Merck’s C. Diff Drug Zinplava Clears FDA With Heart Failure Warning

Following panel recommendation, label includes warning of use of bezlotoxumab in patients with history of congestive heart failure; postmarketing commitments include studies on microbial retention and endotoxin recovery.

FDA approved Merck & Co. Inc.’s Zinplava (bezlotoxumab) with a limited indication to reduce recurrence of Clostridium difficile in patients 18 years or older who are receiving antibacterial drug treatment for C. difficile infection and are at high risk for recurrence.

The labeling states that Zinplava is not indicated for the treatment of C. difficile infection (CDI) and specifies that the drug is not an antibacterial and should only be used in conjunction with an antibacterial.

Merck announced the approval on Oct. 21. Zinplava is the first drug approved for the indication to reduce CDI recurrence.

The unmet medical need prompted an FDA advisory panel to recommend approval despite concerns about the drug’s level of efficacy. In Merck’s two pivotal studies, bezlotoxumab demonstrated an absolute reduction in C. difficile infection (CDI) recurrence of approximately 10% and a relative reduction of approximately 40% compared to placebo in patients receiving standard of care antibiotic therapy. (Also see "C.Diff Unmet Need Overcomes Bezlotoxumab Panel's Efficacy Concerns" - Pink Sheet, 9 Jun, 2016.)

Merck said it expects to launch Zinplava in the first quarter of 2017, at which time it will announce the product’s price.

In June, FDA’s Antimicrobial Drugs Advisory Committee voted 10-5 with one abstention for approval of the monoclonal antibody. One panel member said he would expect bezlotoxumab to provide better than a 10% improvement but noted the possibility that it could prevent 8,000 cases of C. difficile infection per year and 3,000 deaths per year.

FDA had also questioned the drug’s efficacy in briefing documents for the advisory committee meeting. It said that while there appears to be a decrease in CDI recurrence with the use of bezlotoxumab, “there is concern as to whether the efficacy of bezlotoxumab for the prevention of CDI recurrence has been adequately demonstrated.” (Also see "Merck Went Own Way On Bezlotoxumab Endpoint And FDA May Not Follow" - Pink Sheet, 7 Jun, 2016.)

Caution For Congestive Heart Failure Patients

Several panel members suggested that the use of the drug be limited to high risk patients and that the company continue to collect safety data. Some members also voiced concern about a cardiovascular safety signal and recommended that labeling include a warning about use in patients with heart problems.

The approved labeling includes a heart failure warning in the “warnings and precautions” section but it does not contraindicate use. It states that heart failure was reported more commonly in the two Phase III clinical trials in Zinplava-treated patients compared to placebo-treated patients and that it occurred primarily in patients with underlying congestive heart failure (CHF). “In patients with a history of CHF, Zinplava should be reserved for use when the benefit outweighs the risk,” the labeling advises.

“In patients with a history of CHF, 12.7% (15/118) of Zinplava-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period,” the labeling states. “Additionally, in patients with a history of CHF, there were more deaths in Zinplava-treated patients, 19.5% (23/118) than in placebo-treated patients, 12.5% (13/104) during the 12-week study period. The causes of death varied and included cardiac failure, infections, and respiratory failure.”

The most common adverse reactions following Zinplava treatment with standard of care antibacterial drug therapy (reported in ≥4% of patients within the first four weeks of infusion and with a frequency greater than placebo plus standard of care antibacterial drug therapy) were nausea, pyrexia, and headache.

Postmarketing Commitments

In July, Merck announced that FDA had requested the company to submit new data and analyses from the two pivotal Phase III trials, MODIFY I and II, which constituted a major amendment to the biologics license application. The request resulted in an extension of the Prescription Drug User Fee Act goal date from July 23 to Oct. 23.

FDA’s approval letter notes that the agency waived the pediatric study requirement for patients less than one year of age because such studies are impossible or highly impractical because CDI does not commonly occur in this population. The company is required to conduct a postmarketing pediatric study in patients aged one to less than 18 years who are receiving antibacterial therapy for CDI.

Merck made postmarketing commitments to conduct six types of studies. The commitments include:

• Performing low endotoxin recovery studies;
• Repeating the microbial retention study using a more suitable surrogate solution;
• Performing additional testing to support the clonality of the bezlotoxumab master cell bank;
• Conducting a study to support the worst case cumulative hold times in the bezlotoxumab drug substance manufacturing process to demonstrate that the worst case cumulative hold time will not adversely affect the product quality of bezlotoxumab drug substance;
• Developing a valid in vitro endotoxin assay for drug product release testing; and
• Re-evaluating bezlotoxumab drug substance and drug product lot release and stability specifications after a minimum of 30 drug substance lots have been manufactured using the commercial manufacturing process and tested at the time of release using the commercial specification methods.

Other Therapies In The Pipeline

C. difficile infection is caused by bacteria that produce toxins, including toxin B. Bezlotoxumab binds to C. difficile toxin B and neutralizes its activity by preventing it from binding to host cells. FDA granted the drug a priority review designation.

CDI symptoms range from mild to profuse diarrhea that can lead to dehydration and life threatening complications, including death. Merck noted that in 2011, there were an estimated 29,000 deaths associated with CDI in the US.

Merck currently markets Dificid (fidaxomicin), which is one of two antibiotics specifically approved to treat C. difficile infections. (Also see "Merck & Co Expands C Diff Franchise With US Zinplava Approval" - Scrip, 24 Oct, 2016.)

The growth of antibiotic-resistant bacteria has created an urgent need for the development of new therapies. Merck says that although standard of care antibiotic therapy for CDI is generally effective at resolving the symptoms of CDI, recurrences are common due to persistent or newly acquired C. difficile spores, which are facilitated by gut dysbiosis caused by antibiotics.

Several potential competitors to Zinplava are in Phase II.

The company notes that after initial treatment and resolution of diarrhea, up to 35% of CDI patients experience recurrence and of those who have a primary recurrence, 40% will have another CDI episode, and after two occurrences, the likelihood of an additional episode increases to as high as 65%.

Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex Inc. (now part of Bristol-Myers Squibb Co.), and was licensed to Merck in 2009.

Several antibiotic alternatives are in development for treatment of recurrent CDI, including Pfizer Inc.’s vaccine PF-06425090, Rebiotix Inc.’s probiotic RBX2660, Seres Therapeutics Inc.’s probiotic SER-109, and Shire PLC’s probiotic VP20621, all of which are in Phase II clinical trials.