Aditya K. Gupta, MD, PhD, FRCPC1,2 and Catherine Studholme, PhD2
1Department of Medicine, University of Toronto, Toronto, ON, Canada
2Mediprobe Research Inc., London, ON, Canada
Conflict of interest:
Aditya Gupta has been a clinical trials investigator for Valeant Canada, Nuvolase, Bristol Meyers Squibb, Eli Lilly, Merck, Novartis, Janssen and Allergan; and has served as a speaker or consultant for Valeant Canada, Janssen, Novartis, Sandoz, Moberg Pharma, and Bayer. Catherine Studholme is an employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of Aditya Gupta.
Adalimumab (Humira®) is a novel therapy approved by the US Food and Drug Administration, Health Canada, and the European Commission for the treatment of hidradenitis suppurativa (HS). Results of two Phase III trials of adalimumab demonstrate significantly higher efficacies compared to placebo. Primary efficacy outcome of 50% reduction in abscess and inflammatory nodule count was seen in 41.8% and 58.9% of participants receiving adalimumab in PIONEER I and PIONEER II studies, respectively, showing substantial improvement compared with placebo groups in both trials (26.0% and 27.6%, respectively). Although the significance of secondary efficacy measures of adalimumab every week treatment (EW) was not consistent between PIONEER I and PIONEER II studies, participants achieving abscess and inflammatory nodule counts of 0, 1, or 2 were significant (EW 51.8%) compared to placebo (32.2%) in the PIONEER II trial. Participants also demonstrated a marked decrease in skin pain measurements from baseline between EW patients (45.7%) and placebo (20.7%) in the PIONEER II trial. Modified Sartorius scores were decreased from baseline in both PIONEER I (-24.4) and PIONEER II (-28.9) trials versus placebo (-15.7 and -9.5, respectively). Adverse events were mild to moderate and comparable between all treatment groups including placebo. Taken together, these data conclude that treatment of HS with adalimumab is a safe and effective therapy resulting in a significant decrease in abscess and inflammatory nodule counts within the first 12 weeks of treatment.
adalimumab, hidradenitis suppurativa, immune modulators, tumor necrosis factor-alpha inhibitor
Hidradenitis suppurativa (HS), also known as acne inversa, is a severe and chronic inflammatory disease resulting from occlusion and rupture of hair follicles followed by an overreaction of the immune response.1,2 This results in painful inflammation and abscess formation, which can lead to sinus tract development and scarring, as seen in the later stages of HS.1,2 This affliction is generally located in areas where skin-skin contact occurs, but has been observed on atypical areas such as the ears, back, and chest.3 Although the exact etiology of HS remains unknown, prevalence is reported to range from 1%-4%.4-7 There is a lack of regulatory body-approved drugs for the treatment of HS,
leaving surgery as the established treatment option for severe disease; however, surgery is associated with a high risk of HS recurrence.8,9 Therefore, there is an unmet need to find safe and effective therapeutic options for the treatment of HS.
Adalimumab (Humira®) is a human monoclonal antibody that binds to and neutralizes tumor necrosis factor-alpha (TNF-α).10 It has been shown to be effective at treating inflammatory conditions, including rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, and psoriasis.11,12 Since these diseases all involve overreaction of the immune system resulting in inflammation, adalimumab has been used off-label for the treatment of HS for several years.13, Adalimumab is now the first and only approved drug for the treatment of HS by the US Food and Drug Administration (FDA), Health Canada, and the EU’s European Commission. A Phase II clinical trial was initially completed to analyze the safety and efficacy of adalimumab for the treatment of HS, which showed promising results.14 The findings from further analysis through two Phase III trials have
recently been released, and are summarized herein.
Phase II Trial (NCT00918255)
A parallel, randomized, double-blind, Phase II clinical trial to assess the safety and efficacy of adalimumab in the treatment of HS was completed.15 One hundred and fifty-four participants (110 female and 44 male) were measured at baseline. Participants were randomized into three treatment arms: placebo (N = 51), adalimumab every week (EW; subcutaneous [SC] dose of 160 mg week 0, 80 mg week 2, 40 mg weekly from weeks 4-15; N = 51), or adalimumab every other week (EOW; SC 80 mg week 0, 40 mg every other week from weeks 1-15; N = 51). Average age of participants was 36.3 years and all efficacy measures were completed at week 16. Participants in the EW treatment group achieved statistically higher clinical response (17.6%), compared to EOW (9.6%) and placebo (3.9%) groups (P = 0.022; CochranMantel-Haenszel
method). Clinical response was defined as a 2 point reduction or score of 0, 1, or 2 using the Physician’s Global Assessment. The EW treatment group also had significant
improvement in secondary efficacies of decreased inflammatory nodules and plaques (P = 0.019; analysis of covariance [ANCOVA] method), clinical response at week 12 (P = 0.020; Cochran-Mantel-Haenszel method), and Modified Sartorius Scale (P = 0.014; van Elteren test) compared to placebo. The EOW treatment group did not exhibit a significant increase in efficacy compared to placebo. Adverse events were comparable between treatment groups; reported in 71% of EW, 64% of EOW, and 59% of placebo participants.
Phase III Trials
Two Phase III randomized, double-blind clinical trials to assess the safety and efficacy of adalimumab in the treatment of patients with moderate-severe HS were recently completed.16,17 The severity of HS was defined using Hurley Staging: Stage I characterized by single or multiple abscess formations without
sinus tracts or scarring; Stage II characterized by one or more recurrent abscesses with tract formation and scars; and Stage III characterized by abscesses covering an extended area with numerous interconnected tracts and diffuse or near diffuse involvement. Inclusion criteria included adults 18-99 years of age with a diagnosis of HS for at least one year and the presence of at least two areas exhibiting HS lesions with at least one categorized as Hurley Stage II or Stage III, stable HS for at least 60 days prior to screening and baseline visits, previous inadequate response to other HS treatments, and total abscess and inflammatory nodule (AN) count of ≥3 at baseline.
PIONEER I Trial (NCT01468207)
Three hundred and seven participants (196 female and 111 male)
were measured at baseline. The participants were randomized
into the placebo or adalimumab EW (SC 160 mg week 0,
80 mg week 2, and 40 mg weeks 4-12) treatment group for weeks
0-12. The average age of placebo (N = 154) and EW (N = 153)
participants was 37.8, and 36.2 years, respectively. All efficacy
measures were completed at the end of week 12, and results of
primary efficacy measures are summarized in Figure 1. Clinical
response was significantly increased in the EW treatment group
compared to placebo (P = 0.003). Moreover, the clinical response
was significantly greater in participants with Hurley Stage II
(P = 0.048) and Hurley Stage III (P = 0.027) compared to placebo.
However, secondary efficacy measures were not significant
between EW and placebo groups, as less than one-third of all
participants experienced a reduction in their AN count to 0, 1,
or 2 (P = 0.961; chi-squared method) and NRS30 (P = 0.628;
Cochran-Mantel-Haenszel method) by week 12. Finally, there was
a reduction in Modified Sartorius Score of -15.7 and -24.4 in the
placebo and EW treatment groups (P = 0.124; ANCOVA method).
PIONEER II Trial (NCT01468233)
Three hundred and twenty-six participants (221 female and
105 male) were measured at baseline. As in PIONEER I, the
participants were randomized between the placebo and EW
treatment groups for weeks 0-12, where efficacy measures were
completed at the end of week 12. Both groups had a similar mean
participant age of 36.1 and 34.9 years for placebo and EW groups,
respectively. Primary efficacy results are summarized in Figure 2,
which show a significant increase in clinical response in all
adalimumab treatment groups compared to the placebo group
(P < 0.001). In contrast to PIONEER I secondary efficacy studies,
a decrease in AN count of 0, 1, or 2 (P = 0.01) and decrease in
NRS30 (P < 0.001) was found in a significant proportion of
adalimumab EW group participants compared to the placebo
group (Figure 3). Finally, the Modified Sartorius Score for the EW
group (-28.9) was notably improved compared to placebo (-9.5;
P < 0.001; ANCOVA method).
|PIONEER I||PIONEER II|
N = 152
N = 153
N = 151
N = 155
N = 145
N = 48
N = 49
N = 48
|Placebo N = 151||EW*|
N = 51
N = 51
N = 53
|Table 1:Treatment arms for PIONEER I and PIONEER II Phase III clinical trials.|
EW = treatment every week with adalimumab SC 160 mg at week 0, 80 mg at week 2, and 40 mg for weeks 4-12
EW* = treatment every week with adalimumab SC 40 mg for weeks 12-35
EW** = treatment every week with adalimumab SC 160 mg at week 12, 80 mg at week 14, and 40 mg for weeks 16-35
EOW = treatment every other week with adalimumab SC 40 mg for weeks 12-35
PIONEER I primary efficacy measure of HiSCR for patients in the placebo and adalimumab every week treatment groups at week 12.
HiSCR = ≥50% abscess and inflammatory nodule count reduction
EW group = patients receiving treatment every week with adalimumab SC 160 mg at week 0, 80 mg at week 2, and 40 mg weeks for 4-12
* P = 0.003 compared to placebo; Cochran-Mantel-Haenszel method
** P = 0.048 compared to placebo; chi-squared method
*** P = 0.027 compared to placebo; chi-squared method
PIONEER II primary efficacy measure of HiSCR for patients in the placebo and adalimumab every week treatment groups at week 12.
* P < 0.001 compared to placebo; Cochran-Mantel-Haenszel method
PIONEER II secondary efficacy measures of AN count and NRS30 reduction for patients in the placebo or adalimumab every week treatment groups at week 12.
AN = abscess and inflammatory nodule count reduction to 0, 1, or 2
NRS30 = ≥30% and 1 unit reduction in the patient’s global assessment of skin pain numeric rating scale
* P = 0.01 compared to placebo; Cochran-Mantel-Haenszel method
** P < 0.001 compared to placebo; Cochran-Mantel-Haenszel method
Safety and Adverse Events
In the Phase II study, a low percentage of participants from each
treatment arm reported serious adverse events (SAEs), whereas
less serious adverse events (AEs) were reported in 70.59%,
63.46%, and 58.82% of EW, EOW, and placebo treatment groups,
respectively. The most common AEs were nasopharyngitis
(N = 19), headache (N = 17), and hidradenitis (N = 16).
TPIONEER I SAE rates were low in every treatment arm, seen in
only 3.29% of placebo, 1.96% of EW, 3.45% of placebo/EW (SC
placebo weeks 0-12, and SC 40 mg adalimumab weeks 12-35),
4.08% of EW/placebo (adalimumab SC 160 mg week 0, 80 mg
week 2, and 40 mg weeks 4-12, and SC placebo weeks 12-35),
6.25% of EW/EOW (adalimumab SC 160 mg week 0, 80 mg week 2,
and 40 mg for weeks 4-12, and 40 mg adalimumab every other
week for weeks 12-35), and 2.08% of EW/EW (adalimumab SC
160 mg week 0, 80 mg week 2, and 40 mg weeks 4-35) patients.
The most common SAE was hidradenitis, which was experienced
in 5 of the 6 treatment arms (N = 9). Other less serious AEs were
seen in 53.29% for placebo, 41.83% for EW, 46.90% for placebo/
EW, 61.22% for EW/placebo, 50% for EW/EOW, and 58.33%
for EW/EW groups. Common side effects were hidradenitis
(N = 61), headache (N = 47), urinary tract infection (N = 17),
upper respiratory tract infection (N = 23), and nasopharyngitis
(N = 49).
PIONEER II SAEs were also low in each treatment arm, with
occurrences of 3.68% for placebo, 1.84% for EW, 4.64% for
placebo/placebo (placebo for weeks 0-35), 0% for EW/placebo,
3.77% for EW/EOW, and 3.92% for EW/EW groups. The most
common SAE was hidradenitis seen in three treatment arms
(N = 4). Other AEs were reported in 47.24% of placebo, 40.49% of
EW, 37.19% of placebo/placebo, 52.94% of EW/placebo, 47.17%
of EW/EOW, and 41.18% of EW/EW groups. Common side effects
were nasopharyngitis (N = 31), upper respiratory tract infection
(N = 40), headache (N = 58), and hidradenitis (N = 60).
The data reported from two Phase III clinical trials on the
efficacy of adalimumab for the treatment of moderate to
severe HS has been promising. In both trials, patients receiving
adalimumab every week had a significant reduction in abscess
and inflammatory nodule count at week 12 compared to placebo.
Furthermore, adverse events in each treatment arm were
comparable to placebo, with no new adverse events recorded. This
indicates that adalimumab is a safe and effective therapy for the
treatment of HS by demonstrating the potential to achieve disease
control within the first 12 weeks of treatment.
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