XIAPEX Powder and solvent for solution for injection Ref.[7195] Active ingredients: Collagenase

Pharmacotherapeutic group: Other Drugs For Disorders of the Musculo-Skeletal System-Enzymes
ATC code: M09AB02

Xiapex is a lyophilized product for parenteral administration containing collagenase Clostridium histolyticum which is comprised of two collagenases in a defined mass ratio. These collagenases, referred to as AUX-I and AUX-II, are representative of the two major collagenase classes (Class I and Class II) produced by Clostridium histolyticum. AUX-I and AUX-II are single polypeptide chains consisting of approximately 1000 amino acids of known sequence with a molecular weight of 114 kDa and 113 kDa respectively as determined by mass spectrometry. The two polypeptides are purified by chromatographic steps customary for the separation and isolation of biotherapeutic proteins to yield a consistent, well characterized and controlled mixture of two collagenase enzymes.

Because the collagen lysis process following Xiapex administration is localized and does not require or result in quantifiable systemic levels of AUX-I and AUX-II, the primary pharmacodynamic activity of Xiapex cannot be evaluated in subjects and therefore, such studies have not been undertaken.

Mechanism of action

Collagenases are proteinases that hydrolyze collagen under physiological conditions. Xiapex is comprised of a mixture of Class I (AUX-I) and Class II (AUX-II) clostridial collagenases in a defined mass ratio. The two classes of collagenases have similar but complementary substrate specificity. Both collagenases effectively cleave interstitial collagen but at different sites on the molecule; additionally, they prefer different conformations (triple helical versus denatured or cleaved). These differences account for the ability of the two classes of enzymes to digest collagen in a complementary manner. Class I collagenases (α, β, γ, and η) are the products of the colG gene, they initiate collagen hydrolysis near the amino and carboxy termini of triple helical domains and generate large proteolytic fragments. In contrast, the Class II collagenases (δ, ε, and ζ,) are products of colH gene, their initial cleavage sites are located within the interior of the collagen molecule and generate smaller collagen fragments. Both classes of collagenases readily hydrolyze gelatin (denatured collagen) and small collagen peptides, whereas Class II has higher affinity for small collagen fragments. Class I cleaves insoluble triple helical collagen with higher affinity than Class II collagenase. Together, these collagenases work to provide broad hydrolytic activity towards collagen.

Dupuytren’s contracture

Injection of Xiapex into a Dupuytren’s cord, which is comprised mostly of interstitial collagen types I and III, results in enzymatic disruption of the cord.

Peyronie’s disease

The signs and symptoms of Peyronie’s disease are caused by a collagen plaque. Injection of Xiapex 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.

Clinical efficacy and safety

Dupuytren’s contracture

The efficacy of Xiapex 0.58 mg was evaluated in two pivotal randomized, double-blind, placebo-controlled studies, CORD I (AUX-CC-857) and CORD II (AUX-CC-859), in adult patients with Dupuytren’s contracture. The double-blind study population comprised 409 patients of whom 272 received Xiapex 0.58 mg and 137 received placebo. The mean age was 63 years (range 33 to 89 years) and 80% of patients were male. At study entry, patients in the clinical studies 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 MP joint or 20° to 80° in 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. The cord affecting a selected primary joint received up to 3 injections of 0.58 mg of Xiapex or placebo. A finger extension procedure was performed if needed, approximately 24 hours after injection to facilitate disruption of the cord. Each injection was separated by approximately 4 weeks.

The primary endpoint of each study was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to 5° or less of normal, approximately 4 weeks after the last injection of that joint. Other endpoints included ≥50% reduction from baseline in degree of contracture, percent change from baseline in degree of contracture, change from baseline in range of motion, subject global assessment of treatment satisfaction and physician global assessment of severity.

Xiapex demonstrated a clinically significant benefit compared to placebo in the proportion of patients achieving the primary endpoint of a reduction in the contracture of all joints treated to 5° or less, approximately 4 weeks after the last injection (MP plus PIP, MP only, PIP only). For patients who achieved a contracture of the selected joint to 5° or less, the mean number of injections required to achieve this was 1.5 in the 2 studies. Xiapex also demonstrated a clinically significant benefit compared to placebo in decreasing the degree of contracture and increasing both the range of motion from baseline for all joints treated (MP plus PIP, MP only, PIP only) and the subject global assessment of treatment satisfaction.

Table 3 provides demographic and baseline characteristics for the study population and Tables 4-5 provide the results of the major efficacy endpoints measured in the 2 double-blind placebo-controlled studies CORD I (AUX-CC-857) and CORD II (AUX-CC-859).

Table 3. Demographic and baseline characteristics – Phase 3 Double-Blind, Placebo controlled studies (CORD I, CORD II):

Note: Includes all patients who received at least 1 injection of double-blind study medicinal product (Xiapex 0.58 mg or placebo).
¹ Not used to calculate physician rating of severity at baseline percentage-actual denominator of N=247 used.

Table 4. Percentage of patients who achieved reduction in contracture to 5° or less (Last injection):

^a Metacarpophalangeal joint
^b Proximal interphalangeal joint
^c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).

Table 5. Mean increase in range of motion from baseline (Last injection):

^a Metacarpophalangeal joint
^b Proximal interphalangeal joint
^c 2 primary joints were excluded from the efficacy analysis (1 joint from the placebo group was not evaluated and 1 joint from the Xiapex treated group had a baseline contracture of 0 degrees before treatment).
All p-values <0.001 for all comparisons between Xiapex and placebo, except for PIP joints in Study CORD II which was not eligible for statistical testing due to a hierarchical testing procedure.

Physician-rated change in contracture severity was reported as very much improved or much improved in 86% and 80% of the subjects in the Xiapex group compared to 3% and 5% of subjects in the placebo group for the CORD I and CORD II studies, respectively (p<0.001). Based on the Patient Global Assessment of Treatment Satisfaction, more than 85% of subjects in the CORD I and CORD II studies reported either being quite satisfied or very satisfied with their treatment with Xiapex versus approximately 30% treated with placebo (p<0.001). Greater patient satisfaction was correlated with improved range of motion (r=0.51, p<0.001).

Treatment of two concurrent injections

The administration of two concurrent Xiapex injections into Dupuytren’s cords in the same hand was evaluated in clinical study AUX-CC-867, a historically-controlled, open-label multi-centre trial in 715 adult subjects (1450 Xiapex injections) with Dupuytren’s contracture. The finger extension procedures were performed approximately 24 to 72 hours after injection.

Primary efficacy endpoint was fixed flexion contracture in the treated joint pair subgroup. A significant mean improvement (74.4%) from baseline to Day 31 was observed overall in fixed flexion contracture following administration of two concurrent injections of Xiapex 0.58 mg (one injection per joint) in the same hand, see Table 6. Improvement was observed regardless of joint type or finger involvement (range: 60.5% to 83.9%). Improvement of the total fixed flexion contracture was also observed irrespectively of the time of finger extension, 24, 48 or 72 hours after injection, with a mean improvement at Day 31 of 75.2% 74.8% and 72.4% respectively. An improvement from baseline was also seen in range of motion at Day 31 for all the treated joint pair subgroups, see Table 6.

Table 6. Total fixed flexion contracture and range of motion following administration of two concurrent injections of Xiapex 0.58 mg in the same hand, mITT population, study AUXCC-867 (first treatment cycle):

FFC = Fixed flexion contracture
ROM = Range of motion

Clinical success (a reduction of contracture to ≤5° within 30 days) after two concurrent injections of Xiapex (one per joint) in the same hand was achieved for the majority of MP joints (64.6%) compared with 28.6% of PIP joints following a single injection per affected joint. Time of finger extension after injection had no impact on the rate of clinical success for either MP or PIP joints. Clinically meaningful improvement in hand function as determined by the URAM (Unite´ Rhumatologique des Affections de la Main) score was observed at Day 31 (-11.3) and Day 61 (-12.3).

Long-term efficacy and safety

A long-term, non-treatment, Year 2 to Year 5 follow-up study (AUX-CC-860) was undertaken to evaluate recurrence of contracture and long-term safety in subjects who received up to 8 single injections of Xiapex 0.58 mg in a previous Phase 3 open-label or double-blind with open-label extension study. No new safety signals were identified among subjects who were followed for 5 years after their initial injection of Xiapex in a previous clinical study. The majority of adverse events reported during the long-term follow-up period were non-serious, mild or moderate in intensity, and were not related to the local administration of Xiapex. These data support the long-term safety profile of Xiapex confirming that no new safety risks were identified during the 5 year follow-up period.

Recurrence was assessed in successfully treated joints (i.e., subjects had a reduction in contracture to 5° or less at the Day 30 evaluation after the last injection of Xiapex in a previous study) and was defined as an increase in joint contracture by at least 20° in the presence of a palpable cord, or the joint underwent medical or surgical intervention primarily to correct a new or worsening Dupuytren’s contracture in that joint. Data on the long-term recurrence rates following successful treatment with Xiapex are provided in Table 7.

Table 7. Long Term Recurrence Rates for Joints Treated Successfully with XIAPEX:

^a A joint was considered in an interval if the duration of assessment falls in the interval. The duration of assessment started at the day of success (visit after the last injection where the 0° to 5° measurement was first recorded). The duration of assessment ended at the last available measurement or at the day of medical intervention for joints that did not recur and the recurrence day for recurrent joints.
^b A recurrent joint was a joint evaluated by the investigator as having a worsening Dupuytren’s contracture due to a palpable cord. The recurrence day was the visit where the recurrence was reported or the day of intervention if a jointwas treated for a worsening Dupuytren’s contracture. For joints reported as recurring in a previous study, the day of recurrence was the first visit with a fixed flexion contracture measurement of 20° or greater following the report of recurrence.
^c The nominal rate of recurrence was the total number of recurrences occurring prior to the last day of the interval divided by the total number of joints (×100).

Retreatment of recurrent contractures

A study AUX-CC-862 was conducted in patients with Dupuytren’s contracture who had recurrence of contracture in a joint that was effectively treated with Xiapex in a previous clinical study. No new safety signals were identified among subjects who were retreated with Xiapex. Most adverse events were non-serious, mild or moderate in intensity, and related to the local administration of Xiapex or to the finger extension procedure to facilitate cord disruption. The clinical efficacy in study AUX-CC-862 was similar to that reported in studies CORD I and CORD II. In study AUX-CC-862, 64.5% of recurrent MP joints and 45.0% of recurrent PIP joints achieved clinical success after retreatment with up to three injections of Xiapex.

In the retreatment study AUX-CC-862, 150 anti-AUX-I antibody positive samples and 149 anti-AUX-II antibody positive samples were assessed for potential cross-reactivity with human MMPs-1, -2, -3, -8, and -13. Results showed no cross-reactivity with any of the five MMPs tested.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Xiapex in all subsets of the paediatric population in the treatment of Dupuytren’s contracture (see section 4.2 for information on paediatric use).

Peyronie’s disease

The efficacy of Xiapex was evaluated in two randomized, double-blind, placebo-controlled studies, Study 1 (AUX-CC-803) and Study 2 (AUX-CC-804), in adult males with Peyronie’s disease. The double–blind study population comprised 832 male patients of whom 551 patients received Xiapex and 281 received placebo. The median age was 58 years (range 23 to 84 years). 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 studies, patients were given up to 4 treatment cycles of Xiapex 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 Xiapex 0.58 mg or two injections of placebo were administered 1 to 3 days apart. A penile modelling 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 modelling procedures. In addition, patients were instructed to perform penile modelling at home for six weeks after each treatment cycle.

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 of the Peyronie’s Disease Questionnaire (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.

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

Xiapex significantly reduced patient-reported bother associated with Peyronie’s disease compared with placebo (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 8 provides the baseline disease characteristics for the study population and Tables 9-10 provide the results of the co-primary efficacy endpoints measured in the 2 double-blind placebo-controlled studies AUX-CC-803 and AUX-CC-804.

Table 8. Baseline disease characteristics of patients^a with Peyronie’s Disease (PD):

^a Subjects were from ITT population and received at least one dose of study drug in Study 1 or 2
^b Each PDQ assessment required subjects to have had vaginal intercourse in the 3 months prior to completion
^c Higher scores represent worse symptoms

Table 9. Mean percent change in penile curvature deformity from baseline to week 52 – Studies 1 and 2:

^a Mean 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.
^b p-value <0.01

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

^a Mean 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.
^b p-value <0.05.

Xiapex was not associated with shortening of penile length in clinical trials in the treatment of Peyronie’s disease.

An open label phase 3 study, AUX-CC-806, evaluated the safety and efficacy of Xiapex. The study inclusion and exclusion criteria as well as the treatment schedule and the co-primary efficacy endpoints were the same as in the pivotal AUX-CC-803 and AUX-CC-804 studies. Patients were however followed up to 36 weeks. A total of 189 patients were enrolled and treated with Xiapex. All patients had participated in and completed the studies AUX-CC-803 or AUX-CC-804, in which they had received placebo.

The median age of the patients included was 60, ranging between 33 and 77 years. The median duration of disease was 4.9 years (range 2.0 to 27.9 years). Erectile dysfunction was reported in 52.9% of patients, and 27.5% reported previous trauma to penis.

Tables 11-12 provide the results of the co-primary efficacy endpoints measured in the open label phase 3 study AUX-CC-806.

Table 11. Mean Percent Change from Baseline in Curvature Deformity at Week 36 (LOCF) (mITT* Population) – study AUX-CC-806 :

^* 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.
^** Based on the 95% CI of the mean not including zero, the percent change from baseline was considered statistically significant.

Table 12. Mean Change from Baseline in Peyronie’s Disease Bother Score at Week 36 (LOCF) (mITT* Population) – study AUX-CC-806:

^* 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.
^** Based on the 95% CI of the mean not including zero, the mean change from baseline was considered statistically significant.

As an exploratory analysis, female sexual partners completed two questionnaires at both the screening visit and week 36: the PDQ for Female Sexual Partners (an adaptation of Peyronie’s disease bother and psychological symptom domains of the PDQ for men, scoring from 0-12) and the Female Sexual Function Index (FSFI, scale from 2-36, where a higher score represents better sexual functioning). Altogether 30 female partners participated in the study. At baseline, the mean (SD) Female PDQ score was 4.7 (3.61) and 2.7 (3.06) at week 36, i.e. a change from baseline of -2.0. The mean (SD) FSFI score was 20.56 (10.08) at baseline and 26.72 (7.73) at week 36, a change from baseline of 7.54.

Long-term efficacy and safety

A phase 4, non-treatment, long-term follow-up study (AUX-CC-810) was undertaken to evaluate the efficacy and safety up to 5 years after the first injection of Xiapex in the pivotal 12-month doubleblind placebo-controlled phase 3 studies or in the 9-month open-label phase 3 studies. Through the 5 year follow up period (Table 13), subjects demonstrated an improvement in penile curvature and in PDQ bother compared with the last observed value from the previous phase 3 studies. There were no changes in the international index of erectile function (IIEF) scores. No new safety signals were identified during the 5 year follow-up period.

Table 13. Long Term Efficacy variables – study AUX-CC-810:

^a Baseline was defined as the last observation prior to the first injection of Xiapex in the previous phase 3 study (i.e AUX-CC-802, AUX-CC-803, AUX-CC-804 or AUX-CC-806)
^b Reference was defined as the last post-baseline non-missing observed value from the previous phase 3 study (i.e AUX-CC-802, AUX-CC-803, AUX-CC-804 or AUX-CC-806)
^* Note: 29 subjects were excluded from this analysis. 9 subjects received commercial Xiapex and 2 subjects had penile implant during the course of the non-treatment study (AUX-CC-810), and 18 subjects had prior surgical intervention for the treatment of Peyronie´s Disease.
^** Note: 22 subjects were excluded from this analysis. 9 subjects received commercial Xiapex and 1 subject had penile implant during the course of the non-treatment study (AUX-CC-810), and 12 subjects had prior surgical intervention for the treatment of Peyronie´s Disease.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Xiapex in all subsets of the paediatric population in the treatment of Peyronie’s disease (see section 4.2 for information on paediatric use).