Virtual R&D Day September 29, 2021

Virtual R&D Day

September 29, 2021

Forward Looking Statements

This presentation contains forward-looking statements, including, but not limited to, statements related to Horizon’s full-year 2021 net sales and adjusted EBITDA

guidance; expected financial performance and operating results in future periods, including potential growth in net sales of certain of Horizon’s medicines;

development, manufacturing and commercialization plans and strategies; expected timing of clinical trials, studies and regulatory approvals; potential market

opportunity for and benefits of Horizon’s medicines and medicine candidates; and business and other statements that are not historical facts. These forward-looking

statements are based on Horizon’s current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ

materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks that Horizon’s

actual future financial and operating results may differ from its expectations or goals; Horizon’s ability to grow net sales from existing medicines; impacts of the COVID-

19 pandemic and actions taken to slow its spread, including impacts on supplies and net sales of Horizon’s medicines and potential delays in clinical trials; the fact that

Horizon’s full-year 2021 net sales, adjusted EBITDA and TEPEZZA net sales guidance and the expected timing of certain TEPEZZA clinical trials assume that future

committed manufacturing slots for TEPEZZA are not cancelled and are run successfully, which could be impacted by additional government-mandated COVID-19

vaccine production orders and other risks associated with the manufacture of biologic medicines; risks associated with acquisitions, such as the risk that the

businesses will not be integrated successfully, that such integration may be more difficult, time-consuming or costly than expected or that the expected benefits of the

transaction will not occur; the availability of coverage and adequate reimbursement and pricing from government and third-party payers; risks relating to Horizon’s

ability to successfully implement its business strategies, including its manufacturing and global expansion strategy; risks inherent in discovering new medicine targets

and candidates and in developing novel medicine candidates and existing medicines for new indications; risks associated with regulatory approvals; risks in the ability

to recruit, train and retain qualified personnel; competition, including potential generic competition; the ability to protect intellectual property and defend patents;

regulatory obligations and oversight, including any changes in the legal and regulatory environment in which Horizon operates and those risks detailed from time-to-

time under the caption "Risk Factors" and elsewhere in Horizon’s filings and reports with the SEC. Horizon undertakes no duty or obligation to update any forward-

looking statements contained in this presentation as a result of new information.

Dr. Dinesh Khanna, Dr. Martin Kolb and Dr. Bobby Korn serve as consultants to Horizon Therapeutics plc.

Horizon Therapeutics Virtual R&D Day Agenda

CD40L: Cluster of differentiation 40 ligand. | LPAR1: Lysophosphatidic acid receptor 1. | pDC: Plasmacytoid dendritic cell. | TED: Thyroid Eye Disease.

Topic Speakers

Introduction: Vision and Strategy Tim Walbert, Chairman, President and Chief Executive Officer

R&D StrategyElizabeth Thompson, Ph.D., EVP Research & DevelopmentSrini Ramanathan, Ph.D., SVP Research & Development Sciences

Daxdilimab (HZN-7734): First and Only pDC Depleter in Clinical Development; Now Pursuing Five Indications

Bill Rees, Ph.D., VP Translational SciencesTheresa Podrebarac, M.D., M.Sc., SVP Clinical Development

Dazodalibep (HZN-4920): CD40L Antagonist Designed to Block a Central Pathway Involved in Many Autoimmune and Inflammatory Diseases

Bill ReesTheresa Podrebarac

Q&A Session

HZN-825: LPAR1 Antagonist with Early Signals of Benefit in Fibrotic Diseases, Areas with High Unmet Need

Srini RamanathanDinesh Khanna, M.D., M.Sc., Professor, University of Michigan Health

UPLIZNA: Next-Generation B-cell Depleter with a Novel, Targeted ApproachKristina Patterson, M.D., Ph.D., Medical Director, NeuroimmunologyTheresa Podrebarac

Q&A Session

TEPEZZA: Building Evidence to Help Treat More Patients with Chronic TEDBobby S. Korn, M.D., Ph.D., FACS, Professor of Ophthalmology & Plastic Surgery, University of California, San Diego

Q&A Session

Conclusion Tim Walbert

Horizon Leadership Team and Clinical Experts Participating Today

Tim WalbertChairman, President and Chief Executive Officer

Elizabeth Thompson, Ph.D.Executive Vice President, Research & Development

Theresa Podrebarac, M.D., M.Sc.Senior Vice President, Clinical Development

Srini Ramanathan, Ph.D.Senior Vice President, Research & Development Sciences

Bill Rees, Ph.D.Vice President, Translational Sciences

Horizon Participants Key Opinion Leaders

Dinesh Khanna, M.D., M.Sc.ProfessorUniversity of Michigan Health

Bobby S. Korn, M.D., Ph.D., FACSProfessor of Ophthalmology & Plastic SurgeryUniversity of California, San Diego

Tina VenturaSenior Vice President, Investor Relations

Kristina Patterson M.D., Ph.D. Medical Director, Neuroimmunology

Martin Kolb, M.D., Ph.D.Director, Division of RespirologyProfessor, Department of Medicine McMaster University

Tim WalbertChairman, President and Chief Executive Officer

Sept. 29, 2021 | Horizon R&D Day | 5

Key Takeaways for Today

(1) Horizon estimate.

We are building a

•

• announced today and starting in 2022

• anticipated in 2021-2023

• in second half of the decade

Horizon is a with best-in-class commercial execution and a rapidly growing pipeline

We are to bolster our ability to continuously innovate

Our current in total peak annual net sales potential(1)

Horizon is One of the Fastest Growth and Transformation Stories in Biotechnology

(1) Midpoint of full-year 2021 net sales guidance as of Aug. 4, 2021. By this presentation Horizon is not updating or confirming its prior guidance.

$297M

2014 2021E

Inflammation Segment Orphan Segment

$3.075B

10x

Net Sales(1)

Strong Track Record of Execution While Increasing R&D Investment

CAGR: Compound annual growth rate. | DD: Double-digit. | EBITDA: Earnings before interest, taxes, depreciation, and amortization. Adjusted EBITDA is a non-GAAP measure; see reconciliations at the end of the presentation for a reconciliation of GAAP to non-GAAP measures. (1) Midpoint of full-year 2021 net sales guidance as of Aug. 4, 2021. By this presentation Horizon is not updating or confirming its prior guidance.

R&D Investment ($M)

2018 2019 2020 2021E

+37% CAGR

$1,208 $1,300

$2,200

$3,075

Inflammation SegmentOrphan Segment

(1) 2018 2019 2020 2021E

$451 $483

$999

$1,280

+42% CAGR

(1)

2018 2019 2020 2021E

$73

6% of sales

$85

7% of sales

$115

5% of sales

Low DD as % of sales

(1)

Adj. EBITDA Growth ($M)Net Sales Growth ($M)

Consistently Delivering Significant Value for Our Shareholders

NBI: NASDAQ Biotechnology Index. Source: Bloomberg. Note: Peer Index is an equally weighted index of ALXN, ALKS, ALNY, BMRN, BLUE, EXEL, INCY, IONS, JAZZ, NBIX, SRPT, SGEN, RARE, UTHR, VRTX; ALXN was acquired Aug. 2021.

$0

$5

$10

$15

$20

$25

Market Cap in $B

$24.9B

-100%

0%

100%

200%

300%

400%

500%HZNP: 487%

NBI: 85%

Peer Index: 67%

Data through Sept. 24, 2021 Data through Sept. 24, 2021

5-Year Shareholder Return Significantly Exceeded NBI and Peer Index

Driving an Eight-Fold Increasein Our Market Cap

Horizon’s Vision

EBITDA: Earnings before interest, taxes, depreciation, and amortization.(1) Horizon’s goals are to achieve strong double-digit net sales growth and EBITDA margin growth for 3-year CAGR [2021 to 2024].

Strategic Goals Financial Goals

A Top-Tier Biotech Company Focused on Researching, Developing and Commercializing

Medicines for Rare, Autoimmune and Severe Inflammatory Diseases

• Maximize value of on-market medicines through commercial execution and clinical investment

• Invest aggressively in our current pipeline medicines

• Expand our pipeline through focused internal innovation and business development

- Expand beyond rare diseases into areas with high unmet need and alignment with Horizon commercial and development strengths

• Build a global presence

• Generate strong double-digit net sales growth(1)

• Generate strong double-digit adjusted EBITDA growth(1)

• Generate meaningful adjusted EBITDA margin expansion

• Maintain R&D investment at double-digits as a percent of sales

• Generate top-tier performance for our shareholders

Excellence in Commercial Execution

We accelerate the growth trajectory and maximize the

potential of our medicines through best-in-class commercial execution

Proven & Disciplined Business Development

We acquire and license medicines through our strong in-house

business development capability, focused on opportunities where

we are uniquely positioned to drive value

Strong Research & Development Capability

We leverage deep drug development experience and an

agile approach to continually innovate with our

existing medicines and bring new ones to market

What Sets Horizon Apart

(1) Full-year 2021 KRYSTEXXA net sales guidance as of Aug. 4, 2021. By this presentation Horizon is not updating or confirming its prior guidance. (2) Horizon estimate.

2015 2021 Peak Annual Net SalesGuidance

>$500M(1)

>$1B(2)

~$60M

HZNPPre-HZNP

>8x

Increasing Annual Net Sales More Than 8x in Five Years Exemplifies Our Industry-Leading Patient-Centric Approach

• KRYSTEXXA was an underperforming and undervalued medicine when acquired in 2016

• We transformed its growth trajectory through strong commercial execution

• We invested in clinical development to drive our immunomodulation strategy;immunomodulation use >40% at 2Q21

• We redefined the market and repositioned KRYSTEXXA as a medicine with >$1B(2) potential and are driving continued growth

KRYSTEXXA: Example of Horizon’s Ability to Drive the Right Strategy and Execute FlawlesslyApproved in 2010; Relaunched by Horizon in 2016

KRYSTEXXA: Significant Opportunity Exists to Exceed $1B in U.S. Annual Peak Net Sales

Uncontrolled gout: Chronic gout refractory (unresponsive) to conventional therapies.(1) Prevalence of gout and hyperuricemia in the U.S. general population: The National Health and Nutrition Examination Survey (NHANES) 2007-2016. Arthritis Rheum. 2019 Jun;71(6):991-999. (2) Approximate number of patients in our annual addressable target market in rheumatology and nephrology; Horizon estimate. (3) Horizon estimate of patients treated in 2020.

9.5MU.S. gout patients; growing low-single digits(1)

>100K uncontrolled

gout patients(2)

• Growth in use of KRYSTEXXA plus immunomodulation

- Improves physician clinical conviction

- Increases patient’s ability to stay on therapy longer

• Growth in new and existing rheumatology accounts

• Accelerating growth in nephrology

Growth Drivers: Objective to Increase Total Patients and Vials Per Patient

<5% penetration(3); significant opportunity exists

TEPEZZA: Another Example of Best-in-Class Commercial Execution; One of the Most Successful Rare Disease Medicine Launches

(1) Full-year 2021 TEPEZZA net sales guidance as of Aug. 4, 2021. By this presentation Horizon is not updating or confirming its prior guidance. (2) Horizon estimate of TEPEZZA peak U.S. annual net sales of >$3B and TEPEZZA ex-U.S. estimate of >$500M peak annual net sales. (3) In the OPTIC Phase 3 confirmatory trial, 83 percent of patients treated with TEPEZZA achieved the primary endpoint of a 2 mm or more reduction in proptosis at week 24. In the OPTIC-X open-label extension trial, 89 percent of OPTIC placebo patients treated with TEPEZZA achieved the primary endpoint of a 2 mm or more reduction in proptosis at week 24.

Initial 2020Guidance

2020 2021E Peak

>$3.5B(2)

>$1.55B(1)

Exceptional Launch and Significant Net Sales Opportunity

$820M

$30M-40M

Growth Drivers: Objective to Drive Continued Strong Uptake and Expand TEPEZZA to More Patients

• TEPEZZA efficacy is impressive at 83-89%; broad indication(3)

• Severity and disfiguring nature of disease a motivating factor for patients to seek treatment

• Pre-launch, launch and new expansion efforts to drive strong awareness and high demand

- High-touch, patient-centric model

- Investing significantly in direct-to-consumer campaigns

TEPEZZA: Significant Opportunity Exists to Exceed $3.5B in Global Annual Peak Net Sales

TED: Thyroid Eye Disease. (1) Horizon estimate.

More Than $500M Opportunity Outside the U.S. and Europe(1)

• Continuing to advance our clinical program in Japan

• ~3K-5K: Estimated addressable annual patient incidence of acute TED in Japan(1)

• Evaluating launch in several additional countries

More Than $3B Opportunity in the U.S.;Significant Opportunity Exists(1)

• ~15-20K patients: Estimated U.S. annual incidence of acute moderate to severe TED patients (1)

- Acute TED lasts one to three years

• >70K patients: Estimated U.S. prevalence of chronic TED patients(1)

- Symptoms no longer changing but persisting; typically includes patients who have had chronic TED for five years or less

UPLIZNA through Focused Commercial Execution

the Value of UPLIZNA through Collaborative and Clinical Research

UPLIZNABeginning with Europe

• Invest in sales and marketing organization to expand reach and share of voice

• Establish best-in-class patient services, site of care and payer support

• Raise awareness of the benefits of UPLIZNA versus other therapies

• Invest in medical and scientific engagement;establish scientific leadership

• Conduct further analysis of UPLIZNA NMOSD data to expand understanding of differentiation

• Continue to build base of compelling real-world evidence

• Building out European infrastructure to support the potential launch of UPLIZNA for NMOSD

• Adding key capabilities to support UPLIZNA as well as additional medicines

UPLIZNA: Applying Our Success with KRYSTEXXA and TEPEZZA to Relaunch UPLIZNA for NMOSD

NMOSD: Neuromyelitis optica spectrum disorder.

Business Development is a Critical Part of Our Strategy to Build a Robust Pipeline

(1) As of June 30, 2021, cash and cash equivalents were $812.3M, gross debt was $2.614B and the gross debt-to-last-12-months adjusted EBITDA leverage ratio was 2.3x. Adjusted EBITDA is a non-GAAP measure; see reconciliations at the end of the presentation for a reconciliation of GAAP to non-GAAP measures.

Expanding our presence beyond rare diseases

• Autoimmune and severe inflammatory diseases

• Open to larger patient populations

Maintaining strong focus in rare diseases with significant unmet need

Balancing across early to late-stage programs

• E.g., preclinical, clinical, platform technologies

Increasing research-based partnerships and collaborations

• Focused; supported by sound rationale and compelling data

Strong financial position provides flexibility to pursue future business development opportunities(1)

Acquisition Cost Net Sales Achieved Through 2021

Business Development: Strong Track Record Based on a Disciplined Approach and Smart Commercial Perspective

(1) KRYSTEXXA net sales from 2016 through 2021; net sales in 2021 based on Horizon guidance of >$500M as of Aug. 4, 2021. (2) Does not include milestone payments or royalties. (3) Assumes net sales in 2021 based on Horizon guidance of >$1.55B as of Aug. 4, 2021. By this presentation Horizon is not updating or confirming its prior guidance.

>$1.755B(1)

$510M

3x

KRYSTEXXA: Total Net Sales Achieved to Date is Already More Than 3x the Acquisition Cost

Upfront Payment Net Sales Achieved Through 2021

>$2.37B(3)

$145M(2)

16x

TEPEZZA: Total Net Sales Achieved to Date is Already More Than 16x the Upfront Acquisition Cost

Leveraging our combined unique strengths

to make Horizon an even stronger, high-growth,

profitable biotech with the ability to continuously innovate

Horizon: A Leading Biotech

Bringing additional treatments to patients across a wide range of rare, autoimmune and severe inflammatory diseases

Talented R&D team with early-stage research, clinical development

capabilities and a deep, mid-stage biologics

pipeline

Experienced team with proven track record of

late-stage development and commercial expertise

to maximize value of pipeline and on-market medicines

Acquisition of Viela Significantly Expanded the Horizon Pipeline and R&D Talent

Pipeline Added deep, mid-stage biologics pipeline with four candidates now in 13 development programs

Target AreasAdvanced Horizon’s position in rare diseases and key therapeutic areas (i.e., rheumatology, nephrology), including UPLIZNA, a biologic medicine for the rare autoimmune disease NMOSD

Innovation Platform

Added early-stage research and translational capabilities that enhance Horizon’s ability to continuously innovate

R&D TalentEnhanced our accomplished R&D team adding deep scientific knowledge of autoimmune and severe inflammatory diseases

Leadership Position

Advanced Horizon’s position as a leading profitable biotech company by meaningfully adding pipeline breadth, depth and R&D investment to levels approaching profitable biotech peers

How Viela Advanced Horizon’s Transformation

NMOSD: Neuromyelitis Optica Spectrum Disorder.

Phase 2 Preclinical Phase 4

KRYSTEXXA(PROTECT Trial)

Phase 1

TEPEZZA(3)

(Diffuse Cutaneous Systemic Sclerosis)

HemoShear(2)

(Gout)

KRYSTEXXA(MIRROR: Immunomodulation)

HZN-003(Uncontrolled Gout)

HZN-007(1)

(Uncontrolled Gout)

2019 R&D Pipeline

MIRROR: Immunomodulation program evaluating the use of KRYSTEXXA in combination with methotrexate to increase response rate. PROTECT: Clinical trial evaluating the effect of KRYSTEXXA on serum uric acid levels in kidney transplant patients with uncontrolled gout.(1) Being developed under a collaboration agreement with XL Protein GmbH. (2) Gout discovery program in partnership with HemoShear. (3) Exploratory study.

Phase 3

TEPEZZA(Thyroid Eye Disease)

Preclinical

HemoShear(2)

(Gout)


HZN-007(1)

(Uncontrolled Gout)

Phase 3

UPLIZNA(Myasthenia Gravis)

UPLIZNA(IgG4-Related Disease)

Phase 2

UPLIZNA(Kidney Transplant Desensitization)

HZN-825(Diffuse Cutaneous Systemic Sclerosis)

Daxdilimab (HZN-7734)(Systemic Lupus Erythematosus)

HZN-825(Interstitial Lung Diseases)

Dazodalibep (HZN-4920 )(Rheumatoid Arthritis)

Dazodalibep (HZN-4920)(Sjögren’s Syndrome)

Dazodalibep (HZN-4920)(Kidney Transplant Rejection)

Horizon

Viela

Phase 1

TEPEZZA(3)

(Subcutaneous Administration)

TEPEZZA(4)


Daxdilimab (HZN-7734)(COVID-19 Acute Lung Injury)

HZN-1116(Autoimmune Diseases)

Phase 4

KRYSTEXXA(Shorter Infusion Duration)

TEPEZZA(Chronic Thyroid Eye Disease)



KRYSTEXXA(Retreatment)

KRYSTEXXA(Monthly Dosing)


TEPEZZA(OPTIC-X: Phase 3 Extension Trial)

2021 R&D Pipeline – March 2021Viela Added Significant Breadth and Depth to Horizon’s Pipeline

MIRROR: Immunomodulation program evaluating the use of KRYSTEXXA in combination with methotrexate to increase response rate. | PROTECT: Clinical trial evaluating the effect of KRYSTEXXA on serum uric acid levels in kidney transplant patients with uncontrolled gout. | OPTIC-X: Open-label extension trial of the Phase 3 trial evaluating TEPEZZA for the treatment of Thyroid Eye Disease. | IgG4: Immunoglobulin G4. (1) Being developed under a collaboration agreement with XL Protein GmbH. (2) Gout discovery program in partnership with HemoShear. (3) Including collaboration agreement with Halozyme. (4) Exploratory study.

Preclinical Phase 4

KRYSTEXXA(Shorter Infusion Duration)



HemoShear(2)

(Gout)



HZN-007(1)

(Uncontrolled Gout)

Phase 3

UPLIZNA(Myasthenia Gravis)

UPLIZNA(IgG4-Related Disease)

KRYSTEXXA(Retreatment)

KRYSTEXXA(Monthly Dosing)

ARO-XDH(Uncontrolled Gout)

2021 R&D Pipeline – September 2021Six New Programs for a Total of 27 Programs

MIRROR: Immunomodulation program evaluating the use of KRYSTEXXA in combination with methotrexate to increase response rate. | PROTECT: Clinical trial evaluating the effect of KRYSTEXXA on serum uric acid levels in kidney transplant patients with uncontrolled gout. | IgG4: Immunoglobulin G4.(1) Being developed under a collaboration agreement with XL Protein GmbH. (2) Gout discovery program in partnership with HemoShear. (3) Including collaboration agreement with Halozyme. (4) Exploratory study.

Phase 2

UPLIZNA(Kidney Transplant Desensitization)

Daxdilimab (HZN-7734)(Discoid Lupus Erythematosus)

HZN-825(Diffuse Cutaneous Systemic Sclerosis)

Daxdilimab (HZN-7734)(Systemic Lupus Erythematosus)

Daxdilimab (HZN-7734)(Alopecia Areata)

Daxdilimab (HZN-7734)(Lupus Nephritis)

HZN-825(Interstitial Lung Diseases)

Dazodalibep (HZN-4920)(Rheumatoid Arthritis)

Daxdilimab (HZN-7734)(Dermatomyositis)

Dazodalibep (HZN-4920)(Sjögren’s Syndrome)

Dazodalibep (HZN-4920)(Kidney Transplant Rejection)

Dazodalibep (HZN-4920)(Focal Segmental Glomerulosclerosis)

Existing Indications/ Programs

New Indications/ Programs

Phase 1

TEPEZZA(3)

(Subcutaneous Administration)

TEPEZZA(4)


HZN-1116(Autoimmune Diseases)


2021 Net Sales Potential Peak Net Sales of Growth Drivers and Pipeline Medicines

$3.075B(2)

TEPEZZA

KRYSTEXXA

UPLIZNA

Daxdilimab (HZN-7734)

Dazodalibep (HZN-4920)

HZN-825

ARO-XDH

KRYSTEXXA

Other Medicines

UPLIZNA

Significant Future Potential Driven by Seven Potential Blockbuster Medicines(1)

(1) Blockbuster defined as medicine with >$1B in estimated potential peak net sales. (2) Midpoint of full-year 2021 net sales guidance as of Aug. 4, 2021. By this presentation Horizon is not updating or confirming its prior guidance. (3) Horizon estimates. Assumes each development program successfully completes clinical development, attains regulatory approval for Horizon's intended indications and is successfully commercialized.

~$10B(3)

TEPEZZA

Elizabeth Thompson, Ph.D.EVP, Research & Development


R&D Strategy: Building and Expanding Our Pipeline by Broadening Our Ambitions

Foundational Element

Building for the Future

Maximize potential of on-market medicines (e.g., KRYSTEXXA immunomodulation)

Expand our pipeline through business development

Add top talent to R&D function

Maximize pipeline molecules (e.g., five indications for daxdilimab (HZN-7734))

Expand pipeline through earlier-stage partnerships and collaborations

Build research capabilities to generate discovery stage candidates

Expand therapeutic areas of focus to build on established areas of expertise

Significantly Increasing R&D Investment

Theresa Podrebarac, M.D. , M.Sc., Senior Vice President, Clinical Development

• 20+ years clinical development and strategy

• Dr. Podrebarac joined Horizon in early 2021 where she leads the clinical development function

• Prior to Horizon, she served as CMO for two biotech companies. She also served as VP, immunology clinical development for AbbVie, Biogen and EMD Serono leading to several approved therapies

Elizabeth H. Z. Thompson, Ph.D., Executive Vice President, Research and Development

• 20+ years of experience leading the development of multiple novel medicines in the United States and globally

• In her time at Horizon, Dr. Thompson led the expedited filing and approval of TEPEZZA and its successful FDA Advisory Committee meeting

• Prior to Horizon, Dr. Thompson was the clinical lead for SKYRIZI at AbbVie. She also has had a career spanning clinical development, business development and medical communications and has worked at Raptor, InterMune and Amgen

We Have an Experienced R&D Leadership Team

Srini Ramanathan, Ph.D., Senior Vice President, Research and Development Sciences

• 20+ years spanning research and drug development, contributing to 10 new drug approvals

• At Horizon, Dr. Ramanathan leads discovery research, translational sciences and biometrics, and led the scientific discussion at the FDA Advisory Committee meeting and supported the approval of TEPEZZA

• Prior to Horizon, led multiple immunology programs at AbbVie and was global head of clinical pharmacology at Gilead

Melanie Gloria, Senior Vice President, Development Operations

• 20+ years of experience leading operations functions across research and development

• At Horizon, Melanie leads Clinical Operations, Regulatory, Project Management and Pharmacovigilance

• Prior to Horizon, Melanie worked at AbbVie and Abbott. Melanie supported the development programs across the Immunology, Oncology, Women’s Health, and Virology Therapeutic areas

Eliezer Katz, M.D. FACS• Vice President,

Clinical Development • Previously worked at Viela Bio,

MedImmune, Pfizer, CTI Clinical Trial and Consulting Services and University of Massachusetts

Betsy O’Neill, Ph.D.• Vice President, External

Research and Development• Previously worked at BioMarin,

Elan Pharmaceuticals and Tularik

Lisa Pitt, PharmD, M.S.J.• Vice President, Regulatory Affairs• Previously worked at Viela Bio,

Premier Research, FDA, MedImmune, Parexel and Novartis

Bill Rees, Ph.D. • Vice President,

Translational Sciences• Previously worked at Viela

Bio, MedImmune, Amgen and Corixa

Gábor Illei, M.D. • Vice President, Clinical

Development• Previously worked at Viela Bio,

REGENXBIO Inc., MedImmune andNational Institutes of Health

Dewei She, Ph.D.• Vice President, Biometrics• Previously worked at Viela Bio,

MedImmune/AstraZeneca, The EMMES Corporation, Orchid Biosciences, The Degge Group

San Francisco, CA

Deerfield, IL

Rockville, MD

Waterford, Ireland

Dublin, Ireland

Global R&D Presence in Locations to Build and Attract Top TalentNearly Quadrupled R&D Organization Since 2018

MIRROR: Randomized, placebo-controlled trial underway evaluating KRYSTEXXA plus immunomodulator MTX

• Primary and secondary endpoint results after trial completes, expected Q4 2021

• Expect to submit sBLA in 1H 2022

ImproveResponse Rate

Shorter infusion duration (AGILE): Open-label trial underwayevaluating KRYSTEXXA plus MTX at shorter durations (current duration is 2+ hours)

Improve Patient Experience

Monthly dosing (FORWARD): Open-label trial underway to evaluate 16mg monthly dosing of KRYSTEXXA plus MTX (current dosing is 8mg 2x/month)

PROTECT: Open-label trial underway evaluating KRYSTEXXA for uncontrolled gout in kidney transplant patients (most severe)

Demonstrate Benefit in Broader

Populations

Retreatment (ADVANCE): Open-label trial underway to evaluate KRYSTEXXA plus MTX in patients who have previously failed KRYSTEXXA alone

Maximizing the Long-Term Potential of KRYSTEXXA Five Trials Underway

MTX: Methotrexate. | sBLA: Supplemental Biologics License Application.

• Randomized, placebo-controlled trial of TEPEZZA underway in chronic TED patients

• Objective is to generate data supporting TEPEZZA adoption in the already indicated chronic TED patient population

Chronic Disease Subcutaneous Administration Diffuse Cutaneous Systemic Sclerosis

• Pharmacokinetic trial underway to explore subcutaneous TEPEZZA dosing

• Objective is to assess the potential for additional administration options for TEPEZZA

• Partnered with Halozyme to leverage proprietary ENHANZE® drug delivery technology

• Exploratory study to investigate the safety, tolerability and effect on IGF-1/IGF-1R inflammatory/fibrotic biomarkers

• Preclinical data implicate IGF-1/IGF-1R signaling in diffuse cutaneous systemic sclerosis pathology

• Expect to initiate Phase 1 trial in Q4 2021

Thyroid Eye Disease (TED) Programs Maximizing the Future and Long-Term Potential

of TEPEZZA for TED Patients

Potential Additional IndicationHigh Unmet Need in a Rare, Chronic

Autoimmune Disease; Core Therapeutic Area

Maximizing the Long-Term Potential of TEPEZZAAdvancing Three R&D Programs

IGF-1R: Insulin-like growth factor 1 receptor.

Expanding Our Pipeline: How We Think About Choosing New Indications

Unmet Need /Patient Perspective

Competitive Landscape

Scientific Rationale

Feasibility

Horizon Focus

KRYSTEXXA Combination with Immunomodulation in Uncontrolled Gout(1)

UPLIZNA

Myasthenia Gravis (MG)

IgG4-Related Disease (IgG4-RD)

Kidney Transplant Desensitization

HZN-825Diffuse Cutaneous Systemic Sclerosis (dcSSc)(3)

Idiopathic Pulmonary Fibrosis (IPF)(3)


Systemic Lupus Erythematosus (SLE)

Alopecia Areata (AA)(3)

Discoid Lupus Erythematosus (DLE)(3)

Lupus Nephritis (LN)(3)

Dermatomyositis (DM)(3)


Sjögren’s Syndrome

Rheumatoid Arthritis

Kidney Transplant Rejection

Focal Segmental Glomerulosclerosis (FSGS)(3)

TEPEZZASubcutaneous Administration

Diffuse Cutaneous Systemic Sclerosis (dcSSc)(3)

HZN-1116 Autoimmune Diseases

ARO-XDH

Next-Gen Uncontrolled GoutHZN-003

HZN-007

HemoShear Novel Gout Targets

Program Potential Indication

New programs announced today

Ongoing programs

Horizon Pipeline Today: 27 Programs; Five New Indications Announced Today

Preclinical Phase 1 Phase 2 Phase 3

• 27 programs in total(2)

• Five new programs announced today and starting in 2022

• 10 data readouts anticipated in 2021-2023

• 10 potential approvals in second half of the decade

IgG4: Immunoglobulin G4. (1) KRYSTEXXA MIRROR trial is a Phase 4 trial. (2) There are five additional Phase 4 programs included in our pipeline, but not shown here. (3) Planned programs; not yet initiated.

KRYSTEXXA Combination with Immunomodulation in Uncontrolled Gout(1)

UPLIZNA

Myasthenia Gravis (MG)

IgG4-Related Disease (IgG4-RD)

Kidney Transplant Desensitization

HZN-825Diffuse Cutaneous Systemic Sclerosis (dcSSc)(3)

Idiopathic Pulmonary Fibrosis (IPF)(3)



Alopecia Areata (AA)(3)

Discoid Lupus Erythematosus (DLE)(3)

Lupus Nephritis (LN)(3)

Dermatomyositis (DM)(3)



Rheumatoid Arthritis

Kidney Transplant Rejection

Focal Segmental Glomerulosclerosis (FSGS)(3)

TEPEZZASubcutaneous Administration

Diffuse Cutaneous Systemic Sclerosis (dcSSc)(3)

HZN-1116 Autoimmune Diseases

ARO-XDH

Next-Gen Uncontrolled GoutHZN-003

HZN-007

HemoShear Novel Gout Targets

Program Potential Indication

New programs announced today

Ongoing programs

Horizon Pipeline: Our Programs We Will Discuss Today

Preclinical Phase 1 Phase 2 Phase 3


• Five new programs announced today and starting in 2022



IgG4: Immunoglobulin G4. (1) KRYSTEXXA MIRROR trial is a Phase 4 trial. (2) There are five additional Phase 4 programs included in our pipeline, but not shown here. (3) Planned programs; not yet initiated.


• 5 new programs announced today and starting in 2022




• SLE• AA• DLE• LN• DM


• Sjogren’s Syndrome• FSGS

HZN-825

• dcSSc• IPF

UPLIZNA

• MG• IgG4-RD

TEPEZZA

• Chronic TED

Core Therapeutic Areas Areas of Expansion

We Have Meaningfully Expanded Our Therapeutic Areas of Focus

SLE: Systemic Lupus Erythematosus. | AA: Alopecia Areata. | DLE: Discoid Lupus Erythematosus. | DM: Dermatomyositis. | FSGS: Focal Segmental Glomerulosclerosis. | SC: subcutaneous. | IPF: Idiopathic pulmonary fibrosis. | IgG4: Immunoglobulin G4.dcSSc: Diffuse cutaneous systemic sclerosis. | ILD: Interstitial lung diseases. | MG: Myasthenia Gravis.

RheumatologyDeep knowledge and expertise,

market leader in gout; clinical programs:

KRYSTEXXA MIRROR, daxdilimab

(HZN-7734) in SLE and dazodalibep

(HZN-4920) in Sjögren’s Syndrome

NephrologyGrowing presence with KRYSTEXXA;

clinical programs: KRYSTEXXA PROTECT,

dazodalibep (HZN-4920) in kidney

transplant rejection and FSGS

Growing capabilities in ophthalmology, ophthalmology subspecialists

and endocrinology as a pioneer in Thyroid Eye Disease (TED);

clinical programs: TEPEZZA Chronic TED, TEPEZZA SC

Ophthalmology Endocrinology

NeuroimmunologyDeep research and translational

capabilities, academic collaborations

and protein engineering expertise;

clinical programs: UPLIZNA in MG and

IgG4-related disease

RespiratoryFocused investments in areas that fit our research strategy (e.g., ILDs a

large area with high unmet need and mechanistic rationale supports

evaluation); clinical programs: HZN-825 in IPF and dcSSc

DermatologyGrowing field with high unmet need;

immune dysfunction and fibrosis central

to many diseases; clinical programs:

daxdilimab (HZN-7734) in AA, DLE and DM

Earlier-Stage Innovation is Critical for Building a Sustainable and Diversified Pipeline

Internal research to generate innovation in core areas of expertise

Externalcollaborations and business development

to access promising innovation

SVP, Research & Development Sciences

Srini Ramanathan, Ph.D.


Building a Robust Research Organization and Discovery Engine to Drive Long-Term Growth

IND: Investigational New Drug. | IP: Intellectual property.

Building an internal engine to begin to generate high-quality INDs over the next few years

Balanced between internal and external opportunities

Aligned with our therapeutic areas of focus

Focused on matching the right modality to scientific / patient

needs

Built by growing our talented research team and capabilities

Projects Driven by Horizon Research

Areas where Horizon has internal capabilities, insights and IP that make it best equipped to deliver

Projects Driven by External Partnerships

• Seek out specific partners with unique capabilities and expertise that can translate Horizon’s technical vision

• Form collaborations with high-value transformational potential and improved likelihood of success

Example of How Our Research and Translational Teams Partner with Business Development to Build a Next-Generation Gout Franchise

sUA: Serum Uric Acid. | RNAi: Ribonucleic acid interference. (1) Approximate number of patients in addressable target market; Horizon estimates.

• Using RNAi, ability to silence the gene associated with high sUA

• Subcutaneously administered medicine candidate

• Using cell-based models of gout; identified and validated two novel targets for reducing uric acid

• Orally administered medicine candidates• Starting with KRYSTEXXA, built leadership

position in gout

• Built deep expertise via best-in-class commercial and clinical teams

• Realized unmet need for >500K(1) patients who do not respond to standard of care or are not candidates for KRYSTEXXA

Horizon Sought Out External Collaborations to Fill this Unmet Need

As a leader in gout, Horizon is uniquely positioned to successfully develop and

commercialize candidates that result from these programs

CD40/CD40LCo-stimulatory

Pathway

CD40L

T cell

Dazodalibep(HZN-4920)

Plasmablast

Plasma cells

CD19

CD19

Viela Clinical Approach: Focused on Three Biological Pathways Shared Across Various Diseases

CD19: Cluster of Differentiation 19. | CD40: Cluster of Differentiation 40. | CD40L: Cluster of differentiation 40 Ligand. IFNα: Interferon-α. | IL6: Interleukin 6. | ILT7: Immunoglobulin-Like Transcript 7. | mDC: Myeloid Dendritic Cell. MO: Monocytes. | pDC: Plasmacytoid Dendritic Cell | TNF: Tumor Necrosis Factor.

Innate Immunity Pathway

pDC

ILT7

IL-6

TNF

IFNα

Inflammatorymediators

Daxdilimab(HZN-7734)

Tissue Damage,Inflammation and

Fibrosis

Autoimmunity

CD40

B-cell/Autoantibody Pathway

UPLIZNA

CD19

B cell

Daxdilimab (HZN-7734) First and Only pDC Depleter in Clinical Development; Now Pursuing Five Indications


Theresa Podrebarac, M.D., M.Sc., SVP Clinical Development

Bill Rees, Ph.D., VP Translational Sciences

Daxdilimab is an anti-ILT7 fully human monoclonal antibody with a

Plasmacytoid dendritic cells across many autoimmune and inflammatory diseases

provide clear rationale to pursue daxdilimab in multiple diseases

Systemic lupus erythematosus (SLE) is the first indication in development, which in cutaneous lupus erythematosus (CLE)

Today, we are announcing as part of our strategy to fully realize its potential

ILT7: Immunoglobulin-like transcript 7.

Daxdilimab (HZN-7734) Key TakeawaysFirst and Only pDC Depleter in Clinical Development; Now Pursuing Five Indications

• In healthy individuals, pDCs are present in low numbers, driving an appropriate immune response to fight infection

• In individuals with certain autoimmune diseases, pDCs are found in high concentrations in target tissue, which results in significant inflammation and tissue damage that are a hallmark of autoimmune disease

• Daxdilimab was designed to be an efficient pDC depleter, targeting a main driver of inflammation without impairing the body’s overall antiviral response

What are pDCs and Why are They Important in Autoimmune Diseases?


pDCs, Inflammation and Autoimmune Disease

Immune complexes containing nucleic acids bind to pDC

Production of inflammatory molecules

PlasmacytoidDendritic Cell (pDC)

Daxdilimab binds to ILT7

pDCs Play a Critical Role in Driving Inflammation; Daxdilimab (HZN-7734) Directly Targets pDCs

pDCs: Plasmacytoid Dendritic Cells.

https://www.horizontherapeutics.com/Media-Center/Video-Library/Daxdilimab-Mechanism-of-Action

DaxdilimabControl H 4 Control H 4Control

Preclinical Evidence Demonstrated Daxdilimab (HZN-7734) is an Efficient Depleter of pDCs with a Similar Impact on Type 1 Interferon

IFN: Interferon. | PBMC: Peripheral blood mononuclear cell. | pDC: Plasmacytoid Dendritic Cell.Source: Karnell et al (2021) Sci Transl Med, 13(595), 14.

Daxdilimab Had a Similar Impact on Type 1 InterferonDaxdilimab Efficiently Depleted pDCs

Study Day

pD

Cs

(pe

r m

illio

n P

BM

Cs)

Pre-dose Dosing Sustained Effect

Study Day

IFN

α (

pg

/ml)

Pre-dose Dosing Sustained Effect

Clinical Evidence Demonstrated Daxdilimab (HZN-7734) Efficiently Depleted Circulating pDCs

Arrows represent when dosing occurred. | pDC: Plasmacytoid Dendritic Cell. | BL: Baseline. | PBMC: Peripheral blood mononuclear cell.Source: Karnell et al (2021) Sci Transl Med, 13(595), 14.

Rates of adverse events were similar between daxdilimab and placebo

Daxdilimab Rapidly Depleted pDCs and Had a Sustained Effect

Dosing Sustained Effect%

pD

Cs

(of

PB

MC

s)

Study Day

Daxdilimab 50 mg (n=8) lacebo H 4, 0 mg H 4, 1 0 mgPlacebo (n=9)Daxdilimab 150 mg (n=8) lacebo H 4, 0 mg H 4, 1 0 mg

pDCs are Important Drivers of Disease Across Multiple Autoimmune and Inflammatory Diseases

pDC: Plasmacytoid Dendritic Cell.

Systemic autoimmune diseases

Autoimmune kidney diseases

Autoimmune skin diseases

Other inflammatory diseases

Clinical Evidence in Cutaneous Lupus Erythematosus (CLE) Patients Showed that Daxdilimab (HZN-7734) Reduced pDCs and Type 1 Interferon Activity in Target Tissue Based on Skin Biopsies

pDC: Plasmacytoid Dendritic Cell. | IFN: Interferon.Source: Karnell et al (2021) Sci Transl Med, 13(595), 14.

Skin biopsies shown above

Day

85

Bas

elin

e

pDCs IFN response protein

98% Reduction of Skin pDCs with DaxdilimabDaxdilimab Profoundly Reduced pDCs and

Type 1 Interferon in the Skin

% c

han

ge f

rom

Bas

elin

e t

o D

ay 8

5 (

skin

pD

Cs)

Placebo(n=6)

Daxdilimab(n=16)

Daxdilimab (HZN-7734) Demonstrated a Dose Dependent Improvement in Cutaneous Lupus

CLASI-A: Cutaneous Lupus Erythematosus Area and Severity Index-Activity. | BL: Baseline.Source: Karnell et al (2021) Sci Transl Med, 13(595), 14.

Treatment with Daxdilimab Resulted in Clinically Significant Reduction in Skin

Disease Activity

Higher % of Daxdilimab Patients Achieved ≥7 Point Reduction in CLASI-A

vs. Placebo

% C

han

ge f

rom

BL:

CLA

SI-A

Sco

re

% ≥

7-p

oin

t re

du

ctio

n in

CLA

SI-A

Study Day

Higher % of Daxdilimab Patients Achieved ≥50% Reduction in CLASI-A vs.

Placebo

% w

ith

≥5

0%

re

du

ctio

n in

CLA

SI-A

Time (days) Time (days)

Daxdilimab 50 mg (n=8)

(Last Dose)

Daxdilimab 150 mg (n=8) lacebo H 4, 0 mg H 4, 1 0 mg Placebo (n=9) lacebo H 4, 0 mg H 4, 1 0 mg

Daxdilimab (HZN-7734) Phase 2 Trial in Systemic Lupus Erythematosus (SLE) Initiated in June 2021

CLASI-A: Cutaneous Lupus Erythematosus Area and Severity Index-Activity. | LLDAS: Lupus Low Disease Activity State. | PD: Pharmacodynamic(s). | PK: Pharmacokinetic(s). | SRI: SLE Responder Index. | SubQ: Subcutaneous.(1) Defined as oral glucocorticoid (OGC) dose ≤ . mg/day and ≤ Baseline (Day 1) dose of prednisone or equivalent at Week 48.

• proportion of participants achieving a BILAG 2004 Index-based Combined Lupus Assessment (BICLA) response and a reduction in glucocorticoid use(1)

• CLASI-A score at Week 12, SRI-4, LLDAS, sustained steroid reduction, PK/PD, safety and tolerability

Key Inclusion Criteria

• Adults aged ≥ 18 to ≤ 0 years

• Moderate to Severely Active SLE as Defined By: - SLE Disease Activity Index 2000 (SLEDAI-2K)- British Isles Lupus Assessment Group (BILAG) 2004 Index- Physician Global Assessment (PGA)

Phase 2 Trial Design in SLE

Safety Follow-Up

19

5 p

atie

nts

1:1

:1 r

an

do

miz

ati

on

Cohort 1: Daxdilimab 200 mgSubQ Monthly Dosing

Cohort 2: Daxdilimab 200 mgSubQ Dosing Every 12 Weeks + additional 200 mg SubQ at Week 4

PlaceboSubQ Monthly Dosing

Study Week 0

Week 48Primary Endpoint

Week 56Safety Follow-Up

Evaluating Five Indications for Daxdilimab (HZN-7734) where pDCs are Implicated

pDC: Plasmacytoid Dendritic Cell. | IFN: Interferon. (1) Horizon estimate. (2) Werth et al. Arthritis Rheum (2020) 72 (suppl 10). (3) Furie et al. 2020 ACR Annual Meeting. (4) Rahal et al. JEADV (2014) 30(1): 119-123. (5) Ito et. al. Allergology International (2020) 69(1): 121-131. (6) Vermi et. al. Immunobiology (2009) 214: 877–886. (7) Rakhshan et al. An Bras Dermatol. 2020; 95(3): 307-13. (8) Braunstein et al. Br J. Dermatol (2012) 166(5): 971-5. (9) Fiore et al. Mol Immunology (2008) 45: 259–265. (10) Kassianos et al. Am J Physiol. (2013) 305, F1391–F1401. (11) Shimizu et al. Mod Rheum (2018) 28: 661-669. (12) Greenberg et al. Ann Neurol (2005) 57(5):664-678. (13) McNiff et al. J Cutan Pathol (2008) 35: 452-456. (14) Greenberg et al. Arth Res Ther (2010) 12:S4.

Indications Being Pursued


Unmet Need / Competitive Landscape

U.S. Patient Population(1)

Alopecia Areata (AA)

• pDCs detected in AA lesions and Type 1 interferon signatures are elevated in AA lesions(4)

• Preclinical models implicate pDCs in AA(5)

• Treated with off label medicines, subject to significant side effects, variable efficacy

• High rate of relapse (~85%) and need for fast, robust results

>600K patients of which ~40K would be appropriate for novel

therapies including biologics

Discoid Lupus Erythematosus (DLE)

• pDCs reported to be abundant in DLE skin lesions(6-7)

• Significantly elevated Type 1 interferon activity in DLE compared to healthy tissue(8)

• High disease burden• Current standard of care not uniformly effective and is

associated with potential side effects

~30K patients would be appropriate for novel


Lupus Nephritis (LN)

• Presence of pDCs is associated with more advanced disease in LN(9-10)

• Evidence of interferon activity in renal tissue in LN(11)

• High disease burden• May progress to kidney failure• Standard of care associated with potentially dangerous side

effects



Dermatomyositis (DM)

• pDCs reported to be abundant in DM muscle(12-13)

• Increased Type 1 interferon activity in DM and interferon signature is correlated with disease severity(14)

• High disease burden• Treated with off label medicines, subject to significant side

effects, variable efficacy



Indications for Which Clinical Trials are Underway





• Early-stage clinical studies show benefit of targeting pDCs(2-3)

• Many patients have uncontrolled disease activity with available treatment options leading to increased morbidity and mortality

• Approved medicine, but not highly effective

~250-350K patients of which ~50K would be appropriate for

novel therapies including biologics

• AA: an autoimmune disorder characterized by nonscarring hair loss

• Next steps: Phase 2 trial expected to start in 1H 2022

Alopecia Areata (AA)

Five Phase 2 Trials for Daxdilimab (HZN-7734); Initiating Trials in Four New Indications in 2022

• DM: autoimmune, inflammatory disorder characterized by rashes that often burn and debilitating muscle weakness


Dermatomyositis (DM)

• SLE: an autoimmune disease that manifests as skin rashes, arthritis, nephritis, and serositis

• Next steps: Phase 2 trial underway, with first patient enrolled in June 2021


• LN: an autoimmune, inflammatory condition of the kidney; efficacy in LN may increase adoption of daxidilimab in SLE patients


Lupus Nephritis (LN)

• DLE: chronic, inflammatory skin condition characterized by sores that can result in scarring


Discoid Lupus Erythematosus (DLE)

Daxdilimab is an anti-ILT7 fully human monoclonal antibody with a

Plasmacytoid dendritic cells across many autoimmune and inflammatory diseases

provide clear rationale to pursue daxdilimab in multiple diseases

Systemic lupus erythematosus (SLE) is the first indication in development, which in cutaneous lupus erythematosus (CLE)

Today, we are announcing as part of our strategy to fully realize its potential

Daxdilimab (HZN-7734) Key TakeawaysFirst and Only pDC Depleter in Clinical Development; Now Pursuing Five Indications


Dazodalibep (HZN-4920) CD40L Antagonist Designed to Block a Central Pathway Involved in Many Autoimmune and Inflammatory Diseases



Bill Rees, Ph.D., VP Translational Sciences

Dazodalibep (HZN-4920) Key TakeawaysInternally Designed Next Generation CD40L Antagonist

CD40L: Cluster of differentiation 40 ligand.

Dazodalibep is a CD40L antagonist

Dazodalibep was internally designed; the team’s expertise

Pre-clinical and clinical evidence provide

Dazodalibep is , including Sjögren's syndrome, rheumatoid arthritis (RA) and kidney transplant rejection• Promising early data from prior studies in RA demonstrated suppression of autoimmune response and disease activity in a dose

dependent manner• Mechanistic rationale supports evaluation in Sjögren's syndrome, an autoimmune disease with no approved treatments

Today we announced the initiation of a new indication in focal segmental glomerulosclerosis (FSGS),

• CD40/CD40L interactions play a critical role in driving immune responses, including the T-cell-dependent activation of B cells, central to the production of pathogenic autoantibodies

• CD40/CD40L can trigger overstimulation of immune cells leading to an immune response cascade and driving inflammation

• CD40L drives inflammation through its interaction with CD40 which is expressed on several tissues in the salivary gland, spleen, kidney, joint, gut and skin

• The CD40/CD40L pathway is implicated in many autoimmune diseases including Sjögren’s syndrome, RA, immune mediated kidney diseases and transplantation

CD40-CD40L Pathway Plays a Central Role in Autoimmune and Inflammatory Diseases

CD40: Cluster of differentiation 40. | CD40L: Cluster of differentiation 40 ligand. | RA: Rheumatoid arthritis.

Antibody secreting cell produces autoantibodies

APC and T cell produce inflammatory molecules

Memory B cell

Plasmablast

Autoantibodies

T cell

Cytokines

Cytokines Chemokines

Antigen Presenting Cell (APC)

T cell

CD40L

CD40

T cell

B cell

B cell

• First generation antibodies targeting CD40L were unsuccessful

• Dazodalibep is a fusion protein that binds to CD40L

• It was designed as a next-generation CD40L antagonist blocking the CD40 pathway and undesired immune responses that lead to the development of autoimmune diseases

Dazodalibep (HZN-4920) was Designed to Address Immune Overactivation Attributed to the CD40 Pathway

CD40: Cluster of differentiation 40. | CD40L: Cluster of differentiation 40 ligand.

Plasmablast

Autoantibodies

T cell

Antigen Presenting Cell (APC)

T cell

T cell

B cell

Memory B cell

B cell

CD40L

CD40

Dazodalibep

Clinical Evidence Demonstrated that Dazodalibep (HZN-4920) Can Suppress Antibody Response in a Dose Dependent Manner

Source: Karnell JL et al. Sci Transl Med. 2019 Apr 24; 11 (489).(1) Phase 1 randomized, blinded, placebo-controlled, single-ascending dose trial to evaluate the safety and tolerability of dazodalibep in healthy adults. (2) Immune responses stimulated with keyhole limpet hemocyanin (KLH), a T-dependent antigen. (3) Antibody response was measured using anti-KLH IgG titers (ng/ml).

Dazodalibep Suppressed Antibody Response in a Dose Dependent Manner(1)

DazodalibepImmune Response Stimulation(2)

An

tib

od

y R

esp

on

se(3

)

Immune Response Stimulation(2)

Visit Day

3000 mg(n=8)

1000 mg(n=8)

300 mg(n=8)

100 mg(n=8)

30 mg(n=8)

Placebo(n=2)

Dazodalibep (HZN-4920) Decreased Disease Activity in a Dose Dependent Manner in a Phase 1b Study in Patients with Active Rheumatoid Arthritis

TEAE: Treatment emergent adverse event. Source: Karnell JL et al. Sci Transl Med. 2019 Apr 24; 11 (489).DAS28-CRP is a composite clinical disease activity score used in rheumatoid arthritis that takes into account the number of swollen and tender joints, C-reactive protein (CRP) levels, and a patient global health assessment.

75.0%

50.0%

13.0%

1500 mg 1000 mg Placebo(n=12) (n=12) (n=15)

Patients Maintained Low Disease Activity Approximately Three Months Off Therapy

Half or More Patients on Dazodalibep Achieved Low Disease

Activity or Remission

• Balanced distribution of TEAEs between placebo and four active groups was observed

• No thrombotic events or significant coagulation abnormalities

Dazodalibep was Generally Safe and Well Tolerated

DA

S28

-CR

P a

t 3

.2 o

r le

ss

Me

an (

+/-)

Ch

ange

fro

m B

ase

line

in

DA

S28

-CR

P S

core

(Last Dose)

Dazodalibep 1000mg (n=12)Dazodalibep 1500mg (n=12) Placebo (n=15)

Dazodalibep (HZN-4920) is in Development for Four Indications, Each Addressing Immune Overactivation

FSGS photo source: © 1998-2021 Mayo Foundation for Medical Education and Research (MFMER); all rights reserved; https://www.mayoclinic.org/diseases-conditions/fsgs/symptoms-causes/syc-20354693.

• RA: a chronic inflammatory disorder characterized by progressive destruction of joints

• Next steps: Phase 2 trial underway; data readout in 1H 2022

Rheumatoid Arthritis (RA)

• KTR: occurs when the immune system detects an organ transplant as a threat and attacks it; results in organ rejection

• Next steps: Phase 2 open-label trial underway; data readout in 2H 2022

Kidney Transplant Rejection (KTR)

• Sjögren’s: chronic, systemic autoimmune disease attacking the salivary and tear (exocrine) glands, with severe cases affecting multiple organs

• Next steps: data readout in 2023


• FSGS: a rare disease that attacks the kidney’s filtering units (glomeruli) and causes serious scarring, leading to permanent kidney damage and even kidney failure


Focal Segmental Glomerulosclerosis (FSGS)

Sjögren’s Syndrome is an Autoimmune Disease Involving Overexpression of CD40/CD40L with No FDA-Approved Treatments

CD40: Cluster of differentiation 40. | CD40L: Cluster of differentiation 40 ligand.(1) Horizon estimate.

• Chronic, systemic autoimmune disease attacking the salivary and tear (exocrine) glands, with severe cases affecting multiple organs

• Disease manifestations include dry eyes, dry mouth, arthritis and kidney or lung dysfunction

• Overexpression of CD40/CD40L observed at site of inflammation and in circulation

• ~250K-350K patients with Sjögren’s syndrome in the U.S. of which ~50k would be appropriate for novel therapies including biologics(1)


• No FDA-approved treatments

• Current treatments: palliative care (artificial tears, medicines for dry mouth); topical cyclosporine; steroids/immunosuppressants used off-label as needed to manage systemic symptoms

Unmet Need

Phase 2 Trial Evaluating the Safety and Efficacy of Dazodalibep (HZN-4920) in Sjögren’s Syndrome

ESSDAI: European League Against Rheumatism. | EULAR: Sjögren’s Syndrome Disease Activity Index: A Sjögren’s specific disease activity index composed of 12 system domains. | ESSPRI: EULAR Sjögren’s Syndrome Patient Reported Index: Patient reported indexcomposed of three questions assessing dryness, fatigue and pain. | FACIT: Functional Assessment of Chronic Illness Therapy. | PGIS: atient’s Global Impression of Severity. | IV: Intravenous.

Placebo (n=36) 1500mg dazodalibep

1500mg dazodalibep (n=36) Placebo

Day 169: Primary EndpointDay 1 Day 281

Induction followed by monthly IV dosing

Population One (n=72)Moderate-to-High Systemic Disease Activity

• Subjects with ESSDAI ≥

• Primary endpoint: change from baseline in ESSDAI at Day 169

• Secondary endpoint: change from baseline in ESSPRI at Day 169

Population Two (n=102)Moderate-to-Severe Patient-Reported Symptoms

• Subjects with ESS RI score ≥ and residual stimulated salivary flow but with mild systemic disease activity defined by ESSDAI score < 5

• Primary endpoint: change from baseline in ESSPRI at Day 169

change from baseline in FACIT-Fatigue score at Day 169, change from baseline in PGIS at Day 169, safety and tolerability of multiple IV doses of dazodalibep and anti-drug antibodies until the study completion

Placebo (n=51) 1500mg dazodalibep

1500mg dazodalibep (n=51) Placebo

Day 169: Primary EndpointDay 1 Day 281

Induction followed by monthly IV dosing

Indication Being Pursued

Scientific Rationale(1)



Focal Segmental Glomerulosclerosis (FSGS)

A rare disease that attacks the kidney’s filtering units (glomeruli)

and causes serious scarring, leading to permanent kidney damage and

even kidney failure

• Overactivity of the CD40-CD40L pathway likely a key driver of pathogenesis

• CD40-CD40L pathway involved in podocyte damage in FSGS kidney biopsies(3)

• Animal models support blocking CD40-CD40L pathway against renal injury(4)

• Most common glomerular disease resulting in end-stage renal disease in the U.S.

• No FDA-approved treatments; limited treatment options used off-label with moderate efficacy, undesirable side effects and high rates of relapse

~50K patients with primary FSGS and chronic

kidney disease, and not on dialysis

Focal Segmental Glomerulosclerosis (FSGS) is a Compelling Indication with High Unmet Need and No FDA-Approved Treatments

FSGS photos source: © 1998-2021 Mayo Foundation for Medical Education and Research (MFMER); all rights reserved; https://www.mayoclinic.org/diseases-conditions/fsgs/symptoms-causes/syc-20354693.(1) Doublier et al., PLoS One 2017 12(11):e0188045. (2) Horizon estimate. (3) Delville, et al., Sci Transl Med 6 (256) (2014) 256ra136. (4) Kairaitis et al., Kidney Int. 2003 64(4):1265-72.

Blood with impurities is filtered creating urine

Kidney with normal glomerulus

Scarring impairs kidney function

Kidney with FSGS

Dazodalibep (HZN-4920) Key TakeawaysInternally Designed Next Generation CD40L Antagonist

CD40L: Cluster of differentiation 40 ligand.

Dazodalibep is a CD40L antagonist

Dazodalibep was internally designed; the team’s expertise

Pre-clinical and clinical evidence provide

Dazodalibep is , including Sjögren's syndrome, rheumatoid arthritis (RA) and kidney transplant rejection• Promising early data from prior studies in RA demonstrated suppression of autoimmune response and disease activity in a dose

dependent manner• Mechanistic rationale supports evaluation in Sjögren's syndrome, an autoimmune disease with no approved treatments

Today we announced the initiation of a new indication in focal segmental glomerulosclerosis (FSGS),

Q&A


HZN-825


LPAR1 Antagonist with Early Signals of Benefit in Fibrotic Diseases, Areas with High Unmet Need

Srini Ramanathan, Ph.D., SVP Research & Development Sciences

Dinesh Khanna, M.D., M.Sc., Professor, University of Michigan

HZN-825 Key TakeawaysHZN-825 is an LPAR

1Antagonist with Early Signals of Benefit in Fibrotic Diseases, Areas with High Unmet Need

LPA: Lysophosphatidic acid. | LPAR: Lysophosphatidic acid receptor. | IPF: Idiopathic pulmonary fibrosis. | ILD: Interstitial lung diseases. | dcSSc: Diffuse cutaneous systemic sclerosis.

HZN-825 is an that blocks LPA signaling, and has including reversal of established fibrosis in animal studies

Preclinical evaluation and clinical data support the

We are pursuing HZN-825 in : dcSSc and IPF

Our Phase 2a exploratory study of HZN-825 , and such as IPF

The Role of Lysophosphatidic Acid (LPA) and the LPAR1 Receptor in the Pathogenesis of Fibrotic Diseases

• LPA are bioactive molecules

• In healthy individuals, LPA enables beneficial cellular events such as cell growth, migration and survival

• LPA signaling takes place through multiple receptors, including LPAR1

• In people with fibrotic disease, LPAR1 signaling is dysregulated, resulting in inflammation and fibrosis mediated by:

- Vascular leakage

- Epithelial damage

- Fibroblast recruitment

LPAR: Lysophosphatidic acid receptor.

The Role of LPAR1 in Fibrosis

Vascular leakage

Fibroblast recruitment

Epithelial damage

LPAR1

Inflammation and fibrosis

LPA

HZN-825 Selectively Blocks LPAR1 and May Provide Therapeutic Benefit in Fibrotic Diseases

LPAR: Lysophosphatidic acid receptor.

• HZN-825 blocks the LPAR1 pathway and has potential to impact fibrotic diseases

• In preclinical and / or clinical studies, LPAR1 antagonism has been shown to:

- Reduce immune cell infiltration

- Protect against development of fibrosis

- Reverse established fibrosis

HZN-825 Blocks the LPAR1 Pathway; Potential Impact on Fibrotic Diseases

LPAR1

HZN-825

Reduced immune cell infiltration

Reversed established fibrosis

Protected against development of fibrosis

Preclinical Evidence Supports the Broad Anti-Fibrotic Potential of LPAR1 AntagonismAdditionally, HZN-825 Was Proven Safe and Well Tolerated Across Several Phase 1 Studies

LPAR: Lysophosphatidic acid receptor.(1) Castelino et al Arthritis Rheum 63(5):1405–15. (2) Internal HZN Data. (3) Ledein et al Br J Pharmacol. 177:4296–4309. (4) Tager et al Nat Med 14(1):45-54. (5) Swaney et al Br J Pharmacol 160:1699-713. (6) Ninou et al Front Med Volume 5 Article 180. (7) Murphy et al Eur Respir J. 2019; 54(suppl 63):PA5383. (8) Pradere et al J Am S Nephrol 18:3110-3118. (9) Lee et al BBA Molecular Basis of Disease 1865:1332-1340.

HZN-825 was safe and well tolerated in >160 healthy volunteers across several Phase 1 studies

• LPAR1 deletion prevented dermal fibrosis(1)

in mouse models

• LPAR1 antagonism reversed dermal fibrosis(2, 3) in mouse models

Skin

• LPAR1 deletion prevented lung fibrosis(4) in mouse models

• LPAR1 antagonism reduced inflammation, fibrosis, vascular leakage, tissue injury and more(5-7) in mouse models

Lungs

• LPAR1 deletion reduced kidney fibrosis(8) in mouse models

• LPAR1 antagonism reduced fibrosis, improved cardiac and/or kidney function and more(2, 9) in multiple rodent models

Kidney and Heart

Systemic Sclerosis is the Hallmark Disease of Fibrosis Spanning Multiple Organ Systems

PAH: Pulmonary arterial hypertension.Source: Nie LY et al. 2019

• Estimated U.S. prevalence of systemic sclerosis: ~70K-80K

• ~60% limited cutaneous systemic sclerosis (lcSSc)

- Distal skin sclerosis – face, hands, forearms, feet, legs principally

- Pulmonary arterial hypertension and severe gut disease frequent and serious

- Late-stage complications frequent

• ~40% diffuse cutaneous systemic sclerosis (dcSSc)

- Diffuse disease involves the same areas as lcSSc but also more proximal skin areas: chest, thighs, upper arms and back

- High frequency of internal organ involvement including severe lung fibrosis

- Increased risk of renal crisis and cardiac involvement

Organ Complications Associated with Systemic Sclerosis

Interstitial lung diseases

Renal crisis

Gastrointestinal diseases

Digital ulcersRaynaud phenomenonSkin fibrosis

Musculoskeletal problems

Arrhythmias

Pericardial diseases

Valvular Disease

PAH

Myocardial Dysfunction

Interstitial Lung Disease (ILD) is the Leading Cause of Death in Patients with Systemic Sclerosis, and Idiopathic Pulmonary Fibrosis (IPF) is the Most Common ILD

SSc: Systemic sclerosis. (1) Perelas A. et al. 2020.

• ILD is a common comorbidity of SSc

• ILD is also the leading cause of death in patients with SSc with 10-year mortality of up to 40%(1)

SSc-ILD

• IPF is the most common ILD; IPF is a rare progressive lung disease characterized by dyspnea, chronic cough and potentially death

IPF

The Many Physical Characteristics of Systemic Sclerosis

Christopher P Denton ▪ Dinesh Khanna ▪ www.thelancet.com ▪ Published online April 13, 2017.

Digital vasculopathy Gastrointestinal

Lung Fibrosis Pulmonary hypertension

Cardiac Renal Musculoskeletal Calcinosis Acro-osteolysis

Usual Timing of Internal Organ Involvement in Systemic Sclerosis

RP: Raynaud's phenomenon. Arthritis Rheumatol. 2020 Jul;72(7):1049-1058. doi: 10.1002/art.41246. Epub 2020 May 18. Current and Future Outlook on Disease Modification and Defining Low Disease Activity in Systemic SclerosisVivek Nagaraja 1 , Marco Matucci-Cerinic 2 , Daniel E Furst 3 , Masataka Kuwana 4 , Yannick Allanore 5 , Christopher P Denton 6 , Ganesh Raghu 7 , Vallerie Mclaughlin 1 , Panduranga S Rao 1 , James R Seibold 8 , John D Pauling 9 , Michael L Whitfield 10 , Dinesh Khanna 1.

DIFFUSE CUTANEOUS VARIANT

LIMITED CUTANEOUS VARIANT

TIME

Raynaud, digital ischemia

SKIN

TH

ICK

NES

S

2-5 years after first non-RP symptom/sign

Limited Diffuse

tendon/bursal friction rubs;joint contractures

skeletal myopathy

interstitial lungdisease

myocardial involvement “renal crisis”pulmonary

hypertension

interstitial lung disease

esophageal disease

pulmonary hypertension

malabsorption

The Physical and Emotional Impact of Early Systemic Sclerosis

https://journals.sagepub.com/doi/full/10.1177/2397198319866615.

Initial symptoms• Skin thickening

• Raynaud’s phenomenon

• Swelling of hands

• Fatigue

• Pain

Diagnosis• Delays reaching

appropriate specialist

• Shock at severity of disease

• Poor prognosis

Treatment• High treatment

burden

• Limited options

• No cure

Worsening symptoms• Loss of mobility/

dexterity

• Pain

• Exhaustion

• Changed appearance

• Depression/anxiety

• Worry about organ involvement

Fearful Complicated

UnpredictableHopeful

Supported

DepressedWeak

BurdenedIsolated

Tightness Pain

Limiting

Sad

ExhaustedConfused

Frustrated

HZN-825 Showed Early Signals of Benefit in dcSSc Patient Population in a Phase 2a 24-Week Exploratory Study

NS: Not significant. | LPA: Lysophosphatidic acid. | dcSSc: Diffuse cutaneous systemic sclerosis. | mRSS: Modified Rodnan Skin Score is a measure of skin thickness intended to measure disease severity and mortality. The minimal clinically important difference (MCID) is an improvement of 5 units. Source: Allanore et al, Arth & Rheum. Oct 2018. SAR100842 was renamed HZN-825. (1) Responder rate defined as ≥ point improvement/reduction in mRSS.

Clinical Outcomes: Median Decrease in mRSS Responder Rate(1)

24-weeks of continuous HZN-825 treatment -7.5 78.6%

Subjects switched from placebo to HZN-825 -7.0 69.2%

Eight-Week Double-Blind Period (n=32) 16-week Open-Label Extension Period (n=30)

Numerically greater median reduction in mRSS (0-51); baseline to week eightBoxes represent the 25th to 75th percentiles, dark lines in boxes represent the median, the lines outside the box represent 10th and 90th percentiles, and the open circles are outliers

Imp

rove

me

nt

• After week eight, all patients were placed on HZN-825 treatment for 16 weeks

• Biomarker analysis of skin biopsies showed reductions in LPA-related genes

• Similar proportions of adverse events in active and placebo arms

• No safety concerns seen on laboratory parameters

Safety

Ch

ange

in m

RSS

fro

m b

ase

line

P=NS

Evaluating Two Fibrotic Diseases with Significant Unmet Need: dcSSc and IPF (ILDs)

Disease dcSSc IPF

Treatment Options

• No FDA-approved treatment for dcSSc• Two FDA approved therapies for SSc-related lung fibrosis • Current treatments provide symptomatic relief without compelling

evidence of slowing disease progression for overall disease- Exception: Stem cell transplant but associated with toxicity

• Treatment options include immunomodulators, NSAIDs, ACE inhibitors, vasodilators

• First-line options include nonpharmacologic management (oxygen, rehabilitation) and symptomatic care (steroids, beta-2 agonists)

• As IPF progresses, FDA-approved anti-fibrotic treatments can be tried

• Lung transplant is final option

A more comprehensive treatment is needed to address the inflammation and fibrosis that drive dcSSc and IPF

Shortcomings of Current Therapies

• Current treatments slow disease progression but do not stabilize or reverse disease

• Significant tolerability and compliance issues with current anti-fibrotic therapies

• Patients often need multiple treatments• Ineffective at halting disease progression, resulting in high

morbidity and mortality rates

U.S. Prevalence • ~30K dcSSc patients in the U.S.(1) • ~100K IPF patients in the U.S.(2)

Rationale• Clinical proof of concept demonstrated for LPAR1 antagonism in IPF• In a 24-week exploratory study, HZN-825 showed early signals of

benefit in dcSSc patient population

dcSSc: Diffuse cutaneous systemic sclerosis. | IPF: Idiopathic pulmonary fibrosis. | ILD: Interstitial lung diseases. | ACE: Angiotensin-converting enzyme. | NSAID: Nonsteroidal anti-inflammatory drug. | LPAR: Lysophosphatidic acid receptor.(1) Chifflow H Semin Arthritis Rheum 37:223-235. (2) Barratt SL, Creamer A, Hayton C, Chaudhuri N. Idiopathic pulmonary fibrosis (IPF): an overview. J Clin Med. 2018;7(8):201.

Phase 2b Pivotal Trial in Diffuse Cutaneous Systemic Sclerosis (dcSSc) Expected to Initiate Q4 2021

QD: Once daily. | BID: Twice daily. | SSC: Systemic sclerosis

• Change in forced vital capacity (FVC) % predicted after 52 weeks of treatment

• HAQ-DI (Health Assessment Questionnaire Disability Index), Physician Global Assessment (MDGA), Patient Global Assessment (PTGA), SSPRO-18, mRSS (modified Rodnan skin score), ACR-CRISS (American College of Rheumatology Composite Response Index in Systemic Sclerosis)


• Early, active disease with inflammation

• Stable immunosuppressive use

• <36 months since onset of first non-Raynaud's SSc manifestation

Phase 2 Trial Design in dcSSc

Safety Follow-Up

30

0 p

atie

nts

1:1

:1 r

an

do

miz

ati

on Cohort 1: HZN-825 300 mg QD

Cohort 2: HZN-825 300 mg BID

Placebo

Study Week 0



Phase 2b Pivotal Trial in Interstitial Pulmonary Fibrosis (IPF) Expected to Initiate Q4 2021

QD: Once daily. | BID: Twice daily.

• Change in forced vital capacity (FVC) % predicted after 52 weeks of treatment

• Decline in FVC % predicted ≥10%, 6-Minute Walk Test (6MWT), King's Brief Interstitial Lung Disease (K-BILD), Living with IPF (L-IPF), Leicester Cough Questionnaires (LCQ), hospitalization due to respiratory distress, composite endpoint of progression-free survival (PFS)


• Diagnosis of I F ≥1 year to ≤ years

• Not currently treated with IPF therapy

Phase 2 Trial Design in IPF

36

0 p

atie

nts

1:1

:1 r

an

do

miz

ati

on Cohort 1: HZN-825 300 mg QD

Cohort 2: HZN-825 300 mg BID

Placebo

Study Week 0



Safety Follow-Up

HZN-825 Key TakeawaysHZN-825 is an LPAR

1Antagonist with Early Signals of Benefit in Fibrotic Diseases, Areas with High Unmet Need

LPA: Lysophosphatidic acid. | LPAR: Lysophosphatidic acid receptor. | IPF: Idiopathic pulmonary fibrosis. | ILD: Interstitial lung diseases. | dcSSc: Diffuse cutaneous systemic sclerosis.

HZN-825 is an that blocks LPA signaling, and has including reversal of established fibrosis in animal studies

Preclinical evaluation and clinical data support the

We are pursuing HZN-825 in : dcSSc and IPF

Our Phase 2a exploratory study of HZN-825 , and such as IPF

UPLIZNA® (inebilizumab-cdon)Next-Generation B-Cell Depleter with a Novel, Targeted Approach


Kristina Patterson, M.D., Ph.D., Medical Director, Neuroimmunology


UPLIZNA Key Takeaways A Next-Generation B-Cell Depleter with a Novel Targeted Approach

AChR+: Acetylcholine receptor. | MuSK+: Muscle-specific kinase. | CD19: Cluster of differentiation 19. | CD20: Cluster of differentiation 20. | IgG4: Immunoglobulin G4.

UPLIZNA is an anti-CD19, humanized monoclonal antibody with potential in multiple autoimmune diseases

Targets the CD19 antigen, which including plasmablasts and certain plasma cells that anti-CD20 therapies do not target

, which include:

Neuromyelitis optica spectrum disorder (NMOSD), where UPLIZNA is already indicated

, where UPLIZNA has the potential for differentiation; our robust Phase 3 trial is the first with clearly delineated AChR+ and MuSK+ patient populations

, where UPLIZNA has the potential to be the first-ever FDA-approved therapy

B Cells Contribute to the Damaging Pathology of Multiple Autoimmune and Autoinflammatory Diseases

CD19: Cluster of differentiation 19.

• B cells are a white blood cell type, and an integral component of the adaptive immune system

• An important immune system function of B cells is making antibodies

− In a normal state, these antibodies attack foreignpathogens such as bacteria and viruses

− In autoimmune disorders, antibodies attack the body’s own tissues, leading to disease

• B cells also play a role in healthy inflammatory responses through the production of cytokines and chemokines and interactions with T cells

− In excess, this response can lead to prolonged activation of T cells and tissue destruction

B-Cell Dysregulation Plays a Central Role in Many Diseases

Production of Autoantibodies

Production of pro-fibrotic chemokines and cytokines that recruit immune cells with fibrotic potential

Production of long-lived pool of memory T cells

Memory T cell

T cell

B cell

Plasmablast

Plasma cells

CD19

CD19

CD19

UPLIZNA: Next-Generation Humanized Monoclonal Antibody Engineered for Differentiated Mechanistic and Clinical Profile

CD19: Cluster of differentiation 19. | F(ab): Fragment antigen-binding. | Fc: FcγRIIIa; type III Fcy receptor a.

Optimized for human CD19 binding

• Selectively binds to CD19 with high affinity, targeting a broad lineage of B cells for depletion – including plasmablasts and plasma cells

Humanized F(ab) portion

• Humanized structure designed to decrease immunogenicity, improve tolerability and reduce the risk of infusion reactions

Afucosylated Fc portion

• Afucosylated design allows for enhanced therapeutic efficiency with lower doses of the drug, with the potential to improve the efficacy and safety profile

UPLIZNA: Anti-CD19 Provides More Complete B-Cell Depletion

CD19: Cluster of differentiation 19. | CD20: Cluster of differentiation 20. | IgG: Immunoglobulin G. | IgM: Immunoglobulin M. | IgD: Immunoglobulin D.(1) Adapted from Cree et al. Poster presented at the American Association of Neurology 2021 Virtual Annual Meeting, April 17–22, 2021.

Stem cell Pro-B cell Pre-B cell Immature B cell

NaïveB cell

Mature B cellMemory B cell

Plasmablast Plasma cell

Bone marrow Periphery

CD19 expression

IgM IgD

Secreted IgG

IgM

Directly targeted by UPLIZNA but not by anti-CD20 agents

CD19 expression

CD20 expression

IgG

Targets a broader range of B cells for depletion

Demonstrated depletion of B cells to <1 cell/μL

Shown to be effective at preventing attacks for at least four years in the

open-label period(1)

NMOSD is a Chronic Autoimmune Disease of the Central Nervous System

NMOSD: Neuromyelitis optica spectrum disorder. | MS: Multiple sclerosis.

What is NMOSD?

• NMOSD is an autoimmune, inflammatory disease of the central nervous system

• Attacks the optic nerve, spinal cord and can also affect the brain and brainstem

• Severe, rare, relapsing

• Attacks result in accumulation of neurological damage and can result in blindness, paralysis and death

What causes NMOSD?

• Discovery of autoantibodies to aquaporin-4 (AQP4) in 2004 differentiated NMOSD from MS

• In ~80% of cases antibodies to AQP4 are present

• U.S. NMOSD population: ~10K; ~8K AQP4+

Optic neuritis

Myelitis

Brain/brain stem

UPLIZNA is a Well-Studied, Well-Understood Medicine in NMOSD that Prevents Attacks

NMOSD: Neuromyelitis optica spectrum disorder. | HR: hazard ratio. | CI: confidence interval. | NNT: number needed to treat. | RCT: Randomized controlled trial. | CI: Confidence interval. | AQP4-IgG: Aquaporin-4 Immunoglobulin G.(1) Cree et al. Long-term efficacy outcomes with inebilizumab treatment in neuromyelitis optica spectrum disorder: the N-MOmentum trial. Neurology (AAN) 2021 Virtual Annual Meeting April 17-22, 2021. ACTRIMS Forum 2021; February 15-27, 2021.

Phase 3 Data: B-Cell Depletion with UPLIZNA Decreases Attacks and Reduces Possibility of Disability

AQP4-IgG seropositive population

Pro

bab

ility

of

no

att

ack

Time (days)

PlaceboUPLIZNA

87.6%

56.6%Patients with NMOSD attacks (n/N)Inebilizumab, 18/161 (11.2%)Placebo, 22/52 (42.3%)HR (95% CI), 0.227 (0.121, 0.423); p < 0.0001NNT at Day 197 (95% CI), 3.23 (2.72, 4.54)

• UPLIZNA treatment generally well tolerated

Long-Term Data: UPLIZNA Provided Sustained Reduction in NMOSD Attack Risk At Least 4 Years(1)

Originally on UPLIZNA in the RCT and on UPLIZNA during

the open-label period

Originally on placebo in the RCT and on UPLIZNA during

the open-label period

87.7%

% of patients who remained attack-free

83.4%

0

20

40

60

80

100

UPLIZNA is a Well-Studied, Well-Understood Medicine in NMOSD; Positive Disability Data; Positive Rituximab-Switch Data and Sustained B-Cell Depletion

EDSS: Expanded Disability Status Scale. | NMOSD: Neuromyelitis optica spectrum disorder. | CD19: Cluster of differentiation 19. | CD20: Cluster of differentiation 20. | RCT: Randomized controlled trial. (1) Marignier et al. Disability outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2021;8:e978. (2) Levy et al. The safety and efficacy of inebilizumab in those with previous rituximab exposure. ACTRIMS Forum 2021; February 15-27, 2021. (3) Cree et al. Lancet. 2019 Oct 12;394(10206):1352-1363. (4) N-Momentum measured CD20 B cells because UPLIZNA specifically binds CD19, which interferes with the CD19 assay. Therefore, once a patient receives UPLIZNA, CD20 B cells are measured. Likewise, studies in anti-CD20 agents, CD19 cells are measured because the anti-CD20 agents bind CD20.

Disability: UPLIZNA Improved Disability Outcomes Regardless of Baseline Status,

Attack History or Disease Duration(1)

Subgroup analysis

Baseline EDSS <5

Baseline EDSS ≥

Number of prior attacks, <2

Number of prior attacks, ≥2

Disease duration <5 years

Disease duration ≥ years

UPLIZNAbetter

Placebobetter Circulating CD20 B cells at each study visit (3,4)

CD

20

B c

ells

(ce

lls p

er µ

L)

Durability: In the NMOSD Phase 3 Trial, B-Cell Depletion in the UPLIZNA Group vs.

Placebo was Rapid and Sustained (p<0.0001)

Rituximab Switching: Patients with Prior Rituximab Exposure Saw Significant Attack

Reduction on UPLIZNA(2)

Of seven patients with confirmed attacks while treated with rituximab,

, with mean follow-up period of

Time (days)

PlaceboUPLIZNA

• Characteristics and symptoms: Rare autoimmune disease caused by breakdown in communication between nerves and muscles

− Two main types of MG: AChR+ and MuSK+

− Symptoms include weakness, drooping eyelid(s), double vision, difficulties with speech and swallowing, and respiratory impairment

− A hallmark of MG is patient variability and fluctuation in symptoms/impact

• U.S. prevalence: ~55K with generalized MG; 20K-25K appropriate for novel therapies, including a biologic(1)

• Current standard of care: steroids, immunosuppressants (including off-label use of rituximab, a CD20+ B-cell depleter), cholinesterase inhibitors, IVIG, plasmapheresis, complement inhibition

MG is a Debilitating Rare Disease with Significant Unmet Need

AChR+: Acetylcholine receptor. | MuSK+: Muscle-specific kinase. | MG: Myasthenia Gravis. | IVIG: Intravenous immunoglobulin.(1) Horizon estimate.

A Common MG Symptom is Drooping Eyelids (Ptosis)

GERMINAL CENTER

Plasma cell

B cell

T cell

NEUROMUSCULAR JUNCTION

Neuron

Muscle

MG is Caused by Autoantibodies Attacking the Postsynaptic Neuromuscular Junction, Leading to Muscle Weakness

AChR: Acetylcholine receptor. | MuSK: Muscle-specific kinase. | Lrp4: Low density lipoprotein receptor-related protein 4. | MG: Myasthenia gravis.

MG

Anti-Lrp4

Anti-MuSKAnti-AchR

NORMAL

AchR

Lrp4Ach

MuSK

• In MG, autoantibodies target functional proteins (e.g., AChR and MuSK) in the post-synaptic neuromuscular junction

• This interrupts the normal synaptic function needed to signal muscle contraction, and:

• Results in neuromuscular junction damage and remodeling

• Affects voluntary muscles of the body, especially those that control the eyes, mouth, throat, breath and limbs

Phase 3 MG TrialLarge, Robust Pivotal Trial with Clearly Delineated Patient Populations

AChR+: Acetylcholine receptor autoantibody positive. | MuSK+: Muscle-specific kinase autoantibody positive. | MG: Myasthenia Gravis. | ADL: Activities of Daily Living.| QMG Score: Quantitative Myasthenia Gravis score.

Change from Baseline in MG-ADL Profile score at 52 weeks (AChR+) and 26 weeks (MuSK+)

Data readout expected in 2023


• MG-ADL Score ≥6 with > 0% non-ocular symptoms

• QMG Score ≥11

• On standard of care:

- Corticosteroids only; or - One allowed non-steroidal immunosuppressant; or- Corticosteroids plus one allowed immunosuppressant

Phase 3 Trial Design in MG: Aim is to Assess Whether UPLIZNA Can Reduce MG-Related Disability in Two Different Patient Populations

AC

hR

+1

88

p

ati

ents

Mu

SK+

82

pa

tien

ts

18-Month Optional Open-Label Period

UPLIZNA Three infusions (Days 1, 15 and 183); 300mg per infusion

PlaceboThree infusions (Days 1, 15 and 183)

18-Month Optional Open-Label Period

UPLIZNA Two infusions (Days 1 and 15); 300mg per infusion

PlaceboTwo infusions (Days 1 and 15)

Day 1 Week 26MuSK+ Primary Endpoint

Week 52AChR+ Primary Endpoint

+18 MonthsOpen-Label Optional Period

IgG4-Related Disease (IgG4-RD) is a Chronic, Debilitating Rare Disease

IgG4: Immunoglobulin G4.(1) ACR-EULAR 2019 IgG4-RD Classification Criteria, from Perugino, C. A. and Stone, John. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nature Reviews Rheumatology. September 2020. (2) Horizon estimate.

• Characteristics and symptoms(1): Chronic, debilitating rare disease characterized by tumor-like inflammatory and fibrotic mass formation in affected organs

• Affects mostly men (75%)

• Progressive; waxes and wanes; attendant morbidity; potential mortality. Specific symptoms depend on which organs are affected; multiple organ involvement is typical

• Major causes for mortality include liver cirrhosis, portal hypertension, retroperitoneal fibrosis, etc.

• U.S. prevalence: ~20K-40K(2); large variance due to limited epidemiology data

• Current standard of care: steroids, rituximab (off-label)

IgG4-RD is Caused by Multiple Mechanisms of B-Cell Dysfunction

IgG4-RD: Multiple Organ Disease

• Lacrimal glands

• Parotid glands

• Lymph nodes

• Pancreas

• Lungs

• Aorta

• Submandibular glands

• Retroperitoneum

• Biliary tree

• Thyroid

• Kidneys

• Orbits

• Others

• B cells trigger and perpetuate pathogenic processes in IgG4-RD, including:

IgG4 class switch and oligoclonal expansion of CD19+ IgG4+ plasmablasts; massive tissue infiltration and swollen lesions

Production of IL-1 and other factors, driving tissue inflammation

Production of profibrotic molecules (TGFβ, LOXL2, PDGF-B); fibroblast activation, increased collagen production and fibrosis

Autoantibody production and interactions with CD4+ and CD8+ T cells, leading to cycle of CTL-mediated tissue destruction

.

IgG4-Related Disease is Caused by Multiple Mechanisms of B-Cell Dysfunction

CD4: Cluster of differentiation 4. | CD8: Cluster of differentiation 8. | CD19: Cluster of differentiation 19. | IgG4-RD: Immunoglobulin G4-related disease. | IL-1: Immunoglobulin-Like 1. | CTL: Cytotoxic T lymphocytes. TGFβ: Transforming growth factor beta. | LOXL2: Lysyl Oxidase Like 2. | PDGF-B: Platelet-derived growth factor subunit B.Hsieh SC, Shen CY, Liao HT, et al. The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease. Int J Mol Sci. 2020;21(14):5082.Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol. 2020 Dec;16(12):702-714.Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012 Sep;25(9):1181-92.

CD4+ and CD8+ T cells

CD19+ B cells

IgG4 class switch and oligoclonal expansion

IL-1 production

Profibrotic factorproduction

Autoantibodies

T follicular

helper cells

• Cell damage, death• Tissue destruction• Self-antigen release• More autoantibodies

Plasmacytic infiltration and tissue

enlargement

1 2 3 4

Inflammation of tissues

Fibrosis

1

2

3

4

Examples of IgG4-RD Manifestations

IgG4-RD: Immunoglobulin G4-related disease.Source: Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; 366:539.

Phase 3 IgG4-RD TrialFirst Pivotal Randomized Controlled Trial in IgG4-RD

RCT: Randomized controlled trial. | GC: Glucocorticoid. | IgG4-RD: Immunoglobulin G4-related disease. | ACR: American College of Rheumatology. | EULAR: European Alliance of Associations for Rheumatology.

Time to first adjudication committee-determined, investigator-treated disease flare during RCT

Event-based endpoint; data readout expected in 2023


• Clinical diagnosis of IgG4-RD

• Fulfillment of 2019 ACR/EULAR IgG4-RD classification criteria

• Experiencing or recently experienced an IgG4-RD flare that requires GC treatment

• IgG4-RD affecting >2 organs/sites during course of IgG4-RD

Phase 3 Trial Design: Aim is to Define the Efficacy and Safety of UPLIZNA for Prevention of IgG4-RD-Related Flares

~16

0 p

ati

ents

52-Week Optional Open-Label Period

UPLIZNA Three infusions (Days 1, 15 and 183); 300mg per infusion

PlaceboThree infusions (Days 1, 15 and 183)

Day 1 Week 52 +52 WeeksOpen-Label Optional Period

UPLIZNA Key Takeaways A Next-Generation B-Cell Depleter with a Novel Targeted Approach

AChR+: Acetylcholine receptor . | MuSK+: Muscle-specific kinase. CD19: Cluster of differentiation 19. | CD20: Cluster of differentiation 20. | IgG4: Immunoglobulin G4.

UPLIZNA is an anti-CD19, humanized monoclonal antibody with potential in multiple autoimmune diseases

Targets the CD19 antigen, which including plasmablasts and certain plasma cells that anti-CD20 therapies do not target

, which include:

Neuromyelitis optica spectrum disorder (NMOSD), where UPLIZNA is already indicated

, where UPLIZNA has the potential for differentiation; our robust Phase 3 trial is the first with clearly delineated AChR+ and MuSK+ patient populations

, where UPLIZNA has the potential to be the first-ever FDA-approved therapy

Q&A


TEPEZZABuilding the Evidence to Help Treat More Patients with Chronic TED


Bobby S. Korn, M.D., Ph.D., FACS, Professor of Ophthalmology & Plastic Surgery, University of California, San Diego

Thyroid Eye Disease (TED): Debilitating, Vision-Threatening; Severely Impacts Quality of Life

Inflammation and tissue expansion behind the eye causes proptosis, the most disfiguring sign of TED

Can impair ability to close eyes, resulting in pain and corneal ulceration

Associated with diplopia (double vision), which is a result of misalignment of eyes

Impacts quality of life: Working, driving, reading, and sleeping

Natural History of TED – Acute to Chronic

TED: Thyroid Eye Disease.(1) Douglas RS, et al. N Engl J Med. 2020;382(4):341-352. (2) Ozzello DJ, et al. Am J Ophthalmol Case Rep. 2020;19:100744.

Time

Chronic TED

Acute TED

Sign

s &

Sym

pto

ms

Acute inflammatory

<9 months(1)

Chronic noninflammatory

3 years(2)

Inflammatory signs and symptoms, such as pain, redness, swelling, proptosis, diplopia, and eyelid

retraction are at peak levels

Inflammatory signs such as redness and swelling are reduced but the pain, proptosis, diplopia, and eyelid

retraction are persistent throughout life

Acute and Chronic TED Have Similar Signs and Symptoms

TED: Thyroid Eye Disease.Wang, Y et al., Active Versus Inactive Thyroid Eye Disease: Symptom and Quality of Life Comparison in US Patients. ACE May 26-29, 2021, Virtual.

0%

50%

100%

0%

50%

100%

Most commonly reported signs and symptoms of acute TED

Most-commonly reported signs and symptoms of chronic TED

Acute and Chronic TED Have a Similar Impact on Mental Health

TED: Thyroid Eye Disease.(1) US adult population statistics for 2017 as reported by the National Institutes of Health.

19% 19%

7%

37%

28%

19%

36%

26%

17%

0%

10%

20%

30%

40%

Any mental health issue Anxiety Depression

US adult population Acute TED population Chronic TED population

• Mental health issues (anxiety and/or depression) were higher in both the acute and chronic TED populations

• The prevalence of mental health issues was not significantly different between patients with acute and chronic disease

(1) (1) (1)

TE E A’s Mechanism of Action: Common athway in Acute and Chronic TED

TED: Thyroid Eye Disease.Eye Pathology – Eagle R.C. 2017

• Insulin-like growth factor-1 receptor (IGF-1R)/Thyroid stimulating hormone receptor (TSHR) signaling key in TED

• Teprotumumab is a human monoclonal antibody inhibitor of IGF-1R

• Binds to IGF-1R/TSHR complex and blocks downstream signaling

• Targets the pathology at TED’s source, reducing production of hyaluronic acid, halting inflammation and retro-orbital tissue expansion

• Pathway is common in both acute and chronic TED

TEPROTUMUMAB

IGF-1R/TSHR COMPLEX

B CELL

TEPEZZA Phase 3 Trial Demonstrated Impressive Results in Acute Patients

CI: Confidence interval.Throughout the 24-week treatment period, patients treated with TEPEZZA had an average proptosis reduction of 2.82 mm compared with 0.54 mm for those who received placebo (p<0.001).(1) Change from baseline in proptosis as a continuous variable is based on Mixed-Model Repeated-Measures (MMRM) analysis of covariance (ANCOVA) model with an unstructured covariance matrix including the following terms: baseline score, tobacco use status (non-user, user), treatment group, visit, and visit-by-treatment and visit-by-baseline-score interactions.

Proptosis Response (Reduction of ≥2 mm) at Week 24

Pro

pto

sis

Re

spo

nd

ers

(%

)

7.1

14.3 14.39.5

56.1

75.6

82.9 82.9

0

20

40

60

80

100

Baseline Week 6 Week 12 Week 18 Week 24

p<0.001

p<0.001

p<0.001 p<0.001

Difference: 73.45(95% CI 58.89, 88.01)

TEPEZZA (n=41) Placebo (n=42)

Proptosis Reduction of 3.32 mm at Week 24(1)

-0.38-0.64 -0.59 -0.53

-2.00

-2.70

-3.26-3.32

-4

-3

-2

-1

0

Week 0 Week 6 Week 12 Week 18 Week 24

Pro

pto

sis

Re

du

ctio

n (

mm

)

Difference: -2.79(95% CI -3.40, -2.17)

TEPEZZA (n=41) Placebo (n=42)

OPTIC-X Shows Efficacy Across Short- and Long-Term Thyroid Eye Disease

TED: Thyroid Eye Disease.Douglas RS, et al., Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med 2020; 382:341-52. DOI: 10.1056/NEJMoa1910434

Phase 3 OPTIC-X

Timing<9 months since diagnosis of acute TED (average 6 months)

Average of 12 months since diagnosis of TED (up to 16 months)

Response

• 89% proptosis responder rate • 3.5-mm reduction in proptosis at Week 24

Before

After-2.00

-2.70

-3.26 -3.32

-1.78

-2.58

-3.23-3.47

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 6 12 18 24

Pro

pto

sis

Ch

ange

fro

m B

asel

ine

(mm

)

TEPEZZA (OPTIC, N =41) Placebo --> TEPEZZA (OPTIC-X, N=37)

First Published Case Report in AJO with TEPEZZA in a Chronic TED Patient

TED: Thyroid Eye Disease. | CAS: Clinical Activity Score.Ozzello DJ, et al. Am J Ophthalmol Case Rep. 2020 May 15;19:100744. doi: 10.1016/j.ajoc.2020.100744.

• 50-year-old female

• 3-year history of disease

• CAS score of 1

• Nonsurgical candidate

• 6mm proptosis reduction achieved after 3 infusions

• Reduction of extraocular muscles suggest TEPEZZA can modify disease course in chronic disease

Update – First Published Case Report in AJO on TEPEZZA in a Chronic TED Patient

Pre-TEPEZZA After 3 infusions 1 year after 8 infusions

TED: Thyroid Eye Disease. | AJO: American Journal of Ophthalmology.Ozzello DJ, et al. Am J Ophthalmol Case Rep. 2020 May 15;19:100744. doi: 10.1016/j.ajoc.2020.100744.

Ugradar – Eye – 2020: Mean proptosis reduction of 2.6 mm(1)

(N = 4 non-inflammatory TED patients; on average 7 months from diagnosis)

Davis – NANOS – 2021 (Poster): Proptosis reduction of 5-6 mm from baseline after

completing treatment of 8 infusions(N = 1; patient diagnosed with Graves in 1997)

Ozzello – AJO – 2020: Proptosis reduction of 5 mm and 6 mm in the right and left eye

respectively after 3 infusions (N = 1; 24 months of stable eye disease)

Diniz – OPRS – 2021: 71% overall proptosis response rate (proptosis reduction ≥2 mm(2);

N = 6; on average 16 months from onset of TED)(3)

Illustrative Case Studies Demonstrating Efficacy in Chronic TED Patients

TED: Thyroid Eye Disease. | AJO: American Journal of Ophthalmology. | OPRS: Ophthalmic Plastic and Reconstructive Surgery. | NANOS: North American Neuro-Opthalmology Society.(1) After completing treatment of 8 infusions. | (2) After range of 3-8 infusions; photo taken after 3 infusions. | (3) 71% response rate refers to the 21 patients in the study. 6 refers to patients with chronic TED. (4) Mean of 7 infusions.

Ozzello - Orbit - 2021: 78% proptosis reduction of ≥2 mm in at least one eye(1)

(N = 9; on average of 75 months from diagnosis)

Ugradar - Eye - 2021: 90% of study experienced clinically significant improvement

(≥2 mm) in proptosis(4)

(N = 31; on average of 81 months from diagnosis)

Growing Body of Patient Case Studies Supporting the Use of TEPEZZA in Chronic TED

TED: Thyroid Eye Disease.(1) Ozzello DJ, et al. Am J Ophthalmol Case Rep. 2020 May 15;19:100744. doi: 10.1016/j.ajoc.2020.100744. (2) Ugradar S, et al. Eye (Lond). 2020 Nov 21. doi: 10.1038/s41433-020-01297-w. (3) Davis R, et al. NANOS 2021 Feb annual meeting abstract. https://collections.lib.utah.edu/ark:/87278/s6gz077j. (4) Diniz SB, et al. Ophthalmic Plast Reconstr Surg. 2021 Mar 8. doi: 10.1097/IOP.0000000000001959. (5) Ozzello DJ, et al. Orbit. 2021 Jun 1:1-8. doi: 10.1080/01676830.2021.1933081. (6) Ugradar S, et al. Eye (Lond). 2021 Jul 9. doi: 10.1038/s41433-021-01593-z. Note: Data from separate clinical trials may not be directly comparable due to differences in trial protocols, endpoints, conditions and patient populations.

Nu

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f TE

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ZA P

atie

nts

Stu

die

d

41

Chronic Patient Case Studies to Date Acute Patients on TEPEZZA Studied

in Phase 3 Clinical Trial

52

Total Number of Chronic TED Patients Across Case Studies Compared to Number of Acute Patients on TEPEZZA from Phase 3 Clinical Trial

654321Legend (Color-to-Article):

Real World Examples of TEPEZZA in Chronic TED

Before Treatment with TEPEZZA After Treatment with TEPEZZA

TED: Thyroid Eye Disease.Image on right is after 8 TEPEZZA infusions.

First Published Case Report in American Journal of Ophthalmology on TEPEZZA Impact in Chronic TED Patient

TED: Thyroid Eye Disease.Ozzello DJ, et al. Am J Ophthalmol Case Rep. 2020 May 15;19:100744. doi: 10.1016/j.ajoc.2020.100744.

Clinical Trial: A Study Evaluating TEPEZZA Treatment in Patients with Chronic Thyroid Eye Disease; Data Anticipated 2H 2022

Q3W: once every 3 weeks. | TED: Thyroid Eye Disease. | QoL: Quality of Life.

• Change from Baseline at Week 24 in proptosis in the study eye

• roptosis responder rate (% of participants with ≥2-mm reduction from baseline in proptosis in the study eye, without deterioration [≥2-mm increase] of proptosis in the fellow eye) at Week 24

• Additional endpoints on diplopia, QoL, orbital pain, MRI muscle volume


• Initial diagnosis of TED ≥ years but <8 years prior to screening

• Clinical diagnosis of stable, chronic (inactive) TED, as determined by participant medical records indicating a Clinical Activity Score (CAS) ≤1 in both eyes for at least 1 year prior to screening

• CAS ≤1 at the screening and baseline visits

• roptosis ≥ -mm increase from participant’s baseline or roptosis ≥ -mm above normal for race and gender

Randomized, Placebo-Controlled Trial

Safety Follow-Up

57

pat

ien

ts2

:1 r

an

do

miz

ati

on TEPEZZA 10 mg/kg for the first infusion and 20 mg/kg for the remaining 7

infusions Q3W

Placebo

Study Week 0



TEPEZZA: Building the Evidence to Treat More Patients with Chronic TED

TED: Thyroid Eye Disease.

TE E A’s mechanism of action addresses the same underlying pathology in both the acute and chronic TED

Growing body of evidence supporting the use of TEPEZZA in chronic TED

Ongoing clinical trial in patients with chronic TED to establish clinical conviction

Closing Q&A


Conclusion


Key Takeaways for Today

(1) Horizon estimate.

We are building a

•

• announced today and starting in 2022

• anticipated in 2021-2023

• in second half of the decade

Horizon is a with best-in-class commercial execution and a rapidly growing pipeline

We are to bolster our ability to continuously innovate

Our current in total peak annual net sales potential(1)

Reconciliations of GAAP to Non-GAAP Measures


Note Regarding Use of Non-GAAP Financial Measures

EBITDA, or earnings before interest, taxes, depreciation and amortization, and adjusted EBITDA are used and provided by Horizon as non-GAAP financial measures. These non-GAA measures are intended to provide additional information on Horizon’s performance, operations, expenses, profitability and cash flows. Adjustments to Horizon’s GAA figures as well as EBITDA exclude acquisition and/or divestiture-related expenses, gain or loss from divestiture, gain or loss from sale of assets, upfront, progress and milestone payments related to license and collaboration agreements, litigation settlements, loss on debt extinguishment, costs of debt refinancing, drug manufacturing harmonization costs, restructuring and realignment costs, the income tax effect on pre-tax non-GAAP adjustments and other non-GAAP income tax adjustments, as well as non-cash items such as share-based compensation, depreciation and amortization, non-cash interest expense, long-lived asset impairment charges and other non-cash adjustments. Certain other special items or substantive events may also be included in the non-GAAP adjustments periodically when their magnitude is significant within the periods incurred. Horizon maintains an established non-GAAP cost policy that guides the determination of what costs will be excluded in non-GAAP measures. Horizon believes that these non-GAAP financial measures, when considered together with the GAAP figures, can enhance an overall understanding of Horizon’s financial and operating performance. The non-GAAP financial measures are included with the intent of providing investors with a more complete understanding of the Company’s historical and expected 2021 financial results and trends and to facilitate comparisons between periods and with respect to projected information. In addition, these non-GAAP financial measures are among the indicators Horizon’s management uses for planning and forecasting purposes and measuring the Company's performance. For example, adjusted EBITDA is used by Horizon as one measure of management performance under certain incentive compensation arrangements. These non-GAAP financial measures should be considered in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The non-GAAP financial measures used by the Company may be calculated differently from, and therefore may not be comparable to, non-GAAP financial measures used by other companies. Horizon has not provided a reconciliation of its full-year 2021 adjusted EBITDA outlook to an expected net income (loss) outlook because certain items such as acquisition/divestiture-related expenses and share-based compensation that are a component of net income (loss) cannot be reasonably projected due to the significant impact of changes in Horizon’s stock price, the variability associated with the size or timing of acquisitions/divestitures and other factors. These components of net income (loss) could significantly impact Horizon’s actual net income (loss).

2020 2019 2018

GAAP net income 389,796$ 573,020$ (38,380)$

Depreciation 24,303 6,733 6,126

Amortization and step-up:

Intangible amortization expense 255,148 230,424 243,634

Inventory step-up expense - 89 17,312

Interest expense, net (including amortization of

debt discount and deferred financing costs) 59,616 87,089 121,692

Expense (Benefit) for income taxes 11,849 (593,244) (44,752)

EBITDA 740,712$ 304,111$ 305,632$

Other non-GAAP adjustments:

Acquisition/divestiture-related costs 49,196 3,556 4,396

Restructuring and realignment costs (141) 237 15,350

Impairment of long-lived assets 1,713 - 46,096

(Gain)/Loss on sale of assets (4,883) 10,963 (42,985)

Share-based compensation 146,627 91,215 114,860

Litigation settlements - 1,000 5,750

Upfront, progress and milestone payments related to

license and collaboration agreements 33,000 9,073 (10)

Fees related to refinancing activities 54 2,292 937

Loss on debt extinguishment 31,856 58,835 -

Drug substance harmonization costs 542 457 2,855

Charges relating to discontinuation of Friedreich's ataxia program - 1,076 (1,464)

Total of other non-GAAP adjustments 257,964 178,704 145,785

Adjusted EBITDA 998,676$ 482,815$ 451,417$

Twelve Months Ended December 31,

GAAP to Non-GAAP ReconciliationEBITDA and Adjusted EBITDA – Twelve Months Ended December 31

$ in thousands

Virtual R&D Day September 29, 2021

Documents

Transcript of Virtual R&D Day September 29, 2021