Immunomodulators in Dermatology:

When All Else Fails

Neal Bhatia, M.D.Director of Clinical DermatologyTherapeutics Clinical Research

San Diego, CA2017 AAD Annual Meeting Forum120

Dr. Bhatia’s Disclosures: Affiliations with Abbvie, Actavis, Allergan, Aqua, Bayer,

Biofrontera, BiopharmX, Castle, Cipher, Dermira, Encore,

Exeltis, Ferndale, Foamix, Galderma, Intraderm, ISDIN,

LaRoche-Posay, Leo, Novan, Novartis, PharmaDerm, Pfizer,

Promius, Regeneron, Sanofi, SunPharma, and Valeant

Some slides from industry were borrowed for explanation of

data and scientific background, not for promotion

Off-label discussion is likely

Copies of pdf or questions:

bhatiaharbor@gmail.com

Don’t Give Up…

Vitiligo

Alopecia Areata

Severe Atopic Dermatitis

Granulomatous disorders

Recalcitrant Urticaria

Itching

On systemic therapies we might be afraid of

On applying mechanisms we know work on other conditions

How can we get patients what they need?

Work closely with derm specialty pharmacy

Call don’t fax or write the medical director of

the insurance plans

Ally with a rheumatologist/allergist/oncologist

Submit an Investigator Initiated Study for

drug only and no funds

IIS Submission Portal

How can we get patients what they need?

Work closely with derm specialty pharmacy

Call don’t fax or write the medical director of

the insurance plans

Ally with a rheumatologist/allergist/oncologist

Submit an Investigator Initiated Study for

drug only and no funds

www.clinicaltrials.gov

There is often a trial somewhere that fits…

Current Conventional Treatments

for Vitiligo Steroids

Ideally bid for 3 months or qod for 6 mo

Oral doses 5 mg twice weekly for slowing dz

Calcineurin Inhibitors

Off-label use, often 1 year, Combo with steroids

Phototherapy

Topical PUVA outside US

Most of us don’t have NB-UVB light boxes anymore

Surgery—for segmental vitiligo

Depigmentation—Monobenzyl ether of HQ, >50% BSA

Felsten, LM et al, “Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment,: J Am Acad Dermatol, 65(3): 493-

514; Taieb, A et al, “Guidelines for the management of vitiligo: the European Dermatology Forum consensus,” Br J Dermatol, 168(1): 5-19

Options for Vitiligo: Antioxidants

Attempts to counter oxidative stress on melanocytes that can further

progression

28 Pts with nonsegmental vitiligo

2 months before and for 6 months during the NB-UVB treatment

Antioxidant combo: alpha-lipoic acid, vitamins C and E, and polyunsaturated fatty acids

47% of pts > 75% repigmentation vs.18% in placebo group

Improvements in catalase activity and decrease in overall ROS production, enhanced

NB-UVB

Oral supp with antioxidants containing alpha-lipoic acid combined with NB-

UVB enhanced repigmentation by reducing oxidative stress on melanocytes

Picardo M et al, “Antioxidants and narrow band-UVB in the treatment of vitiligo: a double-blind

placebo controlled trial,” Clin Exp Dermatol, 2007 Nov;32(6):631-6

Polypodium leucotomos Vitiligo

Patients with vitiligo treated with narrow-band UVB (NB-UVB)

twice/weekly

Most Fitzpatrick Skin Type II-III (>80%)

Treated with PLE 250mg (n=25) or placebo (n=24) TID x 25-26

weeks

Higher repigmentation of head and neck region in PLE-treated

group (44%) compared to placebo group (27%) [P = 0.06]

Other sites with limited repigmentation

Middlekamp-Hup MA et al. JEADV. 2007;21:942-950

Superiority of combined treatment of NBUVB phototherapy and

oral Polypodium leucotomos extract versus NBUVB therapy alone in vitiligo

57 patients with generalized vitiligo, treated twice weekly for up to 6 months

Randomized to PLE 480 mg once daily (29) + NB-UVB vs. NB-UVB alone (28)

Blinded observer evaluated repigmentation at baseline and at the end of the study

Results:

Response rate of the combined group significantly higher than the NBUVB only group (40% vs. 22%, p<0.0005)

In responders, repigmentation was observed within the first month as compared to a mean of 3 months in the group of phototherapy only patients

Pacifico, et al. Poster #3111. Paper presented at: American Academy of

Dermatology; March 2009; San Francisco, CA.

Afamelanotide(SCENESSE®, Clinuvel Pharmaceuticals Ltd)

Analogue of α–melanocyte-stimulating hormone, induces tanning-like

pigmentation

Binds with the melanocortin-1 receptor (MC1R)

upstream of one of the key pathways for melanogenesis

MC1R is not expressed by melanocyte stem cells

Afamelanotide can stimulate pigmentation and increase proliferation of

melanocytes

the differentiation of melanocyte stem cells.

Grimes et al 2013: First report 16 mg implants in conjunction with NB-

UVB (n=4), all with pigmentation

Lim, H, et al “Afamelanotide and Narrowband UV-B Phototherapy for the Treatment of Vitiligo, A Randomized Multicenter Trial,”

JAMA Dermatol, 2015;151(1):42-50

Afamelanotide and NB-UVB for the

Treatment of Vitiligo 3 sites, 55 pts,15% to 50% total BSA

randomized to combo (n = 28) vs NB–UVB

monotherapy (n = 27)

After 1 month, 16 mg of afamelanotide SQ

added to the combination therapy group

monthly for 4 months

Both groups continued NB–UVB treatments

Lim, H, et al “Afamelanotide and Narrowband UV-B Phototherapy for the Treatment

of Vitiligo, A Randomized Multicenter Trial,” JAMA Dermatol, 2015;151(1):42-50

Afamelanotide and NB-UVB for the

Treatment of Vitiligo Combo therapy group showed superior results (P < .05) at day

56, significant on face and arms, best in skin types IV-VI

face, 41.0 vs 61.0 days [P = .001];

upper extremities, 46.0 vs 69.0 days (P = .003)

Combination therapy group, repigmentation was 48.64% at day 168

vs 33.26% in monotherapy

adverse events: erythema in both groups, minor infections and

nausea in combo group

Each 16mg of Scenesse costs~ $6,200 and lasts 60 days

Lim, H, et al “Afamelanotide and Narrowband UV-B Phototherapy for the Treatment of Vitiligo, A Randomized Multicenter Trial,” JAMA Dermatol, 2015;151(1):42-50

Janus Kinase Inhibitors for Vitiligo

Tofacitinib:

53-year-old pt with vitiligo covering her face, hands and body

5 mg every other day, increased to 5 mg daily after 3 weeks.

2 months: partial repigmentation

5 months: “white patches nearly all gone”

Real world costs: $12,000/year

Craiglow, BG and King, BA “Tofacitinib Citrate for the Treatment of Vitiligo, A

Pathogenesis-Directed Therapy,” JAMA Dermatol, 2015;151(10):1110-1112

Janus Kinase Inhibitors

Ruxolitinib and Tofacitinib STAT: Signal Transducer and Activator of Transcription

Proteins

Courtesy Steven Hays, Pharm D, Pfizer Medical Information

4 JAK (1,2,3, TYK 2) and 6 STAT (1-6) interact

to send cytokine signals to nucleus

Family of 4 tyrosine kinases:

JAK 1, 2, 3 and Tyk 1

Ruxolitinib

JAK 1,2

phosphorylation due to IL-6,

IL-12, or IL-23, resulting in

suppression of Th17

differentiation

reduced lymphocytic

infiltration

inhibited acanthosis,

reduces IFN expression

Tofacitinib

JAK 1,3

Suppression of IL-23

receptors, IL-15, IL-17A, 17F

in mice models

IL-22 suppressed when T cells

were stimulated with IL-6 and IL-23

Growth and Activation signals sent

to nucleus

Amitava Mitra and Ercem Atillasoy (2012). Topical Therapies for Psoriasis, Psoriasis, Dr. Jennifer Soung (Ed.),

ISBN: 978-953-307-878-6, InTech, Available from: http://www.intechopen.com/books/psoriasis/topicaltherapies-

for-psoriasis

Tofacitinib and Alopecia Universalishttps://www.clinicaltrials.gov/ct2/show/NCT02299297?term

=tofacitinib+skin&rank=18

An Open-Label Pilot Study To Evaluate The Efficacy

Of Tofacitinib In Moderate To Severe Alopecia Areata,

Totalis And Universalis

open-label daily for 6 months in the treatment of moderate

to severe AA, and alopecia totalis or universalis, followed

by 6 months follow-up off drug to assess the incidence

and timing of recurrence

Tofacitinib and Alopeciahttps://clinicaltrials.gov/ct2/show/NCT02197455

5 mg bid for 3 months vs

placebo

6 mo hx of >50% scalp

involvement, alopecia totalis,

or alopecia universalis

Currently in phase III

IL-6 activates Janus

kinase (JAK), and whether the

JAK inhibitor, tofacitinib, can

reverse the IL-6-induced,

STAT3-dependent profibrotic

effects on TGF-β1 and

collagen I expression

Tofacitinib for Granuloma Annulare?

Why?

Control against Th-1

inflammation cascade

TNF-α expression and release

Potential use for disseminated

variants

Why not?

Toxicity potential if above 5

mg

Long-term issues of

compliance when unsure of

endpoint

Costs

Conventional (and often unsuccessful)

treatments for Granuloma Annulare Topical and Intralesional steroids

Pentoxyfylline/ Dapsone/ Antimalarials

Isotretinoin

Antibiotics:

6 cases with biopsy-proved resistant GA

resolved after 3 months with rifampin (600 mg),

ofloxacin (400 mg), and minocycline (100 mg)

Complete clearance 3 to 5 months after initiation,

some reported postinflammatory hyperpigmentationMarcus, DV, Mahmoud, BH, Hamzavi, IH, “Granuloma Annulare Treated With Rifampin, Ofloxacin, and

Minocycline Combination Therapy,” Arch Dermatol, 2009;145(7):787-789.

Topical Dapsone Gel for

Granuloma Annulare 41-year-old male, 2 week hx newly formed rapid

onset papules

7mm papule right lateral canthus, 4mm papule on

upper right cutaneous eyelidbx proven GA

Steroids avoided given periorbital location

Dapsone 5% gel bid for 3 weeks led to near resolution

Potential concerns

Penetration into granulomatous inflammation?

Recurrence?

Insurance coverage for off-label use?

Kassardjian, M, Patel, M, Shitabata, P, Horowitz, D, “Management of Periocular Granuloma Annulare Using Topical

Dapsone,” J Clin Aesthet Dermatol, 2015;8(7):48–51.

Steiner A, Pehamberger H, Wolff K. Sulfone treatment of granuloma annulare. J Am Acad Dermatol. 1985;13: 1004–1008

Apremilast Inhibitor of PDE4

Regulates cellular cAMP,

Not thalidomide analog…no CNS metabolism

apremilast lacks the acidic chiral hydrogen it should not

racemize in vivo, unlike thalidomide

Orphan status for Bechet’s disease

Approved and sold for Psoriasis/PsA 2014

Currently in phase III trials for ankylosing spondylitis and

rheumatoid arthritis

Costs without rebate support: $2000/60 tabsMuller, George W.; Corral, Laura G.; Shire, Mary G.; Wang, Hua; Moreira, Andre; Kaplan, Gilla; Stirling, David I. (1 January 1996). "Structural

Modifications of Thalidomide Produce Analogs with Enhanced Tumor Necrosis Factor Inhibitory Activity". Journal of Medicinal Chemistry 39 (17):

3238–3240.

Phosphodiesterase 4 (PDE4)Degrades cyclic AMP levels

Decreased cAMP

decreased protein kinase A

increases NF-kB mediated production of pro-

inflammatory cytokines (e.g., TNF-a, IL-17A)

decreases CREB-mediated production of anti-

inflammatory cytokines (e.g., IL-10)

Immunomodulatory effects of PDE inhibition

• cAMP-PDE activity in leukocytes is significantly

elevated in patients with AD compared to healthy

controls1

• PDE4 increased cAMP conversion to AMP

and increased cytokine production2

• Also expressed in keratinocytes and fibroblasts4

• Increased PDE4 results in immune activation and

overexpression:3

• Th2 cytokines (IL-4, IL-5, and IL-13)

• Th1 cytokines; TNF-α, IL-12

• Th22 cytokine IL-22; Th17 pathway

Sawai T, et al. Br J Dermatol. 1998;138:846-848.;Hanifin J, et al. J Invest Dermatol. 1996;107:51-56.; Leung D, et al. J Clin Invest. 2004;113:651-657; Bäumer W, et al. Inflamm Allergy Drug Targets.

2006;5:17-26.

Apremilast for Lichen Planus

Cutaneous LP

N=10, 20 mg bid for 12 wks then 4 wk holiday

Efficacy end points on grades

30% experienced 2 grade improvement

All had improvement overall

Small n, small rx time, small dosages

Paul et al, “An open-label pilot study of apremilast for the treatment of moderate to

severe lichen planus: a case study,” J Am Amer Dermatol, 2013; 68:255-61

Apremilast for DLE

DLE is Th1 mediated

Apremilast blocks Th1 process

Inhibiting production of IL-12,23, and Th-17

Subsequent suppression of Th-1 & Th-17 profile

8 pts started, 4 finished 85 day course

GI side effects, sensory neuropathy

Larger studies needed

DeSouza et al, JDD, 2012, 11(10): 1224-1226

Apremilast for Rosacea

Primary endpoints were not met

Improvements in erythema and flushing overall but no

reduction in papules

Apremilast for Atopic Dermatitis

Leflunomide (Arava) More commonly use for RA: 100 mg daily x 3d

then 20 mg daily

Gaining interest in Atopic Dermatitis

anti-microbial effects seen with pts infected with

molluscum and verruca vulgaris

2 week half-life, renal clearance

Black box warning for hepatotoxicity, teratogenic

Multiple P450 interactions

30 tabs cost $7.99 to $120 depending on

pharmacy chosen and rebatesSmith, KJ and Germain, M, “Leflunomide: An Immune Modulating Drug That May Have a Role in Controlling

Secondary Infections With Review of Its Mechanisms of Action ,” J Drugs Dermatol, 2015;14(3):230-234

MOA of Leflunomide Converted to metabolite “teriflunomide”

inhibits dihydro-orotate dehydrogenase (DHODH)

Similar pathway for clonal lymphocyte expansion

DHODH inhibition creates accumulation of

pyrimidine precursors

inhibiting T and B cell proliferation, induction of apoptosis

Down-regulates activity of TNF-a

Supplementation with exogenous uridine blocks

Inhibitory effects of teriflunomide

Sehgal VN1, Verma P, “Leflunomide: dermatologic perspective,” J Dermatolog Treat,

2013 Apr;24(2):89-95; Smith, KJ and Germain, M, “Leflunomide: An Immune Modulating

Drug That May Have a Role in Controlling Secondary Infections With Review of Its

Mechanisms of Action ,” J Drugs Dermatol, 2015;14(3):230-234

Immunomodulatory Effects of

Leflunomide on Atopic Dermatitis Inhibition of Tyrosine Kinases “Fyn” and “Lck”

Antibody mediated T-cell suppression

Anti-CD3, 28, also some B-cells

Reduced active NF-kB reduced IL-6, TNF

Diminished mast cell degranulation

Reduction in IL-5 and IL-13 due to STAT 5

Reduction in IL-4 and IL-13 due to STAT 6

Eosinophil receptor proteins “eotaxins” blocked

Also impacts JAK-1, JAK-3, STAT 3

Smith, KJ and Germain, M, “Leflunomide: An Immune Modulating Drug That May Have a Role in Controlling

Secondary Infections With Review of Its Mechanisms of Action ,” J Drugs Dermatol, 2015;14(3):230-234

Retinoids and Vitamin D Analogs are NOT

Keratolytics Regulate transcription

Ligand-dependent inhibition of activator protein-1

Immunomodulation via NF-AT, and NF-KB

Decrease IL-2, IL-6, IL-8, IFN and GM-CSF

Dephosporylation and deactivation of EGF

Stimulate terminal differentiation

Vitamin D receptors on many cells besides keratinocytes

Dermal fibroblasts,T and B lymphocytes

Monocytes and macrophages

Laws et al, Expert Opin. Pharmacother. (2010) 11(12):1999-2009

Vitamin D and Morphea

Topical Calcipotriene

0.005% occluded ointment

12 pts at 1 mo and 3 mo

All improved

Calcipotriol 0.005%

With UVA-1

19 pts

Not studied alone due to

design of trial

Oral Vitamin D

Placebo trial for 6 mo

No significant difference with

various doses but no dropouts

Peds study

Linear PSS and morphea

6/7 pts

8 mo therapy

Zwischenberger, B and Jacobe, H, “A systematic review of morphea treatments and

therapeutic algorithm,” J Am Amer Dermatol, 2011;65:925-41

XX

X

Acitretin and CTCL

Attempt to place acitretin in disease state previously

treated with bexarotene

32 pts with CTCL, 55 yrs, mixed race

6 alone, 26 with existing rx, 28 mo total

Overall response 59%, few side effects

Conclusion: better response with early stage rx

Cheeley, J, Sahn, R, DeLong, L, Parker, S, J Am Acad Dermatol, 2013;68:247-54

What about the patient that can’t stop:

itching scratching HIV

Diabetes

Other meds

Dyslipidemia

Malignancy

Thyroid dz

“Dermatitis Artefacta”

Self-inflicted lesions

Primary gain?

Personality disorders

Recreational Drugs

Trichotillomania

Neurotic Excoriations

“Trendy” diagnoses

Bedbugs

Morgellon’s dz

Finding Nemolizumab:

A biologic for pruritus? Anti-IL-31 mAb; upregulated in atopic dermatitis and other

conditions

Regulator of keratinocyte differentiation

Blockade studied in mice models, affects lesion size,

pruritus and weight

Effects not impacted by antihistamines, steroids, tacrolimus, or

opioid antagonists

Hypothesized to reduce the stimulus threshold of

neuroreceptors (capsaicin receptor, free nerve endings)

Grimstad O et al, “Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis, Exp Dermatol, 2009

Jan;18(1):35-43; Kasutani K, Fujii E, Ohyama S, et al. Anti-IL-31 receptor antibody is shown to be a potential therapeutic option for treating itch and

dermatitis in mice. British Journal of Pharmacology. 2014;171(22):5049-5058. doi:10.1111/bph.12823.

Is Aripiprazole (ABILIFY®)

the new Pimozide? Indicated for similar

psychiatric disorders

Add-on to Major Depressive

Disorder

Manic or Bipolar Disorder

Schizophrenia

Autistic Disorder

Tourette’s Disorder

Some side effects similar

to sedating anti-histamines

Avoid grapefruit juice

Daily dose can be tapered

5 mg or 10 mg

Safer than conventional

antipsychotics

Treatments reported for

over one year with minimal

side effects

Ladizinski B, Busse KL, Bhutani T, Koo JY, “Aripiprazole as a viable alternative for

treating delusions of parasitosis,” J Drugs Dermatol, 2010 Dec;9(12):1531-2.

Reported cases of success with

Aripiprazole for Delusions of Parasitosis

Ladizinski B, Busse KL, Bhutani T, Koo JY, “Aripiprazole as a viable alternative for

treating delusions of parasitosis,” J Drugs Dermatol, 2010 Dec;9(12):1531-2.

Give Azathioprine another chance?

Historically steroid sparing for many dermatoses

Inexpensive: 60 tablets 50 mg $20-$50

Labs get expensive:

TMPT, CBC and Basic Chem at baseline

Basic Chem and CBC x 2 mo then q 3-6 mo

Regular skin exams

Low dose (50 mg) proven safe in IBD

Are dermatologists overly concerned about lymphopoeitic issues?

Hibi T, Naganuma M, Kitahora T, Kinjyo F, Shimoyama T, “Low-dose azathioprine is effective and safe for maintenance of

remission in patients with ulcerative colitis,” J Gastroenterol. 2003;38(8):740-6

Conclusions

Proven dosage protocols often anecdotal, many

treatments will never be studied in clinical trials due to

expense or disinterest

Many fears by dermatologists of systemic options

dispelled in rheumatology and GI literature

Insurance obstacles and costs are always going to be

limiting, but we can still go all out for our patients

Thank You