Conflict of interest disclosure:
None reported.

ABSTRACT
Efinaconazole 10% nail solution is a novel topical antifungal drug for the treatment of onychomycosis. Two Phase III trials were completed using efinaconazole 10% nail solution, where 17.8% and 15.2% of patients achieved complete cure, and 55.2% and 53.4%
achieved mycological cure. Several post hoc analyses were carried out using data from Phase III trials to determine the efficacy of efinaconazole with respect to disease duration, disease progression, and comorbidities of diabetes or tinea pedis with onychomycosis.
Efinaconazole produced higher efficacy rates with patients presenting onychomycosis in a small portion of the toenail (≤25%) for a shorter duration of time ( concurrent treatment, efficacy of efinaconazole increased from 16.1% to 29.4%, suggesting combination therapy improved results. Most interestingly, there was no difference in efinaconazole efficacy between diabetic and non-diabetic groups, indicating efinaconazole could be a safe and effective form of treatment for diabetics. Overall, efinaconazole 10% nail solution shows potential as an antifungal therapy for the treatment of onychomycosis.

Key Words:
antifungal agent, efinaconazole, fungal nail infection, Jublia^®, onychomycosis, topical triazole

Introduction

Onychomycosis is a fungal infection of the nail unit caused
by dermatophytes, yeasts, and nondermatophyte molds.¹
Onychomycosis affects toenails more frequently than fingernails
and accounts for 50% of nail disease.^2,3 Although this infection
can be perceived as merely a cosmetic issue of thickening and
discoloration of the nail plate, onychomycosis can result in
numerous side effects that can impede the use of shoes and make
walking difficult in general, leading to decreased quality of life.^4,5
Additional risks include bacterial infections, foot ulcers, and
gangrene.⁶ As a commonly occurring disease, it affects 2-13% of
the general population, with prevalence of up to 50% in patients
aged 70 years or higher.⁷ Along with advanced age, there are
several other risk factors including diabetes, peripheral arterial
disease, immunosuppression, and other pre-existing nail diseases
like psoriasis.⁸ Due to an increased chance of comorbidity with
onychomycosis, most recent investigational interests have focused
on topical antifungals, which have a lower risk of adverse effects
and drug-drug interactions.

The goal of onychomycosis treatment is restoring the nail to a
normal appearance and complete eradication of fungus. This
can be difficult to achieve as the nail plate acts as a barrier for
topical treatments, and poor circulation in the elderly can prevent
systemic treatments from reaching their target. Although some
therapies can result in complete clinical and mycological cure, the
rates are low (35-50%), and risk of relapse is high (10-53%).⁹
Currently, there are five classes of drugs approved for the
treatment of onychomycosis: allylamines, azoles, morpholines,
hydroxypyridinones, and benzoxaboroles.^10,11 Historically,
systemic therapies have been the most effective, with the oral
allylamine terbinafine being the current gold standard with a
complete cure rate of 38% and mycological cure rate of 74%.^12,13
The recommended dose of terbinafine for toenail onychomycosis
is 250 mg daily for 12 weeks. Patients who are high risk for adverse
effects from oral antifungals are prescribed topical agents. In the
US there are three topical therapies approved for the treatment
of onychomycosis: ciclopirox 8% nail solution, tavaborole 5%
solution, and efinaconazole 10% solution. Given the challenges of
transungual delivery, there is a need for novel topical antifungals
that can increase penetrance, are potent, and carry minimal side
effects.

Efinaconazole 10% solution is a novel topical antifungal of the
azole class that was US FDA approved for the treatment of toenail
onychomycosis in June 2014.¹⁴ Efinaconazole has demonstrated
a broad spectrum of activity against dermatophytes and yeasts
in vitro,¹⁵ and has uniquely low keratin affinity, allowing drug
release from keratin and enhanced penetration through the nail
plate compared to ciclopirox and amorolfine.¹⁶ Due to the unique
formulation of efinaconazole, both transungual and subungual
routes of delivery are achieved as the drug penetrates through
the nail plate into the underlying nail bed, as well as via spreading
around and under the nail plate through the air gap to reach
the fungal infection.^17,18 Recently, a human cadaver nail study
demonstrated that efinaconazole is able to penetrate the nail
even in the presence of nail polish,¹⁹ which may be a potential
advantage for patients concerned with hiding nail abnormalities
while at the same time using a topical treatment. Efinaconazole
works by inhibiting the synthesis of ergosterol, an essential
structural component of fungal cell membranes.^20,21 Its inhibition
results in a loss of cell membrane integrity, thus preventing fungal
cell growth.^20,21

Previously, two identical, randomized, double-blind, vehiclecontrolled
Phase III studies were performed using 1655
patients with mild to moderate toenail onychomycosis.²² The
treatment course was once daily application of efinaconazole
10% nail solution to the affected toenail and underside, as well
as surrounding skin, for 48 weeks followed by a 4 week washout
period.23 At week 52, 17.8% and 15.2% of patients achieved
complete cure, and 55.2% and 53.4% achieved mycological cure.²⁴
Interestingly, female patients demonstrated higher efficacies than
males (27.1% vs 15.8%, respectively, P=0.001), where the only
notable difference between genders were mean weight (73.3 kg
and 90.2 kg).²² Further subgroup analyses were completed using
Phase III data to elucidate the differences in treatment efficacy
in patients with concurrent tinea pedis or diabetes, as well as
duration and severity of disease.^25-28

Clinical Efficacy

Consistent with previous findings,²⁹ 21.3% (352/1655) of
patients from Phase III clinical trials reported onychomycosis
with concurrent tinea pedis, and 61.1% (215/352) underwent
concomitant treatment for tinea pedis with an investigatorapproved
topical antifungal.^26,30 Butenafine, luliconazole, and
ketoconazole were the most commonly used topical antifungal
agents for tinea pedis treatment; used by 64, 52, and 23 patients,
respectively.³⁰ With concomitant treatment of onychomycosis
(efinaconazole) and tinea pedis, complete and mycological cure
rates were 29.4% and 56.2%, respectively (7.8% and 26.6%
vehicle, P=0.003 and P<0.001, respectively). When tinea pedis
was left untreated, complete and mycological cure rates were
16.1% and 45.2% (0% and 12.5% vehicle, P=0.045 and P=0.007,
respectively). Efinaconazole treatment was superior to all vehicle
outcomes, and concurrent treatment for tinea pedis was superior
to untreated tinea pedis measures. Moreover, patients treated with
efinaconazole achieved a higher complete or almost complete
cure and higher treatment success, compared with vehicle (data
summarized in Table 1). Complete or almost complete cure was
defined as ≤5% clinical involvement of the target toenail plus
mycologic cure. Treatment success was defined as ≤10% clinical
involvement of the target toenail.

Of the 1655 patients from Phase III clinical trials, 112 patients
had coexistent onychomycosis and diabetes.²⁵ Only patients
whose diabetes was under control (N=96) were included in the
study. Diabetic (N=69) and non-diabetic (N=993) patients had
similar efficacies when treated with efinaconazole, with complete
cure rates of 13% and 18.8%, respectively and mycological
cure rates of 56.5% and 56.3%, respectively. These values were
significantly higher than vehicle (N=27) for complete cure (3.7%
and 4.7%, P P=0.016, and approximately 17.4%, P<0.001) for diabetic and
non-diabetic patients, respectively. Moreover, patients receiving
efinaconazole treatment had greater success achieving complete
or almost complete cures as well as treatment success at
week 52 (data summarized in Table 2). All secondary endpoints
were identical to those defined above.

Of all patients (1655) from Phase III trials, 1526 were categorized
based on disease duration: 5 years (770 patients).²⁷ Complete cure rates of
42.6%, 17.1%, and 16.2% were observed in efinaconazole-treated
patients with 5 years disease duration,
respectively. Complete cure rates with efinaconazole treatment
were significantly improved over vehicle for patients with baseline
disease durations of 1-5 years (17.1% vs. 4.4%, P<0.001) and >5
years (16.2% vs. 2.5%, P<0.001), however, this was not the case
for patients presenting with onychomycosis for vs. 16.7%, not significant). It is possible that non-significance
may be due to the small sample size (N=33 efinaconazole).
Furthermore, 66.0%, 59.0%, and 53.8% of patients achieved
mycological cure with disease duration of 5 years, respectively. Similar to complete cure, the latter two
durations were significantly different from vehicle (P <0.001).
Lastly, while not significant for any duration, patients receiving
efinaconazole treatment did show numerically higher complete
or almost complete cure rates, as well as treatment success, for
disease durations of 5 years (Figure 3). All secondary endpoints are identical to those
defined above.

Figure 1.Summary of cure rates for patients with baseline disease duration of 27

While cure rates are numerically higher for all efficacy outcomes, efinaconazole cure rates were not significantly greater than vehicle.

Figure 2.Summary of cure rates for patients with baseline disease duration of 1-5 years with efinaconazole.²⁷

^*

Figure 3.Summary of cure rates for patients with baseline disease duration of >5 years with efinaconazole.²⁷

^*P

Finally, effectiveness of efinaconazole based on disease severity
was measured using 414 patients with mild onychomycosis
(≤25% nail involvement), and 1237 patients with moderately
severe onychomycosis (>25% nail involvement).²⁸ Patients
presenting with mild onychomycosis had complete and
mycological cure rates of 25.8% and 58.2%, respectively, which are
significantly higher than vehicle cure rates of 11.3% (P=0.006)
and 25.0% (P<0.001), respectively. Patients with moderately
severe onychomycosis had complete and mycological cure rates
of 15.9% and 55.6%, respectively, again demonstrating significant
improvement over vehicle cure rates of 2.7% and 14.1% (P<0.001
for both), respectively. Moreover, all patients with efinaconazole
treatment had significantly higher complete or almost complete
cure rates and treatment success compare to vehicle (summarized
in Table 3, P to those defined above.

^a P<0.01; ^b P

Discussion

The data from two Phase III clinical trials have been analyzed and
the efficacy of efinaconazole with respect to concurrent treatment
for tinea pedis, diabetic patients, disease duration, and severity
of disease shows promise. Efficacies were highest among patients
with less severe (≤25% nail involvement) and shorter disease
duration.

Efinaconazole treatment was more effective than vehicle for the
treatment of onychomycosis with or without concurrent treatment
of tinea pedis. Since one-third of onychomycosis patients also
have tinea pedis, it is recommended that patients are examined
for concomitant dermatomycoses, and treatment for both fungal
infections (if present) be sought, as pathogens that cause tinea
pedis can also lead to onychomycosis.^29,30 Although concurrent
treatment for tinea pedis and onychomycosis (efinaconazole)
improved complete cure rates from 16.1% to 29.4%, there was
no information about the severity of tinea pedis, or the success
of tinea pedis treatment. Therefore, further testing would need
to be completed to confirm whether combination therapy could
increase treatment efficacy of both fungal infections.

Onychomycosis in diabetic patients is extremely difficult to treat
with traditional antifungals due to hyperglycemia and problematic
foot hygiene.³¹ Moreover, onychomycosis left untreated poses a
significant risk for further complications that can potentially lead
to loss of limb.^32,33 The findings that the efficacy of efinaconazole
was comparable between diabetic and non-diabetic patients
and cure rates for both groups were significantly higher than
respective vehicle groups, indicate that diabetics can now receive
safe and effective treatment for onychomycosis.

In summary, good responders to efinaconazole treatment are
more likely to be patients with mild (≤25% clinical toenail
involvement) onychomycosis and have a low number of nontarget
nail involvement,²⁸ with early or baseline onychomycosis
(27 who receive concurrent
treatment for tinea pedis (if present),^26,30 are female,²² and weigh
22 Most interestingly, whether patients were diabetic
or non-diabetic had no effect on the efficacy of efinaconazole
treatment.

Efinaconazole 10% topical solution is an effective topical
treatment for onychomycosis with favorable clinical and
mycological efficacies, low risk of drug-drug interactions, and a
minimal side effect profile.³⁴ With complete cure rates of 17.8%
and 15.2%,^22,34 and a favorable safety profile, efinaconazole also
looks promising for use in children and in combination therapy.
Moreover, since levels of efinaconazole reach a steady state in
the nail after 2 weeks of daily application, and remain at high
concentrations well above the minimum inhibitory concentration
for dermatophytes for at least 2 weeks off therapy,³⁵ it is possible
that efinaconazole may be used twice weekly as a maintenance
regime. This strategy may be considered after the completion of
the 48 week treatment period in order to prevent relapse; however,
maintenance studies have yet to be conducted. Taken together,
efinaconazole 10% topical solution is an easy to use, safe, and
effective therapy for the treatment of onychomycosis.

References

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2. Gupta AK, Jain HC, Lynde CW, et al. Prevalence and epidemiology of onychomycosis in patients visiting physicians’ offices: a multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):244-8.
3. Faergemann J, Baran R. Epidemiology, clinical presentation and diagnosis of onychomycosis. Br J Dermatol. 2003 Sep;149 Suppl 65:1-4.
4. Elewski BE. The effect of toenail onychomycosis on patient quality of life. Int J Dermatol. 1997 Oct;36(10):754-6.
5. Lubeck DP, Gause D, Schein JR, et al. A health-related quality of life measure for use in patients with onychomycosis: a validation study. Qual Life Res. 1999 8(1-2):121-9.
6. LaSenna CE, Tosti A. Patient considerations in the management of toe onychomycosis – role of efinaconazole. Patient Prefer Adherence. 2015 9:887-91.
7. Tabara K, Szewczyk AE, Bienias W, et al. Amorolfine vs. ciclopirox – lacquers for the treatment of onychomycosis. Postepy Dermatol Alergol. 2015 Feb;32(1):40-5.
8. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis–risk factor identification and active prevention. J Eur Acad Dermatol Venereol. 2005 Sep;19(Suppl 1):13-6.
9. Epstein E. How often does oral treatment of toenail onychomycosis produce a disease-free nail? An analysis of published data. Arch Dermatol. 1998 Dec;134(12):1551-4.
10. Welsh O, Vera-Cabrera L, Welsh E. Onychomycosis. Clin Dermatol. 2010 Mar 4;28(2):151-9.
11. Markham A. Tavaborole: first global approval. Drugs. 2014 Sep;74(13):1555-8.
12. LamisilÆ (terbinafine hydrochloride) tablets [Prescribing information]; revised
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    at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/
    files/Lamisil_tablets.pdf. Accessed September 26, 2016.
13. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013 Sep-Oct;31(5):544-54.
14. Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013 Apr;68(4):600-8.
15. Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013 Apr;57(4):1610-6.
16. Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014 Jul;58(7):3837-42.
17. Gupta AK, Pillai R. The presence of an air gap between the nail plate and nail bed in onychomycosis patients: treatment implications for topical therapy. J Drugs Dermatol. 2015 Aug;14(8):859-63.
18. Gupta AK, Simpson FC. Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis. J Dermatolog Treat. 2016 27(1):2-4.
19. Zeichner JA, Stein Gold L, Korotzer A. Penetration of ((14)C)-efinaconazole topical solution, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol. 2014 Sep;7(9):34-6.
20. Rodriguez RJ, Low C, Bottema CD, et al. Multiple functions for sterols in Saccharomyces cerevisiae. Biochim Biophys Acta. 1985 Dec 4;837(3):336-43.
21. Parks LW, Smith SJ, Crowley JH. Biochemical and physiological effects of sterol alterations in yeast–a review. Lipids. 1995 Mar;30(3):227-30.
22. Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol. 2014 Jul;13(7):815-20.
23. JUBLIA® (efinaconazole) topical solution, 10% [Prescribing information]; revised July 2014. Valeant Pharmaceuticals North America LLC, Bridgewater, NJ. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203567s000lbl.pdf. Accessed September 26, 2016.
24. Lipner SR, Scher RK. Efinaconazole in the treatment of onychomycosis. Infect
    Drug Resist. 2015 8:163-72.
25. Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of
    toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014
    Oct;13(10):1186-90.
26. Lipner SR, Scher RK. Management of onychomycosis and co-existing tinea
    pedis. J Drugs Dermatol. 2015 May;14(5):492-4.
27. Rich P. Efinaconazole topical solution, 10%: the benefits of treating
    onychomycosis early. J Drugs Dermatol. 2015 Jan;14(1):58-62.
28. Rodriguez DA. Efinaconazole topical solution, 10%, for the treatment of mild and
    moderate toenail onychomycosis. J Clin Aesthet Dermatol. 2015 Jun;8(6):24-9.
29. Szepietowski JC, Reich A, Garlowska E, et al, Onychomycosis Epidemiology Study
    Group. Factors influencing coexistence of toenail onychomycosis with tinea
    pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol. 2006
    Oct;142(10):1279-84.
30. Markinson B, Caldwell B. Efinaconazole topical solution, 10% efficacy in patients
    with onychomycosis and coexisting tinea pedis. J Am Podiatr Med Assoc. 2015
    Sep;105(5):407-11.
31. Tan JS, Joseph WS. Common fungal infections of the feet in patients with diabetes mellitus. Drugs Aging. 2004 21(2):101-12.
32. Gupta AK, Humke S. The prevalence and management of onychomycosis in diabetic patients. Eur J Dermatol. 2000 Jul-Aug;10(5):379-84.
33. Papini M, Cicoletti M, Fabrizi V, et al. Skin and nail mycoses in patients with diabetic foot. G Ital Dermatol Venereol. 2013 Dec;148(6):603-8.
34. Lipner SR, Scher RK. Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail. Expert Rev Clin Pharmacol. 2015 8(6):719-31.
35. Sakamoto M, Sugimoto N, Kawabata H, et al. Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vitro fungicidal activity in human nails. J Drugs Dermatol. 2014 Nov;13(11):1388-92.

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.

ABSTRACT
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.

Key Words:
adalimumab, hidradenitis suppurativa, immune modulators, tumor necrosis factor-alpha inhibitor

Introduction

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.

Clinical Efficacy

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).

Figure 1.
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

Figure 2.
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

Figure 3.
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).

Conclusion

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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