What’s New in the Treatment of Psoriasis Mark Lebwohl, … C023...Dr. Lebwohl is also a consultant...
Transcript of What’s New in the Treatment of Psoriasis Mark Lebwohl, … C023...Dr. Lebwohl is also a consultant...
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
AD
ALI
MU
MA
B/U
STEK
INU
MA
B (H
igh
Do
se)3
0-3
2,3
4
ALE
FAC
EPT
(Hig
h D
ose
)38
ETA
NER
CEP
T (L
ow
Do
se)3
9,4
0
ETA
NER
CEP
T (H
igh
Do
se)3
2,4
1-4
4
INFL
IXIM
AB
22
-27
UST
EKIN
UM
AB
(Lo
w D
ose
)30
-34
BR
OD
ALU
MA
B
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
IXEK
IZU
MA
B5
0
SEC
UK
INU
MA
B (H
igh
Do
se)4
7
UST
EKIN
UM
AB
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