Just over a month after adding an indication to the label for Zerbaxa (ceftolozane/tazobactam), Merck & Co. Inc. gained FDA clearance of Recarbrio (imipenem, cilastatin and relebactam) 1.25 g for injection.

The new combo antibacterial is indicated for adults who have limited or no alternatives for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by a handful of susceptible gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa.

Relebactam, Merck's beta-lactamase inhibitor, when given with imipenem, an approved carbapenem antibiotic, restores susceptibility to the latter therapy. Cilastatin, the third ingredient, is a dehydropeptidase inhibitor added to the mix in order to limit the renal metabolism of imipenem. Bacteria develop resistance to imipenem by making beta-lactamases, which weaken the "powerhouse" drug, said Joan Butterton, vice president of infectious disease clinical research at Kenilworth, N.J.-based Merck. Cilastatin lets imipenem stay in the body longer while relebactam attacks the beta-lactamase. "We give a drug that prevents the bacteria from breaking down our other drug, so that our first drug – which we had had on the market for 30 years – can work again," she told BioWorld, adding that the approval was personally gratifying since she oversaw the first-in-human study with relebactam. The imipenem/cilastatin pairing was approved as Primaxin.

"The regulatory agencies have done a good job in trying to ensure we can develop antibodies more quickly," Butterton said. "They've put a lot of pathways into place to allow us to have limited indications with smaller and faster development programs than we've been able to do in the past. You get to do fewer and smaller studies, and you can do them in the easiest population to enroll [such as cUTI], but you end up with a limited label." Estimating the number of patients that will end up with Recarbrio isn't possible because the ecology of resistant infections varies from country to country, from institution to institution, and even from ward to ward in hospitals, she said. "The point is to have the right drug there for the patients who need it."

Relebactam won the FDA's qualified infectious disease product (QIDP) designation for the treatment of cUTI and complicated intra-abdominal infections (cIAI). The NDA gained priority review, too. Merck said Recarbrio will become available later this year. It's not to be given to patients with a history of severe hypersensitivity to any component of the drug, since serious and occasionally fatal anaphylactic reactions have turned up in patients on beta-lactams. Central nervous system (CNS) adverse reactions, such as seizures, confused states, and myoclonic activity, have been reported with imipenem/cilastatin, especially at higher-than-recommended doses of imipenem. Most commonly those have appeared in patients with CNS disorders such as brain lesions or a history of seizures and/or compromised renal function, Merck said. Using the Recarbrio with valproic acid or divalproex sodium may increase the risk of breakthrough seizures.

With resistance an ever-present threat, Recarbrio is arriving to the market with other provisos as well. Merck said in a press release that "when culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy." Lacking those, "local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy."

Imipenem's bactericidal oomph results from binding to PBP 2 and PBP 1B in Enterobacteriaceae and P. aeruginosa and the subsequent blocking of penicillin binding proteins, which leads to the disruption of bacterial cell wall synthesis; the drug is stable in the presence of some beta-lactamases. Relebactam, for its part, brings no antibacterial activity but works to head off degradation of imipenem by certain serine beta-lactamases.

Merck's Zerbaxa, first approved in December 2014 to treat cUTI and cIAI, recently won label language that indicates it for use in adults with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Zerbaxa also contains a beta-lactamase inhibitor. (See BioWorld, June 5, 2019.)

Shares of Merck (NYSE:MRK) closed Wednesday at $81.92.

Research continues in cUTIs, with mixed success. Recently, as its PDUFA date for the compound neared, Dublin-based Nabriva Therapeutics plc disclosed that the FDA struck the fosfomycin NDA with a complete response letter, citing manufacturing deficiencies at one of the contract manufacturers. The company stressed that the agency was not seeking any additional clinical data and had not raised any new safety concerns about the broad-spectrum candidate for cUTI, but Wall Street dinged the stock hard anyway. (See BioWorld, May 2, 2019.)

'Investor sentiment low' in space

Also gaining attention is Cambridge, Mass.-based Spero Therapeutics Inc., with the carbapenem SPR-994. In the second half of this year, confirmatory pharmacokinetic (PK) and data safety monitoring board data readouts are expected. The company is conducting Adapt-PO, a single registrational phase III trial that began in April under fast track designation for cUTI. A double-blind, 1-to-1 randomized trial, the experiment is designed to compare oral SPR-994 with ertapenem, the current standard of care intravenous (I.V.) antibiotic for cUTI, in about 1,200 patients with such infections or acute pyelonephritis. Specifically, an analysis of lead-in PK data from an initial group of 70 patients was designed to confirm SPR-994's dosage and exposure. Wainwright analyst Ed Arce said in a report this week that he "expect[s] Adapt-PO to proceed without any major changes, as a completed phase I study demonstrated that SPR-994 was well-tolerated at daily doses ranging from 100 mg to 900 mg with a linear PK profile over this dose range [and] no observed impact on SPR-994's drug exposure by food intake." He maintained a buy rating with a $27 price target.

Spero shares (NASDAQ:SPRO) closed Wednesday at $10.53. (See BioWorld, July 10, 2018.)

Iterum Therapeutics plc, of Dublin, has phase III trials in uncomplicated UTI, cUTI and uncomplicated IAI – all due to report data in the second half of this year, with an NDA filing by the end of the year. The company is developing oral sulopenem and sulopenem I.V., licensed from New York-based Pfizer Inc., which has gained QIDP designation in four indications: community-acquired bacterial pneumonia, acute bacterial prostatitis, gonococcal urethritis and pelvic inflammatory disease. Wainwright's Arce likes Iterum as well, calling the company in a report last month "not just another antibiotic company," working with the first oral penem-class therapy in the U.S. "Current investor sentiment in antibiotic companies is admittedly quite low, following recent updates" from the likes of Achaogen Inc. and Tetraphase Pharmaceuticals Inc. "With most companies in the space trading at 52-week lows, we acknowledge that many investors may doubt that a viable market for novel drugs in the U.S. exists, despite the growing public health crisis of antibiotic resistance. However, we believe the key issues – restrictions on hospital reimbursement and stewardship best practices – are intrinsic to I.V. drugs, as most antibiotics are. For the few all-oral antibiotics that can directly access the much larger community setting, the market remains open and largely unencumbered, in our view."

In April, nine months after the U.S. launch of its antibiotic, Zemdri (plazomicin), South San Francisco-based Achaogen filed for Chapter 11 bankruptcy and began selling off its assets. Tetraphase, of Watertown, Mass., in June was "battening down the hatches," in Arce's words, by way of a corporate reorganization to realign its financial resources to focus on the sales and marketing of lead drug Xerava (eravacycline), a tetracycline antibacterial for the treatment of adult patients with cIAI. (See BioWorld, April 26, 2019.)

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