Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Antiinfectives for systemic use, specific immunoglobulins
ATC code: J06BB21
Bezlotoxumab is a human monoclonal antitoxin antibody that binds with high affinity to C. difficile toxin B and neutralizes its activity. Bezlotoxumab prevents CDI recurrence by providing passive immunity against toxin produced by the outgrowth of persistent or newly-acquired C. difficile spores.
The toxin B epitope to which bezlotoxumab binds is conserved, though not identical, across all known toxin sequences.
The efficacy of ZINPLAVA (bezlotoxumab) was investigated in two randomised, double-blind, placebo-controlled, multicentre, Phase 3 studies (MODIFY I and MODIFY II) where 810 patients were randomised to bezlotoxumab and 803 to placebo. The number of patients completing the studies and included in the full analysis set (FAS) was 781 in the ZINPLAVA group versus 773 in the placebo group. All patients received concomitant standard of care antibacterial therapy for CDI.
Randomisation was stratified by the antibacterial agent and hospitalisation status (inpatient vs. outpatient) at the time of study entry. Adult patients had a confirmed diagnosis of CDI, which was defined as diarrhoea (passage of 3 or more loose bowel movements as defined in the Bristol stool chart as types 5 through 7 in 24 or fewer hours) and a positive stool test for toxigenic C. difficile from a stool sample collected no more than 7 days before study entry.
Patients received a 10- to 14-day course of oral antibacterial therapy for CDI (metronidazole, vancomycin or fidaxomicin, chosen by the investigator). Patients on oral vancomycin or oral fidaxomicin could have also received IV metronidazole.
A single infusion of ZINPLAVA or placebo was administered prior to completion of antibacterial therapy and patients were followed for 12 weeks following the infusion. The day of the infusion of ZINPLAVA or placebo ranged from prior to the start of antibacterial therapy up to day 14 of treatment, with a median on day 3.
The baseline characteristics of the 781 patients receiving ZINPLAVA and 773 receiving placebo were generally similar across treatment groups. The median age was 65 years, 85% were white, 57% were female, and 68% were inpatients. A similar proportion of patients were receiving oral metronidazole (48%) or oral vancomycin (48%) and only 4% were receiving fidaxomicin as antibacterial treatment for CDI.
The CDI recurrence rates are shown in Table 2.
Table 2. CDI Recurrence Rate Through 12 Weeks After Infusion (MODIFY I and MODIFY II, Full Analysis Set*):
| ZINPLAVA with SoC† Percent (n/N) | Placebo with SoC† Percent (n/N) | Adjusted Difference (95% CI)‡ | p-value |
|---|---|---|---|
| 16.5 (129/781) | 26.6 (206/773) | -10.0 (-14.0, -6.0) | <0.0001 |
n = Number of patients in the analysis population meeting the criteria for endpoint
N = Number of patients included in the analysis population
* Full Analysis Set = a subset of all randomised patients with exclusions for: (i) did not receive infusion of study medication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined standard of care therapy within a 1 day window of the infusion; (iiii) GCP non-compliance
† SoC = Standard of Care antibacterial (metronidazole or vancomycin or fidaxomicin)
‡ One sided p-value based on the Miettinen and Nurminen method stratified by protocol (MODIFY I and MODIFY II), SoC antibacterial (metronidazole vs. vancomycin vs. fidaxomicin) and hospitalization status (inpatient vs. outpatient)
Table 3 shows the results of a prospectively planned combined analysis of the CDI recurrence rates in pre-specified subgroups of patients at high risk for CDI recurrence across the two Phase 3 Trials. Overall, 51% were ≥65 years, 29% were ≥75 years and 39 % received one or more systemic antibacterial agents during the 12 week follow-up period. Of the total 28% had one or more episodes of CDI within the six months prior to the episode under treatment (18% of the patients had one, 7% had two and a few patients had 3 or more prior episodes). Twenty one (21) percent of the patients were immunocompromised and 16% presented with clinically severe CDI. Among the 976/1554 (62%) patients who had a positive baseline stool culture for C. difficile a hypervirulent strain (ribotypes 027, 078 or 244) was isolated in 22% (217 of 976 patients), of which the majority (87%, 189 of 217 strains) were ribotype 027.
These patients presented with risk factors primarily but not exclusively associated with higher risk of CDI recurrence. Efficacy results did not point towards a benefit of ZINPLAVA in patients with no known risk factors for CDI.
Table 3. CDI Recurrence Rate by Risk Factor Subgroup (MODIFY I and MODIFY II, Full Analysis Set*):
| Characteristic at study entry | ZINPLAVA with SoC† Percent (n/m) | Placebo with SoC† Percent (n/m) | Difference (95% CI)‡ |
|---|---|---|---|
| Age ≥65 years | 15.4 (60/390) | 31.4 (127/405) | -16.0 (-21.7, -10.2) |
| History of one or more episodes of CDI in past 6 months | 25.0 (54/216) | 41.1 (90/219) | -16.1 (-24.7, -7.3) |
| Immunocompromised§ | 14.6 (26/178) | 27.5 (42/153) | -12.8 (-21.7, -4.1) |
| Severe CDI** | 10.7 (13/122) | 22.4 (28/125) | -11.7 (-21.1, -2.5) |
| Infected with a hypervirulent strain# | 21.6 (22/102) | 32.2 (37/115) | -10.6 (-22.1, 1.3) |
| Infected with 027 ribotype | 23.6 (21/89) | 34.0 (34/100) | -10.4 (-23.0, 2.6) |
n = Number of patients within subgroup that met the criteria for endpoint
m = Number of patients within subgroup
* Full Analysis Set = a subset of all randomised patients with exclusions for: (i) did not receive infusion of study medication, (ii) did not have a positive local stool test for toxigenic C. difficile; (iii) did not receive protocol defined standard of care therapy within a 1 day window of the infusion
† SoC = Standard of Care antibacterial (metronidazole or vancomycin or fidaxomicin)
‡ Based on the Miettinen and Nurminen method without stratification
§ Based on medical conditions or medications received that may result in immunosuppression
¶ Zar score ≥2
# Hypervirulent strain included the following: 027, 078, or 244 ribotypes
In the studies, the clinical cure rates of the presenting CDI episode were comparable between the treatment arms.
Immunogenicity of ZINPLAVA was evaluated using an electrochemiluminescence (ECL) assay in MODIFY I and MODIFY II.
Following treatment with ZINPLAVA in MODIFY I and MODIFY II, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies. Although ZINPLAVA is intended for single dose administration, the immunogenicity of bezlotoxumab following a second administration of 10 mg/kg, 12 weeks after the first dose, was assessed in 29 healthy subjects. No anti-bezlotoxumab antibodies were detected after the second dose.
There are no data on repeated administration of bezlotoxumab in patients with CDI.
The European Medicines Agency has deferred the obligation to submit the results of studies with ZINPLAVA in one or more subsets of the paediatric populations for the prevention of recurrence of Clostridium difficile infection (see section 4.2 for information on paediatric use).
Bezlotoxumab is dosed via the IV route and therefore is immediately and completely bioavailable. After a single IV dose of 10 mg/kg bezlotoxumab, mean AUC(0-∞) and Cmax were 53,000 mcg.h/mL and 185 mcg/mL, respectively, in patients with CDI. Bezlotoxumab exposures in healthy subjects increased in an approximately dose proportional manner across the 0.3 to 20 mg/kg dose range.
Bezlotoxumab has limited extravascular distribution. The mean volume of distribution of bezlotoxumab was 7.33 L (CV: 16%).
Bezlotoxumab is catabolized through protein degradation processes; metabolism does not contribute to its clearance.
Bezlotoxumab is eliminated from the body primarily by protein degradation. The mean clearance of bezlotoxumab was 0.317 L/day (CV: 41%) and the terminal half-life (t1⁄2) was approximately 19 days (28%).
The effects of various covariates on the pharmacokinetics of bezlotoxumab were assessed in a population pharmacokinetic analysis. The clearance of bezlotoxumab increased with increasing body weight; the resulting exposure differences are adequately addressed by the administration of a weight-based dose.
The following factors had no clinically meaningful effect on the exposure of bezlotoxumab and no dose adjustment is required: age (range 18 to 100 years), gender, race, ethnicity, renal impairment, hepatic impairment, and presence of co-morbid conditions.
The effect of renal impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients with mild (eGFR 60 to <90 mL/min/1.73 m²), moderate (eGFR 30 to <60 mL/min/1.73 m²), or severe (eGFR 15 to <30 mL/min/1.73 m²) renal impairment, or with end stage renal disease (eGFR <15 mL/min/1.73 m²), as compared to patients demonstrating normal (eGFR ≥90 mL/min/1.73 m²) renal function. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with renal impairment and patients with normal renal function.
The effect of hepatic impairment on the pharmacokinetics of bezlotoxumab was evaluated in patients with hepatic impairment (defined as having two or more of the following: 1 albumin ≤3.1 g/dL; 2 ALT ≥2X ULN; 3 total bilirubin ≥1.3X ULN; or 4 mild, moderate or severe liver disease as reported by the Charlson Co-morbidity Index), as compared to patients with normal hepatic function. No clinically meaningful differences in the exposure of bezlotoxumab were found between patients with hepatic impairment and patients with normal hepatic function.
The effect of age on the pharmacokinetics of bezlotoxumab was evaluated in patients ranging from 18 to 100 years of age. No clinically meaningful differences in the exposure of bezlotoxumab were found between elderly patients 65 years and older and patients under 65 years of age.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Genotoxicity and carcinogenic potential have not been evaluated.
Animal reproduction or developmental toxicity studies have not been conducted with bezlotoxumab. There were no notable effects in the male and female reproductive organs in mice based on repeat dose toxicity studies and no binding to reproductive tissues was observed in tissue cross-reactivity studies.
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