Treatment Pearls in Psoriasis

& Eczema

Mark Lebwohl, MD Waldman Professor

And Chairman

Kimberly and Eric J. Waldman Department of Dermatology

Icahn School of Medicine at Mount Sinai

Mark Lebwohl is an employee of Mount Sinai which receives

research funds from: Abbvie, Amgen, Boehringer Ingelheim,

Celgene, Eli Lilly, Janssen / Johnson & Johnson, Kadmon,

Medimmune/Astra Zeneca, Novartis, Pfizer and ViDac.

Dr. Lebwohl is also a consultant for Allergan, Leopharma, and

Promius.

• Dupilumab – Dupixent ®

• Guselkumab – Tremfya ®

• Brodalumab – Siliq ®

• Ixekizumab – Taltz ®

• Secukinumab – Cosentyx ®

• Ustekinumab –Stelara ®

• Adalimumab – Humira®

• Etanercept –Enbrel ®

• Apremilast – Otezla ®

• Certolizumab - Cimzia ®

• Tildrakizumab

• Tofacitinib – Xeljanz ®

• Risankizumab/Mirikizumab

New drugs in

past 15 years

Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure Sheppard JD et al. Adv Ther (2016) 33:532–552

“significant IOP increases was 0.8% in studies evaluating short-term LE treatment and 1.5% in long term studies”

Tip # 1 Management of Dupilumab conjunctivitis

Voyage 1 Guselkumab PASI 75 Responders:

5

91.2

73.1

62.6

91.2

72.2

87.8

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Pe

rce

nta

ge

of

Pa

tie

nts

Guselkumab (n=329) Placebo→Guselkumab (n=174) Adalimumab (n=334)

Weeks

2

Week 24

P<0.001 vs. ADA

Week 48

P<0.001 vs. ADA

Week 16

P<0.001 vs. ADA

A. Blauvelt, et al. FCD 2016.

Tip # 2 IL-23 antibodies are administered q8-12w.

Figure 4 (cont’d). Clinical Efficacy in Guselkumab Maintenance and Withdrawal from Weeks 28 to 48**

J Am Acad Dermatol. 2017;76(3):418-431.

6

Guselkumab

(n=193)

Withdrawal

(n=182)

*P<0.001

PASI 75 PASI 100

VOYAGE 2

PASI 90

Weeks Weeks Weeks

88.6

36.8

**Footnotes in slide notes

PASI 75 Response Over Time

*P<0.001 vs PBO; †P<0.05 vs ETN; §P<0.001 vs ETN; P-values unadjusted for multiplicity.

P-values were calculated using the Cochran-Mantel-Haenszel (CMH) test stratified by body weight (≤90kg, >90kg) and prior exposure to biologic therapy for psoriasis.

Modified intention-to-treat population (ie, all randomized patients who received ≥1 dose of study medication).

The figure represents observed data only; data shown for Week 12 are based on missing data being imputed as non-responders.

PBO=placebo; TIL=tildrakizumab; ETN=etanercept.

0

0

20

40

60

80

100

Weeks

Res

pond

ers

(%)

TIL 100 mgTIL 200 mgPlacebo TIL 100 mgPlacebo TIL 200 mg

4 8 12 16 22 28

TIL 200: 62%*

PBO 3%

TIL 200: 82%

TIL 100: 64%*

PBO/TIL 100: 77%

PBO/TIL 200: 86%

TIL 100: 80%*

0

0

20

40

60

80

100

Weeks

Res

pond

ers

(%)

4 8 12 16 22 28

TIL 200: 66%*†

PBO: 6%

TIL 200: 74§

PBO/TIL 100: 58%

PBO/TIL 200: 74%TIL 100: 74§

TIL 100 mgTIL 200 mgPlacebo TIL 100 mgPlacebo TIL 200 mgETN

ETN: 48%ETN: 56%

TIL 100: 61%*†

reSURFACE 1 reSURFACE 2

TIL100 64%

TIL200 62%

PBO/TIL200 86%

TIL100 82%

TIL200 80%

PBO/TIL100 77%

Tip # 3 Give tildrakizumab time

reSURFACE 1 and 2: Overall efficacy after 2 years of treatment

FAS (full analysis set; subjects with ≥1 dose of extension treatment based on assigned treatment); as observed data

Patients entering OLE after 64 weeks (reSURFACE 1) or 52 weeks (reSURFACE 2) were at least partial responders (PASI ≥50).

For reSURFACE 1, patients had to have received active drug within 12 weeks of end of base study

Papp K, et al. EADV 2017, D3T01.1H Sponsored by Merck & Co., Inc.

84 81 88

84

52 54

66 61

22 23

34 33

58 55

66 67

0

10

20

30

40

50

60

70

80

90

100

TIL 100 mg… TIL 200 mg… TIL 100 mg… TIL 200…

Patients

(%

)

PASI 75

PASI 90

PASI 100

PGA (0/1)

reSURFACE 1 – w.64 reSURFACE 2 – w.52

Ustekinumab in adolescent patients age

12 to 17 years with moderate-to-severe

plaque psoriasis: results of the

randomized phase 3 CADMUS study. Landells I, et al.

J Am Acad Dermatol. 2015;73(4): 594-603.

Tip # 4 Ustekinumab ideal for adolescents going off to college

Ustekinumab package insert

Business Use Only 10

Ustekinumab as therapy for psoriasis in a

2-year-old girl.

Min MS, et al.

J Eur Acad Dermatol Venereol.

2016;30(11):e109-10.

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

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Time until 25% of patients achieve a PASI 75 response. Time estimates based on linear progression. Comparative biologics shown as weighted means based on individual study published results. Current study results in blue.

Weeks

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Dear Dr. Lebwohl,

I prescribed Cosentyx for a 175 pound patient with

severe psoriasis. We showed her how to administer

the shots on Monday. She called me on Friday to say

that she had administered two shots each day from

Monday through Friday and was now out of

Cosentyx. What should I do?

Sincerely,

Dr. XXXXXX

Marked URGENT!

Pearl #6 Anti-IL-17 antibodies are safe

Maximum dose not known

Immunity to infection in IL-17-deficient

mice and humans.

Cypowyj S, Picard C, Maródi L, et al

Eur J Immunol. 2012;42:2246-2254.

Chronic mucocutaneous candidiasis in

humans with inborn errors of interleukin-

17 immunity.

Puel A, Cypowyj S, Bustamante J, et al.

Science. 2011;332(6025):65-68.

Oral fluconazole 150 mg single dose versus intra-

vaginal clotrimazole treatment of acute vulvovaginal

candidiasis.

Sekhavat L, Tabatabaii A, Tezerjani FZ.

J Infect Public Health. 2011;4:195-9.

Pearl #7 oral fluconazole for candidiasis

IL-23 compensates for the absence of IL-12p70 and is essential for

the IL-17 response during tuberculosis but is dispensable for

protection and antigen-specific IFN-ɣ responses if IL-12p70 is

available.

Khader SA, Pearl JE, Sakamoto K, et al.

J Immunol. 2005;175(2):788-795.

• depletion of IL-17A–producing CD4+ T

cells →no effect on disease progression

during primary M. tuberculosis infection

Pearl #8 Secukinumab not associated with Tb reactivation

Secukinumab shows no evidence for reactivation of previous or latent TB infection in psoriasis patients: Pooled Phase 3 safety

Tsai T-F, et al. AAD 2015, P607 Sponsored by Novartis Pharma AG

Treatment Subjects diagnosed with

LTBI in screening (n)

Median duration of

treatment with SKB (days)

Any SKB 150 mg 52 364

Any SKB 300 mg 55 364

Any SKB 107 364

Subjects diagnosed with LBTI during screening in Phase 3 SKB trials

• 1 TB-negative subject (at BL; in ERASURE) was diagnosed with LTBI

following retest according to local guidelines (Argentina) on Day 141 while

on SKB 150 mg; treated with isoniazid 300 mg daily and completed the

study without SKB dose interruption

• At BL, 25 subjects who received SKB

– Had a past history of either pulmonary TB, LTBI or a positive TB test

– Tested negative for LTBI by QFN Gold at screening

– None were on anti-TB medication during the psoriasis study

• None experienced reactivation of TB; median SKB treatment duration was 363

days

Pharmacokinetic Modeling

80mg vs. 40mg at Day 0

Time(week)

Ad

alim

um

ab

co

nce

ntr

atio

n (

mcg

/mL

)

0

5

10

15

20

0 4 8 12 16 20 24

0

40

80

Dose (

mg)

40 mg eow with loading

Time(week)

Ad

alim

um

ab

co

nce

ntr

atio

n (

mcg

/mL

)

0

5

10

15

20

0 4 8 12 16 20 24

0

40

80

Dose (

mg)

40 mg eow without loading

Pearl #9 Use loading doses of adalimumab

19

Etanercept therapy for toxic

epidermal necrolysis.

Paradisi A, et al.

J Am Acad Dermatol. 2014;71(2):278-

83.

• 10 patients

• Single 50mg dose

• Median time to healing was 8.5 days

Time to Onset of Diarrhea*

• Pooled analysis of psoriasis (ESTEEM 1 & 2) and psoriatic arthritis

(PALACE 1-3) trials

*Percentages in each category of onset are based on the total number of events in each treatment group. Subjects who

were randomized to placebo and then switched to apremilast could contribute events to both treatment groups.

Duration of Diarrhea*

• Pooled analysis of psoriasis (ESTEEM 1 & 2) and psoriatic arthritis

(PALACE 1-3) trials

*Percentages in each category of duration are based on the total number of events in each treatment group and exclude

patients with missing or uninterpretable data. Subjects who were randomized to placebo and then switched to

apremilast could contribute events to both treatment groups.

Strategies for Managing Diarrhea

Pearl #11 APR diarrhea starts early, finishes quickly

& can be minimized with OTC treatments

a2/16 infant samples excluded from per protocol analysis set (1 missing data at birth, 1 due to implausible PK data [ie, data not consistent with pediatric CZP

PK model, based on expected range of clearance, volume of distribution, and subsequent elimination t½]); b2 samples not collected; c1 umbilical cord excluded

due to missing data; dUmbilical cords were collected within 1 h of delivery. BLQ, below limits of quantitation of the assay; LLOQ, lower limit of quantitation

Kimball A, et al. EADV 2017, FC04.03 Sponsored by UCB Pharma

Maternal & infant plasma & umbilical cord levels of certolizumab Plasma CZP levels (n=14 mother–infant

pairsa)

CZ

P c

once

ntr

ation

(

g/m

L)

10

100

0.1

1

BLQ

Delivery

(±24 hours)

Week 4

(±7 days)b

Week 8

(±7 days)

LLOQ = 0.032 g/mL

Mothers Infants

1 infant had minimal CZP level of

0.042 μg/mL, mother’s level was

49.4 μg/mL (infant/mother ratio:

0.0009)

Plasma CZP levels in umbilical cord

(n=15c)

CZ

P c

oncentr

ation (

g/m

L)

10

100

0.1

1

BLQ

Delivery

(±24 hours)

Umbilical

cordsd

LLOQ = 0.032 g/mL

Mothers Infants

The infant with a CZP level at birth

of 0.042 μg/mL had a CZP level of

0.040 μg/mL in the umbilical cord

Umbilical cord

Pearl #12 Certolizumab doesn’t cross placenta

Tofacitinib or Adalimumab versus Placebo for

Psoriatic Arthritis.

Mease P, Hall S, FitzGerald O, van der Heijde D,

Merola JF, Avila-Zapata F, Cieślak D, Graham D,

Wang C, Menon S, Hendrikx T, Kanik KS.

N Engl J Med. 2017 19;377:1537-1550.

Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure. Liu LY, Strassner JP, Refat MA, Harris JE, King BA.

J Am Acad Dermatol. 2017 ;77:675-682.e1.

• 5/10 patients repigmented at sites of sun or NB UVB exposure

Pearl #13 Tofacitinib is effective for several off label

Conditions but requires monitoring

Psoriatic Arthritis Recommended dose of XELJANZ is 5 mg twice daily, used in combination with nonbiologic DMARDs. (2.2) Recommended dose of XELJANZ XR is 11 mg once daily, used in combination with nonbiologic DMARDs. (2.2) Recommended dose in patients with moderate and severe renal impairment and moderate hepatic impairment is XELJANZ 5 mg once daily. (2.5, 8.7, 8.8) Use of XELJANZ/ XELJANZ XR in patients with severe hepatic impairment is not recommended. (2.5, 8.7)

XELJANZ® package insert

•Interacts with cytochrome P4503A

Monitoring Recommendations for Tofacitinib

• Tb test baseline and “per applicable guidelines” (annually)

• CBC +plts baseline; after 4-8 weeks; q3mos

• LFT’s “routine monitoring” – baseline and q3-6mos

• Lipids – baseline and at 4-8 weeks