicenter, multinational, double-blind trial comparing the efficacy and safety of plazomicin compared with meropenem, a carbapenem-type antibiotic, in adults (N=609) with pyuria and clinical signs and/or symptoms of acute pyelonephritis (AP) or cUTI. Patients had pretreatment baseline urine cultures obtained within 36 hours before the start of administration of the first dose of the study drug.

Co-primary outcome measures were Composite Cure (a composite of microbiological eradication and clinical cure) rate in the microbiological modified intent-to-treat population (mMITT) population at Day 5 and at the test of cure (TOC) visit at Day 17 +/- 2 days after the study drug was started. Secondary outcomes were the same assessment in the microbiologically evaluable population, as well as the overall incidence of adverse events (AEs) over 34 days.

In March 2018, Achaogen reviewed high-level results in a corporate presentation. Below is a summary of the results based on this presentation. A more detailed presentation of the data provided in the NDA, as well as in-depth analyses by the Sponsor and FDA, will be presented in FDA and Company briefing materials that FDA will post ahead of the meeting. These data will be summarized on the day they are posted in our subsequent report, named the Briefing Summary.

Achaogen has highlighted the following outcomes from the EPIC trial: achievement of non-inferiority on FDA endpoints; lower relapse rate at late follow-up (LFU) for plazomicin-treated patients compared to meropenem-treated patients; and similar treatment emergent adverse events (TEAE) and serious adverse event (SAE) incidence for plazomicin versus meropenem.

The following efficacy outcomes were presented:

·      88.0% Composite Cure at Day 5 for plazomicin-treated patients, compared to 91.4% for meropenem-treated patients, a difference of -3.4% (Confidence interval [CI]: -10.0, 3.1)

·      81.7% Composite Cure at TOC for plazomicin-treated patients, compared to 70.1% for meropenem-treated patients, a difference of 11.6% (2.7, 20.3) (CI: -10.0, 3.1)

·      89.5% Microbiological Eradication (uropathogen reduced to <10^4 CFU/mL) at TOC for plazomicin-treated patients, compared to 74.6% for meropenem-treated patients, a difference of 14.9% (CI: 7.0,22.7)

·      84.3% Microbiological Eradication (uropathogen reduced to <10^4 CFU/mL) at TOC for plazomicin-treated patients, compared to 65.0% for meropenem-treated patients, a difference of 19.3% (CI: 10.4,27.9)

·      1.8% Relapse at LFU (24-32 days from first dose of IV study drug) for patients who were Clinical Cures at TOC for plazomicin-treated patients, compared to 7.9% for meropenem-treated patients

·      0% Relapse at LFU (24-32 days from first dose of IV study drug) for a subgroup of patients with asymptomatic bacteriuria at TOC for plazomicin-treated patients, compared to 21.1% for meropenem-treated patients.

Regarding safety, Achaogen reported that 19.5% of plazomicin-treated patients and 21.6% of meropenem-treated patients in the safety population (N=604) experienced a TEAE. Achaogen says that common TEAEs that occurred in plazomicin-treated patients were diarrhea (2.3%), hypertension (2.3%), headache (1.3%), nausea (1.3%) and vomiting (1.3%). Tarius notes that a graphic on the slide also shows there was a numerical imbalance favoring meropenem for pooled TEAEs related to renal function, with an incidence of 3.5% for plazomicin-treated patients versus 1.3% for meropenem-treated patients. Only patients with normal renal function or with moderate renal impairment were eligible for enrollment. A separate slide showed that 7.0% of plazomicin-treated patients experienced an increase in serum creatinine relative to baseline at any time on study of greater than or equal to 0.5mg/dL, compared to 4.0% for meropenem-treated patients. 3.7% (11/300) of plazomicin-treated patients experienced an increase in serum creatinine relative to baseline while on IV therapy of greater than or equal to 0.5mg/dL, compared to 3.0% (9/297) for meropenem-treated patients. Achaogen says that six of the eleven plazomicin-treated patients who experienced the increase in serum creatinine level while on IV therapy recovered by the end of IV therapy, and four of the nine meropenem-treated patients who experienced the increase in serum creatinine level while on IV therapy recovered by the end of IV therapy. However, the slide states that all eleven of the meropenem-treated patients with elevations recovered by the last follow-up visit, but two of the nine plazomicin-treated patients with elevations had not recovered by the last follow-up visit. Recovery was defined as serum creatinine value <0.5 mg/dL above the baseline value at the end of IV visit or the last post-baseline measurement. There was one death in the plazomicin group due to pre-existing cancer, deemed by the company to be unrelated to the study drug. There was one case of potential ototoxicity in each treatment arm, which the company says were mild cases where the subject recovered.

CARE

CARE was a phase 3 trial with a randomized open-label superiority cohort (Cohort 1) comparing the efficacy and safety of plazomicin with colistin, a polymyxin antibiotic, when combined with a second antibiotic (either meropenem or tigecycline, a glycylcycline antibiotic) in the treatment of adults (N= 69) with bloodstream infection (BSI), hospital-acquired bacterial pneumonia (HABP), or ventilator-associated bacterial pneumonia (VABP) due to carbapenem-resistant Enterobacteriaceae (CRE). An additional cohort of patients with BSI, HABP, VABP, cUTI, or AP due to CRE, not eligible for inclusion in the other cohort, was enrolled into a single arm (Cohort 2) and treated with plazomicin-based therapy. Therapeutic drug management (TDM) was used to help ensure that plazomicin exposures lie within an acceptable range of the target mean steady-state area under the curve (AUC).

The primary outcome was all-cause mortality at Day 28 or significant disease-related complications in Cohort 1. Secondary outcome measures included the following: clinical failure as determined by the adjudication committee at TOC in Cohort 1 (time frame: 14-21 days); all-cause mortality at Day 28 in Cohort 1; time to death through Day 28; all-cause mortality at Day 14 in Cohort 1; overall incidence of AEs (time frame: 60 days); plazomicin pharmacokinetic (PK) parameters including AUC0-24, Cmax (maximum concentration), and Cmin (minimum concentration) (time frame: 14 days); and frequency with which the use of TDM led to a dose adjustment of plazomicin (time frame: 14 days).

Achaogen has highlighted the following outcomes from the CARE trial: improved outcomes for plazomicin-treated patients compared to colistin-treated patients; mortality benefit in the BSI subset; and favorable safety profile for plazomicin versus colistin.

The following efficacy outcomes were presented for Cohort 1:

·      Day 28 all-cause mortality or significant disease-related complications in 23.5% of plazomicin-treated patients, compared to 50.0% of colistin-treated patients, a difference of 26.5% (CI: -0.7, 51.2)

·      Day 28 all-cause mortality in 11.8% of plazomicin-treated patients, compared to 40.0% of colistin-treated patients, a difference of 26.5% (CI: 0.7-52.5)

·      Day 28 all-cause mortality or significant disease-related complications in 14.3% of plazomicin-treated patients in the BSI subset, compared to 53.3% of colistin-treated patients in the BSI subset, a difference of 39.0% (CI: 9.4,65.5)

·      Day 28 all-cause mortality in 7.1% of plazomicin-treated patients in the BSI subset, compared to 40.0% of colistin-treated patients in the BSI subset, a difference of 32.9% (CI: 4.0,60.1)

·      Hazard Ratio for survival in the BSI subset for plazomicin-treated patients compared to colistin-treated patients of 0.37 (90% CI 0.15-0.91).

Regarding safety, Achaogen reported that 88.9% of plazomicin-treated patients and 100% of colistin-treated patients in the safety population (N=39) experienced a TEAE. Tarius notes that a graphic on the slide shows there was a numerical imbalance favoring plazomicin for pooled TEAEs related to renal function, with an incidence of 33.3% for plazomicin-treated patients versus 52.4% for colistin-treated patients. Patients in acute renal failure at the time of randomization were excluded from the study. There were no drug-related deaths or events of ototoxicity reported.

Regulatory Background

US Regulatory Background

June 25, 2018 – PDUFA date

October 26, 2017 – Achaogen announced the submission of the NDA. (NDA number 210303).

Breakthrough Therapy Designation, Qualified Infectious Disease Product (QIDP) designation

February 2015 – The FDA issued Guidance for Industry, entitled “Complicated Urinary Tract Infections: Developing Drugs for Treatment.”

The QIDP designation qualifies plazomicin, if approved, to receive five additional years of marketing exclusivity.

Ex-US Regulatory Background

2H 2018 – Achaogen intends to file a marketing authorization application (MAA) with the European Medicines Agency (EMA) in the second half of 2018.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

Corrections: This report corrects an earlier version.

The following sentences were removed:

·      “Note that the company presented outcomes for the mMITT population, which is listed as a secondary outcome at Clinicaltrials.gov, and it is unknown whether the FDA agrees on this specific mMITT analysis.” (under header EPIC)

·      Note that the company presented outcomes for a modified MITT population, and it is unknown whether the FDA agrees on this specific mMITT analysis. (under header CARE)

Two incidences of the following sentences were replaced (under headers EPIC and CARE):

·      Achaogen has not presented a narrative of trial results via press release; however in March 2018, the company reviewed high-level results in a corporate presentation.

This sentence was replaced with the following sentence:

·      In March 2018, Achaogen reviewed high-level results in a corporate presentation.

The following sentences were replaced (under header CARE):

·      Regarding safety, Achaogen reported that 88.9% of plazomicin-treated patients and 100% of meropenem-treated patients in the safety population (N=39) experienced a TEAE. Tarius notes that a graphic on the slide shows there was a numerical imbalance favoring plazomicin for pooled TEAEs related to renal function, with an incidence of 33.3% for plazomicin-treated patients versus 52.4% for meropenem-treated patients.

These sentences were replaced with the following sentences:

·      Regarding safety, Achaogen reported that 88.9% of plazomicin-treated patients and 100% of colistin-treated patients in the safety population (N=39) experienced a TEAE. Tarius notes that a graphic on the slide shows there was a numerical imbalance favoring plazomicin for pooled TEAEs related to renal function, with an incidence of 33.3% for plazomicin-treated patients versus 52.4% for colistin-treated patients.

METADATA: Sponsor: Achaogen, Inc.  Drug Name: plazomicin Drug Class: antibiotic, aminoglycoside Indication: complicated urinary tract infections and bloodstream infections


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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.