crisaborole (EUCRISA) — Drug Profile | TrialistMD

PDE-4 Inhibitor · Topical Small Molecule · Atopic Dermatitis · NDA 207695

crisaborole

EUCRISA™ · Anacor Pharmaceuticals (Pfizer)

First-in-class boron-based topical phosphodiesterase-4 (PDE-4) inhibitor. Inhibits cAMP degradation in inflammatory cells, reducing cytokine-mediated atopic cascade. Approved for mild to moderate atopic dermatitis in patients ≥2 years of age; non-steroidal with no immunosuppressive boxed warning.

NDA Number207695

FDA ApprovalDecember 14, 2016

Priority StatusStandard Review

FormulationOintment, 2%

Pharmacologic ClassPDE-4 Inhibitor

ApplicantAnacor Pharmaceuticals

Overview

§1

Indication

Mild–Moderate AD ≥2 yr

Topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older

Mechanism

PDE-4 Inhibitor

Boron-based benzoxaborole small molecule; topical non-steroidal

Dose & Schedule

Thin layer BID

Applied twice daily to affected areas; topical use only

Phase 3 Programme

2 trials

N=1,522 (ITT); plus long-term safety trial N=517

Mechanism of Action: Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor. PDE-4 inhibition results in increased intracellular cyclic adenosine monophosphate (cAMP) levels. The specific mechanism(s) by which crisaborole exerts its therapeutic action for the treatment of atopic dermatitis is not well defined. (PI §12.1, Ref ID 4027634)

Clinical Trial Programme

§1.2

Trial Name	Design	N Randomised	Duration	Comparator	Primary Endpoint
AN2728-AD-301 (Trial 1)	Phase 3, R, DB, PC, parallel-group, multicenter (48 US sites)	759 (Crisa 503 : Veh 256)	28 days	Vehicle ointment BID	ISGA success at Day 29 (ITT, MI)
AN2728-AD-302 (Trial 2)	Phase 3, R, DB, PC, parallel-group, multicenter (identical design)	763 (Crisa 513 : Veh 250)	28 days	Vehicle ointment BID	ISGA success at Day 29 (ITT, MI)
AN2728-AD-303	Phase 3, open-label, long-term safety, multicenter	517	48 weeks (intermittent)	None (OL)	Safety/tolerability (no formal efficacy endpoint)
AN2728-AD-203 (MUSE PK)	Phase 2/PK, OL, maximal-use	33	8 days	None	PK characterisation (Cmax, AUC₀₋₁₂)

R=randomised; DB=double-blind; PC=placebo-controlled; OL=open-label; ITT=intent-to-treat; MI=multiple imputation; ISGA=Investigator’s Static Global Assessment. Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Section 6.

Competitive Landscape — Topical AD Therapies

§1.3

Drug (INN)	Brand	Target / Class	Formulation	US Approval	Approved Population
Hydrocortisone / TCS (multiple)	Various	Glucocorticoid receptor	Cream/ointment (multiple strengths)	Various	Varies; some ≥3 months
Tacrolimus	Protopic	Calcineurin inhibitor (TCI)	Ointment 0.03%, 0.1%	December 2000	≥2 years (0.03%); moderate–severe AD; second-line
Pimecrolimus	Elidel	Calcineurin inhibitor (TCI)	Cream 1%	December 2001	≥2 years; mild–moderate AD; second-line
Crisaborole	EUCRISA	PDE-4 inhibitor	Ointment 2%	December 14, 2016	≥2 years; mild–moderate AD

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Section 2.2 Table 1. Highlighted row = current drug.

Key Drug Information

§1.4

Proprietary Name	EUCRISA™
INN / Generic Name	crisaborole
Development Code	AN2728
Manufacturer / Applicant	Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303 USA
Pharmacologic Class	Phosphodiesterase 4 (PDE-4) inhibitor; boron-based benzoxaborole
Molecular Formula & MW	C₁₄H₁₀BNO₃; 251.1 g/mol
Chemical Name	5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole
Dosage Form & Strength	Ointment, 2% (20 mg crisaborole per gram)
NDC — 60 g tube	55724-211-21
NDC — 100 g tube	55724-211-11
Inactive Ingredients	White petrolatum, propylene glycol, mono- and di-glycerides, paraffin, butylated hydroxytoluene, edetate calcium disodium
Storage	20–25°C (68–77°F); excursions permitted 15–30°C (59–86°F) [USP Controlled Room Temperature]. Keep tube tightly closed.
Boxed Warning	None
PI Revision Date	December 2016 (Ref ID 4027634)

Source: FDA PI NDA 207695 (Ref ID 4027634), Sections 1, 3, 11, 16.

Baseline Characteristics

§2

Pooled Pivotal Trials (AN2728-AD-301 + AN2728-AD-302): Combined ITT N=1,522 across two identically designed trials. Randomised 2:1 (crisaborole:vehicle). 86.3% of subjects were 2–17 years of age. Demographic and baseline disease characteristics were comparable between treatment arms in both trials.

Trial AN2728-AD-301 Baseline

§2.1

Parameter	Crisaborole 2% BID (N=503)	Vehicle BID (N=256)
Age range (years)	2–79	2–79
Age 2–11 years, approx. %	~60%	~60%
Age 12–17 years, approx. %	~25%	~25%
Age ≥18 years, approx. %	≤15%	≤15%
Sex: Female	Majority	Majority
Race: White	Majority	Majority
Ethnicity: Not Hispanic/Latino	Majority	Majority
ISGA 2 (Mild) at baseline, % (pooled)	38.5%	38.5%
ISGA 3 (Moderate) at baseline, % (pooled)	61.5%	61.5%
Mean treatable BSA, %	~18%	~18%
Treatable BSA range	5%–95%	5%–95%
Prior biologic therapy	Excluded per protocol	Excluded per protocol

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Tables 12–14 (ITT population). Exact SD and mean values not reported in extractable text form for all parameters; “~” denotes approximate values from narrative descriptions. ISGA pooled percentages per FDA PI §14 (Ref ID 4027634).

Trial AN2728-AD-302 Baseline

§2.2

Parameter	Crisaborole 2% BID (N=513)	Vehicle BID (N=250)
Mean age (years)	12.6	11.8
Age range (years)	2–79	2–79
Age 2–11 years, approx. %	~60%	~60%
Age 12–17 years	~25%	~25%
Age ≥18 years	≤15%	≤15%
Sex: Female	Majority	Majority
Race: White	Majority	Majority
Ethnicity: Not Hispanic/Latino	Majority	Majority
ISGA 3 (Moderate) at baseline	Majority	Majority
Mean treatable BSA, %	18%	18%
Treatable BSA range	5%–95%	5%–95%
Dosing compliance (≥80–120% doses applied)	93.6%	87.6%

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Table 12 and narrative pp. 83–84 (ITT population). Mean age explicitly reported for Trial 302 only; “~” denotes approximate values from narrative descriptions.

Inclusion / Exclusion Criteria

§2.3

Category	Criterion
Inclusion — Age	Male or female ≥2 years at Baseline/Day 1
Inclusion — Diagnosis	Clinical diagnosis of AD per Hanifin and Rajka criteria
Inclusion — Severity	ISGA score of Mild (2) or Moderate (3) at Baseline/Day 1
Inclusion — BSA	AD involvement ≥5% treatable BSA (excluding scalp)
Inclusion — Sub-group quotas	≥20% subjects aged 2–6 years; ≤15% subjects ≥18 years (per Division recommendation)
Exclusion — Disease stability	Unstable AD or consistent requirement for high-potency TCS to manage signs/symptoms
Exclusion — Infection	Significant active systemic or localised infection, including known actively infected AD
Exclusion — Prior treatment	Any history of biologic therapy including intravenous immunoglobulin
Exclusion — Concomitant treatment	Recent or anticipated concomitant use of systemic or topical therapies that might alter the course of AD

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Section 6.1.1 Protocol AN2728-AD-301 Study Population.

Subgroup Analysis Framework

§2.4

Pre-specified subgroup analyses (primary endpoint): Gender, age group (2–11, 12–17, ≥18 years), race (White, Black, Other), ethnicity (Hispanic/Latino vs. not), and baseline ISGA (2 vs. 3). Per FDA Statistical Review (Matthew Guerra, PhD, dated 8/19/2016): treatment effect was greater in females than males, greater in White vs. Black subjects, and greater in subjects with moderate (ISGA 3) vs. mild (ISGA 2) disease at baseline. Treatment effect was greater in Hispanic/Latino vs. non-Hispanic subjects. Age subgroup results were inconsistent across the two trials. Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Tables 26–27, p. 90.

Efficacy

§3

Primary Endpoint: Proportion of subjects achieving ISGA success at Day 29 — defined as ISGA score of Clear (0) or Almost Clear (1) with ≥2-grade improvement from baseline. Statistical framework: Logistic regression with Firth’s penalised likelihood; factors = treatment group + analysis centre. Missing efficacy data: Markov Chain Monte Carlo (MCMC) multiple imputation (MI). Hypothesis testing: two-sided α=0.05. FWER controlled sequentially (primary → secondary ISGA 0/1 → time to ISGA success).

Primary Endpoint — Day 29 (ITT, MI)

§3.1

AN2728-AD-301 (TRIAL 1) · ISGA SUCCESS AT DAY 29 N=759; 2:1 randomisation; vehicle-controlled; p=0.038

Crisaborole 2% BID (N=503)

32.8%

p=0.038

Vehicle BID (N=256)

25.4%

AN2728-AD-302 (TRIAL 2) · ISGA SUCCESS AT DAY 29 N=763; 2:1 randomisation; vehicle-controlled; p<0.001

Crisaborole 2% BID (N=513)

31.4%

p<0.001

Vehicle BID (N=250)

18.0%

ISGA Success Over Time — Chart

§3.2

Data availability note: Intermediate timepoint values (Days 1, 8, 15, 22) are presented graphically only in FDA PI Figure 1 and Medical Review Figure 5; they are not reported in extractable tables. Per data accuracy standards, only the explicitly tabulated Day 29 values are plotted. Intermediate points marked null (spanGaps: false).

ISGA Success Rate (%) at Day 29 — Trials 1 & 2 (ITT, MI)

Source: FDA PI NDA 207695 (Ref ID 4027634), Table 2 (§14); FDA Medical Review NDA 207695 (Ref ID 3983007), Table 17. Only Day 29 values are explicitly tabulated; intermediate timepoints not plotted per data accuracy standards.

Secondary Endpoints — Day 29 (ITT, MI)

§3.3

ISGA SCORE CLEAR (0) OR ALMOST CLEAR (1) AT DAY 29 — NO IMPROVEMENT THRESHOLD Secondary endpoint; LOCF for missing data

Trial 1 — Crisaborole (N=503)

51.7%

p=0.005

Trial 1 — Vehicle (N=256)

40.6%

Trial 2 — Crisaborole (N=513)

48.5%

p<0.001

Trial 2 — Vehicle (N=250)

29.7%

All Efficacy Endpoints Summary

§3.4

Endpoint	Trial 1 — Crisa / Vehicle	p-value	Trial 2 — Crisa / Vehicle	p-value
ISGA success Day 29 (primary, ITT/MI)	32.8% / 25.4%	0.038	31.4% / 18.0%	<0.001
ISGA Clear or Almost Clear Day 29 (2°, ITT/MI)	51.7% / 40.6%	0.005	48.5% / 29.7%	<0.001
Time to ISGA success (2°, log-rank)	Median NC	<0.001	Median NC	<0.001
ISGA success Day 29 (PP population)	32.4% / 26.9%	0.088^a	32.2% / 18.3%	<0.001
ISGA Clear or Almost Clear (PP)	51.7% / 43.8%	0.032	50.0% / 29.8%	<0.001
Time to ISGA success (PP, log-rank)	Median NC	0.003	Median NC	<0.001

^a Trial 1 PP primary endpoint did not reach statistical significance. FDA accepted this given confirmed significance in Trial 2 ITT (replicate trial design) and significant PP secondary endpoints. NC = not calculated (fewer than 50% of subjects reached success). Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Tables 17–18.

Exploratory Endpoints (Not for Labelling)

§3.5

PRO/Endpoint	Instrument / Scale	Finding	Regulatory Status
AD signs improvement (erythema, induration/papulation, exudation, excoriation, lichenification)	4-point global assessment scale; success = None (0) or Mild (1) with ≥1-grade improvement from baseline	Greater proportion of crisaborole subjects improved on all signs vs. vehicle at Day 29 (both trials)	Exploratory — FDA-agreed not for labelling (PRO dossier adequate for exploratory; EOP2 guidance)
Time to pruritus improvement	4-point pruritus severity scale; success = None (0) or Mild (1) with ≥1-grade improvement	Greater improvement in crisaborole arm at Day 29 (both trials)	Exploratory — downgraded from secondary; baseline pruritus PRO dossier not submitted pre-NDA

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Section 7.1.1 Table 19; EOP2 meeting guidance February 26, 2014.

Safety & ADRs

§4

No Boxed Warning. EUCRISA (crisaborole) ointment, 2% carries no boxed warning. This is a key differentiator from topical calcineurin inhibitors (tacrolimus, pimecrolimus) which carry a boxed warning regarding potential malignancy risk. (PI §1, Ref ID 4027634)

Safety Population (Controlled)

1,511

Crisa N=1,012; Vehicle N=499 (pooled Trials 301+302)

Long-Term Safety N

517

AN2728-AD-303; up to 48 weeks intermittent

Follow-up Duration

28 days

Pivotal trials; 48 weeks in LT trial (52.4% completed 12 mo)

Most Common ADR (≥1%)

4.0%

Application site pain (burning/stinging) — crisa vs. 1.0% vehicle

Warnings & Precautions

§4.1

Hypersensitivity Reactions (§5.1): Hypersensitivity reactions including contact urticaria have occurred. Hypersensitivity should be suspected in the event of severe pruritus, swelling, and erythema at the application site or at a distant site. If signs and symptoms occur, discontinue EUCRISA immediately and initiate appropriate therapy.

Adverse Reactions ≥1% — Pooled Controlled Trials (Through Week 4)

§4.2

Adverse Reaction	Crisaborole 2% BID (N=1,012) n (%)	Vehicle BID (N=499) n (%)
Application site pain^a	45 (4%)	6 (1%)

^a Refers to skin sensations such as burning or stinging. Less common (<1%): contact urticaria. Source: FDA PI NDA 207695 (Ref ID 4027634), §6.1 Table 1; FDA Medical Review NDA 207695 (Ref ID 3983007).

Serious Adverse Events (SAEs)

§4.3

Trial	Crisaborole n (%)	Vehicle n (%)	Notable SAE Terms
AN2728-AD-301	5/502 (1.0%)	1/252 (0.4%)	Appendicitis, Kawasaki’s disease, suicide attempt, pneumonia, acute asthma exacerbation — all assessed unrelated
AN2728-AD-302	3/510 (0.6%)	0/247 (0%)	Multiple lacerations (accident), impetigo at application site, suicidal ideation — none clearly related
AN2728-AD-303 (LT, OL)	Multiple (see narrative)	N/A (OL)	Upper respiratory infection, eczema superinfection, asthma exacerbation, MRSA — none drug-related

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Tables 38–39, pp. 110–121.

Deaths

§4.4

No deaths were reported in either pivotal Phase 3 controlled trial (AN2728-AD-301, AN2728-AD-302) or in the long-term safety trial (AN2728-AD-303). Source: FDA Medical Review NDA 207695 (Ref ID 3983007).

Discontinuations Due to AEs

§4.5

Trial / Population	Crisaborole	Vehicle	Leading AE Terms (Crisa arm)
Pooled Trials 301+302 (Safety Pop.)	12/1,021 (1.2%)	6/506 (1.2%)	Majority: application site reactions. Age 2–11 predominant (10/12 subjects). No subject ≥18 years discontinued due to AE.
AN2728-AD-303 (LT Safety)	9/517 (1.7%)	N/A	Dermatitis atopic (5, 1.0%), application site pain (2, 0.4%), application site dermatitis (1, 0.2%), eczema (1, 0.2%)

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Table 42 and Table 69.

Severe TEAEs (>1 subject) — Pooled Pivotal Trials

§4.6

Adverse Event (MedDRA PT)	Crisaborole 2% BID (N=1,012) n (%)	Vehicle BID (N=499) n (%)
Application site pain	8 (0.8%)	0 (0%)
Dermatitis atopic	3 (0.3%)	2 (0.4%)
Pruritus	2 (0.2%)	1 (0.2%)

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Table 45.

Laboratory Abnormalities

§4.7

No clinically meaningful laboratory abnormalities were identified in the pivotal controlled trials. Standard serum chemistry and haematology were assessed at Screening, Baseline, and Day 29. No drug-related laboratory signals were reported in the Medical Review. Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Section 8.

Cardiovascular / QTc Safety

§4.8

Thorough QT Study (AN2728-TQT-108): At doses up to 45 g/day (~60% BSA), no clinically relevant QTc prolongation observed. No subject had QTcF >480 ms; no change in QTcF >60 ms. In Phase 3 ECG subset (N=615), 2 crisaborole subjects aged ≥18 had QTcF 450–480 ms.

QT-IRT caveat: TQT exposures did not cover exposures seen in the Phase 3 pediatric PK study (mean Cmax 127 ng/mL at Day 8; individual Cmax up to 1,170 ng/mL in age 6–11 subgroup). QT effect in the very young, high-BSA population cannot be fully excluded from available data. Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Sections 4.5.2 and 8.4.9.

Psychiatric Adverse Events (Special Monitoring)

§4.9

Long-term safety trial AN2728-AD-303 (N=517): 12 subjects (2.3%) reported events in psychiatric disorders SOC: anxiety (2, 0.39%), ADHD (4, 0.77%), depression (4, 0.77%), insomnia (2, 0.39%), suicidal ideation (1, 0.19%), suicide attempt (1, 0.19%). Only 1 subject was ≥18 years. No correlation between greater drug exposure and greater psychiatric events. Pivotal controlled trials: 1 suicide attempt (Trial 301, crisaborole arm, Day 27 — assessed unrelated; onset of stress 2 months prior); 1 suicidal ideation (Trial 302, vehicle arm). Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Table 55, Section 8.11.

Special Populations Safety

§4.10

Population	Data Available	Key Findings
Pregnancy	No human data	Animal: no adverse fetal effects at ≤5× MRHD (rat) and ≤3× MRHD (rabbit). Maternal toxicity at 18× MRHD associated with stillbirths, pup mortality, reduced pup weights. No fetal malformations noted.
Lactation	No data (human milk)	Systemically absorbed. No data on breast milk presence or infant effects. Weigh breastfeeding benefits vs. potential risk.
Paediatric ≥2 years	1,313 paediatric subjects (pivotal RCTs)	Safety and efficacy established. 86.3% of pivotal trial subjects were aged 2–17 years.
Paediatric <2 years	Not established	Post-marketing deferred study required (open-label safety/PK; ages 3 months–<2 years; N≥100 evaluable).
Geriatric (≥65 years)	Insufficient numbers	Clinical studies did not include sufficient subjects ≥65 years to determine age-specific differences in response.
Renal/Hepatic Impairment	No formal studies	No dosing recommendations in label. Topical route with low systemic exposure.

Source: FDA PI NDA 207695 (Ref ID 4027634), §8.1–8.5; FDA Medical Review NDA 207695 (Ref ID 3983007).

Nonclinical Safety Summary

§4.11

Carcinogenicity (Oral, Sprague-Dawley Rat) Drug-related increased incidence of benign granular cell tumors in uterus with cervix or vagina (combined) at 300 mg/kg/day (2× MRHD on AUC basis). Clinical relevance unknown. No neoplastic findings in dermal study (CD-1 mice) up to 7% crisaborole (2× MRHD).

Genotoxicity Negative in all assays: Ames assay (in vitro); human lymphocyte chromosomal aberration assay (in vitro); rat micronucleus assay (in vivo). No mutagenic or clastogenic potential identified.

Reproductive Toxicity / Fertility No effects on fertility in male or female rats at up to 600 mg/kg/day (18× MRHD). Maternal toxicity at 600 mg/kg/day in prenatal/postnatal rat study: stillbirths, pup mortality, reduced pup weights. No fetal malformations.

Cardiac Safety (hERG) Crisaborole classified as low-potency hERG channel blocker in vitro. Safety pharmacology studies in rats, mice, dogs, minipigs: no cardiac effects at therapeutic exposures. One dog death at 300 mg/kg/day (high-dose); no QTc effects at that dose level. TQT study negative at 45 g/day.

Source: FDA PI NDA 207695 (Ref ID 4027634), §13.1; FDA Medical Review NDA 207695 (Ref ID 3983007), Sections 4.1–4.5.

Long-Term Safety ADRs ≥1% (AN2728-AD-303)

§4.12

Treatment-Related Adverse Reaction	Crisaborole 2% BID (N=517)	Causality
Any treatment-related AE	34 (6.6%)	Possible/Probable/Definite combined
Dermatitis atopic	11 (2.1%) possible; 4 (0.8%) probable; 1 (0.2%) definite	Possible/Probable/Definite
Application site pain	3 (0.6%) possible; 7 (1.4%) probable; 6 (1.2%) definite	Possible/Probable/Definite
Application site infection	Not reported at ≥1%	—

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Table 72.

Weight Change — Long-Term Safety Signal

§4.13

Weight loss signal (AN2728-AD-303): Clinically meaningful weight loss (>10% at any timepoint) was observed in a subset of subjects, particularly in the 2–9 year age group. A correlation between weight change from baseline and total crisaborole usage (g) was observed in the 2–9 year cohort (Figure 7, Medical Review). No similar signal in the 28-day controlled trials. Clinical relevance uncertain. Monitored in post-approval safety programme. Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Tables 58–61, Figures 6–7.

Pharmacology & PK

§5

Cmax (Day 8)

127 ± 196

ng/mL mean ± SD; pediatric AD subjects (n=33); at steady state

AUC₀₋₁₂ (Day 8)

949 ± 1240

ng·h/mL mean ± SD; 0–12 h post-dose; steady state

Steady State

Day 8

Systemic concentrations at steady state by Day 8 (BID × 8 days)

Accumulation (Parent)

1.9×

AUC₀₋₁₂ ratio Day 8/Day 1

Plasma Protein Binding

97%

In vitro; human plasma proteins

Route of Elimination

Renal

Renal excretion of inactive metabolites is the major route of elimination

Source: FDA PI NDA 207695 (Ref ID 4027634), §12.3; FDA Medical Review NDA 207695 (Ref ID 3983007), Section 5 (PK Study AN2728-AD-203/MUSE). PK study in 33 pediatric subjects aged 2–17 years, mean ± SD BSA 49 ± 20% (range 27–92%), BID application of ~3 mg/cm² for 8 days.

Absorption

§5.1

Percutaneous absorption: Plasma concentrations were quantifiable in all 33 pediatric subjects (BSA involvement 27–92%) following topical application of approximately 3 mg/cm² BID. Dose range per application was approximately 6–30 g. Systemic concentrations reached steady state by Day 8, with a mean accumulation factor of 1.9 for the parent compound. Quantifiable systemic exposure confirms that crisaborole is systemically absorbed through affected skin. No food-effect study applicable (topical route). (PI §12.3, Ref ID 4027634)

Distribution

§5.2

Crisaborole is 97% bound to human plasma proteins based on in vitro studies. Volume of distribution data not explicitly reported in the PI or Medical Review for the topical formulation. (PI §12.3, Ref ID 4027634)

Metabolism

§5.3

Metabolite	Pathway	Accumulation Factor (Day 8/Day 1)	Activity
Metabolite 1: 5-(4-cyanophenoxy)-2-hydroxyl benzylalcohol (AN7602)	Hydrolysis of parent crisaborole	1.7×	Inactive
Metabolite 2: 5-(4-cyanophenoxy)-2-hydroxyl benzoic acid	Oxidation of Metabolite 1	6.3× (significant accumulation)	Inactive

Crisaborole is substantially metabolised into inactive metabolites. Both Metabolite 1 and Metabolite 2 were at or near steady state by Day 8. The high accumulation factor for Metabolite 2 (6.3×) was flagged in FDA review as requiring in vitro CYP DDI evaluation. (PI §12.3, FDA Medical Review §5, Ref ID 3983007)

Drug–Drug Interactions

§5.4

CYP Enzyme	Crisaborole / Met-1 (in vitro)	Metabolite 2 (in vitro)	Clinical DDI Study	Recommendation
CYP1A2, 2B6	No inhibition	Weak inhibitor	None conducted	Not clinically relevant at therapeutic exposures
CYP2C8, 2C9	No inhibition	Moderate inhibitor (in vitro)	Warfarin (CYP2C9 substrate) — no DDI observed	No dose adjustment required
CYP2C19, 2D6, 3A4	No inhibition	No inhibition	None conducted	No concern
CYP induction (all)	No induction (parent + Met-1 + Met-2)	No induction	None conducted	No concern

Source: FDA PI NDA 207695 (Ref ID 4027634), §12.3 Drug Interaction Studies; FDA Medical Review NDA 207695 (Ref ID 3983007), Section 5.

Special Population PK

§5.5

Population	Data	Key Finding
Paediatric 2–17 years	PK study AN2728-AD-203 (n=33)	Cmax 127 ± 196 ng/mL; wide inter-subject variability (CV ~154%). Age 6–11 subgroup: highest mean Cmax ~205 ng/mL; individual Cmax up to 1,170 ng/mL. Steady state Day 8.
Adults / Elderly	Not formally studied (topical)	Not reported. ≤15% of pivotal trial subjects were adults; no PK sub-study in adults.
Renal impairment	Not formally studied	Not reported. Low systemic exposure; no dose adjustment recommended.
Hepatic impairment	Not formally studied	Not reported. No dose adjustment recommended.
BSA effect	PK study (range 27–92% BSA)	Wide range of BSA involvement studied; systemic exposure increased with increasing BSA involvement (high variability).

Source: FDA PI NDA 207695 (Ref ID 4027634), §12.3; FDA Medical Review NDA 207695 (Ref ID 3983007), Table 52.

Mechanism of Action

§5.6

PDE-4 inhibition via boron-based scaffold: Crisaborole is a novel benzoxaborole compound in which the boron atom within a cyclic boronate ester provides selective, reversible binding to PDE-4 through interaction with the bidentate chelation site of the catalytic domain. PDE-4 is the primary cyclic AMP-hydrolysing enzyme in inflammatory cells including T lymphocytes, eosinophils, mast cells, and keratinocytes. Inhibition of PDE-4 elevates intracellular cAMP, leading to protein kinase A activation and downstream suppression of pro-inflammatory cytokine production including IL-4, IL-13, IL-31, TNF-α, and IFN-γ. The precise mechanism(s) by which these effects translate to clinical improvement of atopic dermatitis has not been fully elucidated. (PI §12.1, Ref ID 4027634; FDA Medical Review §4, Ref ID 3983007)

Pharmacodynamics

§5.7

QTc pharmacodynamics: At therapeutic doses, EUCRISA ointment is not expected to prolong QTc to any clinically relevant extent based on thorough QT study AN2728-TQT-108 at doses up to 45 g/day (~60% BSA). No formal PK/PD modelling for ISGA response vs. plasma exposure was reported in the available FDA documents. Dose–response relationship was not formally assessed in the Phase 3 design (single dose level). (PI §12.2, Ref ID 4027634)

Dosing & Contraindications

§6

Approved Dose

Thin layer applied BID to all affected areas

Route

Topical

External use only; not ophthalmic, oral, or intravaginal

Frequency

BID

Twice daily; no specific time interval specified

Duration

As needed

No defined maximum treatment duration in label

Standard Dosing

Apply a thin layer of EUCRISA to all affected areas twice daily
No loading dose; no titration schedule
Single approved dose: 2% ointment (no lower strength available)
Approved for patients ≥2 years; same dosing regimen across all age groups ≥2 years
No weight-based dose calculation required

Dose Modifications

Renal impairment: No dose adjustment recommended (no formal PK study; topical route)
Hepatic impairment: No dose adjustment recommended (no formal PK study)
Age ≥65 years: Insufficient data — no dose adjustment specified in label
Body weight: No weight-based adjustment
Paediatric <2 years: Not established — do not use

Preparation & Administration

No reconstitution required (ready-to-use ointment)
Apply to affected skin areas; avoid eyes, mouth, and vagina
No restriction on application site (apply to all affected areas including face, neck, folds, extremities)
Wash hands after application unless hands are the treated area
No restrictions on concomitant use of emollients stated in label; apply emollients separately
Caregiver: wash hands after applying to another person

Missed Dose / Storage

Missed dose: No specific instructions in PI; apply as soon as remembered and resume regular schedule
Store at 20–25°C (68–77°F)
Excursions permitted: 15–30°C (59–86°F) [USP Controlled Room Temperature]
Keep tube tightly closed
Available as 60 g and 100 g laminate tubes

Contraindications

§6.4

Contraindication (PI §4): EUCRISA is contraindicated in patients with known hypersensitivity to crisaborole or any component of the formulation. Source: FDA PI NDA 207695 (Ref ID 4027634), §4.

Warnings Relevant to Dosing

§6.5

Hypersensitivity monitoring: Monitor for signs of hypersensitivity reactions at or distant from the application site (severe pruritus, swelling, erythema). No pre-treatment laboratory monitoring or screening required. No vaccination precautions applicable (non-immunosuppressive mechanism). No TB screening requirement.

Drug Interactions Affecting Dosing

§6.6

No dose adjustments required for drug interactions. CYP2C9 clinical DDI study with warfarin showed no interaction. Metabolite 2 is a moderate in vitro CYP2C8/2C9 inhibitor but no clinically meaningful interaction was demonstrated at therapeutic exposures. No DDI-based dose modifications recommended in PI. Source: FDA PI NDA 207695 (Ref ID 4027634), §12.3.

Administration Instructions

§6.7

Parameter	Recommendation
Application technique	Apply a thin layer with gentle spreading over affected areas; no rubbing instruction specified
Application areas	All affected skin areas (no anatomical restrictions stated in label). Not for ophthalmic, oral, or intravaginal use.
Concomitant emollients	No specific instructions in PI; no restrictions stated
Hand hygiene	Wash hands after applying unless hands are the treatment area. Caregivers must also wash hands after application.
Occlusion	Not addressed in PI
Paediatric administration	Caregiver-applied acceptable; same technique as adult self-application

Source: FDA PI NDA 207695 (Ref ID 4027634), §2 and §17.

Regulatory History

§7

NDA Key Facts

§7.1

Application Number	NDA 207695
Application Type	NDA 505(b)(1) — original NDA; New Molecular Entity (NME)
Applicant	Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303
Original Developer	Anacor Pharmaceuticals (acquired by Pfizer Inc. in 2016 during NDA review)
Submission Date	January 7, 2016
PDUFA Goal Date	January 6, 2017
Actual Approval Date	December 14, 2016
Review Division	Division of Dermatology and Dental Products (DDDP), CDER
Review Type	Standard Review
Breakthrough Therapy Designation	Not granted
Fast Track Designation	Not reported in available documents
Orphan Drug Designation	Not applicable (atopic dermatitis is not an orphan indication)
Advisory Committee	Not convened (no AdCom for this NDA)
Medical Reviewer	Melinda L. McCord, MD (Review completion date: September 7, 2016)
Medical Review Ref ID	3983007
PI Ref ID	4027634

Regulatory Timeline

§7.2

2012–2013 (ESTIMATED)

IND Programme Established

Phase 1/2 programme initiated with crisaborole (AN2728) in psoriasis and atopic dermatitis. Phase 2 trials used intra-subject lesion-level comparisons with ADSI endpoints — acknowledged as limited for informing Phase 3 assumptions.

FEBRUARY 26, 2014

End-of-Phase 2 (EOP2) Meeting

Division agreed to ISGA-based primary endpoint (ISGA 0/1 with ≥2-grade improvement). Recommended: adult enrolment ≤15%; age 2–6 subgroup ≥20%; EASI replaced by global AD sign assessment; pruritus PRO downgraded to exploratory pending dossier. Applicant accepted all recommendations.

JUNE 2014

Advice Letter (Cardiac Safety)

Division recommended addition of ECG assessment at Baseline and Day 8 at selected Phase 3 sites; full physical examination at end of treatment; enhanced safety monitoring per advice letter June 16, 2014.

2014–2015

Phase 3 Pivotal Trials Conducted (AN2728-AD-301 and AN2728-AD-302)

Two identically designed multicenter trials (48 US sites each). Long-term safety trial AN2728-AD-303 initiated concurrently.

SEPTEMBER 23, 2015

Pre-NDA Meeting

FDA requested in vitro CYP inhibition/induction studies for major metabolite AN7602 (Metabolite 1/2) — results from PK study showed exposure >30% of parent. Sponsor agreed to add warfarin DDI study to NDA package.

JANUARY 7, 2016

NDA 207695 Submitted

Standard NDA submission. Data package included AN2728-AD-301, AN2728-AD-302, AN2728-AD-303 (interim), and multiple PK/safety pharmacology studies including warfarin DDI.

APRIL–MAY 2016

FDA Site Inspections

Four sites inspected (Centers 138, 150, 211, 240). Centers 150, 211, 240: NAI (No Action Indicated). Center 138: VAI (Voluntary Action Indicated). Sensitivity analysis excluding Center 138 showed only minor change in response rates — no impact on data integrity.

SEPTEMBER 7, 2016

Medical Review Completed — Recommendation for Approval

Medical reviewer Melinda McCord, MD recommended approval pending labelling negotiations. Benefit-risk: modest but statistically significant efficacy; favourable safety profile; first non-steroidal/non-TCI topical option for mild-moderate AD without malignancy boxed warning.

DECEMBER 14, 2016

FDA Approval — NDA 207695

EUCRISA (crisaborole) ointment, 2% approved for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older. First PDE-4 inhibitor approved for atopic dermatitis in the United States. Approved ahead of PDUFA date (January 6, 2017).

Key Review Issues

§7.3

Effect Size and Statistical Significance (Trial 301 PP) Trial 301 primary endpoint failed to reach statistical significance in the Per Protocol population (p=0.088). FDA accepted this based on: (1) confirmed significance in Trial 302 ITT and PP; (2) identical trial designs (pre-specified replicate strategy); (3) significance on both PP secondary endpoints in Trial 301. Modest absolute effect size (~7–13 percentage points over vehicle) was acknowledged but accepted given non-steroidal mechanism and chronic disease context.

Phase 2 Estimates for Phase 3 Power Calculations FDA noted Phase 3 power was not based on Phase 2 data using the same study population, endpoints, or success definition. Phase 2 used intra-subject comparisons and ADSI (different from ISGA success). Division accepted the design but flagged this limitation in the EOP2 review.

Metabolite 2 CYP Inhibition — In vitro Signal Metabolite 2 showed moderate in vitro inhibition of CYP2C8 and CYP2C9. As the most sensitive enzyme (CYP2C9), a clinical DDI study using warfarin as a probe substrate was required. Results demonstrated no clinically meaningful drug interaction at therapeutic exposures. Resolved in NDA.

Cardiac Safety / QTc Exposure Gap TQT study (AN2728-TQT-108) performed at up to 45 g/day did not achieve exposures comparable to those observed in the Phase 3 pediatric PK study (individual Cmax up to 1,170 ng/mL in age 6–11 subjects). QT-IRT acknowledged no signal but flagged residual uncertainty in high-BSA pediatric subjects. No additional requirements mandated at approval.

Psychiatric AE Signal — Suicidality Two suicidal ideation/attempt events in the pivotal trials (one in each arm). Neither was attributed to crisaborole. AD itself is a risk factor for psychiatric comorbidity. Long-term trial AN2728-AD-303 showed low rates of psychiatric events (2.3%) with no exposure correlation. No labelling requirement for suicidality monitoring.

Paediatric <2 Years — Deferred Study Safety and efficacy in children <2 years not established. Post-marketing study deferred because EUCRISA was ready for approval in ≥2 years population. PMR required: open-label safety/PK study in ages 3 months–<2 years (N≥100 evaluable; N≥16 moderate AD with BSA ≥35% for PK sub-study).

Postmarketing Requirements & Commitments

§7.4

Post-Marketing Requirement (PMR): One post-marketing study required as a condition of approval per Paediatric Research Equity Act (PREA) deferral.

Study	Type	Objective	Key Design Elements
Paediatric safety and PK study (ages 3 months–<2 years)	PMR (PREA deferral)	Establish safety and PK in infants/toddlers <2 years	Open-label; N≥100 evaluable (safety); N≥16 evaluable moderate AD + BSA ≥35% (PK sub-study, maximal use); mild-to-moderate AD; treatable BSA ≥5%

Source: FDA Medical Review NDA 207695 (Ref ID 3983007), Section 1.3 Postmarketing commitments.

Regulatory Notes

§7.5

Domain	Note
Benefit-risk conclusion	Favourable. First non-steroidal, non-calcineurin inhibitor topical option for mild-moderate AD without malignancy boxed warning. Modest efficacy vs. vehicle accepted in context of chronic paediatric disease, clean safety profile, and unmet need for alternative mechanisms.
Labelling negotiations	FDA removed applicant-proposed language (redacted §(b)(4)) from §14 Clinical Studies; revised success rate description; added Figure 1 time-course chart. INN used throughout body text; brand name only in header.
Immunogenicity	Not applicable (small molecule topical agent).
Statistical issues	MCMC multiple imputation (140 datasets for Trial 301; 135 for Trial 302). Site 138 financial disclosure (investigator Anacor stock >$50,000): sensitivity analysis showed negligible impact on results. See FDA Statistical Review, Matthew Guerra, PhD, dated 8/19/2016.
Pharmacovigilance	Standard FDA pharmacovigilance; no REMS required. Post-marketing monitoring for weight change signal in young children (2–9 years) and psychiatric AEs.
Source Documents	FDA PI: Ref ID 4027634 (Revised 12/2016). FDA Medical Review: Ref ID 3983007 (NDA 207695, Melinda McCord MD, 09/07/2016).