Investor Day - Alexion Pharmaceuticals, Inc

Investor Day M A R C H 2 0 , 2 0 1 9

WELCOME Susan Altschuller, Ph.D. | Head of Investor Relations

3 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . D I S C L O S U R E S

FORWA R D - L O O K I N G STATEM E N TS

US/ALL-ALL/18/0002

This presentation contains forward-looking statements, including statements related to: guidance regarding anticipated financial results for 2019; ambition to continue to deliver double-digit revenue growth (and strong financials); expected

growing product portfolio; ambition to convert patients to Ultomiris in the future for PNH (and aHUS); anticipated future product launches (including future subcutaneous products); plans for future clinical programs and the expansion of

those programs (and expanding the Company’s product pipeline and the means expected to achieve such expansion); the nature, timing, and possible success and therapeutic applications of Alexion’s products, product candidates, and

research and clinical programs now underway or planned, including without limitation Soliris, Ultomiris, ALXN1810, CAEL-101, ALXN1830, ALXN1720 and ABY-039 (and subcutaneous formulations of certain products and product

candidates); the anticipated timing for the initiation and completion of clinical trials and product development; the long-term durability of current and future products; Alexion’s earlier stage product candidates; the extent to which the results

from research programs or preclinical testing may lead to advancement of product candidates to clinical trials or therapeutic applications; the likelihood and timing of regulatory filings, possible regulatory approval and commercial launch of

Alexion product candidates and new indications for marketed products (including 10 potential launches over the next five years); the potential success of product development programs; potential for product candidates to be best-in-class,

first-in-class and/or first-to-market; Alexion is significantly increasing addressable patient populations (and the product candidates that could lead to treatment for such patients); the expected benefits of the Four Pillars of growth (and

possible new pillars of growth); the Company is building durable, blockbuster franchises in PNH/aHUS, metabolics, neurology and FcRn; the potential of the therapeutic benefits for our products and product candidates (including the

potential to be transformative therapies for certain indications); future growth trajectories of our products and product candidates (including Strensiq, Kanuma and treatments for patients with gMG); potential for certain Alexion products to

become the standard of care for certain indications; timing of biosimilar entry and that the portion of the business at risk to biosimilars is minimal; future anticipated pricing strategies for certain products (and potential discounts relative to

other indications) and potential cost-savings; expected acceleration of neurology growth with gMG and other potential neurological indications; ambition for gMG patients to comprise largest Soliris treated patient population; anticipated

patient preferences for certain products, dosing schedules and subcutaneous delivery mechanisms; expected increase to Soliris/Ultomiris patient base; goal of providing treatment options for entire spectrum of gMG patients (and Alexion’s

expanding gMG portfolio strategy and path to category leadership); potential for Soliris to be the first approved therapy for NMOSD; certain products in clinical trials (for ALS and PPMS) are high risk/high reward but have the potential to be

transformative for patients; neurology franchise represents a multi-billion dollar revenue potential; potential of FcRn assets as therapy for neurological conditions; certain initiatives may result in identification of more patients for certain of

our products and product candidates and earlier diagnosis of disease states; ALXN 1830 and ALXN1840 have potential to be first line treatment utilization for applicable indications; building a potential leading FcRn portfolio (with the

opportunity to address a range of IgG mediated diseases); there will be multiple INDs over the coming years; plan to develop ALXN 1720 for multiple new indications and therapeutic areas; and Alexion’s 2019 objectives. Forward-looking

statements are subject to factors that may cause Alexion's results and plans to differ materially from those forward-looking statements, including for example: our dependence on sales from our principal product (SOLIRIS); our ability to

facilitate the timely conversion of PNH patients (and any future indications) from Soliris to Ultomiris; payer, physician and patient acceptance of Ultomiris as an alternative to Soliris; appropriate pricing for Ultomiris; future competition from

biosimilars and novel products; decisions of regulatory authorities regarding the adequacy of our research, marketing approval or material limitations on the marketing of our products; delays or failure of product candidates to obtain

regulatory approval; delays or the inability to launch product candidates due to regulatory restrictions, anticipated expense or other matters; interruptions or failures in the manufacture and supply of our products and our product candidates;

failure to satisfactorily address matters raised by the FDA and other regulatory agencies; results in early stage clinical trials may not be indicative of full results or results from later stage or larger clinical trials (or broader patient populations)

and do not ensure regulatory approval; the possibility that results of clinical trials are not predictive of safety and efficacy and potency of our products (or we fail to adequately operate or manage our clinical trials) which could cause us to

halt trials, delay or prevent us from making regulatory approval filings or result in denial of approval of our product candidates; unexpected delays in clinical trials; unexpected concerns that may arise from additional data or analysis

obtained during clinical trials; future product improvements may not be realized due to expense or feasibility or other factors; uncertainty of long-term success in developing, licensing or acquiring other product candidates or additional

indications for existing products; inability to complete acquisitions or grow the product pipeline through acquisitions; the possibility that current rates of adoption of our products are not sustained; the adequacy of our pharmacovigilance and

drug safety reporting processes; failure to protect and enforce our data, intellectual property and proprietary rights and the risks and uncertainties relating to intellectual property claims, lawsuits and challenges against us; the risk that third

party payors (including governmental agencies) will not reimburse or continue to reimburse for the use of our products at acceptable rates or at all; failure to realize the benefits and potential of investments, collaborations, licenses and

acquisitions; the possibility that expected tax benefits will not be realized; potential declines in sovereign credit ratings or sovereign defaults in countries where we sell our products; delay of collection or reduction in reimbursement due to

adverse economic conditions or changes in government and private insurer regulations and approaches to reimbursement; uncertainties surrounding legal proceedings, company investigations and government investigations, including

investigations of Alexion by the U.S. Securities and Exchange Commission (SEC) and U.S. Department of Justice; the risk that estimates regarding the number of patients with PNH, aHUS, gMG, HPP, ALS, PPMS and LAL-D and other

future indications we are pursuing are inaccurate; the risks of changing foreign exchange rates; risks relating to the potential effects of the Company's restructuring; risks related to the acquisition of Syntimmune and other companies and

co-development efforts; and a variety of other risks set forth from time to time in Alexion's filings with the SEC, including but not limited to the risks discussed in Alexion's Annual Report on Form 10-K for the year ended December 31, 2018

and in our other filings with the SEC. Alexion disclaims any obligation to update any of these forward-looking statements to reflect events or circumstances after the date hereof, except when a duty arises under law.

In addition to financial information prepared in accordance with GAAP, this presentation also contains non-GAAP financial measures that Alexion believes, when considered together with the GAAP information, provide investors and

management with supplemental information relating to performance, trends and prospects that promote a more complete understanding of our operating results and financial position during different periods. The non-GAAP amounts

exclude the impact of the following GAAP items: share-based compensation expense, fair value adjustment of inventory acquired, amortization of purchased intangible assets, changes in fair value of contingent consideration, restructuring

and related expenses, upfront payments related to licenses and collaborations, acquired in-process research and development assets, impairment of intangible assets, change in value of strategic equity investments, litigation charges, gain

or loss on sale of a business or asset and certain adjustments to income tax expense. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for, or superior to, the financial measures prepared

and presented in accordance with GAAP, and should be reviewed in conjunction with the relevant GAAP financial measures. Please refer to the Alexion website for GAAP to non-GAAP 2019 Financial Guidance for explanations of the

amounts adjusted to arrive at non-GAAP operating margin and non-GAAP earnings per share amounts for the projected twelve months ending December 31, 2019.

VISION & STRATEGY Ludwig Hantson, Ph.D.| Chief Executive Officer

R A R E I N S P I R A T I O N . C H A N G I N G L I V E S .

Our Mission Serving patients and their families is our unwavering

mission – they are our guiding star and

they inspire us to continue to find answers.

We act with integrity, urgency, and discipline because we know that

l ives are at stake.

6 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . V I S I O N & S T R A T E G Y | L U D W I G H A N T S O N , P H D , C E O

O U R F O C U S I S I N R A R E D I S E A S E

~30M patients diagnosed

in US,

50% are children

Only 500 rare diseases

have approved therapies

>7,000

rare diseases

identified

Atypical Hemolytic

Uremic Syndrome

(aHUS)

Prior to SOLIRIS®, 79% of

patients died, required kidney

dialysis, or had permanent

kidney damage within three

years of diagnosis

Hypophosphatasia

(HPP)

Prior to STRENSIQ®, children

with symptoms prior to 6

months of age had 73%

mortality rate at 5 years

Lysomal Acid Lipase

Deficiency

(LAL-D)

Prior to KANUMA®, Median

age of death was 3.7 months

in infants with rapid disease

progression

Paroxysmal Nocturnal

Hemoglobinuria (PNH)

Prior to SOLIRIS®, up to

35% of patients with

available support did not

survive beyond 5 years

Generalized

Myasthenia Gravis

(gMG)

Debilitating, chronic and

progressive autoimmune

neuromuscular disease that

can lead to inability to walk,

talk, eat or breathe

Source: Caprioli J, Noris M, Brioschi S, et al. The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267-1269, Noris M, Caprioli J, Bresin E, et al. Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype. CJASN. 2010;5:1844-1859, Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995 Nov 9;333(19):1253-8, Whyte MP, Leung E, Wilcox W, et al. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms. Poster presented at the 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting, Vancouver, B.C., Canada, May 5, 2014. Abstract 752416, Jones SA, Valayannopoulos V, Schneider E, et al. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants. Genet Med. 2016;18(5):452-458. doi: 10.1038/gim.2015.108

Four transformative therapies across five rare diseases in our growing portfolio

7 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S .

A L E X I O N ’ S T R A N S F O R M AT I O N B E G A N I N 2 0 1 7

V I S I O N & S T R A T E G Y | L U D W I G H A N T S O N , P H D , C E O

2017 2019 2018


A L E X I O N ’ S N E X T C H A P T E R

Transforming Compliance,

Culture & Talent

Delivering Strong

Financials

Executing on Our

Refocused Strategy



F O C U S O N C U LT U R E , C O M P L I A N C E & TA L E N T

We have strengthened and refreshed our employee base:

Reinforced Culture of Compliance

Strengthened Leadership Team

Refreshed Board of Directors

Restructured to Optimize Organization and Resource

Allocation

Relocated Corporate HQ to Boston

Hired and on-boarded ~30% of our total employee

base in the past year*

Leading with Diversity: >50% women on the Executive

Team and in senior leadership positions

*While reducing total headcount since 2016


https://alexion.sharepoint.com/sites/multimedia/Office Employee Images/D04_5715.jpg


S T R O N G G R O W T H & F I N A N C I A L P E R F O R M A N C E

*Mid-point of 2019 Guidance range provided February 4, 2019

Reconciliations of our GAAP to non-GAAP financial results are available at www.alexion.com

Financial Ambition to Continue to Deliver Double-Digit Revenue and Non-GAAP EPS Growth

Annual Revenues & 2019 Guidance Annual Non-GAAP Operating Margin &

2019 Guidance

43%

45%

53% 54.5%

2016 2017 2018 2019E*

$3,084

$3,551

$4,131

$4,663

$4.62

$5.86

$7.92

$9.20

$0.00

$1.00

$2.00

$3.00

$4.00

$5.00

$6.00

$7.00

$8.00

$9.00

$10.00

$0

$500

$1,000

$1,500

$2,000

$2,500

$3,000

$3,500

$4,000

$4,500

$5,000

2016 2017 2018 2019*

Revenue Non-GAAP EPS



E X E C U T I N G O N O U R R E F O C U S E D S T R AT E G Y

Significant pipeline progress

2017 2019 2021

Extending durability of our legacy business in PNH and atypical HUS

ULTOMIRIS®

SubQ

ULTOMIRIS®

Phase 3 atypical HUS

ULTOMIRIS®

Phase 3 PNH

ULTOMIRIS®

atypical HUS filing

ULTOMIRIS®

PNH launch

Potentially Redefined Standard of Care

in PNH & atypical HUS

Ambition to convert >70% patients to

ULTOMIRIS within 2 years of launch

ULTOMIRIS first-in-class C5

SubQ launched

Ambition to continue to

expand development

programs

16 clinical

programs

At least 6 programs in Ph 3 in 2020

4 clinical

programs



R & D P I P E L I N E A S O F E N D O F 2 0 1 7

Preclinical Early Clinical Advanced Clinical Registration

ULTOMIRIS QW SubQ ULTOMIRIS IV PNH

Hematology & Nephrology

Neurology

ULTOMIRIS IV aHUS

SOLIRIS® IV NMOSD


Internal Complement

Programs


S I G N I F I C A N T P I P E L I N E P R O G R E S S


Metabolics

Neurology

FcRn

TBD

Italicized = plan to initiate in 2019

Internal Complement

Programs

Preclinical Early Clinical Advanced Clinical Registration

ALXN1210 QW SubQ

ALXN1210 New

Indications

ALXN1210 IV PNH SOLIRIS® gMG SOLIRIS® NMOSD

Complement Pharma

Dicerna

ALXN1810 SubQ

(ULTOMIRIS/PH20)

ULTOMIRIS IV PPMS

ULTOMIRIS IV ALS

ALXN1830 (SYNT001)

WAIHA

CAEL-101

AL Amyloidosis

ULTOMIRIS QW SubQ

ULTOMIRIS

High Concentration

ULTOMIRIS IV gMG

ULTOMIRIS IV NMOSD

ALXN1840 (WTX101)

Wilson Disease

ALXN1830 (SYNT001)

gMG

ALXN1830 (SYNT001)

WAIHA

ULTOMIRIS® aHUS

ALXN1720

(Anti-C5 Bi-specific)

ABY-039

Rare Autoimmune

Next-Gen Treatment

for HPP

ULTOMIRIS SubQ

gMG

Zealand


ALXN1720

(Anti-C5 Bi-specific)


B U I L D I N G F O U R D U R A B L E , G R O W I N G B L O C K B U S T E R F R A N C H I S E S

Diversifying

the Alexion

Portfolio


Neurology

Metabolics

FcRn Portfolio

1

2

3

4




L O N G - T E R M D U R A B I L I T Y I N P N H & AT Y P I C A L H U S *

>70% Within 2 years of

launch

Best-in-class

Conversion Target

Continued

underlying high

single-digit

volume growth Compelling value

proposition for all

stakeholders

Transformational

treatments address

critical disease

measures



*ULTOMIRIS is currently not approved for the treatment of aHUS


N E U R O L O G Y P O S I T I O N S A L E X I O N F O R F U R T H E R G R O W T H

SOLIRIS® NMOSD PDUFA date

of June 28, 2019; Priority Review granted

Leverage commercial capabilities of newly expanded,

dedicated Neurology salesforce

SOLIRIS® gMG is best Alexion launch to date

ULTOMIRIS® development programs in four Neurology indications;

ALXN1830 in development for gMG

Neurology



E X P A N D I N G M E T A B O L I C S W I T H A L X N 1 8 4 0 I N W I L S O N D I S E A S E

ALXN1840

(WTX101)

10,000-fold higher

affinity for Cu

Specifically binds to Cu

Safe Cu transport in

blood

Natural Cu excretion

through bile

Oral, once-daily dosing

Rapid onset of action

Differentiated product profile compared to currently

available treatments

Wilson disease poorly managed by current

treatments, low compliance and potential

for neurological worsening

Addressable Population

Prevalence 1 in 30,000

~10K in EU5 and ~10K in US

~50% Diagnosed and Treated

~5K in EU5 and ~5K in US

Ongoing Phase 3 Trial

Powered for Superiority

Metabolics



B U I L D I N G A C O M P E L L I N G F c R n P O R T F O L I O

WAIHA

gMG

No Effect on

Albumin

Rapid Onset

of Action

Potential

Best-in-Class

SubQ

Potent

Binding

Affinity

Long

Half-life

Low

Molecular

Weight

FcRn



S I G N I F I C A N T LY E X PA N D I N G O U R A D D R E S S A B L E PAT I E N T P O P U L AT I O N S

• Continuing to expand addressable

patient populations with SOLIRIS®

and ULTOMIRIS®

• Accelerating neurology growth in

gMG and other potential

neurological indications

• FcRn inhibitors have

potential to become a new

generation of therapeutics

for IgG mediated diseases

• Significant opportunity in

Wilson Disease and AL

Amyloidosis

0

10

20

30

40

50

60

70

80

90

Dia

gn

os

ed

Pre

va

len

ce (

00

0’s

)

~10K Total Patients

~230K Total Patients

Refractory

gMG

Aligned with our strategy to move from a focus on ultra-rare to rare diseases



B U I L D I N G A P O R T F O L I O W I T H D U R A B L E G R O W T H

Organic Clinical Pipeline

Internal Complement Research

Business Development

Other Autoimmune (FcRn)


Neurology

Metabolics

FcRn Portfolio


AGENDA Susan Altschuller, Ph.D. | Head of Investor Relations

22 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . V I S I O N & S T R A T E G Y | D A V I D B R E N N A N , C H A I R M A N O F T H E B O A R D

B O A R D O F D I R E C T O R S ’ P E R S P E C T I V E

DAVID R. BRENNAN, CHAIRMAN • Appointed Chairman of the Board in 2017

• Served as Director of Alexion since July 2014

• Served as Interim CEO of Alexion from December 2016

to March 2017

• Prior to joining Alexion’s Board of Directors, served as

CEO and Executive Director of AstraZeneca PLC


E M B A R K I N G O N A L E X I O N ’ S N E X T C H A P T E R

V I S I O N & S T R A T E G Y | S U S A N A L T S C H U L L E R , P H D H E A D O F I N V E S T O R R E L A T I O N S

Over 10 Potential Launches Over Next Five years Delivering on Our Strategy

Management & Board refresh

Transformed culture, values, talent

SOLIRIS® gMG best Alexion U.S. launch

Positive ULTOMIRIS® data in PNH and aHUS

Internal pipeline refresh and progress

Early PNH U.S. approval; Promising initial conversion

BD execution: 4 clinical, 3 pre-clin deals in 12 months

Delivering on Financials

Remarkable pivotal NMOSD data

2019

2021

2020

2022

2023

SOLIRIS

NMOSD

ULTOMIRIS

PNH

ULTOMIRIS

aHUS

ULTOMIRIS QW SubQ

PNH, aHUS

ULTOMIRIS

IV gMG

ULTOMIRIS

SubQ gMG

ALXN1830

WAIHA

ALXN1840

Wilson

CAEL101

AL

Amyloidosis

ALXN1830

gMG

ULTOMIRIS

IV NMOSD

ULTOMIRIS

SubQ NMOSD



Diversifying

the Alexion

Portfolio


Neurology

Metabolics

FcRn Portfolio

1

2

3

4

V I S I O N & S T R A T E G Y | S U S A N A L T S C H U L L E R , P H D H E A D O F I N V E S T O R R E L A T I O N S


25 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . A G E N D A

I N VESTOR D AY A GEN D A

8:30am

9:00am

9:40 am

1 2

3

VISION & STRATEGY

HEMATOLOGY / NEPHROLOGY

Durability in our legacy business

NEUROLOGY

Continued growth & opportunity to expand

WILSON DISEASE: KOL Perspective | Michael Schilsky, MD

PNH: KOL Perspective | Prof. Regis Peffault De Latour

10:50 am METABOLICS

Transforming liver & bone disease

NMOSD: KOL Perspective | Michael Levy, MD

4 11:20 am 5 11:40am 6

7

FcRn PORTFOLIO

Future of Rare Autoimmune Diseases

INTERNAL RESEARCH

Complement Expertise

CLOSING REMARKS

Q&A SESSION 1 / Break

11:50am

Q&A SESSION 2 & Lunch

10:20 am

12:00 pm

HEMATOLOGY & NEPHROLOGY Brian Goff, Chief Commercial Officer

John Orloff, M.D., Head of R&D



Diversifying

the Alexion

Portfolio


Neurology

Metabolic

FcRn Portfolio

1

2

3

4

H E M A T O L O G Y & N E P H R O L O G Y | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R



M A R K E T L E A D E R I N P N H & AT Y P I C A L H U S *

SOLIRIS®: Established a Legacy

• In the U.S. in 2007 SOLIRIS® was the

first FDA approved treatment for PNH

• In the U.S. in 2011 SOLIRIS® was the

first FDA approved treatment for

aHUS

• 35% of PNH patients died within 5

years despite supportive care

• 79% of aHUS* patients died within 3

years of diagnosis


• As of 2Q2017, over 2,500 PNH and

aHUS patients were treated with

SOLIRIS® in the United States

ULTOMIRIS®: Potential to be the new

Standard of Care

• ULTOMIRIS was approved by FDA

on December 21, 2018 for the

treatment of PNH

• Patients can safely switch from

SOLIRIS® to ULTOMIRIS

• Rapid, complete, sustained

complement inhibition

• Every 8 week IV dosing profile

• Globally sustainable pricing

strategy

• Best-in-class facilitated conversion

target of ≥70% of PNH patients in

two years post-launch

• Similar ambition in aHUS ≥70%

Q8W

Historically

High

Mortality

2,500


29 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . H E M A T O L O G Y & N E P H R O L O G Y | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R

U LT O M I R I S ® VA L U E P R O P O S I T I O N I N P N H

• Efficacy on three

clinically meaningful

disease measures:

‒ Majority achieved

LDH

normalization

‒ Increased rates

of transfusion

avoidance

‒ Low-

breakthrough

hemolysis rates

• Safety demonstrated in

largest-ever Phase 3

PNH clinical program

• Comprehensive

safety data supporting

safe switch from

SOLIRIS®; both target

the same C5 epitope;

no wash-out period

• Strong safety

backbone with

SOLIRIS® on market

for over a decade

• Fewer infusion clinic

visits

• Q8W IV minimizes

treatment burden

• Rapid, complete,

sustained complement

inhibition

• Patient-friendly IV and

potential subQ

treatment options

• Globally sustainable

pricing strategy

• Additional savings from

fewer annual infusions,

reduced incidence of

breakthrough

hemolysis and

increased work

productivity

• Phase 3 program

included broad patient

population; reflective

of real-world setting

Delivery Safety Efficacy Access

More than a decade of experience and trust built upon SOLIRIS® foundation

https://alexion.sharepoint.com/sites/multimedia/Patient Images/PNH Patients/Alxn-Pnt-DanC-0022-150226-213733-Rt.tif


S T R O N G D ATA S U P P O R T S U LT O M I R I S ® VA L U E P R O P O S I T I O N

H E M A T O L O G Y & N E P H R O L O G Y | J O H N O R L O F F , M D , H E A D O F R & D

In Study 301 and 302: No Patients in the ULTOMIRIS Treatment Groups Experienced

Elevated Serum Free C5 Concentrations (≥0.5 µg/mL)

10.7%

5.1% 4.0%*

0.0%

ALXN1210 PNHNaïve Study

ALXN1210 PNHSwitch Study

Rate of Breakthrough Hemolysis

SOLIRIS® ULTOMIRIS(ALXN1210)

ULTOMIRIS Demonstrates Reduced

Incidence of Breakthrough Hemolysis

*ULTOMIRIS breakthrough hemolysis rate

not C5 related 30

2 S

wit

ch

Stu

dy

30

1 N

aïv

e S

tud

y

SOLIRIS® ULTOMIRIS

SOLIRIS® ULTOMIRIS

>440 patients treated in Phase 3 and >650 patient years of exposure across program



K O L P E R S P E C T I V E : P N H

H E M A T O L O G Y & N E P H R O L O G Y | R E G I S P E F F A U L T D E L A T O U R , M D , P H D

REGIS PEFFAULT DE LATOUR, MD, PhD Head of the Reference Center for Aplastic Anemia and PNH,

Saint-Louis Hospital, Paris

• KOL Perspective: The Role and Differentiation of

Intravascular (IVH), Extravascular (EVH), and

Breakthrough (BTH) Hemolysis in PNH

31

32 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . H E M A T O L O G Y & N E P H R O L O G Y | R E G I S P E F F A U L T D E L A T O U R , M D , P H D

P N H : A L I F E T H R E AT E N I N G U LT R A - R A R E D I S E A S E

is a chronic, debilitating, and potentially life

threatening ultra-rare blood disorder, with an

average age of onset in the early 30s1-3

BEFORE SOLIRIS®,

1/3 OF PATIENTS DIED

WITHIN 5 YEARS OF

DIAGNOSIS2

SOME SYMPTOMS OF PNH4-8

• Anemia

• Fatigue

• Dark urine

• Difficulty swallowing

• Abdominal pain

• Shortness of breath

• Formation of blood clots (thrombosis) that could lead to premature death

1. Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2007 May;137(3):181-92. 2. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995 Nov 9;333(19):1253-8. 3. Socié G, Mary JY,

de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet. 1996;348:573-577. 4. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121:4985-4996. 5. Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of

paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004 May;83(3):193-207. 6. Weitz I, Meyers G, Lamy T, et al. Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria. Intern Med J. 2013;43:298-307. 7. Parker C, Omine M, Richards S, et

al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005 Dec 1;106(12):3699-709. 8. Hillmen P, Muus P, Duhrsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8.

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

32


U L T O M I R I S ® A D D R E S S E S I N T R AV A S C U L A R & B R E A K T H R O U G H H E M O LY S I S D U E T O I N A D E Q U AT E C 5 I N H I B I T I O N 1 , 2 , 3


+S

OL

IRIS

®

Breakthrough IVH may occur in

11%-27% of patients with PNH

treated with eculizumab1,13,17,18

EVH may be clinically evident in

about 7% of eculizumab-treated

patients19,a

Residual Hemolysis/ Destruction of RBCs1,4,13,17-19

BMF8

Two-thirds may have AA or MDS8

Decreased Production of RBCs7

• LDH reduction11-14

• Reduction in thrombosis11,13

• Increase in hemoglobin +

reduction in transfusion

requirements15

• Improvement in fatigue15,16

Eculizumab Inhibits C5,

Addressing IVH9,10

Un

tre

ate

d P

NH

pati

en

ts

BMF8

Two-thirds may have AA or MDS8

Decreased Production of RBCs7

IVH5,6

Due to complement-mediated

destruction of RBCs4

Increased Destruction of RBCs4

+U

LT

OM

IRIS

Efficacy of ravulizumab is

noninferior to eculizumab and

safety profile of ravulizumab is

similar to that of eculizumab1-3

Ravulizumab addresses BTH

associated with elevations in free

C5 in patients with PNH1-3,20

Patients with PNH on ravulizumab

who remain dependent on

transfusions may have a

concurrent condition such as

BMF and/ or EVH6

Complement blockade in any

form does not address

underlying BMF. Ravulizumab

clinical trials included

patients with a history of

or concurrent AA3,13,21

AA, aplastic anemia; BMF, bone marrow failure; BTH, breakthrough hemolysis; C3, complement component 3; C5, complement component 5; EVH, extravascular hemolysis; IVH, intravascular hemolysis; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome; PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cell. a Explanation for data on clinically evident EVH in eculizumab-treated patients available in slide notes.

1. Lee JW, et al. Blood. 2019;133(6):530-539. 2. Kulasekararaj AG, et al. Blood. 2019;133(6):540-549. 3. ULTOMIRISTM (ravulizumab-cwvz) [Prescribing Information]. Alexion Pharmaceuticals, Inc; December 2018.

4. Noronha SA. Pediatr Rev. 2016;37(6):235-246. 5. Kelly R, et al. Ther Clin Risk Manag. 2009;5:911-921. 6. Notaro R, Sica M. Semin Hematol. 2018;55(3):130-135. 7. Merck Manual website. https://www.merckmanuals.com/professional/ hematology-and-oncology/anemias-caused-by-deficient-erythropoiesis/aplastic-anemia. Updated July 2018. Accessed February 13, 2019. 8. Morado M, et al.

Cytometry B Clin Cytom. 2017;92(5):361-370. 9. Rother RP, et al. JAMA. 2005;293(13):1653-1662. 10. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; September 2018. 11. Hillmen P, et al. Blood. 2007;110(12):4123-4128. 12. Brodsky RA, et al. Blood. 2008;111(4):1840-1847. 13. Hillmen P, et al. Br J Haematol. 2013;162(1):62-73. 14. Socié G, et al. Poster presented

at: 49th Annual Meeting of the American Society of Haematology; December 8-11, 2007; Atlanta, GA. Poster 891-III (appears in Blood. 2007;110:3672. 15. Hillmen P, et al. N Engl J Med. 2006;355(12):1233-1243. 16. Schrezenmeier H, et al. Haematologica. 2014;99(5):922-929. 17. Nakayama H, et al. Biol Pharm Bull. 2016;39(2):285-288. 18. Peffault de Latour R, et al. Blood. 2015;125(5):775-783.

19. Risitano AM, et al. Blood. 2009;113(17):4094-4100. 20. Brodsky RA., et al. Abstract presented at: 61st Annual Meeting of the American Society of Haematology; December 2, 2018; San Diego, CA. Poster 2330. 21. Brodksy RA. Blood. 2014;124(18):2804–2811.

33


clinically

evident EVH

S O L I R I S ® P N H P A T I E N T S W H O R E M A I N T R A N S F U S I O N D E P E N D E N T M AY B E E X P E R I E N C I N G B T H O R H A V E A C O N C U R R E N T C O N D I T I O N


Hb, hemoglobin. Over 80% (33/41) of patients were transfusion-independent on eculizumab. ~17% (7/41) of patients had breakthrough IVH. All minor responders in this cohort were attributed to underlying AA Partial responders included 5/41 (12%) patients. Patient #11 had breakthrough hemolysis due to IVH, and patient #38 had 5% C3 deposition, which was less than the median C3 deposition in the optimal responder group (~20% C3 deposition in this group). Therefore, clinically significant EVH in this cohort was found in 3/41 patients (7%), possibly also a result of underlying mild to moderate AA in these patients. Risitano AM, et al. Blood. 2009;113(17):4094-4100.

C3-mediated EVH only clinically evident in ~7% of patients

Optimal Responders: Patients achieving transfusion

independence with hemoglobin levels ≥11 g/dL

Major Responders: Patients achieving transfusion

independence with hemoglobin levels ≥8 g/dL

Minor Responders: No significant change in blood

transfusion requirement (reduction ≤50%) or hemoglobin

levels but with marked reduction of LDH levels

Hematological Response to Eculizumab

Hgb >11

36.6%

8 < Hgb <11

43.9%

N=41

Transfusion

independence

(n=15)

(n=18)

7.3%

(n=3)

(n=2)

Transfusion

dependence

(n=3)

12.2%

Partial Responders: Reduction of transfusion requirement

by >50% without abrogation of blood transfusions

3/5 (~7%) patients experienced clinically evident

C3-mediated EVH

7.3%

due to

underlying AA

34


K E Y C O N C L U S I O N S


1. Kelly R, et al. Ther Clin Risk Manag. 2009;5:911-921. 2. Notaro R, Sica M. Semin Hematol. 2018;55(3):130-135. 3. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; September 2018. 4. Rother RP, et al. Nat Biotechnol.

2007;25(11):1256-1264. 5. Lee JW, et al. Blood. 2019;133(6): 530-539. 6. Kulasekararaj AG, et al. Blood. 2019;133(6):540-549. 7. ULTOMIRISTM (ravulizumab-cwvz) [Prescribing Information]. Alexion Pharmaceuticals, Inc; December 2018.

PNH is a life-threatening disease characterized by IVH1,2

SOLIRIS® & ULTOMIRIS® inhibit C5, the cause of complement-mediated IVH; patients with PNH on SOLIRIS® who remain dependent on

transfusions may be experiencing BTH or have a concurrent condition such as BMF and/or EVH2-4

ULTOMIRIS addresses BTH related to inadequate C5 inhibition, a key unmet need in patients with PNH receiving SOLIRIS®5-7

1

2

3

35

At what Hemoglobin levels would you consider a patient in need of transfusion?

What has been your experience treating

PNH patients with ULTOMIRIS®?


U LT O M I R I S ® A D D R E S S E S P N H PAT I E N T N E E D S

“ How do PNH Patients feel about a less frequent IV treatment?

“ “ 93%

of PNH patients

surveyed preferred

ULTOMIRIS over

SOLIRIS®

“…assuming it works

exactly as effectively as

SOLIRIS®…less

frequent infusions would

be my ideal new

treatment

to try.”

1

1: Internal Alexion data from ALXN1210-PNH-302 extension study

“…getting infusions

every 2 weeks is very

difficult and I don't have

home infusions… I have

to go to a facility,

hospital or infusion

center. So I would love

to have access to a

drug that had much

fewer infusions.”

All but one

patient out of

>450 elected to

continue on treatment

with ULTOMIRIS in the

extension study



U LT O M I R I S ® : G O A L T O B E T H E N E W S TA N D A R D O F C A R E


ULTOMIRIS Launch in PNH Lays Foundation for Durability and Leadership

• Best-in-class conversion goal of >70% in first two years following launch

• Compelling value proposition with strength of data, ease of switch and

pricing strategy

2018 2019 2020

>70%

CONVERSION

% o

f A

LX

N P

NH

Pati

en

ts

Illustrative

2021 2022+


K E Y AT T R I B U T E S F O R A S U C C E S S F U L P R O D U C T I N P N H

LDH Normalization

Transfusion avoidance

Low-breakthrough hemolysis rates

Comprehensive data supporting seamless, safe switch from SOLIRIS®

Patient-friendly IV and Potential SubQ treatment options

Fewer infusion clinic visits

Comprehensive safety profile

ULTOMIRIS® Best-in-Class Product Profile



3%

8%

14%

1 2 3 4 5 6 7 8

U LT O M I R I S ® P N H U . S . L A U N C H P R O G R E S S


• Nearly all commercial lives have access; enabling conversion to or naïve

initiation of ULTOMIRIS

• ~1/3 of commercial lives have a specific ULTOMIRIS coverage policy in place

• Planning underway for launches in Germany and Japan in 2019

% Patients

Enrolled in

OneSource™ 5% 19% 13%

% of Total U.S. PNH Patients Converted to ULTOMIRIS

31-Jan-19 27-Feb-19 19-Mar-19

Shaded bars in above graph represents illustrative figures, not actuals

OneSource includes patients already treated and those in the process of getting on therapy (e.g., securing access)


P R I C I N G S T R AT E G Y F O R U LT O M I R I S ®

PNH Pricing

SOLIRIS® ULTOMIRIS®

+10%

-10%

Yr1* Yr2+ Maintenance

Expect to realize additional indirect

cost-savings with fewer infusion visits, low

BTH, and improved productivity

Established globally sustainable pricing strategy

Atypical HUS and higher-volume indications

(gMG & NMOSD)1 expected to realize greater

discount compared with PNH

- ~30% discount to annual SOLIRIS®

maintenance dosing

Consistent with our strategy to shift our focus

from ultra-rare to rare diseases

*Loading dose in Yr1 accounts for the 10% premium to labeled SOLIRIS® PNH maintenance dose

1) ULTOMIRIS is not yet approved in aHUS, gMG, and NMOSD

43 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . H E M A T O L O G Y & N E P H R O L O G Y | J O H N O R L O F F , M D , H E A D O F R & D

C O N S I S T E N T S A F E T Y & E F F I C A C Y F O R U LT O M I R I S ® I N AT Y P I C A L H U S *

Safety consistent with that observed in

301 and 302 Phase 3 PNH trials

Clinical Data

• Often there is poor persistence due to frequent dosing for

SOLIRIS® ,“silent” symptomology, and cost

• Risk of TMA is higher when patients are off treatment

• Opportunity to improve compliance, helping to reduce risk of

life-threatening TMA, with ULTOMIRIS® Q8W dosing and value

proposition

Components

of Primary

Endpoint

Proportion

of patients

Platelet count

normalization 83.9%

LDH

normalization 76.8%

Increase in

renal function* 58.9%

TMA Manifestation Rate1

1) Menne et al. Clinical Kidney Journal 2018.

Impact on TMA

53.6%

30/56

TM

A E

ve

nt

Ra

te

Pe

r 1

00

Pa

tie

nt-

Ye

ars

15.6

Off SOLIRIS® Treatment(n=39)

On SOLIRIS® Treatment(n=76)

~3x 1



U LT O M I R I S ® O N C E - W E E K LY S U B C U TA N E O U S

H E M A T O L O G Y & N E P H R O L O G Y | J O H N O R L O F F , M D , H E A D O F R & D

4-week

Screening Period

10-week Treatment Period 1-year

Extension Period

Active Arm: ULTOMIRIS SC QW

Control arm: ULTOMIRIS IV Q8W

Potential approval end of 2021

o Potential approval in PNH & atypical HUS with current

Phase 3 design

o 100mg/mL subQ formulation

Ongoing Phase 3 in PNH patient population, allows for

approval in atypical HUS pending positive results

Program Overview

Active Arm: ULTOMIRIS SubQ QW

1) West and the diamond logo, SmartDose® and logo, and the external product configuration of West’s SmartDose® drug delivery platform are the intellectual property of West Pharmaceutical Services, Inc. or one of its subsidiaries, in

the United States and other countries.

Control arm: ULTOMIRIS IV Q8W

• Potential first to market SubQ option for PNH

& atypical HUS

• Previously approved by the FDA for use with

another combination product

• Patient friendly device with ~10 min total

infusion time, no visible needle, no need for

reconstitution

West’s SmartDose® drug delivery platform1

45 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . H E M A T O L O G Y & N E P H R O L O G Y | J O H N O R L O F F , M D , H E A D O F R & D

W E S T ’ S S M A R T D O S E ® D R U G D E L I V E R Y P L AT F O R M 1

Remove devices from packaging

(7mL dose requires two 3.5mL devices) Insert drug cartridge Apply directly to skin

LED status indicator will blink green and

emit gentle hum while dose is administered

Light will show solid green once

dose is complete

Remove devices from body and

safely dispose

Easy to Load Cartridge

No Visible Needle

No Reconstitution

Reliable

Familiar

1) SmartDose® and the external product configuration of West’s SmartDose® drug delivery platform are the intellectual property of West Pharmaceutical Services, Inc. or one of its subsidiaries, in the United States and other

countries.


C O N T I N U E D I N N O VAT I O N O N U LT O M I R I S ® D E L I V E R Y P R O V I D E S PAT I E N T S W I T H O P T I O N A L I T Y


Evolution of Our PNH & Atypical HUS Product Offerings

December 2018

U.S. Approval for PNH

2020

Higher

concentration

on market

1H2019

File for Approval for

atypical HUS

2021

Potential first-to-market

SubQ

Across indications,

provides optionality

(e.g., IV, SubQ)

Aligned with patient

preference for

reduced visit length

Infusion time reduced

to ~45 minutes

93% PNH Patients

prefer ULTOMIRIS

Q8W IV dosing

preferred over SubQ

delivery options

1Q2020

Potential approval for

atypical HUS in U.S.


R A P I D LY E V O LV I N G T H E B U S I N E S S F R O M U LT R A - R A R E T O R A R E D I S E A S E

SOLIRIS® and ULTOMIRIS® Patient Growth in the US

• Best Alexion launch with SOLIRIS® in gMG

• Potential for SOLIRIS® approval in NMOSD

Atypical HUS

Approval

Strong foundation & commercial

expertise in PNH & atypical HUS

Ambition for gMG patients to comprise largest SOLIRIS-treated population two years after initial launch

Potential for CAEL-101:

Giving Hope for Patients with AL Amyloidosis Aradhana Sarin, M.D. | Chief Strategy & Business Officer

49 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . H E M A T O L O G Y / N E P H R O L O G Y | A R A D H A N A S A R I N , M D , C H I E F S T R A T E G Y & B U S I N E S S O F F I C E R

A L A M Y L O I D O S I S : A R A R E , F ATA L H E M AT O L O G I C D I S E A S E

OTHER ORGANS KIDNEYS (60-80%)

HEART (55-75%) PERIPHERAL

NERVES (20-45%)

• Neuropathy

• Impotence

• No temperature

sensation in

hands/feet

• Liver (15-30%)

• GI Tract (5-16%)

• Eyes (10-25%)

• Tongue (~10%)

• Soft Tissue (20-35%)

• Large amounts of

protein in urine

• Swelling of feet/legs

• End stage kidney

disease

• Transplant can be

required

• Fatigue


• Irregular heartbeat

• Fainting

• Leads to congestive

heart failure

AL Amyloidosis is a progressive and typically fatal

disease caused by deposition of misfolded

immunoglobulin light-chains resulting in severe

organ damage

Multiple organ/tissue involvement; most frequently

heart & kidneys

Often fatal with a median survival of <18 months

>40% of patients die within one year of diagnosis

– Degree of cardiac damage can determine

survival rate

Affects >20k patients in US and EU5

Patients are managed by multifunctional team (i.e.

hematologists, oncologists, cardiologists,

nephrologists and neurologists)

Sources: Quock, et al. (2018) Epidemiology of AL amyloidosis: A real-world study using US claims data, Blood Advances; Muchtar et al. (2017) Improved

outcomes for newly diagnosed AL amyloidosis over the years 2000-2014: Cracking the glass ceiling of early death, American Society of Hematology


N O A P P R O V E D T R E AT M E N T & L I M I T E D O P T I O N S

H E M A T O L O G Y / N E P H R O L O G Y | A R A D H A N A S A R I N , M D , C H I E F S T R A T E G Y & B U S I N E S S O F F I C E R

Typically, chemotherapy regimens used in AL

Amyloidosis patients

CURRENT TREATMENT

But, does not remove previously deposited

amyloid protein or reverse organ damage

Time to diagnosis is protracted (average ~9

months)

‒ At time of diagnosis, most patients have

significant fibril deposition in tissues/organs

primarily in the heart and kidneys

Chemotherapy +/- autologous stem cell transplant

(ASCT) targets plasma cells the typical treatment

approach

‒ Only ~20% of patients eligible for ASCT due to

severity of disease

Despite these treatments, survival is poor Only ~20% of patients eligible for ASCT due to

severity of disease


C A E L - 1 0 1 D E V E L O P E D T O R E M O V E A L A M Y L O I D I N O R G A N S

CAEL-101 is a chimeric mAb specific to kappa and lambda light chains


Overall Organ Response Rates1 After CAEL-101 Phase 1A/1B

in AL Amyloid Patients

67% 62% 63%

33% 39% 37%

Phase 1a Phase 1b OverallResponse Stable

Mean 1.69% improvement in mean GLS score in

Phase 1b patients after 12 weeks

1) Includes both cardiac and renal responses 2) Surrogate biomarker of survival in AL amyloidosis

In vivo imaging shows CAEL-101 binding to the heart, kidney, liver, spleen, and other deposits in patients

Phase 1a/b in AL (n=27) amyloid patients demonstrated a median time to NTproBNP response2 of 3 weeks vs

10 months with current treatments

Overall survival at 18.6 months was 93%


C A E L - 1 0 1 : B U I L D I N G O U R R A R E H E M AT O L O G Y P O R T F O L I O


Rare hematologic disease affecting >20k patients in US and EU5

Early proof of concept with CAEL101; Binds to light chains in humans, meaningful cardiac improvement

Working towards Phase 2/3 trial initiation in early 2020

ADVANCING OUR NEUROLOGY BUSINESS Brian Goff, Chief Commercial Officer

John Orloff, M.D. Head of R&D



Diversifying

the Alexion

Portfolio


Neurology

Metabolic

FcRn Portfolio

1

2

3

4

A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R


55 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R

g M G : A R A R E A N D D E B I L I TAT I N G D I S E A S E

Generalized Myasthenia Gravis A debilitating, chronic, and progressive autoimmune neuromuscular disease1

10-15% of gMG patients fail to respond adequately to or cannot tolerate multiple

therapies for gMG and continue to suffer profound muscle weakness and severe

disease symptoms that limit function2-4

SOLIRIS® IS

THE FIRST

AND ONLY

APPROVED COMPLEMENT INHIBITOR FOR

gMG9

SOME SYMPTOMS OF gMG5-8

SOLIRIS® QUICK FACTS

• Drooping of one

or both eyelids

• Blurred or double vision

• Difficulty swallowing or choking


• Slurred speech

• Weakness in the arms, hands, fingers, legs, and neck

• First FDA-approved treatment for patients with gMG in 60+ years in 2017

• Approvals include U.S., EU, Japan, and Canada

• Serving patients who suffer from significant unresolved disease symptoms

1. Huda R, Tüzün E, Christadoss P. Targeting complement system to treat myasthenia gravis. Rev. Neurosci. 2014; 25(4): 575–583. 2. Silvestri N, Wolfe G. Treatment-refractory myasthenia gravis J. Clin Neuromuscul Dis. 2014;15(4):167-17 3. Howard J. Targeting the Complement System in Refractory Myasthenia Gravis. Supplement to Neurology Reviews. February 2016. 4. Sanders DB, Wolfe, GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87(4):419-25 5. Howard JF, Barohn RJ, Cutter GR et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with

refractory generalized myasthenia gravis. Muscle Nerve. 2013;48(1):76-84. 6. National Institute of Neurological Disorders and Stroke. Myasthenia Gravis Fact Sheet. Publication date May 2017. http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm. 7. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis:

emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475-490. 8. Sathasivam S. Diagnosis and management of myasthenia gravis. Progress in Neurology and Psychiatry. January/February 2014. 9. Soliris ® [package insert]. New Haven, CT: Alexion Pharmaceuticals Inc; 2018

http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm

56 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | J O H N O R L O F F , M D , H E A D O F R & D

C O M P L E M E N T P L AY S A C E N T R A L R O L E I N A N T I -A C H R A N T I B O D Y + g M G

In anti-AchR+ gMG, complement damages the NMJ, affecting the ability of the nerves to communicate with the muscles

1

2

3

Complement Initiation:

Antibodies bind to receptors (AchRs) and disrupt nerve-

to-muscle communication. They also cause complement

to act at the NMJ

Ongoing Injury:

At the NMJ, complement continually injures the muscle

surface, which is critical for nerve-to-muscle

communication

Consequences:

When the muscle surface is injured, some AchRs are

lost, further decreasing nerve-to-muscle communication,

which contributes to symptoms of muscle weakness and

fatigue


P O S I T I V E L O N G - T E R M S A F E T Y A N D E F F I C A C Y F O R S O L I R I S ® I N R E F R A C T O R Y g M G

1) Muppidi et al Muscle Nerve 2019 Epub

Note: MG-ADL = Myasthenia Gravis-Activities of Daily Living Profile; MGFA = Myasthenia Gravis Foundation of America

∆ f

rom

RE

GA

IN b

aselin

e in

mean

MG

-AD

L t

ota

l sco

re (

95%

CI)

• Long-term safety profile of SOLIRIS® consistent

with REGAIN

• REGAIN had rigorous enrollment criteria for the

most severe patients

– Patients either failed treatment with at least two ISTs

or had failed treatment with at least one IST and

required chronic plasma exhange or IVIg

• Improvements seen with SOLIRIS® in REGAIN

maintained for up to 3 years

• Positive impact on disease burden:

− Reduced exacerbation, MG-related

hospitalization and rescue therapy

− Over half of patients achieved a MGFA post-

intervention status of minimal manifestations

or pharmacologic remission

MG-302 Interim Data1

SOLIRIS / SOLIRIS

PBO / SOLIRIS

LEGEND

Pivotal study

(SOLIRIS vs PBO) Extension study

(all on SOLIRIS)

Double-blind

Double-blind induction

Double-blind SOLIRIS


D E L I V E R I N G C O N T I N U E D U . S . L A U N C H E X C E L L E N C E I N g M G

A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R

*Not full quarter

43

194

375

560

788

948

December 31, 2017 March 31,2018

June 30,2018

September 30,2018

December 31,2018

March 19,2018

US gMG Patients on SOLIRIS®

* March 19,

2019*

Expect gMG to be largest U.S. patient volume

indication for SOLIRIS® by YE19


E X PA N D I N G g M G P O R T F O L I O

gMG Portfolio Strategy

• Expanding treatment options for patients with gMG with ULTOMIRIS® IV and SubQ administration

− Initiating Phase 3 trial in 2019

− No prior failure of IST therapies required for enrollment; MG-ADL score of ≥ 6 required

• Aligned with broader strategy in Neurology and transition from a focus on ultra-rare to rare diseases

• Established proof of concept & mechanism established with FcRn; plan to advance ALXN1830 into gMG by YE19

Less

Severe

Most

Severe Disease Progression

Up to ~8k Refractory

gMG Patients in U.S.

Total U.S. gMG population up to ~80k patients

Anti-FcRn

ALXN1830


N M O S D A N D T H E R O L E O F C O M P L E M E N T A C T I VAT I O N

• Complement activation triggered by the binding of an IgG

autoantibody to aquaporin 4 (AQP4) on the astrocyte membrane

causing CNS inflammation and demyelination

• Complement activity attracts leukocytes, leading to degranulation

and astrocyte destruction

NMOSD Is a Complement-Mediated Disease1,2 Activated Complement

1. Papadopoulos, M.C., et al. Nature Rev Neurol. 2014;10:493-506.

2. Verkman, A.S., Annu Rev Med. 2012;63:303–316.

NMOSD is Characterized By Step-wise Deterioration

Following Each Attack

Relapses can be devastating for

patients, with unpredictable &

cumulative functional decline

Each attack can lead to cognitive

worsening, encephalopathy,

seizures, pain, paralysis, and vision

loss, blindness or death

A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | J O H N O R L O F F , M D , H E A D O F R & D


R E L A P S E P R E V E N T I O N I S T H E G O A L O F T R E AT M E N T I N N M O S D

SOLIRIS® NMOSD sBLA accepted in US, EU and

Japan

Granted priority review in US based on strength of

Ph3 PREVENT clinical data

‒ PDUFA date June 28, 2019

Training and launch excellence planning across

commercial and medical teams

Upon approval, dedicated customer-facing teams,

OneSource™ case managers, as well as payer

and market access

Strong synergies in place with

expanded existing neurology

infrastructure


*In the PREVENT Phase 3 trial, both Soliris and Placebo arm allowed for concomitant use of immunosuppressant therapy (IST)

Time in Study Period (weeks)

Pro

po

rtio

n R

ela

pse F

ree

P < 0.001

98% of patients relapse free at 48 weeks

Relapse prevention is the goal of treatment

Remarkable strength of NMOSD clinical data with 94.2%

reduction in risk for relapse at 48 weeks

48

weeks

~96% of patients relapse free at 3 years

Phase 3 PREVENT study results


P L A N S F O R U LT O M I R I S ® I N N M O S D

ULTOMIRIS Phase 3 NMOSD Study Design

ULTOMIRIS Screening Primary Endpoint

Annualized Relapse

Rate

• Leverage neurology footprint and PREVENT results to drive trial recruitment and optimize product profile

• Phase 3 single arm estimation study in adult patients (n = ~65) leveraging SOLIRIS® PREVENT results as

contemporaneous control

• Plan to initiate in 4Q19 with bridging to ULTOMIRIS SC pending regulatory feedback on study design &

bridging approach

Focused on continuing to advance the standard of care

52 Weeks OLE

63 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | M I C H A E L L E V Y , M D

N M O S D K O L F I R E S I D E C H AT

MICHAEL LEVY, MD Associate Professor, Department of Neurology

Massachusetts General Hospital

• Principal Investigator, PREVENT Phase 3

Panel Moderator:

Laura Gault, MD, PhD

Neurology Clinical Development Head


A D VA N C I N G O U R N E U R O L O G Y P I P E L I N E W I T H U LT O M I R I S ®

Complement confirmed to play a key role in both the CNS and

Neuromuscular Junction with SOLIRIS® in gMG and NMOSD

Neurodegenerative disease characterized by motor

neuron degeneration leading to progressive muscle

weakness

High mortality rate 3-5 years post-diagnosis

Estimated 15-20K addressable population in US, EU5, and

Japan

Plan to initiate POC clinical trial in 2019

Progressive, worsening neurologic disease characterized by

decreased mobility, functional impairment, cognitive changes

Estimated 30-40K addressable population in US, EU5, and

Japan

15% of MS patients diagnosed with PPMS

Plan to explore role of complement in clinical study in 2019

Scientific rationale supports potential role of complement, including MAC

deposition in ALS and elevation of C3 and C4 in PPMS patients

Primary Progressive Multiple Sclerosis (PPMS) Amyotrophic Lateral Sclerosis (ALS)

Central

Nervous

System

Peripheral

Nervous

System


U LT O M I R I S ® I N A L S

Phase 2/3 Adaptive Trial Design

ULTOMIRIS (n=78)

Placebo (n=78) Randomized

1:1 n=156

Patients

• Primary endpoint measures ∆ from baseline in revised ALSFRS-R1

• Plans to initiate in 4Q19

Scientific Rationale

• MAC deposition in motor end plate suggests a role of

complement

• Elevated complement activation products in ALS serum and CSF

1. ALS Functional Rating Scale

24 Weeks Open Label

Extension

Interim Data Analyses

• Early read for futility

• Sample size re-estimation

source: www.alsa.org

66 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . A D V A N C I N G O U R N E U R O L O G Y B U S I N E S S | L U D W I G H A N T S O N , P H D , C E O

B U I L D I N G O N R A R E D I S E A S E E X P E R T I S E T O B R O A D E N N E U R O L O G Y G R O W T H O P P O R T U N I T Y

October 2017

SOLIRIS® approved

with broad label for

gMG

December 2018

SOLIRIS® in gMG best

Alexion launch with 788

patients on therapy

September 2018

Positive SOLIRIS®

Phase 3 data in

NMOSD

February 2019

Granted Priority

Review for SOLIRIS®

in NMOSD PDUFA

June 28th

Year End 2019

Ambition for

neurology to be

largest US franchise

Year End 2019

Initiate Phase 3

trials for

ULTOMIRIS® in

gMG and NMOSD

and clinical trials in

ALS and PPMS

Initiate pivotal trial

for ALXN1830 in

gMG

2021+

Serving broad patient

populations across

numerous indications

Convenient and

long-acting dosing

potential

2017 2019 2021+ 2020 2018

Neurology franchise represents multi-billion dollar revenue potential

Q&A Session 1

METABOLICS:

TRANSFORMING LIVER & BONE DISEASE Brian Goff, Chief Commercial Officer

John Orloff, M.D. Head of R&D



Diversifying

the Alexion

Portfolio


Neurology

Metabolics

FcRn Portfolio

1

2

3

4

M E T A B O L I C S | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R



S H A W N ’ S J O U R N E Y W I T H H P P



S H A W N ’ S J O U R N E Y W I T H H P P


72 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . M E T A B O L I C S | B R I A N G O F F , C H I E F C O M M E R C I A L O F F I C E R

S T R E N S I Q ® : A T R A N S F O R M AT I V E T H E R A P Y F O R P AT I E N T S S U F F E R I N G F R O M H P P

SOME SYMPTOMS OF HPP1-5

QUICK FACTS

• Hypomineralization of

bone

• Fractures and skeletal

abnormalities

• Muscle weakness

• Seizures in

perinatal/infantile forms

• Bone/joint/muscle pain

• Developmental

delays/impaired

mobility

• Respiratory failure due

to rachitic chest,

leading to premature

death in infants

• It is estimated that in the United States, there are

only approximately 1,300 people who have HPP

• STRENSIQ® first approved in 2015

• STRENSIQ® treatment demonstrated a survival rate

of 97% in patients with perinatal/infantile-onset HPP

compared to 42% in untreated historical controls at

one year in the clinical development program7

1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013; 10(suppl 2):380-388. 2. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 1. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598.

3. Whyte MP, Greenberg CR, Salman N, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012; 366(10):904-913. 4. Seshia SS, Derbyshire G, Haworth JC, Hoogstraten J. Myopathy with hypophosphatasia. Arch Dis Child. 1990; 65(1):130-131. 5. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al.

Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007; 40(6):1655-1661 6. Whyte MP, Leung E, Wilcox W, et al. Hypophosphatasia: a retrospective natural history study

of the severe perinatal and infantile forms. Poster presented at the 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting, Vancouver, B.C., Canada, May 5, 2014. Abstract 752416. 7. Whyte MP, Rockman-Greenberg C, Ozono K, et al. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile

Hypophosphatasia. J Clin Endocrinol Metab. 2016;101(1):334-342. doi:10.1210/jc.2015-3462.

Hypophosphatasia

is a progressive,

systemic, inherited,

potentially life-threatening

metabolic disorder

characterized by low

alkaline phosphatase

enzyme activity

27%

Without treatment, only

of infants with HPP

symptom onset in the first

6 months of life survive

beyond 5 years6


S T R E N S I Q ® : O U R C O M M E R C I A L A P P R O A C H

HPP is an ultra-rare disease affecting hundreds of patients in the United States

Diagnose patients earlier

in their disease

Efficient targeting of a

broad range of specialties

that treat patients with

HPP

Expanded Laboratory

Education

(CALIPER Initiative)

Innovative and proactive

contracting for access

sustainability


E X PA N D E D E F F O R T T O E D U C AT E O N A P P R O P R I AT E D I A G N O S T I C R A N G E S

Many laboratories use only

adult reference ranges for

alkaline phosphatase (ALP)

which is indicated as being low

below a value of 40

– 71% of pediatric cases are

not diagnosed due to

incorrect reference ranges

Initiative to drive laboratory

adoption of pediatric age- and

sex- adjusted reference

(CALIPER) ranges

1) ALP values from CALIPER, which has established age- and sex-specific reference intervals using blood samples from more than 9700 healthy children and adolescents. 2) Abbott Clinical Chemistry Architect System ALP reference range lower limit of normal for males >20 and females >15 years of age.

1

2

Pediatric HPP patients potentially missed due to use of adult ALP reference ranges


K A N U M A ® : A T R A N S F O R M AT I V E T H E R A P Y F O R PAT I E N T S S U F F E R I N G F R O M L A L - D

1. Kanuma® [package insert]. New Haven, CT: Alexion Pharmaceuticals, Inc; 2015. 2. Bernstein DL, et al. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58:1230-43. 3. Reiner Z, et al. Lysosomal acid lipase deficiency – an under-recognized cause of

dyslipidemia and liver dysfunction. Atherosclerosis. 2014;235:21-30. 4. Jones SA, et al. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants. Genetics in Medicine. 2016 May;18(5):452-8. 5. Jones S et al. Severe and rapid disease course in the natural history of infants with lysosomal acid lipase deficiency. Mol

Genet Metab. 2014 Feb;111(2):S57-58 6. Jones SA, Rojas-Caro S, Quinn AG, et al. Survival in infants treated with sebelipase alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017; 12(1):25. doi:10.1186/s13023-017-0587-3.

SOME SYMPTOMS OF LAL-D2,3

• Multi-organ damage

• Liver damage

including fibrosis,

cirrhosis, and failure

• Failure to thrive and

premature death

• Cardiovascular disease

manifestations

including dyslipidemia,

accelerated

atherosclerosis,

coronary artery

disease

KANUMA® QUICK FACTS

• KANUMA® treatment demonstrated a survival rate

of 67% in infants with LAL-D vs. 0% in untreated

historical controls at one year in the clinical

development program6

• Continuing to identify new patients

• Potential future strong call point synergies with

Wilson Disease

Lysosomal Acid Lipase

Deficiency (LAL-D)

is a life-threatening

genetic disease with

progressive multi-

organ damage leading

to premature death1

3.7 Months

Without treatment,

median age of death is

In LAL-D patients who

experience symptoms in

infancy4,5



A L X N 1 8 4 0 : A N O V E L , P O T E N T I A L F I R S T - I N - C L A S S S M A L L M O L E C U L E F O R W I L S O N D I S E A S E

High affinity to Cu 1 10,000-fold higher affinity for Cu than chelators, allowing for

removal from intracellular stores in the liver

Specific to Cu 2 Specifically binds Cu, not other metals (Zn, Fe, Ca, Mn, Mg)

typically associated with treatment side effects

Forms stable tripartite

complexes with proteins 3

Safe Cu transport in the blood, reducing the risk of drug

induced neurological and psychiatric deficits

Excretion of Cu through

bile into feces 4

Excretes excess Cu via natural route limiting potential

nephrotoxicity

Simplified dosing

regimen 5 Oral, once daily dosing and rapid onset of action

ALXN1840: A Differentiated Product Profile with Unique MOA

ALXN1840

Copper (Cu)

Protein

SOME SYMPTOMS OF WILSON DISEASE

• Jaundice & fluid retention

• Confusion, psychosis, and

psychiatric disorders

• Increased risk of cirrhosis,

liver failure, and liver cancer

• Fatigue, pain and swelling

• Vomiting and gastrointestinal

bleeding

• Neurological morbidity

ABOUT ALXN1840

• Ongoing phase 3 trial powered for superiority; data expected 1H21

• Differentiated product profile compared to current standard of care

• Potential for first line treatment utilization

M E T A B O L I C S | J O H N O R L O F F , M D , H E A D O F R & D


A L X N 1 8 4 0 : P H A S E 2 E X T E N S I O N D ATA


• Improvements seen at week 24 were maintained

through extension phase

• ALXN1840 reduced NCCcorr1 levels by similar extents in

patients with and without cirrhosis, from baseline to

week 24

1NCC levels were not corrected at baseline, as no ALXN1840 had been received; 2Score range, 0–40; 3score range, 0–143; 4data have been published previously for the whole study population during the core study: Weiss KH et al. Lancet Hepatol

Gastroenterol; b/ddata from an early termination visit for one patient who had discontinued from the core study was included at this time point; BL, baseline; SEM, standard error of the mean; ULN, upper limit of normal reference range (2.3 μmol/L); A.

Czlokowska et al., Presented at European Academy of Neurology – European J Neurol, 2018 (data to 72 wks)

• The Unified Wilson's Disease Rating Scale (UWDRS) was used to assess patient-

reported disability2 and clinician-rated neurological status3

• Improvements occurred during the core study4 and to week 48, regardless of

cirrhosis status

• ALXN1840 stabilized and reduced disability and improved neurological status


A L X N 1 8 4 0 P H A S E 3 T R I A L D E S I G N F O R W I L S O N D I S E A S E


FOCuS: Phase 3 Trial Powered for Superiority vs SoC S

cre

enin

g

Cohort 1

Pre-treated with SoC >28

days

75% Patients

Cohort 2

Treatment naïve or

minimally pre-treated with

SoC ≤ 28 days

25% Patients 2:1

Random

ization

2:1

Random

ization

Switch to

ALXN1840

Start on ALXN1840

Stay on SoC

Start or Stay on

SoC

Extension Phase

All Patients

Treated with

ALXN1840

48 Weeks Until Approval


W I L S O N D I S E A S E K O L F I R E S I D E C H AT

MICHAEL SCHILSKY, MD Medical Director, Adult Liver Transplant

at Yale-New Haven Transplantation Center

• Principal Investigator, ALXN1840 Clinical

Program

Panel Moderator:

Michele Mercuri, MD, PhD

Metabolics Clinical Development Head

M E T A B O L I C S | M I C H A E L S C H I L S K Y , M D

FcRn PORTFOLIO:

Rare Autoimmune Diseases John Orloff, M.D. Head of R&D



Diversifying

the Alexion

Portfolio


Neurology

Metabolic

FcRn Portfolio

1

2

3

4




• Neonatal Fc receptor (FcRn) is a protein that binds all IgG subclasses under acidic pH

• FcRn is involved in regulating IgG turnover:

- FcRn binds to IgG in acidic endosomes, recycles it to cell surface where IgG is released into circulation

- FcRn activity prevents IgG from undergoing lysosomal degradation and contributes to its long half-life

• Disrupting the IgG-FcRn interaction increases the clearance of IgG which is believed to reduce levels of pathogenic autoantibodies

F c R n : A C O M P E L L I N G A N D D I V E R S I F Y I N G O P P O R T U N I T Y T O A D D R E S S A R A N G E O F I G G - M E D I AT E D D I S E A S E S

FcRn inhibitors have potential to become a new generation of therapeutics for IgG-mediated diseases


B U I L D I N G A L E A D I N G F c R n P O R T F O L I O


• Broad applicability across numerous rare autoimmune

diseases

• Strong strategic fit for focus on rare diseases with high

unmet need in hematology, neurology, and other TAs

Multiple Clinical Stage Programs

WAIHA

gMG

SAD/MAD

Phase 1/2

ALXN1830

ALXN1830

ALXN1830

ABY-039

Data 1H19

Phase 3

Planning to initiate in 2019

Planning to initiate in 2019

Data 2H19 De

ve

lop

me

nt

Su

mm

ary

• Additional indications in clinical trials in 2020

• Data from 1830 Phase 1/2 studies in 2019

• A humanized IgG4 monoclonal antibody

• Proof of concept established in Phase 1b/2a

• High specificity to IgG and no reduction in

albumin observed

• Rapid onset of action in early studies

• Anticipate Q2W IV Dosing in Phase 3 Studies

• Plans to pursue SubQ formulation

ALXN1830

• Collaboration with Affibody

• A high affinity protein ligand with extended half-life

conferred by albumin-binding domain

• Expanding FcRn opportunity with potential for

best-in-class SubQ dosing

• Ongoing Phase 1 SAD/MAD clinical trial

ABY-039


Significant Need for Effective

Therapies

• ~65k patients in the US and EU5

• 1/3 continue to have active disease despite

treatment

• No approved treatment options

• Strong strategic fit with existing hematology

franchise

• ALXN1830 remains the first and only anti-FcRn in

development for warm autoimmune hemolytic

anemia

• Complications can include:

o Weakness

o Fatigue

o Dyspnea

o Syncope

o Angina

o Tachycardia

o Heart Failure

o Hepatomegaly

o Splenic Enlargement

ALXN1830 has potential for first-line treatment utilization

W A I H A : P O T E N T I A L F O R F I R S T - T O - M A R K E T F c R n A N D F I R S T - L I N E T R E AT M E N T

W AI H A Pa t i e n t s

R a n d o m i z e d 1 : 1

AL X N 1 8 3 0 ( n =2 5 ) + So C

PB O ( n =2 5 ) + So C

O p e n L a b e l

Ex t e n s i o n

6 month

treatment period

Phase 3 S tudy Des ign


Expanding Alexion Treatment Options

for Pat ients with gMG

• Established proof-of-concept for anti-FcRn mechanism in gMG

• ALXN1830 will complement Alexion’s C5 gMG portfolio

• Aligned with broader company development efforts in

Neurology

• Opportunity to leverage gMG development, regulatory and

commercial expertise in potential earlier-line therapy

Broad gMG Portfolio Strategy Provides

Path to Category Leadership

Note: ULTOMIRIS® is not approved to treat patients with gMG

ALXN1830 Phase 3 Tr ial Design

• Double-blind, placebo-controlled trial to start 4Q19

‒ Adults with mild-to-severe gMG

‒ Expanding addressable population with AcHR+, MuSK+,

LRP4+ patients

• Primary endpoint of Δ in MG-ADL

• Leverage neurology footprint to drive trial recruitment and

optimize product profile

ALXN1830 Dose Optimization

Anticipate Q2W IV Dosing in Phase 3 Studies

Plan to pursue SubQ formulation

A C O M P E L L I N G A N D C O M P L E M E N TA R Y g M G P O R T F O L I O W I T H A L X N 1 8 3 0


A B Y - 0 3 9 : P O T E N T I A L F O R O P T I M I Z E D S U B C U TA N E O U S D O S I N G

Collaboration for ABY-039

Bivalent anti-FcRn

antibody-mimetic affibody

Small Size

(~19 kDa)

• High-dose, low-volume subQ dosing

• Optimal for at home use and self-administration

• Up to 10x higher dose per injection volume compared to mAbs

Potent

Binding

Affinity

• Rapid onset

• Surface optimized designed proteins with high binding affinity

• Efficient autoantibody reduction

Long

Half-Life

• Long duration of action

• Half-life of ABY-039 significantly longer than a standard anti-

FcRn antibody due to the Albumod technology and albumin tether

• Potential for longer-acting subQ dosing

ABY-039

FcRn binding

domain

ABY-039

FcRn binding

domain

ABY-039

albumin

binding

domain

FcRn Target

COMPLEMENT RESEARCH EXPERTISE:

Driving the Next Generation of Treatments Sharon Barr, Ph.D. | Head of Research

88 | R A R E I N S P I R A T I O N . C H A N G I N G L I V E S . R E S E A R C H | S H A R O N B A R R , P H D , H E A D O F R E S E A R C H

R E F O C U S E D R E S E A R C H S T R AT E G Y

Goal to create novel therapeutics to treat patients

with rare diseases, leveraging industry-leading

expertise in complement biology

A RELENTLESS PURSUIT OF INNOVATION

• Research concentrated in New Haven with expertise in Ab engineering

• Numerous promising internal projects and collaborations with trusted partners

• Innovative assays, novel biomarkers, and new diagnostics to support efficient clinical trials

• Robust, diverse complement pipeline to deliver sustainable value

• Multiple INDs over the coming years


TA R G E T I N G D I S E A S E S O F C O M P L E M E N T D Y S R E G U L AT I O N

Complement is a master sensor that

discriminates between foreign or altered

and healthy cell surfaces

Rationale for complement inhibition across

multiple rare disease indications and

therapeutic areas

Complexity of complement biology allows

for multiple targeting approaches

Pursuing novel molecules and targets

across terminal, lectin, and alternative

pathways


A L X N 1 7 2 0 : A N O V E L A N T I - C 5 / A N T I - A L B U M I N B I S P E C I F I C

Bi-specific mini -body C5 Antagonist

Bi-specific mini-body that binds and prevents

activation of human C5

Specifically designing for long-acting, SubQ

dosing:

‒ 25 kDa size with potential for auto-injector

or pre-filled syringe

‒ Long half-life by binding to human serum

albumin

On track for first-in-human study in 2019

Linker

C5 Blocker

Albumin

Binder

Plans to develop for multiple new indications and therapeutic areas (e.g., Nephrology)


C O L L A B O R AT I O N T O D E V E L O P C 6 A N TA G O N I S T

MAC

Peripheral C6 crosses BBB into CNS

C6

Circulating C6 in CNS leads to formation of

MAC complex

C6

C6 C6

C6C6

C6

Peripheral C6 crosses

the blood brain barrier to

enter the CNS

Circulating C6 in CNS

leads to formation of

MAC which can cause

neurodegeneration

C6

CP010 binds to

peripheral C6 to reduce

the levels of C6 in the

CNS and decrease MAC

formation

• Expands our complement franchise with a novel asset (CP010) addressing neurological disorders

• Membrane attack complex (MAC) formation in central nervous system is dependent upon peripheral C6 as evidence

suggests C6 is not produced in the CNS

• CP010 binds to peripheral C6 to decrease the level of C6 in the CNS to achieve effective inhibition of MAC formation


C O L L A B O R AT I O N O N R N A i C O M P L E M E N T T H E R A P E U T I C S

Innovative RNAi technology with potential for multiple

targets

Clinical proof-of-concept in Primary Hyperoxaluria

Broad therapeutic applicability in complement-

mediated diseases

Low volume (up to 2 mL) injection with long duration

of effect supporting monthly-to-quarterly dosing

Theoretical off-target effects from breakdown

products are minimized through chemical

modifications

Guide Strand

GalNAc-conjugated Tetraloop

Passenger Strand

GALXC’s RNAi platform silences hepatic

gene expression

The GalNAc sugars enable specific

delivery to hepatocytes through binding to

asialoglycoprotein receptor (ASGPR)


PA R T N E R S H I P T O D E V E L O P P E P T I D E T H E R A P E U T I C S

Cutting Edge Peptide Drug Candidates

Physical Stability

Solubility

Chemical Stability

Potency

Adds additional preclinical assets to

complement pipeline

Innovative technology platform already

commercialized for other targets

Peptide therapies offer a highly selective

targeted approach with high potency, low

concentrations and small size for ease of

administration

Potential for multiple targets within the

complement cascade

Broad therapeutic applicability in complement

mediated diseases

CLOSING REMARKS Ludwig Hantson, Ph.D.| Chief Executive Officer


2 0 1 9 O B J E C T I V E S

ULTOMIRISTM Conversion in PNH; aHUS filing 1

Accelerate Neurology Portfolio

Execute and Expand the Pipeline

Grow our Metabolics Portfolio

Deliver on Financial Ambitions

2

3

4

5


P O S I T I O N I N G A L E X I O N F O R T H E F U T U R E

Diversifying

the Alexion

Portfolio


Neurology

Metabolics

FcRn Portfolio

1

2

3

4

Report Phase 3 aHUS data

File aHUS in US, EU & Japan

Facilitate PNH

Conversion to

ULTOMIRISTM,1

Expand Metabolic Portfolio

Grow STRENSIQ® & KANUMA®

Execute Phase 3

ALXN1840 superiority

trial

Grow SOLIRIS® in gMG

Initiate ULTOMIRIS Phase 3

studies in gMG & NMOSD

Launch SOLIRIS® in

NMOSD in the US2

Dose-optimization data read-out

Initiate two ALXN1830 pivotal trials ALXN1830 Phase 1/2

data in WAIHA read-

out

1Ex-US upon regulatory approval 2Upon regulatory approval



S T R AT E G Y F O R D U R A B L E , L O N G - T E R M G R O W T H

Organic Clinical Pipeline

Internal Complement Research

Business Development

Other Autoimmune (FcRn)


Neurology

Metabolics

FcRn Portfolio


Q&A Session 2

Documents

Investor Day - Alexion Pharmaceuticals, Inc