Drug Trials Snapshots: EXBLIFEP
EXBLIFEP (cefepime and enmetazobactam)
EX-BLEE-FEP
Allecra Therapeutics SAS
Original Approval date: February 22, 2024
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
EXBLIFEP is a combination of cefepime and enmetazobactam that is indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible microorganisms.
How is this drug used?
EXBLIFEP is administered as an intravenous (IV) infusion every eight hours for 7 days, or up to 14 days for patients with concurrent bacteremia.
Who participated in the clinical trials?
The FDA approved EXBLIFEP based on evidence from a clinical trial of 1,041 patients (intent-to-treat population) with cUTI, including pyelonephritis. The trial was conducted at 90 sites in 19 countries including Argentina, Bulgaria, Belarus, Spain, Estonia, Georgia, Croatia, Hungary, Lithuania, Latvia, Mexico, Peru, Poland, Russia, Serbia, Slovakia, South Africa, Ukraine, and the United States. All but one subject were enrolled outside of the United States.
How were the trials designed?
EXBLIFEP was evaluated in a multinational, double-blind, noninferiority clinical trial of 1,041 patients with cUTI, including pyelonephritis.
Patients were randomized in a 1:1 ratio into one of the two treatment groups, EXBLIFEP and piperacillin/tazobactam. The medications were intravenously infused over a period of two hours, every eight hours for 7 days, or up to 14 days for patients with concurrent bacteremia. The primary efficacy endpoint was a composite endpoint of clinical cure and microbiological response, at the test of cure (TOC) visit (seven days after the end of treatment).
How were the trials designed?
The dose of EXBLIFEP was cefepime 2 g and enmetazobactam 0.5 g, and the dose of piperacillin/tazobactam was piperacillin 4 g and tazobactam 0.5 g.
The microbiological modified intent-to-treat population (m-MITT) was the primary efficacy analysis population and included all randomized patients who received any study drug and had at least one baseline gram-negative pathogen at ≥105 CFU/mL in urine culture or the same pathogen in blood and urine cultures that was not resistant to EXBLIFEP or piperacillin/tazobactam. This included 345 patients treated with EXBLIFEP and 333 patients treated with piperacillin/tazobactam. The primary efficacy endpoint was defined as clinical cure and microbiological response at the TOC visit.
DEMOGRAPHICS SNAPSHOT
Figure 1 summarizes how many male and female patients were included in the clinical trial used to evaluate the efficacy of EXBLIFEP.
Figure 1. Baseline Demographics by Sex (Primary Efficacy Population)
Figure 2 summarizes how many patients by race in the clinical trial used to evaluate the efficacy of EXBLIFEP.
Figure 2. Baseline Demographics by Race (Primary Efficacy Population)
Figure 3 summarizes how many patients by age included in the clinical trial used to evaluate the efficacy of EXBLIFEP.
Figure 3. Baseline Demographics by Age (Primary Efficacy Population)
Figure 4 summarizes how many patients by ethnicity included in the clinical trial used to evaluate the efficacy of EXBLIFEP.
Figure 4. Baseline Demographics by Ethnicity (Primary Efficacy Population)
Who participated in the trials?
Table 1. Baseline Demographics of Trial by Age, Race, Sex, and Ethnicity (Primary Efficacy Population)
|
Characteristic |
EXBLIFEP N=345 |
Piperacillin/Tazobactam N=333 |
Total N=678 |
|
Age, years |
|||
|
Mean (SD) |
55.4 (18.67) |
52.4 (19.68) |
53.9 (19.22) |
|
Median |
60.0 |
57.0 |
59.0 |
|
IQR |
41.0, 70.0 |
35.0, 68.0 |
37.0, 69.0 |
|
Minimum, maximum |
17.0, 89.0 |
17.0, 92.0 |
17.0, 92.0 |
|
Age group, years, n (%) |
|||
|
<18 |
1 (<1) |
2 (<1) |
3 (<1) |
|
18 to 65 |
212 (61.4) |
227 (68.2) |
439 (64.7) |
|
>65 |
132 (38.3) |
104 (31.2) |
236 (34.8) |
|
Race, n (%) |
|||
|
Asian |
3 (<1) |
1 (<1) |
4 (<1) |
|
Black or African American |
1 (<1) |
0 |
1 (<1) |
|
Other |
14 (4.1) |
16 (4.8) |
30 (4.4) |
|
White |
327 (94.8) |
316 (94.9) |
643 (94.8) |
|
Sex, n (%) |
|||
|
Male |
144 (41.7) |
127 (38.1) |
271 (40.0) |
|
Female |
201 (58.3) |
206 (61.9) |
407 (60.0) |
|
Ethnicity, n (%) |
|||
|
Hispanic or Latino |
26 (7.5) |
27 (8.1) |
53 (7.8) |
|
Not Hispanic or Latino |
318 (92.2) |
305 (91.6) |
623 (91.9) |
|
Unknown |
1 (<1) |
1 (<1) |
2 (<1) |
Source: Adapted from FDA Review
Abbreviations: IQR, interquartile range; SD, standard deviation
What are the benefits of this drug?
Clinical trial evidence from the single controlled study demonstrates that EXBLIFEP was noninferior to piperacillin/tazobactam. Composite response was achieved in 273/345 (79%) patients in the EXBLIFEP group and 196/333 (59%) patients in the piperacillin/tazobactam group at the TOC visit in the m-MITT population.
The primary efficacy endpoint demonstrated the noninferiority of EXBLIFEP to piperacillin/tazobactam with a -10% margin. Clinical cure was similar between the two treatment groups. Microbiological response was 286/345 (82.9%) and 216/333 (64.9%) in the EXBLIFEB group and piperacillin/tazobactam group, respectively.
Table 2. Efficacy Results (Primary Efficacy Population)
|
Response at TOC Visit |
EXBLIFEP N=345 n (%) |
Piperacillin/ Tazobactam N=333 n (%) |
Difference% (95% CI)* |
|
Composite response (clinical cure and microbiological response) |
273 (79.1) |
196 (58.9) |
21.2 (14.3, 27.9) |
|
Clinical cure |
319 (92.5) |
296 (88.9) |
3.5 (-1.0, 8.0) |
|
Microbiological response |
286 (82.9) |
216 (64.9) |
19.0 (12.3, 25.4) |
Source: Adapted from EXBLIFEP Prescribing Information
* The 95% CI was based on the stratified Newcombe method.
Abbreviation: CI, confidence interval; TOC, test of cure
Were there any differences in how well the drug worked in clinical trials among sex, race, and age?
- Sex: EXBLIFEP worked similarly in males and females.
- Race: The number of patients of races other than White was small; therefore, differences in how EXBLIFEP worked among races could not be determined.
- Age: EXBLIFEP worked similarly in patients in all age groups.
Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?
EXBLIFEP worked similarly in male and female patients, in White and other races (excluding Asian and Black or African American), in patients across different age groups, and in patients with different ethnicities.
Table 3. Composite Response at the TOC Visit by Sex, Race, Age, and Ethnicity (Primary Efficacy Population)
|
Subgroup |
EXBLIFEP N=345 n/Ns (%) |
Piperacillin/ Tazobactam N=333 n/Ns (%) |
Difference % (95% CI) |
|
Sex |
|||
|
Male |
114/144 (79.2) |
74/127 (58.3) |
20.1 (8.7, 30.8) |
|
Female |
159/201 (79.1) |
122/206 (59.2) |
21.9 (12.9, 30.4) |
|
Age, years |
|||
|
<65 |
172/209 (82.3) |
137/220 (62.3) |
21.5 (12.9, 29.6) |
|
65 to <75 |
65/85 (76.5) |
36/70 (51.4) |
25.3 (9.2, 40.2) |
|
≥75 |
36/51 (70.6) |
23/43 (53.5) |
24.0 (2.8, 43.0) |
|
Race |
|||
|
Asian |
2/3 (66.7) |
0/1 (0) |
NA |
|
White |
260/327 (79.5) |
186/316 (58.9) |
21.6 (14.5, 28.5) |
|
Black or African American |
0/1 (0) |
0/0 |
NA |
|
Other |
11/14 (78.6) |
10/16 (62.5) |
19.2 (-13.4, 46.9) |
|
Ethnicity |
|||
|
Hispanic or Latino |
21/26 (80.8) |
16/27 (59.3) |
20.5 (-6.9, 43.9) |
|
Not Hispanic or Latino |
252/318 (79.2) |
180/305 (59.0) |
21.8 (14.5, 28.7) |
Source: Adapted from FDA Review
* The 95% CI was based on the stratified Newcombe method.
Abbreviation: CI, confidence interval; N, number of patients in treatment arm; n, number of patients meeting criteria; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm; TOC, test of cure
What are the possible side effects?
EXBLIFEP may cause serious allergic reactions, neurological adverse reactions, and severe diarrhea caused by Clostridioides difficile.
Common side effects that were associated with the use of EXBLIFEP include abnormal liver tests, headache, and phlebitis/infusion site reactions.
Table 4 summarizes the most common adverse reactions observed in the trial.
Table 4. Selected Adverse Reactions Occurring in 1% or Greater of Patients Receiving EXBLIFEP in the Trial (Safety Population)
|
Adverse Reactions |
EXBLIFEP N=516 n (%) |
Piperacillin/Tazobactama N=518 n (%) |
|
Transaminases increasedb |
101 (20) |
103 (20) |
|
Bilirubin increasedc |
36 (7) |
21 (4) |
|
Headached |
26 (5) |
12 (2) |
|
Phlebitis/Infusion site reactionse |
24 (5) |
2 (<1) |
|
Diarrhea |
21 (4) |
26 (5) |
|
Anemiaf |
16 (3) |
16 (3) |
|
Hypersensitivityg |
10 (2) |
3 (<1) |
|
Vomiting |
9 (2) |
6 (1) |
|
Nausea |
6 (1) |
3 (<1) |
Source: EXBLIFEP Prescribing Information
a Piperacillin/Tazobactam 4.5 g (piperacillin 4 g/tazobactam 0.5 g) IV infused over 2 hours every 8 hours.
b Transaminases increased includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, liver function test increased, transaminases increased, and hypertransaminasemia.
c Bilirubin increased includes blood bilirubin increased, bilirubin conjugated increased, and hyperbilirubinemia.
d Headache includes headache and tension headache.
e Phlebitis/Infusion site reactions includes phlebitis, thrombophlebitis, thrombophlebitis superficial, injection site inflammation, infusion site extravasation, injection site thrombosis, vessel puncture site pain, vessel puncture site hematoma, and rash erythematous.
f Anemia includes anemia, hypochromic anemia, iron deficiency anemia, and normocytic anemia.
g Hypersensitivity includes allergic cough, dermatitis allergic, hypersensitivity, periorbital edema, pruritus, rash, and urticaria.
The Trial was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the EXBLIFEP and Piperacillin/Tazobactam treatment groups.
Abbreviations: IV, intravenous
Were there any differences in side effects among sex, race, and age?
- Sex: The occurrence of side effects was similar between males and females.
- Race: The number of participants of races other than White was small; therefore, differences in side effects among races could not be determined
- Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.
Table 5 summarizes the incidence of treatment-emergent adverse events by subgroup.
Table 5. Summary of Incidence of Treatment-Emergent Adverse Events by Subgroup (Safety Population)
|
Characteristic |
EXBLIFEP n/Ns (%) |
Piperacillin/Tazobactam n/Ns (%) |
|
Sex |
||
|
Female |
149/281 (53.0) |
129/287 (44.9) |
|
Male |
109/235 (46.4) |
99/231 (42.9) |
|
Age group, years |
||
|
<65 |
148/312 (47.4) |
148/324 (45.7) |
|
65 to <75 |
70/126 (55.6) |
52/118 (44.1) |
|
≥75 |
40/78 (51.3) |
28/76 (36.8) |
|
Race |
||
|
American Indian or Alaska Native |
0/3 (0) |
0/3 (0) |
|
Asian |
2/4 (50.0) |
0/1 (0) |
|
Black or African American |
0/1 (0) |
NA |
|
Other |
19/25 (76.0) |
19/26 (73.1) |
|
White |
237/483 (49.1) |
209/488 (42.8) |
|
Ethnicity |
||
|
Hispanic or Latino |
28/40 (70.0) |
27/44 (61.4) |
|
Not Hispanic or Latino |
229/475 (48.2) |
201/470 (42.8) |
|
Unknown |
1/1 (100) |
0/4 (0) |
Source: Adapted from FDA Review
Abbreviation: N, number of patients in treatment arm; n, number of patients meeting criteria; NA, not applicable; Ns, total number of patients for each specific subgroup and were assigned to that specific arm
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.
