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MEETING SUMMARY November 14-15, 2016 ALOPECIA AREATA RESEARCH SUMMIT Building & Crossing the Translational Bridge New York City · New York · USA

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Page 1: Alopecia Areata Research Summit Summary

MEETING SUMMARY

November 14-15, 2016

ALOPECIA AREATA RESEARCH SUMMITBuilding & Crossing the Translational Bridge

New York City · New York · USA

Page 2: Alopecia Areata Research Summit Summary

Opening Session

Bill Ju: Building the Ecosystem for Research Translation

• Identify the problems worth solving – novel diseases/targets

• Need a deep understanding of the biology/investigators

• Importance of both basic and clinical researchers

• Understand the clinical outcome assessments and measures

• No market data in AA – must be overcome to establish $$ model

• Must have IP protection – what is the asset?

• Ecosystem building – interest from the business community

• Success stories – small companies that engage in the ecosystem early to get advice,guidance, access to early funds for pilot studies; role of catalysts such as AdvancingInnovation in Dermatology.

22016 AA Research Summit

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Session 1 - Setting the Stage & Raising the Bar

Maria Hordinsky: Clinical Update in AA

The Clinic Visit in 2016 – patients are armed with information! Discussion of new treatment optionssuch as JAK inhibitors are no longer ‘emerging’ they have emerged! Still many clinical unsolvedmysteries, such as patchy persistent disease. More work to be done to test efficacy of new agents inplacebo-controlled trials. Lots of new questions to be answered!

David Norris: Overview of Past NAAF Research Summits

Five Research Summits up to now: 2008, 2009, 2010, 2012, 2014. First summit 2008 in Bethesda.Genetics and Immunology…repurposing of autoimmune drugs was the goal. Second summit 2009 inDenver focused on Immunology, animal models, drugs used in other diseases. Third summit in 2010 inNYC, was focused on demand of new treatments by AA patients. What tools were needed to fosterclinical research – tools, biomarkers, outcome measures. Fourth summit in 2012 – focused onconsolidating the mechanisms recently uncovered in AA and how these could be targeted by moderntherapies used in other diseases. Fifth summit in 2014 – New drugs showing promising results in AA.Larger meeting with 90 participants, focus on new technologies and directions, new tools. Developmentof core uniform protocol. Sixth summit in 2016 – here we are! Advanced understanding of genetics andimmunology, new animal models, epidemiology, QOL, translational research opportunities. First Summitto have participation of Industry partners! Welcome everyone!

32016 AA Research Summit

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Session 1 (Continued)

Angela Christiano: Update on Genetics and Immunology

GWAS studies have provided at least 14 genes involved in AA, with more to be discovered if GWASstudies can be expanded. Immunological studies have focused on the role of CD8+ T cells in mediatingdisease, and the use of JAK inhibitors to prevent and treat AA in the C3H/H3J mouse model. Thesepreclinical studies paved the way for early clinical investigation in patients, which has been done inseveral centers to date. Gene expression Studies have uncovered biomarker signatures that can be usedto follow response to treatment. Goals for the coming year include investigation of new pathways,including autophagy, pigmentation and ‘stress’ pathways in the hair follicle. Environmental factors suchas the microbiome are also under study in patients with AA.

42016 AA Research Summit

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Session 1 (Continued)

5

Ralf Paus: Revising the Immune Privilege Hypothesis

Overview of the concepts of IP and how they relate to AA. New physiological role of gamma delta Tcells – to scout for stressed HF signals and sentinel cells that then kick off the immune cascade. Newimmune cell types were discussed including Langerhans cells, Mast cells, gamma delta T cells amongothers. The need to understand these cell types as well as Tregs, NK Tregs and additional cytokinepathways and mechanisms still need to be discovered. As a step toward a truly ‘curative’ therapy wouldinvolve restoration of peripheral tolerance – multimodal therapies may be needed!

Madeleine Duvic: Update on AA Registry

There are 11,180 AA patients now registered. Of those, 8528 were diagnosed by a dermatologist. Allsubtypes of AA are represented: AU 2617; AT 1088; AAP 2422; AAT 2401. All ethnic/racial groupsrepresented. The registry has supplied DNA, serum, samples to enable wide range of studies. There are6000 patients that have not yet been sampled, this needs to happen! Importantly, many Registrypatients have overwhelmingly consented to be re-contacted for participation clinical trials.

2016 AA Research Summit

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Lunchtime Keynote

Yaron Tomer: Autoimmune Thyroid Disease• Th1 vs Th2 in the thyroid gland. Th1 – apoptosis in Hashimoto’s hypothyroidism;

versus Th2 – hyperthyroidism in Graves• Shared genes with AA, Graves and Hashimoto’s• Most genes participate in antigen presentation (CD40, HLA, PTPN22, Thyroglobulin,

TSHR, CTLA4) hence the focus on small molecule targeting• HLA DRB1 must have Arginine 74 to predispose to AITD. Glutamine 74 is protective• Interaction studies of Thyroglobulin and HLADR AA 74 – synergistic not adaptive• Hypothesis; the Arg pocket enables presentation of thyroid autoimmunity antigens• Screen of small molecules that block binding of peptide to the A74 binding pocket• Registry has supplied DA, serum, samples to enable wide range of studies• Three small molecules were positive; one of them was in the compound library• In vitro validation using humanized mouse molecule (Li CW, et al., 2016)

• Cepharanthine is the S53 compound from Stephania cepharantha Hayata plant;natural alkaloid (Rogosnitzky M and Danks R, 2011/Tabata et al, 2012)

• Looking now into human clinical studies to take place in the US

62016 AA Research SummitAdapted from Abbas, Cellular and Molecular Immunology, 5th Edition

Page 7: Alopecia Areata Research Summit Summary

Session 2 - Tools of the Trade: Clinical Trial Design & Outcome Measures

Elise Olsen: A new visual Aid for Assessing Hair Loss in AA

ALODEX score – Alopecia Density and Extent Score (JAAD, in press). Can track absolute hair loss, andsmall changes in density that may otherwise go undetected with SALT score. Can do lesional scoring.ALODEX and SALT cannot really be compared. But they tend to trend in the same direction. New validmetric for hair loss in AA. Unique properties of ALODEX – determines % scalp hair loss vs % scalpbaldness. Only electronic capture. Instantaneous mathematical calculation. More time consuming.Allows tracking of areas of baldness new and old.

72016 AA Research Summit

Leslie Castelo-Soccio: Using Computer Vision to Quantitate Pediatric AAMeasurements were developed for adult heads – not kids! Steps to developing a new tool: photo libraryof more than 800 images that was used to develop new algorithm. Key collaboration with a computerscientist to develop App!

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Session 2 (Continued)

8

Tito Mendoza: Update on the Use of the AA Symptom Impact Scale

AASIS – AA Symptom Impact Scale is a 13 item questionnaire uses a 0-10 scale (10=worst). Data collected fromRegistry (202 pts), plus new data (250 pts) = pooled data (total of 452 pts). Several pharma companies have askedpermission to use the AASIS in their clinical trials, some of whom are here. AASIS is free to use. New directions:cognitive debriefing to identify minimum age of participants who can take the AASIS. Currently it is 18 yrs. old.One pharma company has expressed interest in pediatric instrument. Validation is an iterative process; Tito wouldappreciate if industry can share their results.

Amy Paller: Pediatric Clinical Trial Design

Children are not just small adults! Recruitment is a greater challenge. Parental consent is time consuming. Moreintense requirements by IRB – invasive tests for trials. Assent for older kids. Greater fears in peds population forsafety. Children are less cooperative than adults. Difficulty in scheduling visits (during school, work hours). Moretime required for every visit – blood, biopsies. How to minimize the number of visits/missed school and work.Outcome measures – SALT for children, CDLQI validated in children, but is not specific for AA. Need a validatedand specific instrument for peds. Intervention studies are desperately needed for AA in kids. Topical studies wouldbe welcome!

Joel Gelfand: Clinical Trials, Epidemiology and Biostatistics in Skin Diseases

Epidemiology considerations – get help early in study design! To call the statistician after the experiment is doneis a post-mortem analysis! Ask a well formulated study question. Define exposure, outcomes, confounding factors.Minimize selection and information bias. Plan for statistical error. Develop an analysis plan. Overview of differenttype of study designs: cross-sectional, population-based, cohort studies, case control studies. Interesting statistic:What percent of observational studies of treatment effect are confirmed by RCTs? 10% confirmation rate ofpreclinical studies (such as in mice). 75% confirmation rate of observational research (open label pilot studies) inpatients. Concept of Equipoise – weighing the benefit versus risk.

2016 AA Research Summit

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Session 3 - Success Stories: Lessons from Clinical Studies with JAK Inhibitors

92016 AA Research Summit

Julian Mackay-Wiggan: Update on Clinical Research in AA

Ruxolitinib study – 12 patients, 20mg BID. Regrowth as early as 4 weeks. 9 of 12 had 50% regrowth.8 of 9achieved their endpoint by week 12 (75% response rate). Tofacitinib study – 12 patients 5mg BID up to10mg BID. Followed for 6 months. 7 of 12 had 50% regrowth. 6 of 7 responders needed dose escalation(approx. 65% response rate). Relapse 4-8 weeks after stopping. Abatacept study – one complete responderout of 15 treated – continued to regrow even after end of treatment. Biomarker analysis using geneexpression performed in all studies.

Wilma Bergfeld: Cleveland Clinic AA Tofacitinib Results

Open retrospective study. Moderate to severe, recalcitrant patients, some with RA and AA. Thirteenpatients, all recalcitrant to other therapies. Average regrowth at 4 months, some as late as 9 months .Some are on drug for 18 months. One AU patient was African American, regrew his eyebrows and lashesbut not scalp and not body hair. Three patients had total regrowth. One was duration of 30 yrs. Responserate = approx. 54%.

Justin Ko: Oral Tofa in Severe AA – Stanford/Yale Study

All patients are on 5mg BID and for 3 months duration only. Enrolled 70 patients – 66 finished study. Longdurations 1-43 years; average 5 years duration. ¾ were AU/AT patients. Biomarker analysis using geneexpression studies. Outside the study – treating approx. 80 patients. About 2/3 of patients grow clinicallyacceptable patients at 6 months or longer. Roughly 66% overall response rate.

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Session 3 (Continued)

10

Brett King: Tofa in AA in Adults and Adolescents

Approx. 90 adult patients treated and 13 adolescents with tofa alone or tofa with pulse steroid. Overallresponse rate approx. 60% in adults, 75% in teenagers. Patients with disease duration less than 11 yearshave better responses. Relapses seen while on treatment, and after drug stopped. Topical studiestreating one patient with compounded ruxo, regrow brows. Three compounded tofa formulations, nopositive results.

Elise Olsen: Topical INCB018424 in AA in Open-label Treatment Period (Abstract #006)

Study evaluated topical ruxo 1.5% cream in AA patients. Part A: open label 24 week study in 12 subjects.18-70 years of age. Current episode of either 6 months 50-99% loss, or 12 months 25-50% loss. Exclusionof AT AU or ophiasis. 6 of 12 patients (approx. 50% response rate) reached SALT50 response at end of 24weeks. Promising data to encourage further development of topical JAKs.

Alice Gottlieb: Topical JAK Inhibitors in Psoriasis

Lessons and cautions from topical psoriasis JAK inhibitor studies. These were published early in 2011-2012but no further development. Why? Systemic absorption? Biopsies limit accrual. Get early formulationdata, assess systemic exposure with penetration enhancers, and put biomarker studies into subtotalinunction studies, so that accrual moves faster. Submitted paper on vitiligo, and JAK inhibitors may beuseful for lupus, dermatomyositis and others.

2016 AA Research Summit

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Session 3 (Continued)

11

Take Home Lessons from Combined Studies

• Relapse seen in all studies after treatment; sometimes worse than baseline, starting 4-8 weeks after stopping drug.• Flares observed while on treatment in several studies, sometimes in different pattern (ophiasis) than original AA (12% in Yale

study, 4 pts Stanford, 1 pt. Columbia).• African American individuals in non-responder groups (though also in responder groups).• Ruxo treated patients regrowth visible earlier than tofa treated patients. Tofa required dose escalation in all studies, longer

treatment periods.• Each study had responses in patients with long durations of disease; however, two studies suggested that less than10 years

duration had better responses; one study suggested shorter duration of current episode correlated with better responses.• Regional differences in regrowth: Eyebrows, lashes and body and facial hair don’t correspond to scalp hair. Patients respond

differently on different body sites.• One study (Yale) added pulse prednisone 300mg Q4 weeks for 3 doses, in addition to elevated dose of tofa to improve

responses. Comment by Dr. Shapiro that he has combined oral tofa with ILK and seen faster responses to tofa.• Two studies (Stanford/Yale and Columbia) conducted gene expression biomarker analysis.• No study reported improvement in AGA hair loss in patients taking JAK inhibitors. Perhaps not surprising; this may require

topical administration.• AE: generally mild. Acne (8% in Yale study); trace hematuria (Columbia), eczema herpeticum (Stanford); LFT, lipid

abnormality (Cleveland), URIs.

Despite widely heterogeneous groups of patients, durations of disease, different dosing regimens, and length oftreatment, response rates were highly consistent across sites (range 50-75%):

Columbia: Response to oral ruxo = 75%, oral tofa = 65%.Cleveland: Response rate =approx. 54% oral tofa.Stanford: 66% overall response rate oral tofa.Yale: approx. response rate 60% in adults, 75% in adolescents for oral tofa.Duke/Incyte: approx. response rate 50% for topical ruxo.

2016 AA Research Summit

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Session 4 - Emerging Technologies & Targets

122016 AA Research Summit

Ali Jabbari: Biomarkers for AA and Clinical Trials

AA Gene expression biomarker led to development of ALADIN – AA Disease Activity Index. Ruxolitinib trial– responders had high scores at baseline that normalized on treatment, and non-responders did not.Tofacitinib trial – responders at baseline had high scores, and normalized on treatment, albeit at differentdosages. ALADIN may distinguish responders from non-responders at early treatment time points, aftertreatment, to predict who will and won’t respond and on what dosages.

Zhenpeng Dai: AA Reversal by IL7R Blockade via Upregulation of PD-1

IL7 is a gamma chain cytokine that is dysregulated in AA in humans as well as C3H-HeJ mice. Investigationof its potential utility in prevention and treatment of AA in C3H/HeJ mice. Unlike the other antibodiestested, blockade of IL7R can reverse early onset AA in mice, potentially via PD-1 pathway. Potential newtherapeutic target for AA.

Amos Gilhar: Non-conventional T-cells in the Pathogenesis of AA

NKG2D is expressed on other cells than CD8 T cells, such as ILCs. Incubation of ILC1 with hair follicles.More catagen follicles in ILC1 co cultured cells and human hair follicles. iNKT cells are present in AA lesions.Used humanized mouse AA model. Alpha-GalCer induced expansion of NKT10 cells. Alpha-GalCerprevented development of AA in the humanized biopsy model.

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Session 4 (Continued)

13

Pantelis Rompolas: HF Regeneration and Pathophysiology Live Imaging

Mouse model of stem cell dynamics. Live imaging of mice. Ability to follow individual hair folliclesduring regeneration process. Mechanisms of hair growth – is a niche required? Is DP required? Ablationof epithelial stem cells does not prevent regeneration – it can readily recover after damage andcontinue with HF growth. Dermal input is absolutely required. Epidermal niche not required. Non-HFepithelial cells can enter the niche and acquire a HF fate. Clearance of catagen debris does not appearto occur via immune cells.

Jerry Shapiro: Hype or Hope? Data Review of Microneedling and PRP

Blood is 45% cells, and 55% plasma. 0.15 of cells are platelets. Plasma has lots of good nutrients thatcould support hair growth. Platelets have a lot of growth factors contained in platelets. Some are PDGF,IGF-1, FGF, EGF, VEGF etc may help create a better environment for hair to grow. Need to get rid ofRBCs, and WBCs, inflammation, toxicity, etc. Only the Platelets are desired – plus the plasma. Can bedone from a blood sample that is spun in the office in front of the patient, they can see the centrifugeto be sure they get their own cells back! One study of PRP in AA, half head study from Rinaldi et al.Three groups – PRP, ILK, placebo. 3 treatments 1x monthly. One lesion was injected. 60% of patientsshowed regrowth. Microneedling. 1.5-2mm needle depth. Mechanism of action – poor man’s PRP?Angiogenesis? Breach of stratum corneum. Use a SkinPen device to make the needle holes.Microneedling study in AA showed no improvement in 3-4 months. Roller needle device went 0.5mm indepth, painful. After 3 months, 8 of 15 showed response, 12 of 15 after 6 months. No relapse. Howdoes it work – perhaps factors stimulated with wounding – VEGF, wnt3a and wnt3b.

2016 AA Research Summit

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Dinner Keynotes

142016 AA Research Summit

Angela Rodgers: What Treatment Means to Patients

No safe, affordable, accessible treatment for AA is a problem. Skin, as a tangible and visible part ofthe body, can have a magnificent effect on psychological status which is continuously involved insocialization processes from childhood to adulthood (Shahin, A. et al., 2014). Increased prevalenceof mental health issues in the alopecia areata community. Developing a breakthrough treatment forthose with AA would be good for combating the disease but also restore the mental health of thecommunity.

Eleanor Perfetto: Activating the Patient Voice in Drug Development

Patients are experts on their disease. PDUFA VI guidance to solidify patient engagement in burden ofdisease, holistic sets of impacts, measures for identified impacts, and clinical outcomes assessments.The goal is active engagement over passive study enrollment. Studies that are patient-directed or inpartnership with patients offer the most active participation.

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Session 5 – Industry Roundtable

152016 AA Research Summit

Nine industry representatives! Stakeholder support of new products for alopecia areata. Engaging the patient voice in therapeutic development.

Company Speaker Title

Aclaris Therapeutics, Inc. Dr. Kimberley Forbes-McKean Senior Vice President, Drug Development

BiologicsMD, Inc. Mr. J. David Owens President & CEO

Concert Pharmaceuticals, Inc. Dr. Roger Tung Co-Founder, President & CEO

Gilead Sciences, Inc. Dr. Thomas O'Riordan Senior Director, Clinical Research

Incyte Corporation Dr. Richard L. Leff Group VP, Drug Development

Legacy Healthcare Mr. Saad Harti President

LEO Pharma Inc. Dr. Michael Sierra Vice President, LEO Science & Tech Hub

Pfizer, Inc. Dr. Elena PeevaExecutive Director, Inflammation & Immunology Clinical Research

RXi Pharmaceuticals Corp Dr. Geert Cauwenbergh President & CEO

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Session 6 – Introduction & Review

162016 AA Research Summit

David Norris: Review and Summary of Day One Discussions

Spectacular progress in genetics and immunology to understand mechanisms of AA. Development of AAtranslational research program: biobank, uniform trial platform including biomarkers, extensive clinicalmaterial and investigators.

Positive feedback loop in AA

Divito & Kupper, Nature Medicine 20, 989–990 (2014).

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Session 7 - What Lies Beneath: Elusive AA Auto-Antigens

172016 AA Research Summit

Chris Nagao: Regulation of Skin Immunity by the Hair Follicle

Hair follicle keratinocyte-derived cytokines (such as IL7 and IL15) maintain resident memory T cells in theHF. Both CD4 and CD8 Trm reside in the HF. ADAM10 ablation model leads to patchy hair loss withexclamation point hairs. See infiltration of mainly CD4+ T cells and DCs in the isthmus and bulb area, whichhappens first, and then disrupts HF morphology. Loss of HF immune privilege, measured by CD200decrease, and increase of ICAM1 in ablated mice. Differential sensitivity to IFN among HF keratinocytepopulations and breakdown of IP and/or enhanced leukocyte recruitments.

Marta Bertolini: Identification of Antigenic Mimotopes inAA Specific CD8+ T cells

Isolation of CD8+ T cells in AA and TCR sequencing. Take Tcells from lesional skin around the HF. RT-PCR to clone theBeta chain, and then alpha chain in four patients withdifferent HLA types, several Vbeta clonotypes that differand vary greatly between AA patients. Eventually, screeninga peptide library with TCRs to identify antigens, which canfacilitate immunotherapy to eliminate pathogenic T cells.

Hou et al., Genes and Immunity, 2016

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Session 7 (Continued)

18

Annemieke de Jong: Identifying Pathogenic TCRs in AA

TCR repertoire sequencing revealed that in the AA graft model, the skin graft carries with it a number ofT cells, which are then expanded in the recipient to generate a new repertoire which contains somedonor cells, but mainly these cells are newly primed T cells that do not overlap with grafted repertoire.In humans, in lesional skin, there are many CD4 cells in some patients, CD8 in others. Compared toblood, which are primarily CD8. These CD4 cells are comprised both of Tregs as well as non-Tregs; AUpatients may have less Tregs. Increase in clonality in AU compared to normal scalp. Several TCRs similarin lesional skin and support antigenic drive.

2016 AA Research Summit

Alessandro Sette: Epitope Identification Screening in AA

Large scale screening for antigen discovery –complementary to the two previous talks which werevery specific and focused on HF cells. Starting material israte-limiting. Collected 18 AA patients to donate a pint ofblood and collected PMBCs to be used in this screen. HLAtyping done in this cohort and 13 of 18 have A-0201allele. Total of 311 peptides have been predicted, nowwill be synthesized and conduct large scale screen!

Schulten et al. PNAS 2013

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Session 7 (Continued)

192016 AA Research Summit

Teresa DiLorenzo: Similarities Between T1D and AAT1D and AA have many similarities – infiltrates, ‘patchy’ disease – some islets have B cells that aredestroyed, others are intact. Similar prevalence of 0.15 for AA and 0.19 for T1D. No female to malegender bias. Incidence of T1D is increasing, maybe AA too in AA from Olmsted study. Environmentalfactors – microbes, food, pollutants? Shared genetics – increased T1D in relatives of AA patients. BMCMedicine 2013. Comorbid – vitiligo, psoriasis, AITD in both AA and T1D families. Many T1D and AAgenes are associated with general immune function. There are also susceptibility genes expressed in thetarget organ (in Beta cells in T1D, and in AA HF cells). CD8 as well as CD4 cells important in both. Modelsof Human TCR transfer into NOD.scid mice – may be useful for us in the future.

13 Y.O. with type 1 diabetes for 5 years

Diabetes (2016) 65:719

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Session 8 - Just Skin Deep: Immunology of the Skin

202016 AA Research Summit

Dan Kaplan: T cells, DCs Autoimmunity and the Hair Follicle

Signals that recruit and keep immune cells in the skin. Adult human Langerhans cells require TGFß forepidermal residence – autocrine loop. LCs secrete and require TGFß. In epidermis, only two factors activatelatent TGFb – avB6 (required for LC residence) and avB8 integrins. In bulge, LC are excluded; in isthmus, LCare included. avB8 is expressed in the isthmus, whereas avB6 is in the interfollicular epidermis (patternedwith respect to integrin localization). Loss of TGFb is required for UV-induced LC migration. UV reducesintegrin expression in epidermis, What about Tfm cells? Same mechanism exists for Trm; maybegeneralizable for other epithelia, such as intestine. Application to AA – targeting TGFB or its activationcould be used to deplete Trm from epidermis.

Michael Rosenblum: Tregs in Skin and HF Stem Cell Differentiation

Traditional role of Tregs – suppressing inflammation. Non-traditional functions –glucose metabolism, muscle repair, lung epithelium repair after injury. Do they alsohave a similar specialized function in skin? Tregs are active around mouse hair follicle,send appendages into HF milieu for sampling environment. In human HF, same thing,Tregs cluster around HF. Depilated mice in telogen with Treg depletion fail to enterthe next anagen. Treg are required for bulge HF stem cell activation/proliferation (notseen in other KC populations) as well as KC differentiation during anagen induction.Mechanism: Treg expression of JAG1, a notch ligand, and expression of Notch targetgenes in HFKCs. Targeting of JAG1 in Tregs and depilation attenuates anagen entry,failure of Notch dependent differentiation in HFKCs. AA GWAS genes reflect Treggenes (Eos, IL2, IL2RA) and low-IL2 clinical study may reflect influence on Tregs in hairregeneration function as well as immune responses.

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Session 8 (Continued)

212016 AA Research Summit

Niroshana Anandasabapathy: Making and Breaking ToleranceTissue DCs in skin in epidermis and around HF. Tissue factors (nurture) may override nurture (ontogenyor origin) of immune cells. Skin DC subsets contain 23 cancer IO targets. Many of these are in NFkBpathway. Do monocytes and macrophages also share this signature? Yes – same signature in the skin.Signature is conserved in mouse and human, conserved upon skin entry, and shared acrossmonophagocytes. Most highly differentially expressed gene – SOCS2. Loss of SOCS2 reveals novel IOtarget in cancer, and expanded immune priming and adaptive anti-tumor immunity. How does this link

to disease states? Single cell sequencing in human melanoma metastasis and other diseases states. Trmcells and DC cells are relatively under-studied populations in AA, may represent areas for futureresearch.

Michel Gilliet: Commensal Bacteria Control pDC Recruitment in SkinpDCs accumulate in the dermis in early psoriasis lesions and production of IFN1 triggers cascade leadingto full disease expression, upstream of TNFa, IL23, IL17 and IL22. What activates pDCs? Antimicrobialpeptides in the skin not expressed in healthy skin, but are upregulated in wound healing andmechanical stress and injury. Complexes of AMPs and DNA enter via pDCs to initiate immune processesleading to psoriatic plaque. In AA, reported elevation of IFNa and pDCs (2016 reference). Is the Koebnerphenomenon as a shared feature? Tape stripping recruits pDC to skin in humans and skin wounding inmice. Interestingly, skin microbiota are required for pDC activation in injured skin. AMPs kill bacteria,bind to bacterial DNA and lead to inflammation and wound healing. In humans, microbiota depletiondecreases IFNa.

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Session 9 - Genes, the Hair Follicle & the Microenvironment

222016 AA Research Summit

George Cotsarelis: Nutritional Factors Influencing Alopecia

Micronutrients create optimum conditions for hair shaft formation – Vitamin D, Zinc, Iron.

Is telogen effluvium a trigger for AA? TE pushes anagen follicles into telogen prematurely (dysregulatedcatagen?), commonly due to fever, medications, malnutrition. If catagen goes awry, can this precipitate AA,expose antigens? Examples – hairless, VDR mutations cause dysregulated catagen, also interact withthyroid hormone receptor. Does low iron decrease the threshold for developing AA? Hair phenotypes Irondeficient mouse models, appear to have abnormal catagen. Iron related genes, there are many in the hairfollicle. Could micronutrient deficiencies contribute to non-responders to AA therapies?

Michael Rendl: Niche Control of HF Formation and Regeneration

Hair-GEL.net is a resource to catalogue hair genes from at least 7 different cell populations in HFmorphogenesis. Recently updated, 14 different cell types in adult HF. Searchable database for candidate AAgenes/antigens to see where they are localized in the HF. Now working on hair regeneration wave profiling.

Sennett et al, Developmental Cell 2015

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Session 9 (Continued)

232016 AA Research Summit

Natasha Botchkareva: Role of miRNAs in AAComparison of miRNAs in C3H affected vs unaffected skin. The downregulation of miR- 486 and -451 inAA-affected mouse skin suggests their putative role in prevention of the collapse of hair follicle immuneprivilege in normal anagen hair follicles. Possible roles in inflammation or apoptosis. Treated AA micewith miRNA mimics and saw reduction in CD4+ and CD8+Tcells; do they delay AA onset. Mir486 isexpressed in human HF (but not mir451). Organ culture assay treated with mir486 upregulates MHCI,HLA, etc. Downstream targets not yet known – CADM1, FGF9, SP5. Overexpression of CADM1 can causeAA (Fiona Watt lab, JI, 2012).

Tiffany Scharschmidt: Commensal Microbes and HF Morphogenesis Drive Treg Migration into SkinA wave of Tregs into neonatal skin mediates tolerance to commensals; Tregs are required for this (p6-13). HF morphogenesis directs Tregs into skin. Commensals are required for this process to occur.Search for: chemokines expressed in HF x receptors on Tregs at same time points. Identified onepathway involved: CCL20 and CCR6. CCL20 expressed near isthmus, and CCR6 expressed in skin Tregs.CCL20 preferentially drives neonatal Tregs into skin in vitro. CCR6 promotes Treg accumulation in skin.

Anastasia Khvorova: RNA Chemistry toward Modulation of Gene Expression in SkinDelivery much improved with targeting molecules attached to siRNA to get into cells. Recent paper inNEJM shows one-year knockdown of target with single subQ injection. Field has matured enough totarget any gene in skin – delivery easier than many other tissues.

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Session 10 - Understanding the Commonalities Across Autoimmune Diseases

242016 AA Research Summit

Lynn Petukhova: Comorbidities in the AA Registry

Identifying disease subtypes and mechanisms and overlaps in genes and phenotypes. Using EHR data toidentify comorbidities among AA patients (showed T1D, RA, Ps, Lupus, others) in one study from Columbiaas well as a Danish health study. PheWAS studies – a cohort that has been GWAS analyzed and comparedto EHR data. AA SNPs are represented in 275 different conditions, including autoimmune, inflammatory,cancer, and behavioral disorders.

John Harris: Understanding Parallels betweenVitiligo and AA

Both vitiligo and AA are mediated thru IFNgpathway, but treated differently. Location ofthe inflammation is what differs, not theinfiltrate itself. Systemic drugs should work inboth. Vitiligo has prominent IFNg signature butfew psoriasis pathway cytokines. TargetingJAK1/2 using tofa and ruxo can reverse vitiligoin mouse model. Two case reports –one tofa,and one ruxo in human patients. Levels ofCXCL10 dropped when patient started ruxo,showing drug hits target IFNg pathway.

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Session 10 (Continued)

252016 AA Research Summit

Emma Guttman: Cytokine Targeted Therapy: Lessons from AD and Other DiseasesHighest comorbidity for AA is AD (38%). Previous genetic study showing IL13 SNPS, and Th2 cytokinesand several other studies. Th2 axis picked up on RT-PCR not array studies, since they may be expressedat low levels. Dupilumab study patient who had AD as well as AA. One patient with apremilast hadpatchy regrowth. Three patients with ustekinumab, must be used at higher dose in AD than psoriasis.Two other patients had regrowth of some hair. Higher inflammation at baseline was associated withbetter clinical responses. Targeting AA with multiple drugs aimed at different pathways.

Brian Kim: Neuronal Type 2 Cytokine Signaling Regulates Chronic Itch in ADItch is the most debilitating symptom of AD. IL31secreted by Th2 cells stimulates sensory neuronsdirectly as a pruritogen. Do Th2 cytokines induceitch? IL4R and IL13R expressed on dorsal rootganglia. Deletion of IL4R on the DRG neurons ledto reduction in itch over time. Dupilumab leads toreduction in itching in AD clinical trials. Additionalmechanism of action of this drug on sensoryneurons and central itch. Nerve bundles wraparound HF, reminding us to think about commonmechanisms for AA.

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Session 11 - Challenges and Opportunities: Advancing Drugs to Patient Care

262016 AA Research Summit

Bozena Michniak-Kohn: Topical & Microneedle Drug Delivery

New methods for topical drug delivery. Two new approaches –targeted delivery – microneedles and tyrospheres. Nanoformulation that can encapsulate cargo and deliver cargospecifically to the hair follicles and upper epidermis.

Raphael Clynes – Inflammatory Biomarkers: Informing Clinical Trials

Can we borrow from immunological biomarkers being developed in the immuno-oncology field thatmight be applicable to AA. Lessons from oncology that are applicable to autoimmunity – in reverse. Newways to look at infiltrate (immunophenotyping CD8 cells, serum chemokines, TCR repertoire, Functionalmarkers in blood (pSTAT, IFN, CD107) as well as end organ (Immunoscore IHC, RNA profiling, TCRrepertoire, crawl-out studies, Immunophenotyping CD8 cells, RNAscope). Are drugs reducing clonalityof T cells in AA skin (for example).

Pharmaceutics 2015, 7, 90-105.

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Session 11 (Continued)

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Antonella Tosti: Repurposing Drugs for AA - VytorinInvestigation of statins in AA. Block IFNg and modulate JAK/stat pathway. Small study of 19 patientswith moderate AA. At 24 weeks, 14/19 patients responded. Stop treatment and 7 patients maintainedtheir hair. A second study was done on severe AA, 20 patients, treated for 24 weeks. One patient had aclinical response with patchy regrowth. What about topical statins – Dr. Jimenez study on topical statinsin C3H-HeJ mice, restored hair growth. Can statins be utilized to prevent relapse (in mouse)? Heattreatment to induce AA in C3H model (by cellular stress). Series of 42 patients with AA in practice,added statin to their treatment regimen once they have regrown with another treatment. 30 patientshad severe AA (including ophiasis) and 12 AT/AU. After 6 months 31/42 patients had minimal or norelapses. After 12 months, 11 of 31 patients had relapse when discontinued treatment. Statins mayhave utility in helping to prevent relapse after response to other therapies. Patient reported musclepain as expected side effect.

Natasha Mesinkovska: Unconventional TherapiesCommon questions: medications, lifestyle, devices. Use of Allegra antihistamines (fexofenadine) formast cells in AA. Perhaps useful in early AA. Ice caps for chemotherapy alopecia. Cryotherapy for AA353 cases over 22 yrs. For Patchy AA, face and neck, children, adjunct to JAK inhibitors. Low-dosenaltrexone for autoimmune disorders. Opiate antagonist used for drug addiction. Case reports in otherautoimmune disorders and inflammatory alopecia's.

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Session 12 - Regulatory Matters & Funding Opportunities

282016 AA Research Summit

Dory Kranz: Patient-Focused Drug Development Initiative

Incorporating the voice of the patient in AA clinical research. Upcoming PFDDI meeting in FY2016-2017.Great opportunity to make the case for AA to the FDA. Paper: AA is not a cosmetic disease. New initiative:Patient-centered outcomes consortium, to create a single outcome measure that can be shared acrossindustry partners.

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Session 12 (Continued)

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Devanand Jillapalli: FDA Orphan Drug Designation and Funding Opportunities

Orphan designation if a disease occurs in less than 200,000 individuals. Importantly, the subset must bespecifically tied into the use of the drug. Properties of the drug could involve: mechanism of action (i.e.:antibody-specific or biomarker-based drug); or toxicity of the drug limits is use to refractory patients,for example. Drug must be useful in the orphan subset, and not in the rest of the indication/patients.Clinical Trial Grants Program – awarded $23M this year. Natural History Grant Program. $400kyr/5yrs.See OPDD website for more information.

Ricardo Cibotti: NIAMS Funding Opportunities

Alopecia Areata is a quickly growing area of NIAMS research! In 2007, skin immunology and diseaseprogram was created within NIAMS. Clinical trials grant program – many opportunities but needpartnership with drug companies to donate drugs for these grants!

Kara Odom Walker: PCORI - Engaging Patients in Clinical Trials and Outcomes Research

Comparative effectiveness research – phase 4 studies, real world assessments. Five areas focused onhealthcare. Funding deadline Jan 17 2017. Send inquiries prior to submission. PCORnet – big datanetworks. Questions that can be answered in a real-world setting – questions important to patients,caregivers, payers. Information that can be disseminated and implemented in the future.

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NAAF SUMMIT 2016 - WE DID IT!!

On behalf of NAAF and Co-Chairs, Drs. MariaHordinsky, Angela Christiano and John Harris, wethank you for your interest in alopecia areata, yourthoughtful participation in the Summit, and yourenthusiasm for the future of alopecia areata research.