Xiaflex

CLINICAL PHARMACOLOGY

Mechanism Of Action

Collagenases are proteinases that hydrolyze collagen in its native triple helical conformation under physiological conditions, resulting in lysis of collagen deposits.

Injection of XIAFLEX into a Dupuytren's cord, which is comprised mostly of collagen, may result in enzymatic disruption of the cord.

The signs and symptoms of Peyronie's disease are caused by a collagen plaque. Injection of XIAFLEX into a Peyronie's plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque. Following this disruption of the plaque, penile curvature deformity and patient bother caused by Peyronie's disease are reduced [see Clinical Studies].

Results of in vitro studies, including those of explant tissues containing Peyronie's plaques, suggest that XIAFLEX disrupts the predominant collagen found in plaques (Types I and III). At higher doses and longer incubation times, non-fibrillar Type IV collagen was affected causing collagen lysis in small veins, but did not cause structural damage to arteries, nerves or large veins which contain Type IV collagen in in vitro or in vivo studies.

Results of in vitro studies suggest that the collagenases (AUX-I and AUX-II) worked synergistically to provide hydrolyzing activity towards collagen. However, there are no clinical data regarding the relative contributions of the individual collagenases (AUX-I or AUX-II) to the efficacy of XIAFLEX in the treatment of Dupuytren's contracture or Peyronie's disease.

Collagen fragments generated from clostridial collagenase have been shown to generate increased vascular permeability, inflammatory responses, and regenerative changes. However, the effects of the formation of the collagen fragments derived from the collagen plaque are unknown.

Pharmacokinetics

Following administration of a single XIAFLEX dose of 0.58 mg into a Dupuytren's cord in 20 patients, no quantifiable levels of XIAFLEX (AUX-I or AUX-II) were detected in plasma up to 30 days post injection.

Following each of two intralesional administrations, separated by 24 hours, of XIAFLEX 0.58 mg into the penile plaque of 19 subjects with Peyronie's disease, plasma levels of AUX-I and AUX-II in subjects with quantifiable levels (79% and 40% for AUX-I and AUX-II, respectively) were minimal and short-lived. The maximal plasma concentrations of AUX-I and AUX-II were < 29 ng/mL and < 71 ng/mL, respectively, and were observed approximately within 10 minutes after injection. All plasma levels were below the limits of quantification within 30 minutes following dosing. There was no evidence of accumulation following two sequential injections of XIAFLEX administered 24 hours apart. No subject had quantifiable plasma levels 15 minutes after modeling of plaque on Day 3 (i.e., 24 hours after Injection 2 on Day 2).

Animal Toxicology And/Or Pharmacology

Single or repeat-dose intravenous studies of collagenase Clostridium histolyticum in rats were conducted to evaluate the toxicological impact of injection of collagenase Clostridium histolyticum directly into the systemic circulation. Dose-dependent liver toxicity was noted at exposures greater than or equal to approximately 11 times the MRHD on a mg/m² basis as characterized by elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, increased liver weights, mild regenerative anemia with secondary changes in the spleen and histologic findings of chronic active inflammation, hemorrhage/hematoma, fibrosis, bile duct hyperplasia and/or hepatocellular necrosis. The histologic findings remained unresolved following a 2-week recovery period, while the other findings resolved completely. Animals that were found dead or prematurely euthanized had histopathological findings of hemorrhage and necrosis in the liver and extramedullary hematopoiesis in the liver and/or spleen. Death occurred at approximately 25 times the MRHD on a mg/m² basis between study days 7 and 15 following 8 repeat intravenous administrations of collagenase Clostridium histolyticum over 16 days or after single intravenous doses at approximately 40 times the MRHD on a mg/m² basis.

In intermittent 13-week subcutaneous repeat-dose studies in rats or dogs administered doses up to approximately 3 times the MRHD on a mg/m² basis, respectively, there was no evidence of systemic toxicity. In a single-dose phase or 61-day repeat-dose phase (3 times a week every 3 weeks for 3 cycles) study of intrapenile administration of collagenase Clostridium histolyticum in dogs at exposures lower than or equal to the MRHD on a mg/m² basis, there was no evidence of systemic toxicity.

Clinical Studies

Dupuytren's Contracture

The efficacy of 0.58 mg of XIAFLEX was evaluated in two randomized, double-blind, placebo-controlled, multi-centered trials in 374 adult patients with Dupuytren's contracture (Studies 1 and 2). At study entry, patients must have had: (1) a finger flexion contracture with a palpable cord of at least one finger (other than the thumb) of 20 °to 100 °in a metacarpophalangeal (MP) joint or 20 °to 80 °in a proximal interphalangeal (PIP) joint and (2) a positive “table top test” defined as the inability to simultaneously place the affected finger(s) and palm flat against a table top. Patients could not have received a surgical treatment (e.g., fasciectomy, fasciotomy) on the selected primary joint within 90 days before the first injection of study medication and patients could not have received anticoagulation medication (except for up to 150 mg of aspirin per day) within 7 days before the first injection of study medication.

The cord affecting the selected primary joint received up to 3 injections of 0.58 mg of XIAFLEX or placebo on Days 0, 30, and 60. About 24 hours after each injection of study medication, if needed, the investigator manipulated (extended) the treated finger in an attempt to facilitate rupture of the cord (finger extension procedure). Following manipulation, patients were fitted with a splint, instructed to wear the splint at bedtime for up to 4 months, and instructed to perform a series of finger flexion and extension exercises each day.

Table 5 shows the baseline disease characteristics of patients with Dupuytren's contracture in Studies 1 and 2.

Table 5: Baseline Disease Characteristics of Patients with Dupuytren's Contracture

  Study 1 Study 2
Proportion of patients with prior surgery for Dupuytren's contracture1 38% 53%
Proportion of patients with prior surgery for Dupuytren's contracture on the same finger as the primary joint1 8% 18%
Mean number of affected joints 3 3.3
1Prior surgery for Dupuytren's contracture included fasciotomy and fasciectomy

In Studies 1 and 2, the primary endpoint was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to within 0° to 5° of normal, 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections). As shown in Table 6, a greater proportion of XIAFLEX-treated patients compared to placebo-treated patients achieved the primary endpoint.

Table 6: Percentage of Patients Who Achieved Reduction in Contracture of the Primary Joint to 0° to 5° After Up to 3 Injections in Studies 1 and 2a

Treated Joint Study 1 Study 2
XIAFLEXb Placebo XIAFLEXb Placebo
  N=203 N=103 N=45 N=21
All Joints (MP and PIP)c,d 64% 7% 44% 5%
Difference (CIe) 57%
(47%, 67%)
- 40%
(14%, 62%)
-
  N=133 N=69 N=20 N=11
MP Jointsc 77% 7% 65% 9%
Difference (CIe) 69%
(57%, 79%)
- 56%
(19%, 83%)
-
  N=70 N=34 N=25 N=10
PIP Jointsd 40% 6% 28% 0%
Difference (CIe) 34%
(14%, 52%)
- 28%
(-10%, 61%)
-
aPatients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90).
bFor XIAFLEX-treated patients, the mean (±SD) number of injections given to the cord associated with the contracture was 1.7 (±0.8) in the 90-day controlled period in each trial.
cMP joints are metacarpophalangeal joints
dPIP joints are proximal interphalangeal joints
e95% confidence interval

The proportion of patients who achieved a contracture reduction of the primary joint to 0° to 5° after the first injection was 39% and 1% in Study 1 and 27% and 5% in Study 2 in the XIAFLEX and placebo groups respectively.

XIAFLEX-treated patients, compared to placebo-treated patients, showed a greater increase from baseline in the range of motion of MP and PIP joints (see Table 7).

Table 7: Mean Increase in Range of Motion from Baseline in Degrees After Up to 3 Injections in Studies 1 and 2a

Treated Joint Study 1 Study 2
XIAFLEX Placebo XIAFLEX Placebo
All Joints b,c N=196 N=102 N=45 N=21
Baseline 44 (20) 45 (19) 40 (15) 44 (16)
Final 80 (20) 50 (22) 76 (18) 52 (20)
Increase 36 (21) 4 (15) 35 (18) 8 (15)
MP Joints b N=129 N=68 N=20 N=11
Baseline 43 (20) 46 (19) 40 (12) 41 (21)
Final 83 (16) 50 (21) 80 (11) 50 (22)
Increase 41 (20) 4 (13) 40 (13) 9 (15)
PIP Joints c N=67 N=34 N=25 N=10
Baseline 46 (20) 44 (18) 41 (18) 47 (10)
Final 75 (24) 49 (24) 73 (21) 54 (18)
Increase 28 (22) 5 (19) 32 (20) 7 (16)
aPatients may have received up to 3 injections of study medication into the cords associated with contracture of the primary joints on Days 0, 30, and 60. Assessments were made 30 days after the last injection (on Days 30, 60, or 90). Baseline and final range of motion degree values are expressed in mean (SD).
bMP = Metacarpophalangeal joint
cPIP = Proximal interphalangeal joint
Range of Motion = Degrees of Full Flexion minus Degrees of Fixed Extension Not all patients had range of motion values at both time points.

Peyronie's Disease

The efficacy of XIAFLEX was evaluated in two randomized, double-blind, placebo-controlled, multi-centered trials in 832 adult males with Peyronie's disease (Studies 1 and 2). At study entry, patients must have had penile curvature deformity of at least 30 degrees in the stable phase of Peyronie's disease. Patients were excluded if they had a ventral curvature deformity, an isolated hourglass deformity or a calcified plaque that could have interfered with the injection technique. At baseline, penile pain was either not present or was mild in most (98%) patients.

In these trials, patients were given up to 4 treatment cycles of XIAFLEX or placebo (weeks 0, 6, 12, 18), and were followed in a non-treatment follow-up period (weeks 24 52). In each treatment cycle, two injections of XIAFLEX or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed on patients at the study site 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately six-week intervals for up to three additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures. In addition, patients were instructed to perform penile modeling at home for six weeks after each treatment cycle [see Medication Guide].

Table 8 shows the baseline disease characteristics of patients with Peyronie's disease in Studies 1 and 2.

Table 8: Baseline Disease Characteristics of Patientsa with Peyronie's Disease (PD)

  Study 1 Study 2
XIAFLEX
N=277
Placebo
N=140
XIAFLEX
N=274
Placebo
N=141
Mean age (years) (Min-Max) 57.9 (28 -79) 58.2 (30 -81) 57.3 (23 -84) 57.6 (33 -78)
Mean duration of PD (years) (Min-Max) 3.9 (1.0 -35.9) 4.8 (1.0 -50.8) 4.2 (1.1 -30.9) 3.4 (1.1 -47.1)
Mean Penile Curvature Deformity (degrees) (Min-Max) 48.8 (30-90) 49.0 (30-89) 51.3 (30-90) 49.6 (30-85)
Peyronie's Disease Questionnaire (PDQ)b, – Mean Patient-Reported PD Bother Domain Score (range: 0-16) c 7.5 7.4 7.4 8.4
History of Erectile Dysfunction N (%) 128 (46.2) 75 (53.6) 134 (48.9) 76 (53.9)
aSubjects were from ITT population and received at least one dose of study drug in Study 1 or 2
bEach PDQ assessment required subjects to have had vaginal intercourse in the 3 months prior to completion
cHigher scores represent worse symptoms

Before the first dose of study drug was administered, eligible subjects were stratified by the degree of curvature deformity (30 to 60 degrees, and 61 to 90 degrees) and then randomized into two treatment groups to receive either XIAFLEX or placebo in a 2:1 ratio. The efficacy population (modified intent-to-treat (mITT) population) comprised a total of 612 intent-to-treat subjects who had both a curvature deformity measurement and a PDQ assessment at baseline, and at one or more subsequent time points in Studies 1 and 2, and had engaged in vaginal intercourse within 3 months prior to each PDQ assessment.

In Studies 1 and 2, the co-primary endpoints were:

  • the percent change from baseline to Week 52 in penile curvature deformity and;
  • the change from baseline to Week 52 in the Bother domain score of the PDQ

The Bother domain score is a composite of the following patient-reported items: concern about erection pain, erection appearance, and the impact of Peyronie's disease on intercourse and on frequency of intercourse.

Penile curvature deformity (co-primary endpoint)

XIAFLEX treatment significantly improved penile curvature deformity in patients with Peyronie's disease compared with placebo (see Table 9). The improvement in curvature deformity was numerically similar among subjects with baseline curvature deformity from 30 to 60 degrees and those with curvature deformity from 61 to 90 degrees.

Table 9: Mean Percent Change in Penile Curvature Deformity from Baseline to Week 52 – Studies 1 and 2

  Study 1 Study 2
XIAFLEX
N=199
Placebo
N=104
XIAFLEX
N=202
Placebo
N=107
Baseline Mean (degrees) 48.8° 49.0° 51.3° 49.6°
Mean Percent Change a -35.00% -17.80% -33.20% -21.80%
Treatment Difference (95% CI) -17.2% b (-26.7%, -7.6%) -11.4% b (-19.5%, -3.3%)
aMean percent change, treatment difference, 95% CI, and p-value were based on an ANOVA model with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population. The mITT population was defined as all randomized subjects who had both a penile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.
bp-value < 0.01

Figure 1: Mean Percent Change in Penile Curvature Deformity – Study 1

Mean Percent Change in Penile Curvature Deformity – Study 1 - Illustration

Figure 2: Mean Percent Change in Penile Curvature Deformity – Study 2

Mean Percent Change in Penile Curvature Deformity – Study 2 - Illustration

Peyronie's Disease Questionnaire Bother domain score (co-primary endpoint)

XIAFLEX significantly reduced patient-reported bother associated with Peyronie's disease compared with placebo (see Table 10). The reduction in the bother domain score was numerically similar between patient groups stratified by degree of baseline curvature deformity (30 to 60 degrees, and 61 to 90 degrees).

Table 10: Mean Change in Peyronie's Disease Bother Domain Score from Baseline to Week 52 -Studies 1 and 2

  Study 1 Study 2
XIAFLEX
N=199
Placebo
N=104
XIAFLEX
N=202
Placebo
N=107
Baseline Mean 7.5 7.4 7.4 8.2
Mean Change a -2.8 -1.6 -2.6 -1.5
Treatment Difference (95% CI) -1.2 b (-2.4, -0.03) -1.1 b (-2.1, -0.002)
aMean change, treatment difference, 95% CI, and p-value all based on an ANOVA model with factors for treatment, stratum of baseline penile curvature, and their interaction and using last observation carried forward (LOCF) in the modified intent-to-treat (mITT) population. The mITT population was defined as all randomized subjects who had both a penile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.
bp-value < 0.05.

Figure 3: Mean Change in Patient-Reported Peyronie's Disease Bother Domain Score – Study 1

Mean Change in Patient-Reported Peyronie’s Disease Bother Domain Score – Study 1 - Illustration

Figure 4: Mean Change in Patient-Reported Peyronie's Disease Bother Domain Score – Study 2

Mean Change in Patient-Reported Peyronie’s Disease Bother Domain Score – Study 2 - Illustration

There were no clinically meaningful differences in the mean percent improvement in curvature deformity or mean reduction in the bother domain score following treatment with XIAFLEX based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.

Last reviewed on RxList: 12/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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