Merck & Co. Inc. succeeded in overcoming regulatory friction to win FDA approval for Zinplava (bezlotoxumab), a monoclonal antitoxin antibody targeting Clostridium difficile infection (CDI) in adults at high risk for recurrence of the infection who are also on antibacterial therapy. The Kenilworth, N.J.-based company anticipates making the therapy available in the first quarter of 2017.

CDI can damage the colon and cause stomach pain and severe diarrhea. When people are infected with the bacteria, they often take an antibiotic to get rid of the infection. But even with antibiotic treatment, the infection can come back within weeks to months.

Two pivotal phase III studies of the antitoxin, MODIFY I and MODIFY II, found that the rate of C. difficile infection recurrence was lower in the bezlotoxumab arms compared to the placebo arms in patient subgroups known to be at high risk for CDI recurrence. It significantly reduced the rate of recurrence in combination with standard-of-care antibiotics by 17.4 percent in MODIFY I, and 15.7 percent in MODIFY II vs. recurrence rates of 27.6 percent and 25.7 percent, respectively, seen in patients receiving placebo plus standard-of-care antibiotics.

The rate of C. difficile infection recurrence was also lower compared with placebo in patient subgroups at high risk for C. difficile recurrence, including those with any prior episode of C. difficile infection within the previous six months, those infected with the hypervirulent BI/NAP1/027 strain, patients 65 years or older and patients with compromised immunity, according to Cortellis Clinical Trials Intelligence.

However, the studies also found that people with a history of congestive heart failure (CHF) who took Zinplava had a higher rate of heart failure and death than those who did not. In patients with a history of CHF, 12.7 percent of Zinplava-treated patients and 4.8 percent of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period.

Though granted an FDA priority review, the drug's path to approval was not as expedient an Merck may have hoped. Following FDA acceptance of the company's biologics license application and assignment of a July 23 PDUFA date, the agency's Antimicrobial Drugs Advisory Committee arrived at a split in supporting a recommendation for approval.

Voting 10-to-5, with one abstention, the committee supported the idea that Zinplava had shown substantial evidence of efficacy and safety in preventing CDI recurrence. However, some panelists expressed several concerns about the first-in-class drug, which is designed to neutralize C. difficile toxin B. Most of those concerns stemmed from a desire for more data and questions about which patients would most benefit. (See BioWorld Today, June 10, 2016.)

Following the panel, in late July 2016, the FDA requested new data and analyses from MODIFY I and II, the provision of which was considered a major amendment to the BLA, pushing out the PDUFA date to Oct. 23.

Because clinical guidelines recommend the already-approved Merck Dificid (fidaxomicin) for treating multiple recurrent but nonsevere CDI, Zinplava might only be prescribed for C. diff strains resistant to Dificid, reducing its market potential. Furthermore, the drug might see competition too from Sanofi Pasteur's phase III ACAM-CDIFF, an injectable toxoid vaccine based on Clostridium toxins A and B, a drug that company picked up in its acquisition of Acambis plc, or Pfizer Inc.'s phase II PF-06425090, which is presumed to be an adjuvant-formulated modified virulence factor vaccine also targeting toxins A and B.

A consensus forecast based on estimates by three analysts following the program suggest sales could reach $245 million annually by 2021, or about $68 million less than the antibacterial Primaxin, the lowest-selling product listed in a company-defined selection of the company's 2015 Hospital and Specialty market sales included in its 2015 10-K report. It was not clear how much Zinplava will cost at launch.

Merck licensed Zinplava in 2009 from Medarex, now part of Bristol-Myers Squibb Co. It is protected by a key U.S. patent anticipated to expire in 2025. The drug remains under review in the EU. (See BioWorld Today, April 22, 2009.)