FDA Approves Zemdri
Zemdri (plazomicin) Approved by FDA for the Treatment of Adults with Complicated Urinary Tract Infections (cUTI)
SOUTH SAN FRANCISCO, Calif., June 26, 2018 (GLOBE NEWSWIRE) -- Achaogen, Inc., a biopharmaceutical company developing and commercializing innovative antibacterial agents to address multidrug resistant (MDR) gram-negative infections, today announced that the U.S. Food and Drug Administration (FDA) has approved Zemdri (plazomicin) for adults with complicated urinary tract infections (cUTI), including pyelonephritis, caused by certain Enterobacteriaceae in patients who have limited or no alternative treatment options. Zemdri is an intravenous infusion, administered once daily.
"The approval of Zemdri marks a significant milestone for Achaogen and we are excited to offer healthcare practitioners a new treatment option for patients with certain serious bacterial infections. Zemdri is designed to retain its potent activity in the face of certain difficult-to-treat MDR infections, including CRE and ESBL- producing Enterobacteriaceae," said Blake Wise, Achaogen's Chief Executive Officer. "Today's milestone was made possible by our employees, by patients and investigators involved in our clinical trials, and by BARDA, who contributed significant funding for the development of Zemdri. This marks an important step in our commitment to fighting MDR bacteria and we are excited to launch Zemdri, a much needed once-daily antibiotic."
"Bacteria continue to circumvent existing antibiotics, making certain infections notoriously hard to treat and putting some patients at high risk for mortality," said James A. McKinnell, Assistant Professor of Medicine at the David Geffen School of Medicine and LA Biomed at Harbor-UCLA. "Aminoglycosides are a familiar and very effective class of antibiotics. I look forward to adding plazomicin to my short list of available treatment options and to its potential impact on patient outcomes."
Regarding the potential indication for plazomicin for the treatment of bloodstream infection (BSI), the FDA issued a Complete Response Letter (CRL) stating that the CARE study does not provide substantial evidence of effectiveness of plazomicin for the treatment of BSI. The Company intends to meet with the FDA to determine whether there is a feasible resolution to address the CRL.
Achaogen will work with hospitals, providers, and insurers to ensure patients are able to receive this treatment. Patients, physicians, pharmacists, or other healthcare professionals with questions about Zemdri should contact 1.833.252.6400 or visit www.ZEMDRI.com.
Zemdri Phase 3 Clinical Results
The approval of Zemdri is supported in part by data from the EPIC (Evaluating Plazomicin In cUTI) clinical trial, which was the first randomized controlled study of once-daily aminoglycoside therapy for the treatment of cUTI, including pyelonephritis.
In the Phase 3 EPIC cUTI trial, Zemdri demonstrated non-inferiority to meropenem for the co-primary efficacy endpoints of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat (mMITT; N=388) population at Day 5 and test-of-cure (TOC) visit (Day 17 + 2). Composite cure rates at Day 5 were 88.0% (168/191) for Zemdri vs 91.4% (180/197) for meropenem (difference -3.4%, 95% CI, -10.0 to 3.1). Composite cure rates at TOC were 81.7% (156/191) for Zemdri vs 70.1% (138/197) for meropenem (difference 11.6%, 95% CI, 2.7 to 20.3). Composite cure at the TOC visit in patients with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the Zemdri group and 56.5% (13/23) of patients in the meropenem group. The most common side effects (≥1% of patients treated with Zemdri) were decreased kidney function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension.1
The FDA approved a breakpoint of <= 2 mcg/mL; greater than 99% of Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae in U.S. surveillance are susceptible to Zemdri when applying this breakpoint.2
cUTI is defined as a UTI occurring in a patient with an underlying complicating factor of the genitourinary tract, such as a structural or functional abnormality.3 Patients with pyelonephritis, regardless of underlying abnormalities of the urinary tract, are considered a subset of patients with cUTI.4 An estimated 3 million cases of cUTI are treated in the hospital setting in the US each year.5 Enterobacteriaceae are the most common pathogens causing cUTIs6, and resistance within this family is a global concern. High rates of resistance to previous mainstays of therapy necessitate alternative treatment options. Ineffectively managed cUTI can lead to increased treatment failure rates, recurrence of infection, increased re-hospitalization, and increased morbidity and mortality. cUTI infections place an economic burden on hospitals and payers.6,7
Zemdri is an aminoglycoside with once-daily dosing that has activity against certain Enterobacteriaceae, including CRE and ESBL- producing Enterobacteriaceae. Achaogen's EPIC clinical trial successfully evaluated the safety and efficacy of Zemdri in adult patients with cUTI, including pyelonephritis. Zemdri was engineered to overcome aminoglycoside-modifying enzymes, the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and has in vitro activity against ESBL- producing, aminoglycoside- resistant, and carbapenem- resistant isolates. The Centers for Disease Control and Prevention (CDC) has characterized ESBL- producing Enterobacteriaceae as a "serious threat" and CRE as "nightmare bacteria", which is an immediate public health threat that requires urgent and aggressive action.
Indications and Usage
Zemdri (plazomicin) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible microorganism(s): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae.
As only limited clinical safety and efficacy data for Zemdri are currently available, reserve Zemdri for use in cUTI patients who have limited or no alternative treatment options.
To reduce the development of drug-resistant bacteria and maintain effectiveness of Zemdri and other antibacterial drugs, Zemdri should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible microorganisms.
Important Safety Information
BOXED WARNINGS: NEPHROTOXICITY, OTOTOXICITY, NEUROMUSCULAR BLOCKADE AND FETAL HARM
Nephrotoxicity has been reported with Zemdri. The risk of nephrotoxicity is greater in patients with impaired renal function, the elderly, and in those receiving concomitant nephrotoxic medications. Assess creatinine clearance in all patients prior to initiating therapy and daily during therapy. Therapeutic Drug Monitoring (TDM) is recommended for complicated urinary tract infection (cUTI) patients with CLcr less than 90 mL/min to avoid potentially toxic levels.
Ototoxicity, manifested as hearing loss, tinnitus, and/or vertigo, has been reported with Zemdri. Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy. Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss, patients with renal impairment, and in patients receiving higher doses and/or longer durations of therapy than recommended.
Aminoglycosides have been associated with neuromuscular blockade. During therapy with Zemdri, monitor for adverse reactions associated with neuromuscular blockade particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents. Aminoglycosides, including Zemdri, can cause fetal harm when administered to a pregnant woman.Contraindications: Zemdri is contraindicated in patients with known hypersensitivity to any aminoglycoside.
Additional Warnings and Precautions
Nephrotoxicity: Reported with the use of Zemdri. Most serum creatinine increases were ≤ 1 mg/dL above baseline and reversible. Assess CLcr in all patients prior to initiating therapy and daily during therapy with Zemdri, particularly in those at increased risk of nephrotoxicity, such as those with renal impairment, the elderly and those receiving concomitant potentially nephrotoxic medications. In the setting of worsening renal function, the benefit of continuing Zemdri should be assessed. Adjust the initial dosage regimen in cUTI patients with CLcr ≥ 15 mL/min and < 60 mL/min. For subsequent doses, TDM is recommended for patients with CLcr ≥ 15 mL/min and < 90 mL/min.
Ototoxicity: Reported with Zemdri (manifested as hearing loss, tinnitus, and/or vertigo). Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy. Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss (excluding age-related hearing loss), patients with renal impairment, and in patients receiving higher doses and/or for longer periods than recommended. The benefit-risk of Zemdri therapy should be considered in these patients.
Neuromuscular Blockade: Aminoglycosides have been associated with exacerbation of muscle weakness in patients with underlying neuromuscular disorders, or delay in recovery of neuromuscular function in patients receiving concomitant neuromuscular blocking agents. During therapy with Zemdri, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as patients with underlying neuromuscular disorders (including myasthenia gravis) or those patients concomitantly receiving neuromuscular blocking agents.
Fetal Harm: Aminoglycosides, including Zemdri, can cause fetal harm when administered to a pregnant woman. Patients who use Zemdri during pregnancy, or become pregnant while taking Zemdri should be apprised of the potential hazard to the fetus.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving aminoglycoside antibacterial drugs. Before therapy with Zemdri is instituted, careful inquiry about previous hypersensitivity reactions to other aminoglycosides should be made. Discontinue Zemdri if an allergic reaction occurs.
Clostridium difficile-Associated Diarrhea (CDAD): Reported for nearly all systemic antibacterial drugs and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile. Careful medical history is necessary. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued.
Development of Drug-Resistant Bacteria: Prescribing Zemdri in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Please click here to see the full Prescribing Information, including BOXED WARNINGS, for additional Important Safety Information.
You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Achaogen at (833) AKAO-402.
Achaogen is a biopharmaceutical company passionately committed to the discovery, development, and commercialization of innovative antibacterial treatments for MDR gram-negative infections. Achaogen's first commercial product is Zemdri (plazomicin), for the treatment of serious bacterial infections due to MDR Enterobacteriaceae. The Achaogen Zemdri program has been funded in part with federal funds from the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO100201000046C. The Company is also developing C-Scape, an orally-administered beta-lactam/beta-lactamase inhibitor combination, which is also supported by BARDA. Achaogen has other programs in early and late preclinical stages focused on other MDR gram-negative infections and additional disease areas. All product candidates are investigational, have not been determined to be safe or efficacious, and have not been approved for commercialization. For more information, visit the Achaogen website at www.achaogen.com.
This press release contains forward-looking statements. All statements other than statements of historical facts contained herein are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, Achaogen expectations regarding the timing of commercial availability of Zemdri, the potential uses and advantages of Zemdri, Achaogen commercial objectives and the Achaogen pipeline of product candidates. Such forward-looking statements involve known and unknown risks, uncertainties, and other important factors that may cause Achaogen's actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the risks and uncertainties of the regulatory approval process; market size and growth; timing of activities, including launch dates of products; statements about the efficacy, safety and tolerability of Zemdri; the risks and uncertainties of product sales; the risk of when bacteria will evolve resistance to Zemdri; Achaogen's reliance on third-party contract manufacturing organizations for manufacture and supply, including sources of certain raw materials; risk of third party claims alleging infringement of patents and proprietary rights or seeking to invalidate Achaogen's patents or proprietary rights; and the risk that Achaogen's proprietary rights may be insufficient to protect its technologies and product candidates. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the Achaogen business in general, see Achaogen current and future reports filed with the Securities and Exchange Commission, including its Annual Report on Form 10-K filed on February 27, 2018, and its Quarterly Report on Form 10-Q filed on May 7, 2018. Achaogen does not plan to publicly update or revise any forward-looking statements contained in this press release, whether as a result of any new information, future events, changed circumstances, or otherwise.
2 Castanheira M. Antimicrob Agents Chemother. 2018. doi: 10.1128/AAC.00313-18. [Epub ahead of print]
3 Nicolle LE. J Infect Dis. 2001;183(Suppl 1):S5-8.
4 U.S. Food & Drug. Complicated Urinary Tract Infections: Developing Drugs for Treatment Guidance for Industry. https://www.fda.gov/downloads/Drugs/Guidances/ucm070981.pdf. Accessed June 25, 2018.
5 Decision Resources Disease Landscape & Forecast, Hospital-Treated Gram-Negative Infections, September 2017; data on file.
6 Bader MS et al. Postgrad Med. 2010;122(6):7-15.
7 Turner RM et al. Clin Ther. 2015;37(9):2037-2047.
Source: Achaogen, Inc.
Posted: June 2018
- Achaogen Announces FDA Advisory Committee Voted Unanimously in Favor of Plazomicin for Treatment of Adults with Complicated Urinary Tract Infections - May 2, 2018
- Achaogen Announces FDA Acceptance of New Drug Application with Priority Review for Plazomicin for Treatment of Complicated Urinary Tract Infections and Bloodstream Infections - January 2, 2018
- Achaogen Submits Plazomicin New Drug Application (NDA) to the U.S. FDA for Treatment of Complicated Urinary Tract Infections and Bloodstream Infections - October 26, 2017
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