Policy
Bezlotoxumab (Zinplava) is considered MEDICALLY NECESSARY to reduce recurrence of Clostridium difficile infection (CDI) in members who are receiving antibacterial drug treatment of CDI such as metronidazole, vancomycin, or fidaxomycin and are at high risk for CDI recurrence when the following criteria are met:

1. Member is 18 years of age or older; and
2. Member has a confirmed diagnosis of Clostridium difficile infection (CDI) with documentation of the following: diarrhea (passage of three or more loose bowel movements in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a stool sample collected no more than seven days prior; and
3. Member is at high risk of CDI recurrence, defined as any of the following:
   1. Age greater than or equal to 65 years; or
   2. Long term use of systemic antibacterial drugs (excluding standard of care antibiotics); or
   3. History of one or more prior episodes of CDI within the previous six months; or
   4. Immunocompromised (defined as having an active hematologic malignancy, using an antineoplastic or immunomodulating agent, using corticosteroids, having received a prior solid organ transplant, being asplenic, being neutropenic/pancytopenic, or having AIDS/immunodeficient condition); or
   5. Clinically severe CDI (as defined by a Zar score of greater than or equal to 2); or
   6. Hypervirulent strain (ribotypes 027, 078 or 244); and
4. Bezlotoxumab will be given in conjunction with standard of care antibiotics (Infusion will be given during the antibiotic treatment course). 

Combination of bezolotoxumab and other human monoclonal antibodies to C. difficile toxin is investigational/unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of CDI because the effectiveness of this approach has not been established.

Bezlotoxumab is investigational/unproven is considered NOT MEDICALLY NECESSARY for all other indications.

Dosing Recommendations
The recommended dose of bezlotoxumab is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes. Bezlotoxumab should be administered during antibacterial treatment for CDI.

Repeat administration of bezlotoxumab is investigational/unproven and therefore considered NOT MEDICALLY NECESSARY. The safety and efficacy of repeat administration of bezlotoxumab in persons with CDI has not been studied.

Rationale  
Clostridium difficile infection (CDI) is caused by bacteria that produce toxins, including toxin B. Symptoms of CDI include mild-to-severe diarrhea, abdominal pain and fever (Merck, 2016). The incidence of recurrent CDI is higher in certain patient populations, including people 65 years of age or older and those with compromised immune systems.

The U.S. Food and Drug Administration (FDA) has approved bezlotoxumab (Zinplava) injection 25 mg/mL to reduce recurrence of CDI in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence (Merck, 2016). The labeling states that bezlotoxumab is not indicated for the treatment of CDI. Bezlotoxumab is not an antibacterial drug and should only be used in conjunction with antibacterial drug treatment of CDI.

The safety and efficacy of bezlotoxumab was investigated in two randomized, double-blind, placebo-controlled, multicenter, Phase 3 trials (Trial 1 and Trial 2) in patients receiving Standard of Care (SoC) antibacterial drugs for treatment of CDI (Merck, 2016). Randomization was stratified by SoC (metronidazole, vancomycin, or fidaxomicin) and hospitalization status (inpatient vs. outpatient) at the time of study entry. Enrolled patients were 18 years of age or older and had a confirmed diagnosis of CDI, which was defined as diarrhea (passage of three or more loose bowel movements in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a stool sample collected no more than seven days before study entry. Patients were excluded if surgery for CDI was planned, or if they had uncontrolled chronic diarrheal illness. Patients received a 10- to 14-day course of oral SoC and a single infusion of bezlotoxumab or placebo was administered during the course of SoC. Patients on oral vancomycin or oral fidaxomicin could have also received intravenous metronidazole. Choice of SoC was at the discretion of the health care provider. The day of the infusion of bezlotoxumab or placebo in relation to the start of SoC ranged from the day prior to the start of SoC to 14 days after the start of SoC with the median being day 3 of SoC.

In Trial 1, 403 patients were randomized to receive bezlotoxumab and 404 patients were randomized to receive placebo (Merck, 2016). In Trial 2, 407 subjects were randomized to receive bezlotoxumab and 399 patients were randomized to receive placebo. The Full Analysis Set (FAS) was a subset of all randomized subjects with exclusions for: (i) not receiving infusion of study medication; (ii) not having a positive local stool test for toxigenic C. difficile; (iii) not receiving protocol defined standard of care therapy within a one day window of the infusion.

The baseline characteristics of the 1,554 patients randomized to bezlotoxumab or placebo in the FAS were similar across treatment arms and in Trial 1 and Trial 2. The median age was 65 years, 85% were white, 57% were female, and 68% were inpatients. A similar proportion of patients received oral metronidazole (48%) or oral vancomycin (48%) and 4% of the patients received oral fidaxomicin as their SoC. 

The following risk factors associated with a high risk of CDI recurrence or CDI-related adverse outcomes were present in the study population: 51% were ≥ 65 years of age, 39% received one or more systemic antibacterial drugs (during the 12-week follow-up period), 28% had one or more episodes of CDI within the 6 months prior to the episode under treatment (15% had two or more episodes prior to the episode under treatment), 21% were immunocompromised and 16% presented at study entry with clinically severe CDI (as defined by a Zar score of ≥ 2) (Merck, 2016). A hypervirulent strain (ribotypes 027, 078 or 244) was isolated in 22% of patients who had a positive baseline culture, of which 87% (189 of 217 strains) were ribotype 027.

Patients were assessed for clinical cure of the presenting CDI episode, defined as no diarrhea for two consecutive days following the completion of a ≤ 14 day SoC regimen (Merck, 2016). Patients who achieved clinical cure were then assessed for recurrence of CDI through 12 weeks following administration of the infusion of bezlotoxumab or placebo. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic C. difficile following clinical cure of the presenting CDI episode. Sustained clinical response was defined as clinical cure of the presenting CDI episode and no CDI recurrence through 12 weeks after infusion.

In Trial 1, the sustained clinical response rate was 60.1% (232/386) in the bezlotoxumab arm compared to 55.2% (218/395) in the placebo arm, an adjusted difference of 4.8 (-2.1 to 11.1) which failed to achieve statistical significance (Merck, 2016). The clinical failure rate was higher in the bezlotoxumab arm (22.5%) than in the placebo arm (17.2%). The rate of recurrence was 17.4 in the bezlotoxumab arm and 27.6 in the placebo arm. In Trial 2, the sustained clinical response rate was 66.8% (264/395) in the bezlotoxumab arm versus 52.1% (197/378) in the placebo arm, an adjusted difference of 14.6 (7.7 to 21.4) which was a statistically significant difference. The clincial failure rate was lower in the bezlotoxumab arm (17.5%) than in the placebo arm (22.2%). The rate of recurrence was 15.7% in the bezlotoxumab arm and 25.7% in the placebo arm.

In Trial 1, the clinical cure rate of the presenting CDI episode was lower in the bezlotoxumab arm as compared to the placebo arm and in Trial 2, the clinical cure rate was lower in the placebo arm compared to the bezlotoxumab arm (Merck, 2016). Patients in the bezlotoxumab and placebo arms who did not achieve clinical cure of the presenting CDI episode (no diarrhea for two consecutive days following the completion of a ≤ 14-day SoC regimen) received a mean of 18 to 19 days of SoC and had a mean of four additional days of diarrhea following completion of SoC. Additional analyses showed that by 3 weeks post study drug infusion the clinical cure rates of the presenting CDI episode were similar between treatment arms.

Efficacy results in patients at high risk for CDI recurrence (i.e., patients aged 65 years and older, with a history of CDI in the past six months, immunocompromised state, severe CDI at presentation, or C. difficile ribotype 027) were consistent with the efficacy results in the overall trial population in Trials 1 and 2 (Merck, 2016).

Zinplava is available as bezlotoxumab in single-dose vials of 1,000 mg/40 mL (25 mg/mL). The prescribing information recommends administering bezlotoxumab during antibacterial drug treatment for CDI (Merck, 2016). The recommended dose of bezlotoxumab in adults is a single dose of 10 mg/kg administered as an intravenous infusion over 60 minutes. The labeling states that the safety and efficacy of repeat administration of bezlotoxumab in patients with CDI have not been studied.

Heart failure was reported more commonly in the two Phase 3 clinical trials in bezlotoxumab-treated patients compared to placebo-treated patients (Merck, 2016). These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of bezlotoxumab-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. Additionally, in patients with a history of CHF, there were more deaths in bezlotoxumab-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. In patients with a history of CHF, bezlotoxumab should be reserved for use when the benefit outweighs the risk.

The most common adverse reactions occurring within four weeks of infusion with a frequency greater than placebo and reported in ≥ 4% of patients treated with bezlotoxumab and Standard of Care (SoC) antibacterial drug therapy versus placebo and SoC antibacterial drug therapy included nausea (7% vs 5%), pyrexia (5% vs 3%) and headache (4% vs 3%) (Merck, 2016).

Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of bezlotoxumab-treated patients and 33% of placebo-treated patients (Merck, 2016). Heart failure was reported as a serious adverse reaction in 2.3% of bezlotoxumab-treated patients and 1.0% of placebo-treated patients.

In bezlotoxumab-treated patients, 10% experienced one or more infusion specific adverse reactions compared to 8% of placebo-treated patients, on the day of or the day after the infusion (Merck, 2016). Infusion specific adverse reactions reported in ≥ 0.5% of patients receiving bezlotoxumab and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%) and hypertension (1%). Of these patients, 78% experienced mild adverse reactions and 20% of patients experienced moderate adverse reactions. These reactions resolved within 24 hours following onset.

There is a potential for immunogenicity following administration of bezlotoxumab (Merck, 2016). The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bezlotoxumab in two Phase 3 studies with the incidence of antibodies in other studies or to other products may be misleading. Following treatment with bezlotoxumab in these two studies, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.

Risk factors for CDI recurrence include:

• Age greater than or equal to 65 years.
• Long-term use of systemic antibacterial drugs (excluding standard of care antibiotics).
• History of one or more prior episodes of CDI within the previous six months.
• Immunocompromised (defined as having an active hematologic malignancy, using an antineoplastic or immunomodulating agent, using corticosteroids, having received a prior solid organ transplant, being asplenic, being neutropenic/pancytopenic, or having AIDS/immunodeficient condition).
• Clinically severe CDI (as defined by a Zar score of greater than or equal to 2).
• Hypervirulent strain (ribotypes 027, 078 or 244).

Johnson and Gerding (2019) stated that CDI is mediated by actions of toxin A and toxin B. Fully human monoclonal antibodies directed against the binding domains of these toxins were developed. Despite pre-clinical studies suggesting efficacy for the anti-toxin A monoclonal, actoxumab, the anti-toxin B monoclonoal, bezolotoxumab, alone was shown to be effective in clinical trials. Intravenous infusion of bezlotoxumab at a 10 mg/kg dosage as adjunctive treatment reduced the risk of recurrent CDI over placebo for adult patients at increased risk for CDI recurrence in 2 large randomized, double-blind, clinical trials. Significant benefit was noted for patients with one or more of the following pre-defined risks; age greater than 65 years, history of CDI, immuno-compromise, severe CDI. Overall, bezlotoxumab appeared to be safe; however, an unexplained increased risk of heart failure (HF) was noted for patients with underlying congestive heart failure (CHF). They authors concluded that further refinement of who would benefit most and when best to administer bezlotoxumab is needed.

Combination of Bezolotoxumab and Other Human Monoclonal Antibodies to C. Difficile Toxin for the Treatment of Clostridium Difficile Infection
Dzunkova and associates (2016) stated that antibiotics have significant and long-lasting impacts on the intestinal microbiota and consequently reduce colonization resistance against CDI. Standard therapy using antibiotics is associated with a high rate of disease recurrence, highlighting the need for novel treatment strategies that target toxins, the major virulence factors, rather than the organism itself. Human monoclonal antibodies (HuMabs) MK-3415A (actoxumab-bezlotoxumab) to C. difficile toxin A and toxin B, as an emerging non-antibiotic approach, significantly reduced the recurrence of CDI in animal models and human clinical trials. Although the main mechanism of protection is through direct neutralization of the toxins, the impact of MK-3415A on gut microbiota and its restoration has not been examined. Using a CDI murine model, these researchers compared the bacterial diversity of the gut microbiome of mice under different treatments including MK-3415A, vancomycin, or vancomycin combined with MK-3415A, sampled longitudinally. These investigators showed that CDI resulted in the prevalence of Enterobacter species; 60% of mice in the vehicle group died after 2 days and their microbiome was almost exclusively formed by Enterobacter. MK-3415A treatment resulted in lower Enterobacter levels and restoration of Blautia, Akkermansia, and Lactobacillus, which were the core components of the original microbiota. Vancomycin treatment led to significantly lower survival rate than the combo treatment of MK-3415A and vancomycin. Vancomycin treatment decreased bacterial diversity with predominant Enterobacter and Akkermansia, while Staphylococcus expanded after vancomycin treatment was terminated. In contrast, mice treated by vancomycin combined with MK-3415A also experienced decreased bacterial diversity during vancomycin treatment. However, these animals were able to recover their initial Blautia and Lactobacillus proportions, even though episodes of Staphylococcus overgrowth were detected by the end of the experiments. The authors concluded that MK-3415A (actoxumab-bezlotoxumab) treatment facilitated normalization of the gut microbiota in CDI mice. Moreover, they stated that it remained to be examined if the prevention of recurrent CDI by the antitoxin antibodies observed in clinical trials occurred through modulation of microbiota.

Posteraro and colleagues (2018) noted that CDI is the most common healthcare-associated infection worldwide. As standard CDI antibiotic therapies can result in unacceptably high recurrence rates, novel therapeutic strategies for CDI are necessary. A recently emerged immunological therapy is a monoclonal antibody against C. difficile toxin B. These investigators summarized the available pharmacological, pre-clinical, and clinical data for the CDI treatment based on anti-toxin A (actoxumab) and anti-toxin B (bezlotoxumab) HuMabs, and discussed the potentiality of a therapy that includes HuMab combined administration for CDI. The authors concluded that although only bezlotoxumab is indicated to reduce recurrence of CDI, experimental studies using a combination of HuMabs actoxumab and bezlotoxumab have shown that bolstering the host immune response against both the C. difficile toxins may be effective in primary and secondary CDI prevention. Besides neutralizing both the key virulence factors, combination of 2 HuMabs could potentially offer an advantage for a yet to emerge C. difficile strain, which is a steady threat for patients at high risk of CDI. However, as actoxumab development was halted, passive immunotherapy with actoxumab/bezlotoxumab is actually impracticable. They stated that future research will be needed to evaluate HuMab combination as a therapeutic strategy in clinical and microbiological cure of CDI.

Reference  

1. Merck & Co., Inc. FDA approves Merck’s Zinplava (bezlotoxumab) to reduce recurrence of Clostridium difficile infection (CDI) in adult patients receiving antibacterial drug treatment for CDI who are at high risk of CDI recurrence. Press Release. Kenilworth, NJ: Merck; October 21, 2016.
2. Merck & Co., Inc. Zinplava (bezlotoxumab) injection, for intravenous use. Prescribing Information. uspi-mk6072-iv-1610r000. Whitehouse Station, NJ: Merck; revised October 2016.
3. Wilcox MH, Gerding DN, Poxton IR, et al.; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent clostridium difficile infection. N Engl J Med. 2017;376(4):305-317.
4. Villafuerte Galvez JA, Kelly CP. Bezlotoxumab: anti-toxin B monoclonal antibody to prevent recurrence of Clostridium difficile infection. Expert Rev Gastroenterol Hepatol. 2017;11(7):611-622.
5. Deeks ED. Bezlotoxumab: A review in preventing clostridium difficile infection recurrence. Drugs. 2017;77(15):1657-1663.
6. Dzunkova M, D'Auria G, Xu H, et al. The monoclonal antitoxin antibodies (actoxumab-bezlotoxumab) treatment facilitates normalization of the gut microbiota of mice with Clostridium difficile infection. Front Cell Infect Microbiol. 2016;6:119.
7. Chapin RW, Lee T, McCoy C, et al. Bezlotoxumab: Could this be the answer for Clostridium difficile recurrence? Ann Pharmacother. 2017;51(9):804-810.
8. Chahine EB, Cho JC, Worley MV. Bezlotoxumab for the prevention of Clostridium difficile recurrence. Consult Pharm. 2018;33(2):89-97.
9. Posteraro B, Pea F, Masucci L, et al.  Actoxumab + bezlotoxumab combination: What promise for Clostridium difficile treatment? Expert Opin Biol Ther. 2018;18(4):469-476.
10. Johnson S, Gerding DN. Bezlotoxumab. Clin Infect Dis. 2019;68(4):699-704.
11. Kaako A, Al-Amer M, Abdeen Y. Bezlotoxumab use as adjunctive therapy with the third fecal microbiota transplant in refractory recurrent Clostridium difficile colitis; a case report and concise literature review. Anaerobe. 2019;55:112-116.
12. Montgomery DL, Matthews RP, Yee KL, et al. Assessment of bezlotoxumab immunogenicity. Clin Pharmacol Drug Dev. 2019 Aug 14 [Epub ahead of print].
13. Zinplava [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; October 2016.
14. Lexicomp Online, AHFS DI (Adult and Pediatric) Online. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc. http://online.lexi.com/. Accessed March 2019.
15. Micromedex (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. http://www.micromedexsolutions.com/. Accessed March 2019.

Coding Section 

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