Accepted Manuscript

Phosphodiesterase 4 (PDE4) Inhibitors

Rema Zebda, DO, Amy S. Paller, MD

PII: S0190-9622(17)32823-2
DOI: 10.1016/j.jaad.2017.11.056
Reference: YMJD 12183

To appear in: Journal of the American Academy of Dermatology

Received Date: 10 November 2017

Accepted Date: 22 November 2017

Please cite this article as: Zebda R, Paller AS, Phosphodiesterase 4 (PDE4) Inhibitors, Journal of the
American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2017.11.056.

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1 Article Type: Original article

2 Title: Phosphodiesterase 4 (PDE4) Inhibitors

3 Rema Zebda, DO1, Amy S. Paller, MD1

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4 Department of Dermatology, Northwestern University Feinberg School of Medicine,

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5 Chicago, Illinois USA

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6 Corresponding author:

7 Amy S. Paller, MD

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8 Department of Dermatology

9 Northwestern University Feinberg School of Medicine

10 676 North St. Clair St, Suite 1600

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11 Chicago, IL 60611

12 Phone: 312-227-6060
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13 Fax: 312-227-9402
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14 Email: apaller@northwestern.edu
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15 Funding sources: Bayer, LEO Pharma, Sanofi

16 IRB approval status: N/A

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17 Clinicaltrials.gov (or equivalent) listing (if applicable): N/A

18 Conflicts of Interest:
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19 Amy S. Paller, MD, has received funds for serving as an investigator for Anacor and as
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20 a consultant for Pfizer.

21 Rema Zebda, DO, has no relevant conflicts of interest.

22 Reprint requests: Amy S. Paller, MD, Northwestern University, Feinberg School of

23 Medicine, 676 St Clair St, Suite 1600, Chicago, IL 606011. APaller@northwestern.edu.

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24 Manuscript word count: 1,851 words

25 Abstract word count: 179 words

26 Capsule summary word count: 46 words

27 References: 62

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28 Tables: 1

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29 Figures: 1

30 Attachments: none

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31 Keywords: Atopic dermatitis; phosphodiesterase, crisaborole, apremilast, adenylyl

32 cyclase, cyclic adenosine monophosphate, cytokines, pruritus

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33 Abstract

34 Historically, drugs available for treating atopic dermatitis (AD) have been limited to

35 topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI), with systemic

36 immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy,

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37 with long term use, these agents have associated safety concerns and limitations. More

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38 targeted options with fewer systemic and cutaneous side effects are needed for treating

39 atopic dermatitis. Phosphodiesterase 4 is involved in the regulation of proinflammatory

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40 cytokines via the degradation of cAMP. Phosphodiesterase 4 (PDE4) activity is

41 increased in the inflammatory cells of patients with AD, leading to increased production

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of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production
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43 of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a

44 favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now FDA-approved

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45 for children >2yrs of age and adults in the treatment of AD. Crisaborole 2% ointment
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46 shows early and sustained improvement in disease severity and pruritus/ other AD
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47 symptoms, with burning/stinging upon application as the only related adverse event.

48 Other PDE4 inhibitors are currently in trials with promising efficacy and safety.
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49
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50 Capsule Summary

51 • Elevated phosphodiesterase 4 (PDE4) activity is associated with increased

52 production of proinflammatory cytokines in atopic dermatitis

53 • The FDA-approved PDE4 inhibitor, crisaborole ointment, reduces the severity

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54 and pruritus of mild-to-moderate atopic dermatitis with a favorable safety profile

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55 • PDE4 inhibition is a non-steroidal alternative for treating atopic dermatitis.

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57 Introduction

58 Atopic dermatitis is a common chronic eczematous skin disorder1-3 affecting 13% of

59 children and 7% of adults4. Its associated pruritus and comorbidities often lead to sleep

60 deprivation, missed school/work days, adverse psychosocial effects, and reduced

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61 quality of life.5-7 The mainstay of therapy for mild-to-moderate atopic dermatitis (AD) has

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62 long been emollients and topical corticosteroids. Topical corticosteroids (TCS) are

63 highly effective, but their use has been limited by concerns about side effects,

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64 particularly skin atrophy, striae and systemic absorption. Although adverse events are

65 infrequent, phobia about the use of steroids has limited patient adherence to physician-

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prescribed regimens that include topical steroids.8 Topical calcineurin inhibitors (TCIs),
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67 tacrolimus ointment for moderate-to-severe AD and pimecrolimus cream for mild-to-

68 moderate AD, became available for children 2 years and older and adults in 2000
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69 (tacrolimus)9 and 2001 (pimecrolimus).10 These agents showed anti-inflammatory

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70 effects on a par with low- to moderate-strength topical corticosteroids without the

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71 atrophogenic potential side effects of steroids and with minimal evidence of potential

72 absorption. However, burning or stinging with application can occur, especially when
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73 applied to more inflamed areas of skin. Furthermore, concerns about the theoretical

74 increased risk of cutaneous lymphoma and non-melanoma skin cancer, despite no

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75 evidence of systemic immunosuppression, led to the introduction of a black box warning

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76 for the entire TCI class in 2006.11,12 To date, there has been no published evidence of

77 any malignancy signal with their use, but the black box warning persists.13-15

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79 Phosphodiesterase 4 (PDE4) activity is increased in AD and associated with pro-

80 inflammatory cytokines

81 Alterations in nucleotide metabolism in atopic disease were first described in 1968 by

82 Szentivanyia et al.16 Elevated PDE activity in a variety of inflammatory cells involved in

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83 AD has been described in adults with AD17-20 and the cord blood of children born to

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84 atopic parents.21 Intracellular cyclic adenosine monophosphate (cAMP) levels depend

85 on the relative rate of cAMP production and degradation. PDE4 degrades cAMP, a

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86 negative regulator of the production of pro-inflammatory cytokines (Fig. 1) such as

87 interleukin (IL)-4, IL-31,22,23 and prostaglandin-2 (PGE-2).24 Elevated PDE activity is

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associated with increased histamine release from AD inflammatory cells and
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89 spontaneous IgE synthesis in cultured B lymphocytes from patients with AD.25,26 These

90 in vitro studies suggested that PDE could be a potential therapeutic target.

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91
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92 The first medicinal use of a PDE inhibitor was by Henry Hyde Salter, an asthmatic. He
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93 noted that his breathing eased when he drank two cups of strong coffee on an empty

94 stomach in the morning – an effect that he attributed to the bronchodilator properties of

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95 caffeine, later found to be a weak non-selective PDE inhibitor.27,28 Weak PDE inhibitors

96 such as the caffeine, theophylline, and papaverine were investigated in AD patients,29-32

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97 with largely negative results, including in double-blinded, placebo controlled studies.

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98 Although topically applied caffeine 30%-hydrocortisone 0.5% ointment was found to be

99 equivalent to betamethasone valerate 0.1% ointment and superior to hydrocortisone

100 0.5% ointment in AD,33 these studies from the 1990’s were largely abandoned.

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102 Ultimately, several isoforms of PDE were tested, and PDE4 was determined to be the

103 most specific target for decreasing secretion of proinflammatory cytokines in AD.34,22

104 Early PDE4 inhibitors, such as cilomilast, AWD 12-281, and KF66490, reduced

105 inflammation in mouse and guinea pig models, including suppression of both Th2 and

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106 Th1 cytokines.35,36 Schafer et al found that apremilast inhibited peripheral blood

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107 mononuclear cell cytokines and chemokines (CXCL9, CXCL10, IFN-γ, TNF-α, IL-2, IL-

108 12, and IL-23), TNF-α expression by stimulated natural killer cells and UVB-activated

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109 keratinocytes, and psoriasiform features in a mouse model.37 The PDE4 inhibitor E6005

110 has been shown to directly inhibit mechanisms leading to pruritus in addition through

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reducing cytokine/chemokine production.38 In mouse models and cultured cells, E6005
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112 inhibited PAR2-associated itching through its effect on increasing cAMP,39,40 but also

113 through reducing expression of nerve growth factor41 and attenuation of capsaicin-
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114 induced depolarization of dorsal root ganglion neurons.42

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115
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116 Clinical studies of PDE4 inhibitors

117 During the past two decades, several oral and topical PDE4 inhibitors have been
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118 studied and approved for the treatment of a variety of inflammatory disorders, including

119 AD, asthma, chronic obstructive pulmonary disease, psoriasis and psoriatic arthritis,
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120 and rheumatoid arthritis.43

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122 Oral PDE4 inhibitors are minimally immunosuppressive, in contrast to other systemically

123 administered medications for inflammatory skin disease, but have a narrow therapeutic

124 window, with nausea, vomiting, abdominal pain, dyspepsia, and diarrhea as common
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125 adverse events at therapeutic doses.44 Apremilast is FDA-approved for psoriasis and

126 psoriatic arthritis, but early studies for AD have led to mixed results. In open-label

127 adult studies, apremilast is well tolerated with dose-dependent mild side effects

128 (headache, nausea, and soft stools/diarrhea).45,46 However, efficacy has been limited.

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129 In one 12 week, open-label, phase II study in 10 adults with AD and/or allergic contact

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130 dermatitis the primary endpoint (at least 2 point improvement in Investigator Global

131 Assessment [IGA]) was met in only 20% of subjects; only 10% achieved EASI-75 and

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132 an additional 10% also reached EASI-50.45 Response in patients with AD vs. allergic

133 contact dermatitis was not clarified. In a second study or adults with moderate-to-

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severe AD, significant reduction in EASI-50 was observed after 3 months of 20 mg
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135 (n=6) and 30 mg (n=10) twice daily, but this too was an open-label trial without a

136 control group to consider the placebo effect. A phase II, multicenter, randomized,
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137 double-blind, study was recently completed, with placebo vs. 30 vs. 40 mg twice daily
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138 for 12 weeks, followed by re-randomization to 30 or 40 mg twice daily for an additional

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139 12 weeks in 191 adult subjects with moderate-to-severe AD (NCT02087943); results

140 are pending.47

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141 The small size of PDE4 (251 Da) enables consideration as a topical anti-inflammatory

medication. Crisaborole is currently the only FDA-approved selective PDE4 small

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molecule inhibitor, approved in late 2016 for the treatment of mild-to-moderate AD in

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144 adults and children 2 years of age and above; other topical agents are in development

145 (Table 1). The novel boron chemistry and small size of crisaborole contribute to its

146 ability to penetrate the epidermis and dermis to target skin inflammation.48 Crisaborole

147 is rapidly metabolized to an inactive form, thus limiting systemic exposure and off-target
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148 side effects. Preclinical studies in animal models at doses as high as 7% demonstrated

149 safety and lack of carcinogenicity.49

150 A Phase 1 study in 32 healthy volunteers showed excellent tolerability at 13 sensitive

151 and nonsensitive anatomic sites50 although 12% experienced local application–site

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152 reactions in a 6-week, vehicle-controlled study in adults with mild-moderate AD.51

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153 Limited systemic exposure was demonstrated in pK studies in adolescents52 and an 8-

154 day maximal-use systemic exposure (MUSE) study in children 2-17 years of age.53 A

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155 phase 2, randomized, controlled, dose-ranging study found greatest improvement in 2%

156 (vs. 0.5%) crisaborole and twice (vs. once) daily in adolescents.54 In two parallel

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randomized, double-blinded, vehicle-controlled, phase 3 pivotal studies, twice daily
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158 application of crisaborole ointment (vs. vehicle) for 28 days had a favorable efficacy and

159 safety profile in patients 2 years and older with mild-to-moderate AD.55 In each study
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160 crisaborole ointment 2% treatment met its primary endpoint of statistically greater
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161 reduction in the Investigator Static Global Assessment (ISGA) by at least two points to
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162 reach ISGA clear (0) or almost clear (1) at day 29 compared to vehicle-treated

163 patients.55 Crisaborole treated patients achieved earlier success in ISGA score and
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164 improvement in pruritus than those treated with vehicle as early as day 8 of treatment

165 and sustained throughout the study. Each AD sign (erythema, exudation, excoriation,
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166 induration/papulation, and lichenification) was significantly reduced when the results of
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167 the two parallel studies were pooled at day 29,55 crisaborole also led to significant

168 improvement over vehicle in both individual trials for erythema, exudation, excoriation

169 and lichenification (all p<0.05) and in one of the two trials for induration/population.55

170 Based on patient diaries, improved pruritus was seen earlier in crisaborole-treated
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171 patients than in those treated with vehicle (1.37 vs. 1.70 days, p=0.001). With pruritus

172 measured on a 4-point scale (0-3), pruritus improvement occurred more often at each

173 time point with the crisaborole vs. vehicle (pooled data; days 8, 15, 22; p<0.001; day 29,

174 p=0.002).

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175 The use of crisaborole ointment twice daily for 28 days was associated with a favorable

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176 safety profile without evidence of skin atrophy or telangectasias during the 4 weeks of

177 testing. The major adverse effect was stinging/burning with application (4.4%),

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178 compared to historical rates of application site burning reported by tacrolimus (11%) and

179 pimecrolimus (10%);56 no head-to-head trials have been performed. Of the subjects who

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experienced application site stinging/burning, 76% reported it on the first day of
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181 treatment and 77% reported resolution within 24 hours of onset. There were no reports

182 of serious adverse events. Gastrointestinal side effects were described in crisaborole
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183 treated patients at low frequency (2.7%) and were not considered treatment related.55
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184 To assess long-term safety of crisaborole ointment, a multicenter, open-label, 48-week

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185 safety study was conducted of 517 patients >2 years of age with mild-to-moderate AD

186 who completed the 28-day phase 3 pivotal study. Few treatment-emergent adverse
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187 events considered related to the topical crisaborole were noted, most of which were of

188 mild-to-moderate in severity.

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189 Most frequently reported treatment-related AES were application site pain
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190 (stinging/burning), worsening or flare of atopic dermatitis, and infection. GI side effects

191 (nausea, vomiting), which are a common side effect of apremilast (oral PDE4 inhibitor),

192 occurred in <1% of subjects and were not thought to be treatment-related.57

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194 Other selective PDE4 inhibitors are currently in the pipeline (Table 1). Of these, the only

195 one with phase 2 trial reported outcomes in the US is OPA-15406. In an 8-week dose-

196 finding study of twice daily use, 20.9% of those on OPA-15406 1% (p=0.017) and 14.6%

197 of those on OPA-15406 0.3% (p=0.07) achieved the endpoint of IGA reduction >2 to

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198 clear or almost clear by 4 weeks vs. 2.7% of those on vehicle. Mean EASI scores in the

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199 OPA-15406 1% treatment group were decreased by 31.4% at week 1 and 39.0% by

200 week 2, and the mean visual analogue scale pruritus score improved from moderate-to-

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201 mild within 1 week. Improvement was sustained throughout the 8-week trial, but the

202 difference in improvement between the OPA-15406 and vehicle arms diminished by 8

203 weeks.58
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204 E6005 (parent of RVT-501) has completed phase 2 trials in Japan. In phase 1 trials in

205 adult healthy volunteers and patients with AD, application of E6005 ointment was well
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206 tolerated and led to very low systemic exposure.59 In phase 2 dose-finding studies,
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207 0.2% was found to give the most significant improvement in lesions60 and similarly was
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208 found to be more effective than lower dosing in children.61 An additional, double-blind,

209 randomized, vehicle-controlled multicenter trial of 78 adult patients showed significant

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210 reduction in EASI and SCORAD scores after 12 weeks.62 This compound has now

211 completed its first clinical trial in the US in adolescents and adults, comparing 28 days
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212 of 0.2 vs 0.5% vs. vehicle ointment for mild-to-moderate AD; results are not yet
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213 available.

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215 Conclusions:
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216 There is a need for additional topical treatments for AD. PDE4 activity is increased in

217 inflammatory cells of patients with AD, leading to degradation of intracellular cAMP, with

218 subsequent increased production of proinflammatory cytokines. PDE4 inhibitors are a

219 promising targeted treatment option for children and adults with mild-to-moderate AD.

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220 Future studies will be needed explore the efficacy and safety of PDE4 compounds

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221 beyond crisasborole and in pediatric patients below the age of 2 years.

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351 48. Jarnagin K, Chanda S, Coronado D, et al. Crisaborole topical ointment, 2%: a
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352 nonsteroidal, topical, anti-Inflammatory phosphodiesterase 4 inhibitor in clinical

353 development for the treatment of atopic dermatitis. J Drugs Dermatol.

C

354 2016;15:390-6.
AC

355 49. Ciaravino V, Coronado D, Lanphear C, et al. 2-Year animal carcinogenicity

356 results for crisaborole, a novel phosphodiesterase 4 inhibitor for atopic dermatitis.

357 J Dermatol Sci. 2017;87:116-22.

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358 50. Zane LT, Hughes MH, Shakib S. Tolerability of crisaborole ointment for

359 application on sensitive skin areas: a randomized, double-blind, vehicle-

360 controlled study in healthy volunteers. Am J Clin Dermatol. 2016;17:519-26.

361 51. Murrell DF, Gebauer K, Spelman L, et al. Crisaborole topical ointment, 2% in

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362 adults with atopic dermatitis: a phase 2a, vehicle-controlled, proof-of-concept

RI
363 study. J Drugs Dermatol. 2015;14:1108-12.

364 52. Tom WL, Van Syoc M, Chanda S, et al. Pharmacokinetic profile, safety, and

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365 tolerability of crisaborole topical ointment, 2% in adolescents with atopic

366 dermatitis: an open-label phase 2a study. Pediatr Dermatol. 2016;33:150-9.

367
U
53. Zane LT, Kircik L, Call R, et al. Crisaborole topical ointment, 2% in patients ages
AN
368 2 to 17 years with atopic dermatitis: a phase 1b, open-label, maximal-use

369 systemic exposure study. Pediatr Dermatol. 2016;33:380-7.

M

370 54. Stein Gold LF, Spelman L, Spellman MC, et al. A phase 2, randomized,
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371 controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and
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372 2% in adolescents with mild to moderate atopic dermatitis. J Drugs Dermatol.

373 2015;14:1394-9.
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374 55. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole

375 ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the

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376 topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad
AC

377 Dermatol. 2016;75:494-503.e6.

378 56. Paller AS, Lebwohl M, Fleischer AB, et al. Tacrolimus ointment is more effective

379 than pimecrolimus cream with a similar safety profile in the treatment of atopic
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380 dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol.

381 2005;52:810-22.

382 57. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole

383 ointment 2% in children and adults with mild to moderate atopic dermatitis. J Am

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384 Acad Dermatol. 2017;77:641-9.e5.

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385 58. Hanifin JM, Ellis CN, Frieden IJ, et al. OPA-15406, a novel, topical, nonsteroidal,

386 selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and

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387 adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II

388 randomized, double-blind, placebo-controlled study. J Am Acad Dermatol.

389 2016;75:297-305.
U
AN
390 59. Ohba F, Matsuki S, Imayama S, et al. Efficacy of a novel phosphodiesterase

391 inhibitor, E6005, in patients with atopic dermatitis: An investigator-blinded,

M

392 vehicle-controlled study. J Dermatolog Treat. 2016;27:467-72.

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393 60. Ohba F, Nomoto M, Hojo S, et al. Safety, tolerability and pharmacokinetics of a
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394 novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in

395 patients with atopic dermatitis. J Dermatolog Treat. 2016;27:241-6.

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396 61. Nemoto O, Hayashi N, Kitahara Y, et al. Effect of topical phosphodiesterase 4

397 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a
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398 randomized, vehicle-controlled exploratory trial. J Dermatol. 2016;43:881-7.

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399 62. Furue M, Kitahara Y, Akama H, et al. Safety and efficacy of topical E6005, a

400 phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis:

401 results of a randomized, vehicle-controlled, multicenter clinical trial. J Dermatol.

402 2014;41:577-85.
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403 Abbreviation and Acronym List:

404 AC – Adenylyl cyclase

405 AD – Atopic Dermatitis

406 ATP – Adenosine triphosphate

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407 cAMP – cyclic adenosine monophosphate

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408 Da – Dalton

409 EASI – Eczema Area Severity Index

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410 IFN-γ - Interferon gamma

411 IGA – Investigator Global Assessment

412 IFN-γ - Interferon gamma

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413 IgE – Immunoglobulin E
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414 IL – Interleukin

415 ISGA – Investigator Static Global Assessment

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416 NFAT – Nuclear factor of activated T-cells

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417 NFκB – Nuclear factor kappa-light-chain-enhancer of activation B cell

418 PAR-2 – Proteinase-activated receptor-2

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419 PDE – Phosphodiesterase

420 PGE-2 – Prostoglandin E2

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421 pK – Pharmacokinetics
AC

422 PKA – Protein kinase A

423 SCORAD – Scoring of Atopic Dermatitis

424 TCI – Topical calcineurin inhibitor

425 TCS – Topical corticosteroid

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426 Th1 – T helper cell 1

427 Th2 – T helper cell 2

428 TNF-α - Tumor necrosis factor alpha

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AN
M
D
TE
C EP
AC
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429 Table 1. Studies performed or in progress with a PDE4 inhibitor for AD

430

PT
Study Study Primary Results
Study type Location Indication Age Duration References
Number Size Endpoints posted
AN2728 (crisaborole)

RI
No SAEs, 10
out of 23 https://clinicalt

SC
Phase I/II - Treatment-
subjects with rials.gov/ct2/s
Two, Open- related
NCT016 treatment how/NCT0165
Label, Single- USA AD 12-17y 23 28 Days AEs/SAEs,
52885 related AE. 2885
group pharmaco-

U
53 Limited
Studies kinetics.
systemic

AN
exposure.
https://clinicalt
Phase II - Improvement Greatest rials.gov/ct2/s

M
Multi-center, in Atopic improvement how/NCT0160
NCT016
Randomized, USA AD 12-17y 86 29 Days Dermatitis at day 8 and 2341
02341
Double-Blind, Severity Index 29 with 1%

D
Parallel-group (ADSI) score. concentration.

TE
% with ISGA
Primary
score clear or
endpoint and
almost clear at
Phase III - reduced
day 29; Time https://clinicalt
EP
Multicenter, pruritus
to ISGA rials.gov/ct2/s
NCT021 Randomized, Mild/Mod achieved with
USA >2y 764 28 Days treatment how/NCT0211
18792 Double-Blind, AD crisaborole
success; 8792
C

Vehicle- more than

Change from https://clinicalt
Controlled vehicle. Local
baseline in AD rials.gov/ct2/s
AC

application site
signs at day how/NCT0211
pain reported
29. 8766
by 4.4% of
Phase III - % with ISGA
active vs. 1.2%
Multicenter, score clear or
NCT021 Mild/Mod placebo+I19.
Randomized, USA >2y 763 28 Days almost clear at
18766 AD No SAEs
Double-Blind, day 29; Time
reported.
Vehicle- to ISGA
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Controlled treatment
(parallel success;
to NCT0211- Change from
55
8792) baseline in AD
signs at day

PT
29.
At day 28,
greater

RI
decrease in
Phase III - ADSI score in
Multi-Center, active-treated https://clinicalt

SC
Randomized, (68%) vs. rials.gov/ct2/s
NCT013 Double-Blind, Mild/Mod Improvement vehicle-treated how/NCT0130
Australia 18-75y 46 6 Weeks
01508 Vehicle- AD in ADSI score. (20%) lesion. 1508

U
Controlled, Local
Parallel- application site

AN
51
group reactions in
12% of
subjects. No

M
SAEs.
https://clinicalt
Phase I -
rials.gov/ct2/s
Single-center,

D
how/NCT0326
NCT032 Randomized, Healthy Skin irritation Open for
Japan 20-55y 32 4 Days 0595
60595 Vehicle- Men index enrollment

TE
controlled,
Parallel-group
EP
https://clinicalt
rials.gov/ct2/s
Phase II - how/NCT0323
C

Randomized, Total Sign 3529

NCT032 Double-blind, Mild/Mod Score (TSS) Open for
AC

Canada >18y 40 4 Weeks

33529 Vehicle- AD and enrollment
controlled biomarkers.
(Biomarker)
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https://clinicalt
Phase IV - Impact of rials.gov/ct2/s
Randomized, internet- how/NCT0325
NCT032 Mild/Mod Open for
Double-blind, USA 2-64y 40 12 Month reporting 0663
50663 AD enrollment
Parallel-group intervention on

PT
(Adherence) adherence.

RI
OPA-15405

Phase I -

SC
Multi-center,
Randomized, https://clinicalt
Blinded, rials.gov/ct2/s

U
NCT017 Vehicle-and- AEs/SAEs, how/NCT0170
USA AD 18-65y 92 4 Weeks None
02181 active drug levels. 2181

AN
Comparator-
controlled,
Sequential

M
Dose Cohort
Highest
Phase I -
AUC12h with https://clinicalt
Single-center,

D
OPA-15406 rials.gov/ct2/s
Randomized,
Pharmaco- 3%. No how/NCT0233
NCT023 Double-blind, Healthy

TE
Japan 20-40y 32 2 Weeks kinetic reported AEs 4787
34787 Parallel- Men
parameters. or SAEs.
group,
Placebo-
EP
controlled
Phase II -
Multi-center,
C

Randomized, https://clinicalt
Double-blind, rials.gov/ct2/s
AC

NCT029 IGA response

Parallel- Japan AD 15-70y 200 Not Listed None how/NCT0291
14548 rate.
group, 4548
Vehicle-
controlled,
Comparison
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Phase II -
Multi-center, https://clinicalt
The number
Randomized, rials.gov/ct2/s
and
NCT030 Double-blind, how/NCT0301
Japan AD 2-14y 73 4 Weeks percentage of None
18691 Parallel- 8691

PT
subjects with
group,
AEs.
Vehicle-
controlled

RI
Improvement
in IGA, EASI,
pruritus with

SC
Phase II - OPA-15406
Multi-center, 1%. Negligible
Incidence and https://clinicalt
Randomized, blood levels.
severity of AEs rials.gov/ct2/s

U
NCT020 Double-blind, Mild/Mod Most common
USA 10-70y 94 8 Weeks and incidence how/NCT0206
68352 Vehicle- AD treatment-

AN
of success in 8352
controlled, related AEs:
IGA score.
Three-arm, worsening
Parallel-group AD/pruritus,

M
headache,
naso-
pharyngitis.

D
https://clinicalt
Plasma rials.gov/ct2/s
Phase II -

TE
NCT029 concentrations how/NCT0294
Multi-center, USA AD 2-18y 32 28 Days None
45657 drug and 5657
Open-label
metabolite.
EP
E6005/RVT-501
C

Phase I/II -
No skin
Two https://clinicalt
AC

irritation or
Randomized, rials.gov/ct2/s
Males with photosensiti-
Investigator- Pharmaco- how/NCT0117
NCT011 AD or zation. Plasma
blind, Japan 20-65y 76 Not Listed kinetic 9880
79880 Healthy concentrations
Parallel- parameters.
Men below the
group,
limit of
Vehicle-
quantification.
controlled
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60
Studies

PT
RI
A Phase I/II -
Two https://clinicalt

SC
Randomized, rials.gov/ct2/s
Pharmaco-
Double-blind, how/study/NC
NCT020 Mild/Mod kinetic
Parallel- Japan 2-15y 62 Not listed None T02094235
94235 AD parameters
group,

U
and AEs.
Vehicle-

AN
controlled
Studies
Phase II -
Randomized,

M
https://clinicalt
Single-
Changes in rials.gov/ct2/s
NCT014 blinded, 4 wks, 8 wk
Japan AD 20-64y 78 pruritus and None how/NCT0146
61941 Parallel- extension

D
EASI score. 1941
group,
Vehicle-

TE
controlled
Phase II - https://clinicalt
Randomized, rials.gov/ct2/s
EP
NCT029 Double- Pharmaco- how/NCT0295
50922 blinded, USA, AD (<25% kinetics and 0922
12-70y 157 28 Days None
Parallel- Canada mild) safety
C

group, parameters.
Vehicle-
AC

controlled

DRM02
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https://clinicalt
Phase II - Change in
rials.gov/ct2/s
Randomized, Physician
NCT019 how/NCT0199
Double-blind, Canada AD 18-70y 21 6 Weeks Lesion None
93420 3420
Vehicle Assessment

PT
Controlled (PLA).

GW842470X

RI
https://clinicalt

SC
Phase I - rials.gov/ct2/s
Single + repeat Safety and
NCT003 Randomized, how/NCT0035
Europe AD 18-67y 45 10 day expo- pharmaco- None
56642 Single-Blind, 6642
sure kinetics.
Dose-Rising

U
https://clinicalt

AN
Phase II - rials.gov/ct2/s
Randomized, Clinical how/NCT0035
NCT003
Double-blind, Europe Mod AD 18-65y 190 21 days efficacy (EASI None 4510

M
54510
Placebo- score).
controlled

D
Leo-29102

Phase I -
Multi-center, TE https://clinicalt
rials.gov/ct2/s
EP
Pharmaco-
Randomized, how/NCT0144
NCT014 7 days or 6 wks kinetics and
Double-blind, Germany AD 18-65y 58 None 7758
47758 (2 sets) safety
Parallel-
parameters.
C

group,
Prospective
AC

https://clinicalt
Phase I - rials.gov/ct2/s
NCT010 Randomized, how/NCT0100
Europe AD 18-55y 36 7 days AEs None
05823 Double-blind, 5823
Parallel-group
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https://clinicalt
rials.gov/ct2/s
Phase I - how/NCT0095
Male adults
Double-blind, 8516
NCT009 with skin Phototoxic
Single-group, Europe 18-65y 32 5 days None

PT
58516 irritation on reaction
Vehicle-
exam.
controlled

RI
https://clinicalt
Phase I -
rials.gov/ct2/s

SC
Randomized,
how/NCT0089
NCT008 Double-blind, Healthy Safety and
Europe 18-55y 64 Not Listed None 1709
91709 Vehicle- Men tolerability.
controlled,

U
Parallel-group

AN
https://clinicalt
Phase I -
rials.gov/ct2/s
Randomized,
NCT014 how/NCT0142
Single- Europe Healthy 18-55y 102 Not Listed AEs None

M
23656 3656
blinded,
Parallel-group

D
Phase II -
Randomized,

TE
Double-
blinded,
Parallel- https://clinicalt
group, rials.gov/ct2/s
EP
NCT010 Canada, Mild/Mod Change in
Treatment 18-65y 183 4 Weeks None how/NCT0103
37881 Europe AD EASI score.
Efficacy 7881
of LEO
C

29102 vs.
Vehicle vs.
AC

Elidel®
Cream

Roflumilast
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No significant
change (day
Phase II - 15) in
Multi-center, SCORAD,
https://clinicalt
Randomized, TEWL,

PT
Change in rials.gov/ct2/s
NCT018 Double-blind, pruritus. 5
Europe Mod AD 18-65y 40 15 Days Modified Local how/NCT0185
56764 Parallel- reported AEs -
SCORAD. 6764
group, application site

RI
Vehicle- pain, elevated
controlled LFTs, and
naso-

SC
pharyngitis.

U
AN
M
D
TE
C EP
AC
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431 Figure legend

432 Figure 1. PDE4 is increased in atopic dermatitis. PDE4 regulates the production of

433 inflammatory mediators via the degradation of cAMP. Inhibition of PDE4 leads to

434 increased intracellular cAMP, which activates protein kinase A (PKA). Activation of PKA

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435 inhibits NFAT and NFkB signaling pathways and downstream cytokine and chemokine

RI
436 release.

437

U SC
AN
M
D
TE
EP

438
C
AC