Merck Looks To Add Pneumonia To Zerbaxa Label; Market Value Not Clear

Merck unveiled Phase III data showing efficacy in hospital-acquired bacterial pneumonia, but branded drugs with this indication currently have not scored significant sales.

Merck & Co. Inc. hopes to boost sales of its combination antibiotic Zerbaxa by adding hospital-acquired bacterial pneumonia to its labeling, but even with Phase III data in hand showing non-inferiority to meropenem in that setting, the value proposition for this indication is uncertain.

On Sept. 11, the pharma unveiled top-line data from the Phase III ASPECT-NP study showing that Zerbaxa (ceftolozane/tazobactam) demonstrated non-inferiority to the broad-spectrum antibiotic meropenem in 726 patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) on both primary endpoints: all-cause mortality at day 28 and clinical cure at the test-of-cure follow-up visit.

Merck said it plans to file for supplemental approval for HABP and VABP in the US and Europe based on the full data from this trial. A novel cephalosporin (ceftolozane) combined an existing beta-lactamase inhibitor (tazobactam), Zerbaxa obtained approval from the US FDA in December 2014 for Gram-negative complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). (Also see "Cubist’s Zerbaxa Approval Marks Firm’s Second Novel Antibiotic In 2014" - Pink Sheet, 19 Dec, 2014.) Zerbaxa was one of the first novel antibiotics approved under the qualified infectious disease product program and was the first that targeted Gram-negative pathogens.

Theravance Biopharma Inc.’s lipoglycopeptide antibiotic Vibativ (telavancin) and Allergan PLC’s Avycaz (ceftazidime/avibactam), a cephalosporine/beta-lactamase inhibitor combination product like Zerbaxa, are already approved in the US to treat HABP, but the condition is also largely treated with widely available generics.

Neither Vibativ nor Avycaz has yielded especially high sales to date. Avycaz totaled $67.2m in sales in 2017 and posted $45.3m in sales during the first six months of this year. Vibativ, relaunched in 2013 after being removed from the commercial market due to manufacturing issues, tallied $14.8m in full-year 2017 sales, while bringing in $5.4m during the second quarter of 2018. It is approved to treat HABP/VABP caused by Staphylococcus aureus as well as complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens. (Also see "ICAAC 2015: Data Help Theravance's Ongoing Vibativ Relaunch" - Scrip, 22 Sep, 2015.)

The market leaders for HABP cases remain four long-ago approved antibiotics that are now available generically – Bristol-Myers Squibb Co.’s Azactam (aztreonam), Johnson & Johnson’s Levaquin (levofloxacin) and Pfizer Inc.’s Zosyn (piperacillin/tazobactam) and Zyvox (linezolid).

Antibiotics A Blockbuster Franchise For Merck

Although Merck is one of the few big pharmas still active in antibiotic R&D and commercialization, it does not break out annual or quarterly sales totals for Zerbaxa, suggesting that the product’s sales have been minimal to date. For the first six months of 2018, Merck reported nearly $1.2bn in combined revenue for its five antibiotics, which comprise its Hospital Acute Care portfolio, along with the anesthesia-reversal drug Bridion (sugammadex). (See chart below.)

Datamonitor Healthcare analyst David Dahan said the data should enable Zerbaxa to obtain supplementary approval for HABP/VABP, and he increased Biomedtracker’s likelihood of approval for that indication by eight percentage points to 69%. An approval in this setting would put the Merck product in direct competition with Avycaz, which added those indications to its label this past February. Avycaz obtained FDA approval to treat cIAI and cUTI patients in 2015, but did not get approved for HABP/VABP at that time. (Also see "Actavis antibiotic combo Avycaz OK'd for 2 infections" - Scrip, 26 Feb, 2015.)

Dahan pointed out that those two indications account for an estimated 22% of nosocomial infections in the US and about 60% are caused by Gram-negative pathogens. Both Zerbaxa and Avycaz work against Gram-negative infections.

“Zerbaxa and Avycaz provide comparable antimicrobial coverage against a range of Gram-negative organisms, including Pseudomonas aeruginosa, and extended-spectrum beta-lactamase-producing organisms,” Dahan told Scrip. “Avycaz provides better activity against KPC (Klebsiella pneumoniae carbapenemase) type CRE (carbapenem-resistant Enterobacteriaceae), but neither antimicrobial is considered effective against NDM (New Delhi metallo-beta-lactamase) type CRE.”

The two products also offer similar tolerability profiles, he noted, including those side effects typically related to beta-lactams such as hypersensitivity, nausea and diarrhea. The class is also associated with lower cure rates in patients with renal impairment.

Despite the apparent unenthusiastic market response to Zerbaxa to date, antibiotics have proven to be a steady business niche for Merck. In 2017, the five marketed antibiotics for which Merck broke out individual sales yielded annual revenue ranging from $280m to $636m, for an aggregate total exceeding $2.3bn. Those five products are slightly exceeding that sales pace through two quarters this year.

Merck’s Antibiotic Portfolio Sales, 2017-2018
Product	Indication	Full-Year 2017 Sales	2018 sales through June 30
Cubicin (daptomycin)	Infections of the skin and underlying tissues	$382m	$192m
Noxafil (posaconazole)	Antifungal for Aspergillus and Candida infections	$636m	$363m
Invanz (ertapenem)	Skin, lung, stomach, pelvis, urinary tract infections	$602m	$300m
Cancidas (caspofungin)	Fungal infections, neutropenia	$422m	$178m
Primaxin (cilistatin/imipenem	Peritonitis, flesh-eating disease, pneumonia	$280m	$140m
Total		$2.322bn	$1.173bn
Source: Merck & Co., Inc.

Zerbaxa obtained FDA approval in December 2015, nearly simultaneously with Merck’s $9.5bn acquisition of Cubist Pharmaceuticals Inc., a deal which also added Cubicin (daptomycin) to the New Jersey-based pharma’s portfolio. (Also see "Cubist wins FDA nod for antibiotic Zerbaxa " - Scrip, 20 Dec, 2014.) That purchase price got called into question almost immediately, however, due to a patent infringement lawsuit decision enabling generic daptomycin to enter the US market in 2016, two years earlier than previously expected. PS056528 Cubicin topped the blockbuster threshold in 2015 and 2016, yielding sales of $1.127bn and $1.087bn, respectively.

Active Pipeline For HABP Treatment

Beyond the label-expansion effort for Zerbaxa, the pipeline for new HAP therapies appears encouraging, though paradigm-changing antibiotics remain a big unmet need. Phase III candidates include Shionogi & Co. Ltd.’s cefiderocol; Motif Bio PLC’s intravenous iclaprim; Melinta Therapeutics Inc.’s Vabomere (meropenem/vaborbactam), approved in 2017 for urinary and reproductive tract infections; and Basilea Pharmaceutica Ltd.’s Zeftera (ceftobiprole medocaril). Merck also has two late-stage HABP programs – a label-expansion effort for Sivextro (tedizolid), approved for skin and skin structure infections in 2014, and an investigational combo of Primaxin (cilistatin/imipenem) with the novel beta-lactam relebactam. Relebactam (MK-7655) obtained Qualified Infectious Disease Product (QIDP) status in 2014. (Also see "Merck's relebactam dubbed qualified infectious disease product " - Scrip, 5 Sep, 2014.)

The HABP pipeline includes three other clinical candidates, according to Biomedtracker. These include Savara Inc.’s amikacin/fosfomycin inhalation solution and Melinta’s Baxdela (delafloxacin) in Phase II and Nabriva Therapeutics PLC’s Contepo (fosfomycin) in Phase I.

DMHC analyst Dahan specified Shionogi’s cefiderocol as a candidate to watch as a modified cephalosporin containing an iron-binding catchecol.

“The catchecol allows uptake by the iron active-transport system in Gram-negative bacteria, thereby bypassing the outer membrane permeability barrier and concentrating cefiderocol at its active site,” he noted.

The candidate produced positive results for urinary tract infections in a pivotal Phase II study in January 2017. Meanwhile, it is also being studied in a pivotal Phase III trial in HABP/VABP with an estimated completion date of January 2019 and a 150-patient, Phase III trial for carbapenem-resistant Gram-negative infections that is expected to complete by Sept. 30, Dahan pointed out.