PiPeline Plus
Companies Take Aim at MRSA Infections Chris Fellner
M
ethicillin-resistant Staphylococcus aureus (MRSA) is one of the most widespread and virulent nosocomial pathogens.1 MRSA is categorized as either health care-associated MRSA (HA-MRSA)2 or communityassociated MRSA (CA-MRSA),3 depending on the setting where the infection was acquired. In medical facilities, MRSA may cause life-threatening bloodstream infections, pneumonia, or surgical-site infections. In the community, most MRSA infections affect the skin.4 Although MRSA remains a major Chris Fellner is a medical writer and the Editor of PTCommunity.com.
patient threat, data from the Centers for Disease Control and Prevention (CDC) have shown that the rate of invasive (life-threatening) MRSA infections in health care settings is declining. Invasive MRSA infections that began in hospitals dropped 54% between 2005 and 2011, with 30,800 fewer severe infections. The study showed 9,000 fewer deaths in hospital patients in 2011 than in 2005.1 Most patients who present to U.S. hospitals with suspected MRSA infections receive empiric antimicrobial therapy before the causative pathogen has been diagnosed and confirmed. Culture-based methods are still the gold standard for detecting MRSA.5
At least 10 marketed antibiotics have demonstrated potent activity against MRSA and are used to treat invasive HA-MRSA infections in the U.S. (Table 1). Vancomycin, a generic glycopeptide, is the most frequently prescribed antibiotic for infections in which MRSA is the suspected or known cause, followed by linezolid (Zyvox, Pfizer), an oxazolidinone, and daptamycin (Cubicin, Merck), a lipopeptide.5 The late-stage clinical pipeline for MRSA includes an array of treatments aimed at acute bacterial skin and skinstructure infections (ABSSSIs) and/or community-acquired bacterial pneumocontinued on page 128
Table 1 Antibacterial Agents Most Commonly Used to Treat U.S. Hospital-Acquired MRSA Infectionsa Product Company Cephalosporin Ceftaroline fosamil (Teflaro) Actavis, Inc. Glycycycline Tigecycline (Tygacil) Pfizer
Indication(s)
Dosageb
Cost of Treatmentc
ABSSSIs, CABP
600 mg every 12 hours by IV infusion administered over 5–60 minutes for 5–14 days (ABSSSIs) or 5–7 days (CABP) in adults (18 years of age or older)
5–14 days: $1,831–$5,127
ABSSSIs, CABP, CIAIs
Initial dose: 100 mg, followed by 50 mg every 12 hours IV over 5–14 days: approximately 30–60 minutes for 5–14 days (ABSSSIs and CIAIs) $1,888–$4,977 or 7–14 days (CABP)
Glycopeptides and Lipoglycopeptides Dalbavancin (Dalvance) ABSSSIs Allergan Oritavancin (Orbactiv) ABSSSIs The Medicines Company Telavancin (Vibativ) ABSSSIs, HABP, VABP Theravance Biopharma US
Vancomycin Generics
Serious or severe infections caused by susceptible methicillinresistant (beta-lactamresistant) staphylococci
Two-dose regimen: 1,000 mg IV followed 1 week later by 500 mg IV, both administered over 30 minutes 1,200-mg single dose by IV infusion over 3 hours in adults • ABSSSIs: 10 mg/kg by IV infusion over 60 minutes every 24 hours for 7–14 days • HABP/VABP: 10 mg/kg by IV infusion over 60 minutes every 24 hours for 7–21 days • Adults: 2 g IV daily, divided as 500 mg every 6 hours or 1 g every 12 hours, administered at no more than 10 mg/min or over a period of at least 60 minutes, whichever is longer, for 7–10 daysd • Pediatric patients: 10 mg/kg IV every 6 hours over a period of at least 60 minutes for 7–10 daysd
$5,364 $3,480 7–21 days: M, $3,523–$10,568; F: $3,002–$9,007e 7–10 days (adults): $101–$144
Lipopeptide Daptomycin (Cubicin) Merck
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ABSSSIs, S. aureus bacteremia
• February 2016 • Vol. 41 No. 2
• Adults with ABSSSIs (for 7–14 days): ° CLCR ≥ 30 mL/min: 4 mg/kg once every 24 hours ° CLCR < 30 mL/min: 4 mg/kg once every 48 hours • Adults with bacteremia (for 14–42 days): ° CLCR ≥ 30 mL/min: 6 mg/kg once every 24 hours ° CLCR < 30 mL/min: 6 mg/kg once every 48 hours
• 4 mg/kg, 7–14 days: M, $2,634–$5,269; F, $2,245–$4,491 • 6 mg/kg, 14–42 days: M, $7,903– $23,710, F, $6,736– $20,208e
Pipeline Plus Table 1 Antibacterial Agents Most Commonly Used to Treat U.S. Hospital-Acquired MRSA Infections (Continued)a Product Company Oxazolidinones Linezolid (Zyvox) Pfizer
Indication(s)
Dosageb
ABSSSIs, CABP, HABP, uncomplicated SSSIs, vancomycin-resistant Enterococcus faecium infections
• ABSSSIs, CAP, HABP in adults/adolescents: 600 mg IV or oral every 12 hours for 10–14 days • Uncomplicated SSSIs in adults: 400 mg oral every 12 hours for 10–14 days • Uncomplicated SSSIs in adolescents: 600 mg oral every 12 hours for 10–14 days • Vancomycin-resistant E. faecium infections in adults/adolescents: 600 mg IV or oral every 12 hours for 14–28 days 200 mg once daily IV or oral over 1 hour for 6 days
Tedizolid phosphate (Sivextro) ABSSSIs Merck
Cost of Treatmentc
• 600 mg, 10–28 days: IV, $1,920– $5,376; oral, $4,082–$11,429 • 400 mg, oral, 10–14 days: $2,978–$4,169 • IV: $1,777 • Oral: $2,230
a Agents are listed alphabetically, not by preferred use. This list is not all-inclusive. Additional therapies may be available. b Based on prescribing information; doses and schedules may vary due to patient-specific requirements. c Costs calculated using average wholesale price for regimens in prescribing information for adults with normal kidney function, rounded to the nearest dollar. d Representative dosing for sterile vancomycin hydrochloride USP (Pfizer). e Price calculated using weights of 88 kg for men and 75 kg for women.
ABSSSIs = acute bacterial skin and skin-structure infections; CABP = community-acquired bacterial pneumonia; CIAIs = complicated intra-abdominal infections; CLCR = creatinine clearance; F = female; HABP = hospital-acquired bacterial pneumonia; IV = intravenous; M = male; SSSIs = skin and skin-structure infections; VABP = ventilator-associated bacterial pneumonia. Sources: GlobalData, product prescribing information, Red Book Online
Table 2 Promising Drugs in Late-Stage Clinical Development for the Treatment of MRSA Infections Product Company Brilacidin Cellceutix Corp.
Therapeutic Class Defensin-mimetic
Lead Status Indication ABSSSIs Phase 3
Debio 1450 (Debio 1452 Fabl enzyme prodrug) inhibitor Debiopharm International Delafloxacin (RX-3341) Fluoroquinolone Melinta Therapeutics
ABSSSIs
KRP-AM1977X Kyorin Pharmaceutical
Fluoroquinolone
CABP
Lefamulin (BC-3781) Nabriva Therapeutics
Systemic pleuromutilin
CABP
ABSSSIs
Omadacycline (PTK-0796) Aminomethylcycline ABSSSIs, Paratek Pharmaceuticals (tetracycline CABP derivative) Solithromycin Fluoroketolide Cempra Pharmaceuticals (macrolide derivative)
CABP
Taksta Fusidic acid Cempra Pharmaceuticals (proprietary oral formulation)
ABSSSIs
Expected U.S. Pricing Strategy
Priced at 5% premium over average daily cost of linezolid due to its first-in-class status and ability to be administered as single IV infusion; estimated cost of 7-day regimen, $2,711 Phase 2 Priced at 25% premium over average daily cost of linezolid because of its first-in-class status and narrow spectrum of activity; estimated cost of 10-day regimen, $4,611 Phase 3 Priced at 10% premium over average daily cost of ceftaroline fosamil due to its status as novel fluoroquinolone specifically indicated for MRSA and because of its oral and IV formulations; estimated cost of 10-day regimen, $3,055 Phase 3 Priced equal to average daily cost of delafloxacin (Japan) (Baxdela, Melinta Therapeutics, now in phase 3 development for ABSSSIs); estimated U.S. cost undetermined Phase 2/3 Priced at 20% premium over average daily cost of ceftaroline fosamil because of its first-in-class status; estimated cost of 12-day regimen, $3,999 Phase 3 Priced at 15% premium over average daily cost of tigecycline (Tygacil, Pfizer) because of more-convenient oncedaily dosing, oral and IV formulations, and improved safety profile; estimated cost of 10-day regimen, $2,741 Phase 3 Priced at 5% premium over average daily cost of ceftaroline fosamil because of its next-generation macrolide status and oral and IV formulations; estimated cost of 5-day regimen, $1,458 Phase 2/3 Priced at 5% premium over average daily cost of linezolid because of its first-in-class status; estimated cost of 10-day regimen, $4,058
Expected U.S. Launch Date 2019
2020
2017
2018
2019
2019
2017
2018
ABSSSIs = acute bacterial skin and skin-structure infections; CABP = community-acquired bacterial pneumonia. Sources: GlobalData (December 2015),5 company websites
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nia (Table 2). Three of these products— brilacidin (Cellceutix Corp.), Debio1450 (Debiopharm International), and lefamulin (Nabriva Therapeutics)—are expected to be first-in-class agents. The others include a new macrolide derivative (solithromycin, Cempra Pharmaceuticals); a next-generation tetracycline derivative (omadacycline, Paratek Pharmaceuticals); a proprietary oral formulation of fusidic acid (Taksta, Cempra Pharmaceuticals); and two anti-MRSA fluoroquinolones (delafloxacin, Melinta Therapeutics; and KRP-AM1977X, Kyorin Pharmaceutical).5–7 While these new treatments are expected to succeed, analysts foresee stiff competition from generic products, spurred by the loss of patent protection for two leading MRSA therapies, linezolid and daptamycin.5
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Dantes R, Mu Y, Belflower R, et al. National burden of invasive methicillinresistant Staphylococcus aureus infections, United States, 2011. JAMA Intern Med 2013;173:1970–1978. Stefani S, Chung DR, Lindsay JA, et al. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int J Antimicrob Agents 2012;39:273–282. David MZ, Daum RS. Community- associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010;23:616–687. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus (MRSA) infections. August 4, 2015. Available at: http://www.cdc.gov/mrsa. Accessed January 4, 2016. Pace CJ, Junker M, Fu K, et al. Methicillinresistant Staphylococcus aureus (MRSA)— Global Drug Forecast and Market Analysis to 2024. New York, New York: GlobalData; December 2015. Kumar K, Chopra S. New drugs for methicillin-resistant Staphylococcus aureus: an update. J Antimicrob Chemother 2013;68:1465–1470. Rodvold KA, McConeghy KW. Methicillinresistant Staphylococcus aureus therapy: past, present, and future. Clin Infect Dis 2014;58(suppl 1):S20–S27. n
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Companies Take Aim at MRSA Infections Chris Fellner
M
ethicillin-resistant Staphylococcus aureus (MRSA) is one of the most widespread and virulent nosocomial pathogens.1 MRSA is categorized as either health care-associated MRSA (HA-MRSA)2 or communityassociated MRSA (CA-MRSA),3 depending on the setting where the infection was acquired. In medical facilities, MRSA may cause life-threatening bloodstream infections, pneumonia, or surgical-site infections. In the community, most MRSA infections affect the skin.4 Although MRSA remains a major Chris Fellner is a medical writer and the Editor of PTCommunity.com.
patient threat, data from the Centers for Disease Control and Prevention (CDC) have shown that the rate of invasive (life-threatening) MRSA infections in health care settings is declining. Invasive MRSA infections that began in hospitals dropped 54% between 2005 and 2011, with 30,800 fewer severe infections. The study showed 9,000 fewer deaths in hospital patients in 2011 than in 2005.1 Most patients who present to U.S. hospitals with suspected MRSA infections receive empiric antimicrobial therapy before the causative pathogen has been diagnosed and confirmed. Culture-based methods are still the gold standard for detecting MRSA.5
At least 10 marketed antibiotics have demonstrated potent activity against MRSA and are used to treat invasive HA-MRSA infections in the U.S. (Table 1). Vancomycin, a generic glycopeptide, is the most frequently prescribed antibiotic for infections in which MRSA is the suspected or known cause, followed by linezolid (Zyvox, Pfizer), an oxazolidinone, and daptamycin (Cubicin, Merck), a lipopeptide.5 The late-stage clinical pipeline for MRSA includes an array of treatments aimed at acute bacterial skin and skinstructure infections (ABSSSIs) and/or community-acquired bacterial pneumocontinued on page 128
Table 1 Antibacterial Agents Most Commonly Used to Treat U.S. Hospital-Acquired MRSA Infectionsa Product Company Cephalosporin Ceftaroline fosamil (Teflaro) Actavis, Inc. Glycycycline Tigecycline (Tygacil) Pfizer
Indication(s)
Dosageb
Cost of Treatmentc
ABSSSIs, CABP
600 mg every 12 hours by IV infusion administered over 5–60 minutes for 5–14 days (ABSSSIs) or 5–7 days (CABP) in adults (18 years of age or older)
5–14 days: $1,831–$5,127
ABSSSIs, CABP, CIAIs
Initial dose: 100 mg, followed by 50 mg every 12 hours IV over 5–14 days: approximately 30–60 minutes for 5–14 days (ABSSSIs and CIAIs) $1,888–$4,977 or 7–14 days (CABP)
Glycopeptides and Lipoglycopeptides Dalbavancin (Dalvance) ABSSSIs Allergan Oritavancin (Orbactiv) ABSSSIs The Medicines Company Telavancin (Vibativ) ABSSSIs, HABP, VABP Theravance Biopharma US
Vancomycin Generics
Serious or severe infections caused by susceptible methicillinresistant (beta-lactamresistant) staphylococci
Two-dose regimen: 1,000 mg IV followed 1 week later by 500 mg IV, both administered over 30 minutes 1,200-mg single dose by IV infusion over 3 hours in adults • ABSSSIs: 10 mg/kg by IV infusion over 60 minutes every 24 hours for 7–14 days • HABP/VABP: 10 mg/kg by IV infusion over 60 minutes every 24 hours for 7–21 days • Adults: 2 g IV daily, divided as 500 mg every 6 hours or 1 g every 12 hours, administered at no more than 10 mg/min or over a period of at least 60 minutes, whichever is longer, for 7–10 daysd • Pediatric patients: 10 mg/kg IV every 6 hours over a period of at least 60 minutes for 7–10 daysd
$5,364 $3,480 7–21 days: M, $3,523–$10,568; F: $3,002–$9,007e 7–10 days (adults): $101–$144
Lipopeptide Daptomycin (Cubicin) Merck
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ABSSSIs, S. aureus bacteremia
• February 2016 • Vol. 41 No. 2
• Adults with ABSSSIs (for 7–14 days): ° CLCR ≥ 30 mL/min: 4 mg/kg once every 24 hours ° CLCR < 30 mL/min: 4 mg/kg once every 48 hours • Adults with bacteremia (for 14–42 days): ° CLCR ≥ 30 mL/min: 6 mg/kg once every 24 hours ° CLCR < 30 mL/min: 6 mg/kg once every 48 hours
• 4 mg/kg, 7–14 days: M, $2,634–$5,269; F, $2,245–$4,491 • 6 mg/kg, 14–42 days: M, $7,903– $23,710, F, $6,736– $20,208e
Pipeline Plus Table 1 Antibacterial Agents Most Commonly Used to Treat U.S. Hospital-Acquired MRSA Infections (Continued)a Product Company Oxazolidinones Linezolid (Zyvox) Pfizer
Indication(s)
Dosageb
ABSSSIs, CABP, HABP, uncomplicated SSSIs, vancomycin-resistant Enterococcus faecium infections
• ABSSSIs, CAP, HABP in adults/adolescents: 600 mg IV or oral every 12 hours for 10–14 days • Uncomplicated SSSIs in adults: 400 mg oral every 12 hours for 10–14 days • Uncomplicated SSSIs in adolescents: 600 mg oral every 12 hours for 10–14 days • Vancomycin-resistant E. faecium infections in adults/adolescents: 600 mg IV or oral every 12 hours for 14–28 days 200 mg once daily IV or oral over 1 hour for 6 days
Tedizolid phosphate (Sivextro) ABSSSIs Merck
Cost of Treatmentc
• 600 mg, 10–28 days: IV, $1,920– $5,376; oral, $4,082–$11,429 • 400 mg, oral, 10–14 days: $2,978–$4,169 • IV: $1,777 • Oral: $2,230
a Agents are listed alphabetically, not by preferred use. This list is not all-inclusive. Additional therapies may be available. b Based on prescribing information; doses and schedules may vary due to patient-specific requirements. c Costs calculated using average wholesale price for regimens in prescribing information for adults with normal kidney function, rounded to the nearest dollar. d Representative dosing for sterile vancomycin hydrochloride USP (Pfizer). e Price calculated using weights of 88 kg for men and 75 kg for women.
ABSSSIs = acute bacterial skin and skin-structure infections; CABP = community-acquired bacterial pneumonia; CIAIs = complicated intra-abdominal infections; CLCR = creatinine clearance; F = female; HABP = hospital-acquired bacterial pneumonia; IV = intravenous; M = male; SSSIs = skin and skin-structure infections; VABP = ventilator-associated bacterial pneumonia. Sources: GlobalData, product prescribing information, Red Book Online
Table 2 Promising Drugs in Late-Stage Clinical Development for the Treatment of MRSA Infections Product Company Brilacidin Cellceutix Corp.
Therapeutic Class Defensin-mimetic
Lead Status Indication ABSSSIs Phase 3
Debio 1450 (Debio 1452 Fabl enzyme prodrug) inhibitor Debiopharm International Delafloxacin (RX-3341) Fluoroquinolone Melinta Therapeutics
ABSSSIs
KRP-AM1977X Kyorin Pharmaceutical
Fluoroquinolone
CABP
Lefamulin (BC-3781) Nabriva Therapeutics
Systemic pleuromutilin
CABP
ABSSSIs
Omadacycline (PTK-0796) Aminomethylcycline ABSSSIs, Paratek Pharmaceuticals (tetracycline CABP derivative) Solithromycin Fluoroketolide Cempra Pharmaceuticals (macrolide derivative)
CABP
Taksta Fusidic acid Cempra Pharmaceuticals (proprietary oral formulation)
ABSSSIs
Expected U.S. Pricing Strategy
Priced at 5% premium over average daily cost of linezolid due to its first-in-class status and ability to be administered as single IV infusion; estimated cost of 7-day regimen, $2,711 Phase 2 Priced at 25% premium over average daily cost of linezolid because of its first-in-class status and narrow spectrum of activity; estimated cost of 10-day regimen, $4,611 Phase 3 Priced at 10% premium over average daily cost of ceftaroline fosamil due to its status as novel fluoroquinolone specifically indicated for MRSA and because of its oral and IV formulations; estimated cost of 10-day regimen, $3,055 Phase 3 Priced equal to average daily cost of delafloxacin (Japan) (Baxdela, Melinta Therapeutics, now in phase 3 development for ABSSSIs); estimated U.S. cost undetermined Phase 2/3 Priced at 20% premium over average daily cost of ceftaroline fosamil because of its first-in-class status; estimated cost of 12-day regimen, $3,999 Phase 3 Priced at 15% premium over average daily cost of tigecycline (Tygacil, Pfizer) because of more-convenient oncedaily dosing, oral and IV formulations, and improved safety profile; estimated cost of 10-day regimen, $2,741 Phase 3 Priced at 5% premium over average daily cost of ceftaroline fosamil because of its next-generation macrolide status and oral and IV formulations; estimated cost of 5-day regimen, $1,458 Phase 2/3 Priced at 5% premium over average daily cost of linezolid because of its first-in-class status; estimated cost of 10-day regimen, $4,058
Expected U.S. Launch Date 2019
2020
2017
2018
2019
2019
2017
2018
ABSSSIs = acute bacterial skin and skin-structure infections; CABP = community-acquired bacterial pneumonia. Sources: GlobalData (December 2015),5 company websites
Vol. 41 No. 2 • February 2016 • P&T 127 ®
Pipeline Plus continued from page 126
nia (Table 2). Three of these products— brilacidin (Cellceutix Corp.), Debio1450 (Debiopharm International), and lefamulin (Nabriva Therapeutics)—are expected to be first-in-class agents. The others include a new macrolide derivative (solithromycin, Cempra Pharmaceuticals); a next-generation tetracycline derivative (omadacycline, Paratek Pharmaceuticals); a proprietary oral formulation of fusidic acid (Taksta, Cempra Pharmaceuticals); and two anti-MRSA fluoroquinolones (delafloxacin, Melinta Therapeutics; and KRP-AM1977X, Kyorin Pharmaceutical).5–7 While these new treatments are expected to succeed, analysts foresee stiff competition from generic products, spurred by the loss of patent protection for two leading MRSA therapies, linezolid and daptamycin.5
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Dantes R, Mu Y, Belflower R, et al. National burden of invasive methicillinresistant Staphylococcus aureus infections, United States, 2011. JAMA Intern Med 2013;173:1970–1978. Stefani S, Chung DR, Lindsay JA, et al. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int J Antimicrob Agents 2012;39:273–282. David MZ, Daum RS. Community- associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010;23:616–687. Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus (MRSA) infections. August 4, 2015. Available at: http://www.cdc.gov/mrsa. Accessed January 4, 2016. Pace CJ, Junker M, Fu K, et al. Methicillinresistant Staphylococcus aureus (MRSA)— Global Drug Forecast and Market Analysis to 2024. New York, New York: GlobalData; December 2015. Kumar K, Chopra S. New drugs for methicillin-resistant Staphylococcus aureus: an update. J Antimicrob Chemother 2013;68:1465–1470. Rodvold KA, McConeghy KW. Methicillinresistant Staphylococcus aureus therapy: past, present, and future. Clin Infect Dis 2014;58(suppl 1):S20–S27. n
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