• R&D DAY

BIOCRYST PHARMACEUTICALSNOVEMBER 3, 2023

FORWARDLOOKING
STATEMENTS

BioCryst’s presentation may contain forward-looking
statements, including statements regarding future results,
unaudited and forward-looking financial information andcompany performance or achievements. These statements are
subject to known and unknown risks and uncertainties which
may cause our actual results, performance or achievements to
be materially different from any future results or performances
expressed or implied in this presentation. You should not place
undue reliance on the forward-looking statements. For
additional information, including important risk factors, pleaserefer to BioCryst’s documents filed with the SEC and located at
ir.biocryst.com/financial-information/sec-filings

2

TODAY’S AGENDA
1:00-1:05 (ET)

WelcomeJohn Bluth, Chief Communications Officer

1:05-1:15

Introduction

Jon Stonehouse, President and Chief Executive Officer

1:15-2:15

BioCryst’s DifferentiatedApproach to R&D

Dr. Helen Thackray, Chief R&D Officer

2:15-3:15

New Molecules
and Programs

Charlie Gayer, Chief Commercial Officer
Dr. Ryan Arnold, Chief Medical Officer
Dr. Bill Sheridan, Chief Development Officer

3:15-3:30

Disciplined Capital
Allocation Approach

3:30 – 4:00

Q&A

Anthony Doyle, Chief Financial Officer

3

WELCOMEJon Stonehouse, President & Chief Executive Officer

4

HELPING RESTORE A SENSE OF FREEDOMFOR PATIENTS WITH HAE

5

6

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

7

ADVANCING FUTURE FIRST-IN-CLASS,
BEST-IN-CLASS DRUGS FOR PATIENTS WITH
RARE DISEASES
Dr. Helen Thackray, Chief Research & Development Officer

8

DELIVERING BETTER OUTCOMES FOR PATIENTS:
FIRST-IN-CLASS, BEST-IN-CLASS THERAPIES FOR RARE DISEASE
Specialized approach to solve the challenges indrug design
Focus on first-in-class or best-in-class drugs
Expanding platform technology producing a diverse
pipeline with speed
Delivering differentiated drugs for better patient outcomes9Advancing a broadened pipeline
Plans to deliver proof-of-concept data for
6 molecules in the next 5 years

10OVERCOMING THE CHALLENGES OF DEVELOPING AFIRST-IN-CLASS OR BEST-IN-CLASS THERAPY

Designing a Molecule
High potency
Target specificity
Bioavailability

11

Amino acid sequence

defines how complex 3-D structure folds

1212

To design a differentiated drug

we need to know the final 3-D structure of the protein

13
13

PREDICTING THE SHAPE OF AMINO ACIDS STRING IS ONLY A
START TO SOLVING FOR COMPLEX DRUG DESIGN
3 Challenges to Overcome
3-dimensional protein structureHigh-resolution atomic structure

14

Predictive models

provide a basic understanding of
the 3-D protein structure

15
15

Visibility to theatomic level

is what BioCryst sees to inform
designing a best-in-class drug

1616

UNDERSTANDING HOW A PROTEIN CHANGES SHAPE WHILE
MOLECULES BIND TO IT IS CRITICAL
3 Challenges to Overcome
3-dimensional protein structureHigh-resolution atomic structure
Conformational change with binding17

Protein active site

is dynamic and continues tochange shape after binding

We design ourmolecules to fit
like a key in a lock18
18

OVERCOMING THE CHALLENGES OF DEVELOPING AFIRST-IN-CLASS OR BEST-IN-CLASS THERAPY
Designing a Molecule

3 Challenges to Overcome

High potency

3-dimensional protein structure

Target specificity

High-resolution atomic structure

Bioavailability

Conformational change with binding

Solving for the Challenges
Defining the high-resolution, 3-D structureof the protein

Seeing how this structure changes when our drug
binds to the active site

19

Determining structure
at the atomic level
The art and science ofprotein crystallography

20
20

21
21

Expanding
our structure-guided
approach to generate
opportunities inprotein therapeutics
22Designing a KLK5 inhibitor for Netherton syndrome
KLK5 Native Ligand: SPINK9Amino acids (A, B, and C)• Suboptimal geometric fit• Empty space in active site
• Limited charge complementarity

A

C
B

SPINK9We saw the opportunity
to design a better
ligandKLK5Poor binding affinity to KLK5

KLK5, kallikrein 5; SPINK9; serine peptidase inhibitor kazal type 9.

23

Designing a KLK5 inhibitor for Netherton syndrome
KLK5 Native Ligand: SPINK9Engineered Protein: BCX17725

Amino acids (A, B, and C)

Amino acids (X, Y, and Z)• Suboptimal geometric fit• Empty space in active site
• Limited charge complementarity

A

X

Z

C
B

KLK5

Poor binding affinity to KLK5

KLK5, kallikrein 5; SPINK9; serine peptidase inhibitor kazal type 9.

Replaced amino acids for:• Better geometric fit• Spatially filled out the active site
• Improved charge complementarity

Y
BCX17725

SPINK9KLK5Final protein increased
binding affinity increasedby 1 million-fold

24

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

25

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

26

ORLADEYO® (BEROTRALSTAT)Charlie Gayer, Chief Commercial Officer

27

ORLADEYO® : THE FIRST AND ONLY ONCE-DAILY ORAL PROPHYLACTIC
THERAPY FOR HAE IS ON A PATH TO $1 BILLION PEAK REVENUEORLADEYO®:$1 Billion

in Peak Revenue≥$320M

In hereditary angioedema (HAE),

this is big.

$252M
$122M

In your day,this is small.

2021

2022

FY 2023 Company
Guidance

28
FY, fiscal year. 1. BioCryst Pharmaceuticals data on file 2023.

ORLADEYO® FILLS AN UNMET NEED FOR PATIENTSWITH HAE

50%

of US patients receiving ORLADEYO®
switched from another prophylactic therapy

Injectables add treatment burden

TAKHZYRO1:
SC injection

HAEGARDA2:
SC injection

CINRYZE3:
IV infusion

TREATMENT SCHEDULE•

Scheduling

Week 1•

Preparation and administration

Week 2•Complications with travel

Week 3•

Discomfort

Week 4

HAE, hereditary angioedema; IV, intravenous; SC, subcutaneous. 1. Takhzyro [package insert]. Takeda Pharmaceuticals. 2023. 2. Haegarda [package insert].
CSL Behring. 2020. 3. Cinryze [package insert]. ViroPharma Biologics LLC, Takeda Pharmaceuticals. 2022.

29

COMMERCIAL OPPORTUNITY INCOMPLEMENT-MEDIATED DISEASES

30

BIOCRYST’S PORTFOLIO OF COMPLEMENT INHIBITORSCLASSICALPATHWAY
Complement-fixing
antibodies bind antigens

Oral C2
inhibitor

LECTINPATHWAY
Lectins bindsugars

ALTERNATIVEPATHWAY
Pathogens or damaged
tissues & constitutively active
BCX10013

BCX C2

FACTOR D

C2

mAb
Bifunctional
inhibitor
Oral Factor D
inhibitor

C3

C5

BCX C5

Oral C5
inhibitor

Membrane Attack
Complex (MAC)

C2, complement component 2; C3, complement component 3; C5, complement component 5; mAb, monoclonal antibody.
1. Barratt J. Front Immunol. 2021;12:712572. 2. West EE, et al. Nat Rev Nephrol. 2023;19(7):426-439.

31

MANY POTENTIAL OPPORTUNITIES TO HELP PATIENTS WITH
UNMET NEEDS
CLASSICALPATHWAY
Complement-fixing
antibodies bind antigens
C2 inhibition
Hematology• CAD• wAIHA• HSCT-thrombotic
microangiopathy• ITP
Ophthalmology• Dry AMD/Geographic atrophy
Nephrology• IgAN• IgAV-N• Lupus nephritis• PMN

ALTERNATIVEPATHWAY
Pathogens or damaged
tissues & constitutively active

LECTINPATHWAY
Lectins bindsugarsBCX10013

BCX C2

FACTOR D

C2
C3

C5 inhibition
BCX C5C5Dermatology• Hidradenitis suppurativa• Bullous Pemphigoid
Neurology• Generalized myasthenia gravis• Multifocal motor neuropathy• Guillain-Barré syndrome

Membrane Attack
Complex (MAC)

Dermatology• Hidradenitis suppurativa• Bullous Pemphigoid
Neurology• Generalized myasthenia
gravis• Neuromyelitis optica• Immune-mediatednecrotizing myopathymAb
Bifunctional
inhibitor
Factor D inhibition
Hematology• PNH• ANCA-V• HSCT-thrombotic
microangiopathy
Ophthalmology• Dry AMD/Geographic atrophy• Wet AMD
Nephrology• IgAN• C3G• aHUS• IgAV-N• Lupus nephritis• PMN

Combination therapy legend:
C2 + Factor D inhibition
C2 + C5 inhibition

aHUS, atypical hemolytic uremic syndrome; AMD, age-related macular degeneration; ANCA-V, antineutrophilic cytoplasmic antibody vasculitis; C2, complement component 2;
C3, complement component 3; C5, complement component 5; C3G, C3 glomerulopathy; CAD, cold agglutinin disease; DME, diabetic macular edema; HSCT, hematopoietic stem
cell transplant; IgAN, IgA nephropathy; IgAV-N, IgA vasculitis-nephritis; ITP, immune thrombocytopenia purpura; mAb, monoclonal antibody; PMN, primary membranous
nephropathy; PNH, paroxysmal nocturnal hemoglobinuria; wAIHA, warm autoimmune hemolytic anemia.1. Barratt J. Front Immunol. 2021;12:712572. 2. West EE, et al. Nat Rev
Nephrol. 2023;19(7):426-439.

32

ORAL C5 INHIBITOR AS POTENTIAL THERAPY FOR
GENERALIZED MYASTHENIA GRAVIS
Target Profile

Competition

First targeted oral for generalized
myasthenia gravis (gMG) with competitive
efficacy to injected and infused therapies•

Opportunities••

Switch from infused therapies
Earlier use in treatment paradigm

US Patient Population1••~15 min SC
infusion

Vyvgart3:
1 hour IV
infusion

VyvgartHyrtrulo4:30-90 sec SC
injection$2.3B in 2023
$6.1B in 2028

Ultomiris5:~1 hour IV
infusion

TREATMENT SCHEDULE
Week 1
Week 2
Week 3
Week 4Overall: ~70K, 80-85% AChR+
Refractory steroids and ISTs: 5K-10K

Sales Estimates6••

Rystiggo2:

Q8W*“A key unmet need is to have a high efficacy drug
like Ultomiris or Vyvgart but in oral form. It would
make it much easier with taking it long-term thanto keep going to an infusion center or having anurse come for hours to your house to do it.”
– US Neurologist7*Maintenance dosing begins 2 weeks after the initial loading dose and occurs once every 4 or 8 weeks depending on body weight; AChR+, positive acetylcholine receptor antibody;C5, complement component 5; ISTs, immunosuppressive therapies; IV, intravenous; Q8W, once every 8 weeks; SC, subcutaneous; US, United States.
1. Dresser et al. J Clin Med. 2021; Myasthenia Gravis Foundation of America; 2. Rystiggo [package insert]. UCB, Inc. 2023. 3. Vyvgart [package insert]. argenx. 2021. 4. Vyvgart Hytrulo[package insert]. argenx. 2023. 5. Ultomiris [package insert]. Alexion Pharmaceuticals. 2022. 6. Evaluate Pharma. 7. BioCryst Pharmaceuticals Market Research Q2 2023.

33

ORAL C2 INHIBITOR AS POTENTIAL THERAPY FOR
AUTOIMMUNE HEMOLYTIC ANEMIAS
Target Profile•

Switch from infused therapies
Earlier use in treatment paradigm
Potential first targeted therapy (wAIHA)US Patient Population••

Enjaymo5(C1s inhibitor) :1 hour IV
infusion for CAD

First-in-class oral C2 inhibitor

Opportunities•••

Competition

Cold agglutinin disease (CAD)1,2: 5K
Warm autoimmune hemolytic anemia(wAIHA)3,4: 25K

TREATMENT SCHEDULE

Week 1
Week 2
Week 3
Q2W

Week 4

ARGX-117, an intravenous C2 inhibitor,
is in phase 2 for multifocal motor
neuropathy (MMN)6

C2, complement component 2; IV, intravenous; Q2W, once every 2 weeks. 1. Berensten et al. Hematologica. 2006;91(4):460-6. 2. Mullins et al. Blood Adv.
2017;1(13):839-848. 3. Kalfa et al. Hematology Am Soc Hematol Educ Program. 2016;2016(1):690-697. 4. Tranekaer et al. J Clin Med. 2021;10(6);1244.
5. Enjaymo [package insert]. Bioverativ USA Inc, Sanofi. 2023; 6. https://www.us.argenx.com/pipeline#immunology-solutions.

34

BCX10013 AS POTENTIAL THERAPY FOR KIDNEY DISEASES
Target Profile•

Best-in-class AP inhibitor with once-daily
dosing and efficacy similar to iptacopan

Opportunities••

Potential standard of care complement
inhibitor (both)
Earlier use in treatment paradigm (IgAN)

Competition•

Iptacopan, a twice-daily oral factor B
inhibitor, is in phase 3 for IgAN and C3G•

Pegcetacoplan, a twice-weekly
subcutaneous infusion, is in phase 3 for C3G

US Patient Population••

Immunoglobulin A nephropathy (IgAN)1:~160K overall, ~30K high risk of progression2
C3 glomerulopathy (C3G)3: ~6K“I like the new MOA, it's
unique [and] something I
can use to complement
my current treatment of
IgAN."– US Nephrologist2"[BCX10013] is a targeted therapy
for C3G, that's what we need.
We've been dabbling with all
kinds of immunosuppression. Thistakes you to why C3G ishappening."– US Nephrologist2

AP, alternative pathway; 1. Schena et al. Epidemiology of IgA Nephropathy: A Global Perspective. Sem Nehprol. 2018.. 2. BioCryst Pharmaceuticals Market Research
Q2 2022. 3. Medjeral-Thomas NR et al. C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome. Clin J Am Soc Nephrol. 2014;9(1):46-53.

35

BIFUNCTIONAL COMPLEMENT INHIBITOR AS POTENTIAL
THERAPY FOR KIDNEY DISEASES
Target Profile•

First-in-class combo inhibitor of CP, LP, AP,
as a low-volume, subcutaneous injection

Competition•

KP104 (C5+factor H inhibitor) from Kira
Pharmaceuticals is in phase 2 forsystemic lupus erythematosus, IgAN and
PNH12

•

GL-0719 (CP + LP inhibitor) from Gliknik
is in a phase 1 trial13

Opportunities•

Best-in-class 2L or 3L treatment forpatients at high risk or refractory to SoC
due to multiple complement pathway
involvement

US Patient Population•

Immunoglobulin A nephropathy (IgAN)1:~160K overall, ~30K high risk of progression2•

Lupus nephritis (LN)*3,4,5: 55K, up to 30K
addressable6-11*Prevalance reflects patients with Class III/IV disease. 2L, second-line; 3L, third-line; C5, complement component 5; AP, alternative pathway; CP, classical pathway; LP, lectin
pathway; SoC, standard of care.1. Schena et al. Epidemiology of IgA Nephropathy: A Global Perspective. Sem Nehprol. 2018. 2. BioCryst Pharmaceuticals Market Research Q2
2022. 3. GlobalData; Cantor Research on LN from September 2021. 4. JonesTrading Equillium (Mar 2021). 5. Wedbush Nephrology Survey. 6. Cantor Fitzgerald Research on LN(Sep 2021). 7. Jones Trading Equillium (March 2021). 8. Wedbush Nehrology Survey (Feb 2023). 9. Tektonidou et al. Arthritis & Rheumatology. 2016. 10. Yo et al. Open AccessRheumatology. 2019. 11. Kalloo et al. 2013. 12. https://www.kirapharma.com/pipeline. 13. https://www.gliknik.com/gl-0719/.

36

MULTIPLE PATHS TO COMPLEMENT MARKET LEADERSHIP
Multiple programs, small molecule and protein
therapeutics, applicable to many diseases
01

Best-in-class for ultra-rare disease
Disease02

First-in-class oral in injectable/infused market

03

First-/best-in-class for patients needing combo
therapy within larger disease populations

04

Potential to help more patients at different stagesof disease pathology or progression

05

Diverse portfolio spreads development risk andincreases commercial opportunity

IgAN

BCX10013

C5

X
X

gMG

C2

Bifunctional

X

X

X

X

CAD

X

X

X

LN

X

X

X

C3G

X

wAIHA

C2, complement component 2; C3G, C3 glomerulopathy; C5, complement component 5; CAD, cold agglutinin disease; IgAN, Immunoglobulin A nephropathy;
LN, lupus nephritis; gMG, generalized myasthenia gravis; wAIHA, warm autoimmune hemolytic anemia.

X

37

SPOTLIGHT ON COMPLEMENT DISEASES
Dr. Bill Sheridan, Chief Development Officer

38

BIOCRYST’S PORTFOLIO OF COMPLEMENT INHIBITORSCLASSICALPATHWAY
Complement-fixing
antibodies bind antigens

Oral C2
inhibitor

LECTINPATHWAY
Lectins bindsugars

ALTERNATIVEPATHWAY
Pathogens or damaged
tissues & constitutively active
BCX10013

BCX C2

FACTOR D

C2

mAb
Bifunctional
inhibitor
Oral Factor D
inhibitor

C3

C5

BCX C5

Oral C5
inhibitor

Membrane Attack
Complex (MAC)

C2, complement component 2; C3, complement component 3; C5, complement component 5; mAb, monoclonal antibody.
1. Barratt J. Front Immunol. 2021;12:712572. 2. West EE, et al. Nat Rev Nephrol. 2023;19(7):426-439.

39

OVERVIEW OF BIOCRYST COMPLEMENT PROGRAM
Developing 4 programs to create a comprehensive portfolio of single
pathway and multiple pathway complement inhibitors

Goals for each program are first-in-class or best-in-classThis approach creates opportunity to treat many complementmediated diseases across multiple therapeutic areas
We aim to start 3 NME phase 1 studies, deliver POC results for
3 programs, and start 1 pivotal study in the next 4 years

AP, alternative pathway; C2, complement component 2; C5, complement component 5; CP, classical pathway; IND, investigational new drug; LP, lectin pathway;
NME, new molecular entity; POC, proof of concept.

40

C5 INHIBITOR: FIRST-IN-CLASS ORAL INHIBITOR

41

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

42

TARGETING C5 HAS BEEN THOROUGHLY VALIDATED AS A
SUCCESSFUL THERAPEUTIC STRATEGY IN SEVERAL INDICATIONS
C5 is the initiatorof the terminal phase for all 3 complement
pathways.1

For all complement pathways,
C5 activation leads to theformation of the membrane
attack complex (MAC).1

C5 activation also leads
to production of C5a, ananaphylatoxin thattriggers inflammation.1,2

Inhibiting C5 is a promising therapeutic approach formultiple complement-mediated disorders including gMG,
PNH, aHUS, NMOSD, and ANCA-V, among others.1,2

aHUS, atypical hemolytic uremic syndrome; ANCA-V, antineutrophilic cytoplasmic antibody associated vasculitis; C5, complement component 5;
C5a, complement component 5a; gMG, generalized myasthenia gravis; NMOSD, neuromyelitis optica spectrum disorder; PNH, paroxysmal
nocturnal hemoglobinuria. 1. Giorgio C, et al. Biomedicines. 2021;9(399):1-18. 2. Mantegazza R, et al. ImmunoTargets and Therapy. 2020;9:317-331.

43

LEAD OPTIMIZATION OF AN ORAL SMALL MOLECULE C5 INHIBITOR IS
PROGRESSING RAPIDLY TO IND CANDIDATE SELECTION
Goals are high potency, selectivity, oral bioavailability, sustained exposure,favorable metabolic profile, and typical small molecule physicochemical properties.

Selectivity

Low risk of off-target effects

Oralbioavailability

F > 40%, similar tomarketed small molecule therapeutics

Sustained
exposure

C24/IC50 ratio > 10, predictive of sustained
PD effect

Physicochemical
properties

MW < 500 D, typical of other oral small
molecules

10000

Plasma level, ng/mL

Potency

Inhibition assay for cell lysis by MAC
which is dependent on thecleavage/breakup of C5 IC50 < 10 nM

Nonclinical
PK Profile
of 11
ElevenBioCryst Potent
C5 InhibitorsDog
PK Profiles
BioCryst
PotentC5 Inhibitors

1000
100
10
1
0

4

8

12

16

20

24

Time after one oral 10 mg/kg dose, hours

C24, concentration 24 hours post-dose; C5, complement component 5; D, Dalton; F, oral bioavailability; IC50, half maximum inhibitor concentration;
IND, investigational new drug; MAC, membrane attack complex; MW, molecular weight; nM, nanomolar; PD, pharmacodynamic; RBC, red blood
cell. BioCryst Pharmaceuticals data on file 2023.

44

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

45

C2 PROGRAM: A FIRST-IN-CLASS ORAL SERINEPROTEASE INHIBITOR TO BLOCK BOTH THE
CLASSICAL AND LECTIN PATHWAYS

46

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

47

COMPLEMENT-FIXING IgG AND IgM (CP) OR LECTIN-ACTIVATING IgG4
AUTOANTIBODY (LP) DISEASES ARE KEY TARGETS FOR C2 BLOCKADE
C2 is a serine proteasethat provides catalytic activity for the C3
and C5 convertases of the classical andlectin complement pathways.1
Inhibiting C2 can decrease inflammation incomplement-mediated diseases by blocking
the classical and lectin pathways.2

Developing an oral
small molecule
inhibitor of C2,
while challenging,
would be highly
valuable.

Structure of Human Complement C2a

Serine Protease
DomainBlocking the CP and/or
LP is a promising
approach for several
diseases, including
bullous pemphigoid
and autoimmune
hemolytic anemias.2,3C2, complement component 2; C2a, complement component 2a; C5, complement component 5; CP, classical pathway; IgG, immunoglobulin G;
IgG4, immunoglobulin G4; IgM, immunoglobulin M; LP, lectin pathway. 1. Krishnan V, et al. Act Cryst. 2009;D65:266-274. 2. Berentsen S. Transfus
Med Hemother. 2015;42:303-310. 3. Papara C, et al. Front. Immunol. 2022;13:973702.

Linker Region

vWFA
Domain48

THE ORAL SMALL MOLECULE C2 INHIBITOR PROJECT IS PROGRESSING
THROUGH LEAD IDENTIFICATION
Goals are high potency, selectivity, oral bioavailability, sustained exposure,favorable metabolic profile, and typical small molecule physicochemical properties.
Potency

CP inhibition assay IC50 < 10 nM

Selectivity

Low potency against other serine proteases,>1,000-fold less potent than for C2

Oralbioavailability

F > 40%

Sustained
exposure

C24/IC50 ratio > 10

Physicochemical
properties

MW < 500 D

C2, complement component 2; C24, concentration 24 hours post-dose; CP; classical pathway; D, Dalton; F, oral bioavailability; IC50, half maximum inhibitor
concentration; MW, molecular weight; nM, nanomolar. BioCryst Pharmaceuticals data on file.

49

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

50

BCX10013: BEST-IN-CLASS, ONCE-DAILY,
ORAL FACTOR D INHIBITOR TO BLOCKTHE ALTERNATIVE PATHWAY

51

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

52

BCX10013 IS A POTENTIAL BEST-IN-CLASS, ONCE-DAILY,
ORAL FACTOR D INHIBITOR FOR AP-MEDIATED DISEASES
Several diseases are now known to be driven
by dysregulation of the alternative
pathway.1

Structure of Human Factor D

Factor D initiates the first step in the alternative

pathway of complement and amplifies complement
signaling.1
Factor D is a promising therapeutic target
for several complement-mediated diseases.1,2•

IgAN, C3G, PNH, aHUS

BCX10013, an investigational, oral Factor D
inhibitor, is being studied in a dose-ranging trial inpatients with PNH.

aHUS, atypical hemolytic uremic syndrome; AP; alternative pathway; C3G, complement 3 glomerulopathy; IgAN, Immunoglobulin A nephropathy;
PNH, paroxysmal nocturnal hemoglobinuria. 1. Barratt J, et al. Front Immunol. 2021 Sep 9;12:712572. 2. Cheung CK, et al. J Clin Med. 2021;10(2493):1-19.

53

IN PHASE 1 HEALTHY VOLUNTEER MAD STUDY, 160 MG ONCE-DAILYBCX10013 SHOWED COMPLETE SUPPRESSION* OF AP

n=10 active
n=2 placebo per cohort

Generally safe and well tolerated in healthy volunteers.
No safety signals have been identified in humans to date.

*On day 14, approximately 96% suppression pre-dose and 99% suppression 24 hours post-dose.
AP, alternative pathway; MAD, multiple ascending dose; MG, milligram; QD, once daily. BioCryst Pharmaceuticals data on file 2023.

54

WE ARE NOW EVALUATING BCX10013, A POTENTIAL BEST-IN-CLASSONCE-DAILY ORAL, IN A PNH STUDY WITH STRICT SUCCESS CRITERIAAn open-label, Phase 1b intra-subject dose-escalation study evaluating safety
and tolerability of BCX10013 in up to 15 adults with PNH has started dosing.

Dosing of BCX10013 is once daily, with dose increased in steps
to achieve optimum control of disease.

Efficacy goal
Control of hemolysis similar to that reported for iptacopanwith LDH < 1.5 x ULN.

Safety goals
Safe and generally well tolerated with once-daily chronic dosing
at dosages meeting efficacy goal.

55
LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit normal.

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

56

FIRST-IN-CLASS BIFUNCTIONAL COMPLEMENTINHIBITOR TARGETS CP, LP AND AP

57

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

58THE BIFUNCTIONAL INHIBITOR PROJECT COMBINES ANTI-C2 MAB
WITH AP INHIBITOR IN ONE MOLECULE
Many serious disorders are driven by
activation of multiple complement
pathways.1

C2 activation leads to the production of C3 and C5

convertases of the classical and lectin complement
pathways.2

The Alternative Pathway amplifies both
CP- and LP-driven complement cascades.2

C2 mAb+AP inhibitor

Bifunctional inhibitor project targets C2 and AP
inhibition in the same molecule.

AP, alternative pathway; C2, complement component 2; C3, complement component 3; C5, complement component 5; CP; classical pathway; LP; lectin
pathway; mAb, monoclonal antibody. 1. Barratt J, et al. Front Immunol. 2021 Sep 9;12:712572. 2. Dunkelberger JR, et al. Cell Research. 2010;20:34-50.

59

SERIOUS DISEASES WITH PATHOLOGIC ACTIVATION OF
MULTIPLE COMPLEMENT PATHWAYS*
Progressive IgA
Nephropathy

Lupus Nephritis
LP

CP

MBL1

LP

IgG3

AP

Bb + C5b-92

C4d4

CP

AP

C1q3

FHR54

*Examples. Ab, antibody; AP, alternative pathway; Bb, activated factor B; C1q, complement component 1q; C3d, complement component 3d; C4d, complement component 4d;
C5b-9, complement component 5b-9; CP, classical pathway; FHR5, factor H-related protein 5; IgG, immunoglobulin G; LP, lectin pathway; MBL, mannose binding lectin.
1. Sato N, et al. Lupus. 2011;20(13):1378-1386. 2. Song D, et al. Am J Medical Sci. 2017;353(3):247-257. 3. Javeed S, et al. Cureus. 2022;14(5)e25363. 4. Medjeral-Thomas NR, et al. Kidney
Int Reports. 2018;3(2):426-438.

60

POTENT INHIBITION OF THE CLASSICAL PATHWAY*
5 assays evaluating the Classical Pathway
of complement
Assays measure 3 critical complement
effector functions: C3 opsonization,
C5b-9 (MAC) formation, and cell lysis

Low nM or sub-nM potency across each
CP assayMore potent than:• Eculizumab• Sutimlimab• Anti-C5 FH1-5 bifunctional Ab• Anti-C2 AbClassical Pathway Assays
C3 Deposition on
Ab-sensitized Sheep RBCs
5% C5-depleted NHS
C3 deposition on
Ab-sensitized Sheep RBCs
1% C5-depleted NHS
Quidel CH50
14% NHS
Weislab CP
1% NHS
Hemolysis of
AB-sensitized Sheep RBC
1% NHS

0.001

0.01

0.1

1

IC50, nM

*Representative example
Ab, antibody; AP, alternative pathway; C2, complement component 2; C3, complement component 3; C5, complement component 5; C5b-9, complement
component 5b-9; CAD, cold agglutinin disease; CP, classical pathway; FH1-5, factor H 1-5; IC50, half maximum inhibitor concentration; LP, lectin pathway; MAC,
membrane attack complex; NHS, normal human serum; nM, nanomolar; RBC, red blood cell. BioCryst Pharmaceuticals data on file 2023.

10

100

61

POTENT INHIBITION OF THE ALTERNATIVE PATHWAY*
Alternative Pathway Assays

2 different assays evaluating theAlternative Pathway of complement
Assays measure 2 critical complement
effector functions: C3 opsonization andC5b-9 (MAC) formation

Sub-nM potency in both alternative
pathway (AP) assays

More potent than:• Eculizumab• Sutimlimab• Anti-C5 FH1-5 bifunctional Ab• Anti-C2 Ab

C3 Deposition
Rabbit RBC
in 15% C5-depleted NHS

Wieslab AP
5.6% NHS

0.001

0.01

0.1

1

IC50, nM

*Representative example
Ab, antibody; AP, alternative pathway; C2, complement component 2; C3, complement component 3; C5, complement component 5; C5b-9, complement
component 5b-9; CP, classical pathway; FH1-5, factor H 1-5; IC50, half maximum inhibitor concentration; LP, lectin pathway; NHS, normal human serum; nM,
nanomolar; RBC, red blood cell. BioCryst Pharmaceuticals data on file 2023.

10

100

62

POTENT INHIBITION OF THE LECTIN PATHWAY*
Lectin Pathway Assay

Commercial assay evaluating the Lectin
Pathway of complement

Assay measures critical complement
effector function: C5b-9 (MAC) formation

Weislab LP
1% NHS

Sub-nM potency

More potent than:• Eculizumab• Sutimlimab• Anti-C5 FH1-5 bifunctional Ab• Anti-C2 Ab

0.001

0.01

0.1

1

IC50, nM

*Representative example
Ab, antibody; C2, complement component 2; C5, complement component 5; C5b-9, complement component 5b-9; FH1-5, factor H 1-5; IC50, half maximum
inhibitor concentration; LP, lectin pathway; MAC, membrane attack complex; NHS, normal human serum; nM, nanomolar; RBC, red blood cell. BioCryst
Pharmaceuticals data on file 2023.

10

100

63

POTENT INHIBITION OF RED BLOOD CELL OPSONIZATION IN COLD
AGGLUTININ DISEASE PATIENT SAMPLE*
CAD Patient Sample

In CAD, the IgM antibodies bind to RBCs
and activate complement. This assay
directly tests a CAD patient sample
The assay measures the critical pathologic
step in CAD: C3 opsonization

C3 Deposition on
CAD plasma-sensitized
Human Type O RBC
25% C5-depleted NHS

Picomolar range potency>1,000 fold more potent than:• Eculizumab• Sutimlimab (approved to treat CAD)
• Anti-C5 FH1-5 bifunctional Ab• Anti-C2-CCP2 Ab

0.001

0.01

0.1

1

IC50, nM

*Representative example
Ab, antibody; C3, complement component 3; C5, complement component 5; C5b-9, complement component 5b-9; CAD, cold agglutinin disease;; FH1-5, factor H
1-5; IC50, half maximum inhibitor concentration; IgM, immunoglobulin M; NHS, normal human serum; nM, nanomolar; RBC, red blood cell. BioCryst
Pharmaceuticals data on file 2023.

10

100

64

BIFUNCTIONAL COMPLEMENT INHIBITOR BLOCKS MULTIPLECOMPLEMENT PATHWAYS*CP

9 different assays evaluating CP, LP, AP,and combined CP+AP of complement
Assays measure critical complement
effector functions: C3 opsonization,
C5b-9 (MAC) formation, and cell lysis

AP

C3 Deposition on
Ab-sensitized Sheep RBCs
5% C5-depleted NHS
C3 deposition on
Ab-sensitized Sheep RBCs
1% C5-depleted NHS

C3 Deposition
Rabbit RBC
in 15% C5-depleted NHS

Quidel CH50
14% NHS
Weislab CP
1% NHS

Wieslab AP
5.6% NHS

Hemolysis of
AB-sensitized Sheep RBC
1% NHS

0.001 0.01

0.1

1IC50, nM

10

100

LP

Low nM or sub-nM potency acrossdifferent assays of CP, AP and LP

0.1

1

IC50, nM

10100

CAD Patient Sample

C3 Deposition on
CAD plasma-sensitized
Human Type O RBC
25% C5-depleted NHS

Weislab LP
1% NHS

More potent than:• Eculizumab• Sutimlimab• Anti-C5 FH1-5 bifunctional Ab• Anti-C2 Ab

0.001 0.01

0.001 0.01

0.1

1IC50, nM

BioCryst Bifunctional
Monoclonal Antibody

10

100

anti-C2-CCP2

0.001 0.01

sutimlimab*Representative example
Ab, antibody; AP, alternative pathway; C2, complement component 2; C3, complement component 3; C5, complement component 5; C5b-9, complement
component 5b-9; CAD, cold agglutinin disease; CP, classical pathway; FH1-5, factor H 1-5; IC50, half maximum inhibitor concentration; LP, lectin pathway;
MAC, membrane attack complex; NHS, normal human serum; nM, nanomolar; RBC, red blood cell. BioCryst Pharmaceuticals data on file 2023.

0.1

1IC50, nM

anti-C5 FH1-5

10

100

eculizumab

65

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

66

BCX17725: A NOVEL PROTEIN THERAPY FORNETHERTON SYNDROME
Dr. Ryan Arnold, Chief Medical Officer

67

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

68

NETHERTON SYNDROME (NS) – A RARE, GENETIC SKIN DISORDER
WITH SIGNIFICANT BURDEN
Often presents as
red, scaly,
inflamed skinin newborn or
infant.
Dehydration andinfection arecommon and canbe serious.1
Leclerc-Mercier S, et al. American Journal of Dermatopathology. 2016;38(2).

There are no approved treatments for NS2,3

KLK5 inhibition can restore normal skinturnover2
BCX17725 is an investigational potential
disease modifying fusion protein KLK5 inhibitor
SPINK9

Caused by deficiency of a natural inhibitor(SPINK5) of KLK5, a serine protease responsible forregulating skin shedding2-4
Excessive KLK cascade activity leads tobreakdown of the skin barrier and is associatedwith various inflammatory skin diseases5

hIgG1
Fc

KLK5

KLK, kallikrein; KLK5, kallikrein-related peptidase 5; SPINK5, serine protease inhibitor kazal type 5; SPINK9, serine protease inhibitor kazal type 9.
1. NIH. Netherton syndrome. February 2023. Accessed August 24, 2023. https://rarediseases.info.nih.gov/diseases/7182/netherton-syndrome 2. Furio L,
et al. PLoS Genetics. 2015;11(9):e1005389. 3. Saleem HMK, et al. Cureus. 2018;10(7):e3070. 4. Zani MB, et al. Frontiers in Medicine. 2022;8(777619):1-11.
5. Nauroy P, et al. Matrix Biol Plus. 2020;1-12.

BCX17725

SPINK9-variant.Fc

69

BCX17725 NONCLINICAL CHARACTERIZATION: POTENTIAL FOR
BEST-IN-CLASS TARGETED TREATMENT FOR NETHERTON SYNDROME

Favorable PK in NHP, compatible with
Q2Weeks or longer intervals ofadministration in the clinic
Low in-silico immunogenicity score – lower thanunmodified normal human IgG-Fc, predicting
minimal risk of anti-drug antibodies
More than 10-fold higher potency on KLK5
than DI-50055 SPINK5 Fc fusion protein,consistent with lower clinical doses

μg/mL in plasma, mean

75% bioavailability after SC injection in NHP,
supporting SC injection administration in theclinic1000

Nonclinical
BCX17725PK
PKProfileProfileofinBCX17725
NHP

100
10
1
0.1
0.01
0

4

8

12

16

20

24

28

Days after single 10 mg/kg SC injection

Fc, fragment crystallizable; IgG-Fc, immunoglobulin G-fragment crystallizable; KLK5, kallikrein-related peptidase 5; NHP, non-human primate; PK,pharmacokinetics; Q2Weeks, once every 2 weeks; SPINK5, serine protease inhibitor kazal type 5; SC, subcutaneous. BioCryst Pharmaceuticals data on file 2023.

70

BCX17725 PRECLINICAL DATA SHOW RAPID DISTRIBUTIONTO EPIDERMIS OF SKIN FOLLOWING IP ADMINISTRATION IN MOUSE
BeforeDosing

In a nonclinical study, BCX17725
was dosed by IP injection

Skin samples were assayed for
BCX17725 using a specificantibody and peroxidase
reaction – this shows up as
brown with intensity
proportional to drug content

4 hourPostdose

BCX17725 gets to theepidermis, the target tissue
required for treating
Netherton syndrome
Magnification = 400x

Epidermal layer
DermisWild-type mice were administrated 100 mg/kg BCX17725 (version suitable for murine studies)’
IP, intraperitoneal; BioCryst Pharmaceuticals data on file 2023.

71

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

72

BCX17725: BEST-IN-CLASS COMMERCIAL POTENTIAL
Prevalence•

Commercial Opportunities

Up to 5,000 individuals in the US likely have Netherton
syndrome1 with ~1,600 estimated from claims analysis*Target Profile•≤ 2mL SC injection, every 2 weeks or longer, pediatric and adult

Dosing /Administration•

Best-in-class dosing and efficacy•

Patient diagnosis/market expansion•

Ultra-rare disease pricing potential•

Indication expansion

Development
Stage

Competitor

MoA

QRX003 (Quoin)

Broad spectrum
serine proteaseinhibitor

TopicalPhase 2/3

DS2325a (Daiichi Sankyo)

KLK5 inhibitor

Weekly SC (600mg)

Phase 1/2

Spesolimab (Boehringer)

IL36 inhibitor

Monthly IV

Phase 2/3

How BCX17725 Likely to be Best-in-Class••

Lower treatment burden
Improved bioavailability with systemic delivery,leading to better efficacy•

Lower dose, smaller volume, less frequent
dosing••Better efficacy based on KLK5 target
Self-administered dosing*BioCryst Pharmaceuticals Data on file estimation based on US claims analysis.
IL36, interleukin-36; IV, intravenous; KLK5, kallikrein-related peptidase 5; SC, subcutaneous.
1. NIH. Netherton syndrome. February 2023. Accessed August 24, 2023. https://rarediseases.info.nih.gov/diseases/7182/netherton-syndrome73

KEY TAKEAWAYS: BCX17725 FOR NETHERTON SYNDROME
Netherton syndrome is a serious ultra-rare disease caused by loss of function
mutations of a natural KLK5 inhibitor
There are no approved treatments for Netherton syndrome

BCX17725 is an Fc fusion bioengineered natural human inhibitor of KLK5
Favorable nonclinical profile of BCX17725 supports potential forbest-in-class profile
We aim to deliver POC results in Netherton syndrome in 2026
74
Fc, fragment crystallizable; KLK5, kallikrein-related peptidase 5; PK, pharmacokinetics; POC, proof of concept.

AVORALSTATFOR DIABETIC MACULAR EDEMA (DME)75

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

76

TARGETING PLASMA KALLIKREIN AS AN OPTION TO IMPROVE VISION
IN PATIENTS WITH DIABETIC MACULAR EDEMA (DME)DME continues to be most common causeof vision loss in individuals with diabetes1

Analysis of VEGF and Plasma Kallikreinin Human DME Vitreous
Plasma Kallikrein

32%-66%of patients have persistent DME
despite anti-VEGF therapies2

VEGF(fold increase)25(pg/mL)

Plasma Kallikrein
VEGF

20

4,000
3,500
3,000
2,500

15

2,000
10

Plasma kallikrein may be asignificant contributor to retinal
edema and dysfunction in DME,

independent of VEGF mechanisms3

1,500
1,000

5
0

500
6 2 1 8 17 12 11 19 20 9 16 4 18 15 5 10 13 14 7 3

0

DME Pat. ID(ordered by VEGF concentration, low to high)Immunoassays of DME vitreous samples4

pg, picograms; mL, milliliter; SoC, standard of care; VEGF, vascular endothelial growth factor.
1. Lee R, et al. Eye Vis (Lond). 2015;2:17. 2. Bressler NM, et al. JAMA Ophthalmol. 2018;136(3):257-269. 3. Bhatwadekar AD, et al. Expert Opin
Investig Drugs. 2020;29(3):237-244. 4. Kita T, et al. Diabetes. 2015;64(10):3588-3599.

77

THE IMPORTANCE OF THE RIGHT DRUG, THE RIGHT MECHANISM,& OPTIMAL LOCATION OF DELIVERY Suprachoroidal
space

RetinaChoriocapillaris Sclera

Normal eye1
RetinaIn an eye with DME3,4:• Diabetes causes microangiopathy (vessel
damage in eye)• Micro vessel damage → contact activation•
Plasma kallikrein levels•
Bradykinin receptor expression•
Retinal vascular permeability

pKK
HMWK

Endothelial
cells

MaculaRetinal blood vessels

Choroid blood vessels

Diabetic macular edema1
Bradykinin
B2 & B1
receptors

SwollenretinaFluid

Fluid
leakage

pKK

BK

cHK

Fluid
BK
Macular edema

BK, bradykinin; cHK, cleaved high molecular weight kininogen; HMWK, high molecular weight kininogen; pKK, plasma kallikrein
1. Trinh HM, et al. World J Pharmacol. 2016;5(1):1-14. 2. Yang S, et al. Front. Pharmacol. 2021;12:727870. 3. Kita T, et al. Diabetes. 2015;64(10):3588-3599.
4. Lang GE, et al. TVST. 2020;9(4)1-12. v.

blood vessel

78

SUPRACHOROIDAL ADMINISTRATION OFFERS SEVERAL ADVANTAGESFOR DELIVERING AVORALSTAT TO TARGET TISSUES IN DME
Potential Advantages
 Provides targeted delivery of drug into a natural depot reservoir
 Establishes gradient for drug suspension to slowly release into retina, RPE & choroid Minimizes potential adverse events, such as vitreous hemorrhage

Suprachoroidal
injector**SCS Microinjector® is licensed from Clearside Biomedical, Inc. RPE, retinal pigment epithelium; SCS, suprachoroidal space.

79

AVORALSTAT: AN OCULAR PLASMA KALLIKREIN INHIBITOR
Avoralstat Levels after 1 Suprachoroidal
Injectionin NonclinicalModels inj
Avoralstat
levelsafter 1 suprachoroidal

Oral administration of avoralstat was safe
and well tolerated in 98 individuals livingwith HAE and 178 healthy individuals
μg/mgµg/g tissue
tissueThe AE profile of avoralstat was similar to placebo
in a randomized controlled trial1

10000
1000
100
10
1
0.1

The low solubility of
avoralstat supports
evaluation of asuspension depot
formulation forophthalmic injection

AE, adverse effects; HAE, hereditary angioedema; RPE, retinal pigment epithelium.
1. Riedl MA, et al. Allergy. 2018;73(9):1871-1880. 2. BioCryst Pharmaceuticals data on file 2023.

EC99 level in healthy subject plasma

0.01

retina

RPE, choroid & sclera

0

30

60

90

Dayspost
postadministration
adminstrationofof2mg
2mgavoralstat
avoralstat
Days

High levels of avoralstat are maintained
for at least 90 days in nonclinical studyof suprachoroidal injection2

80

PIPELINE PROGRAM MILESTONES
ASSET

2024

2025

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

2026

POC data

Start pivotal

BCX17725
Protein Therapeutic

Initiate phase 1

Start POC

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Start POC

Select lead molecule

Initiate phase 1

Select lead molecule

Oral C2 Inhibitor

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

2028

Submit sNDA

BCX10013
Oral Factor D Inhibitor

Oral C5 Inhibitor

2027

Select lead molecule

Initiate phase 1

POC data

POC data

Start POC

POC data

Initiate phase 1

Start POC

Start POC

POC data

POC data

AP, alternative pathway; C2, complement component 2; C5, complement component 5;CP, classical pathway; LP, lectin pathway; POC, proof of concept; sNDA, supplemental new drug application.

81

AVORALSTAT COULD MEET THE NEED FOR AN EFFECTIVESECOND-LINE THERAPY
Target Profile: Suprachoroidal injections every 3 months or better,with BCVA improvement (mean ≥ 6 letters) in patients with suboptimal
response to VEGF inhibitors• Anti-VEGF therapies are the backbone of DME treatment and require intravitreal
injections every 1 to 4 months1,2• Current guidelines recommend up to 3 attempts at anti-VEGF therapy, with offlabel Avastin (bevacizumab), Eylea (aflibercept), and Lucentis (ranibizumab)
being the top 3 recommended agents• The American Academy of Ophthalmology (AAO) estimates that anti-VEGF
therapy is unsuccessful or inadequate in 40% of patients with DME3

“The MOA is not what we know, it’s akallikrein inhibitor. That’s good, we don’t
need another anti-VEGF inhibitor, we needsomething in another pathway.”– Diabetic Macular Edema KOL4

“Any new MOA is exciting to me. I love that
it is not another recycle of an old anti-VEGF.
We have been swirling around different
ways to make different anti-VEGFs and weneed more options.”– Diabetic Macular Edema KOL4

Primary opportunities for avoralstat

Loss of vision acuity withcenter-involved DME

Anti-VEGF
monotherapy

Switch to adifferent antiVEGF

Switch again to adifferent anti-VEGF

BVCA, best-corrected visual acuity; DME, diabetic macular edema; MOA, mechanism of action; VEGF, vascular endothelial growth factor.
1. McFadden E., Decision Resources Group, 2018. 2. Diabetic Macular Edema- Epidemiology Forecast to 2032, 2018. 3. Elyasi N, et al. EyeNet
Magazine. 2021;35-37. 4. BioCryst Pharmaceuticals Market Research Q2 2023.

Laser
photocoagulation

Glucocorticoid
implants

82

DME IS A LARGE POPULATION BUT TREATMENTS ARE DELIVERED BY A
SMALL NUMBER OF SPECIALISTS, COMPATIBLE WITH A RARE DISEASE
Retina Care Provider Universe6-8

DME PROGRESSION1-5
Type I
Diabetes~3.7M US
Patients~75% Type I patientsdevelop diabetic retinopathy

Diabetic
Retinopathy~11M US
Patients

Type II
Diabetes~33.3M US
Patients

Ophthalmologists
17,000 – 18,000>25% Type II patientsdevelop diabetic retinopathy~10-17% of patients with diabetic
retinopathy develop DME

Retina Providers~3,300Retina Specialists~2,300Diabetic
Macular Edema~1.5M US
Patients

BioCryst has called on nearly
4,000 US physicians in 2023
alone for ORLADEYO

DME, diabetic macular edema; 1. BioMedTracker, Accessed August 2023; Prevent Blindness: Bringing Americans to Eye Care. 2. McFadden E., Decision
Resources Group, 2018. 3. Diabetic Macular Edema - Epidemiology Forecast to 2032, 2022. 4. National Diabetes Education Program; BioMedTracker.
5. Romero-Aroca P. Managing diabetic macular edema: The leading cause of diabetes blindness. World J Diabetes. 2011, accessed August 2023. 6.
Healio “Access to Retina Providers Shows no Geographic Bias” (March 2019). 7. AAO “Facts and Figures” (Jan 2020). 8. Pandit, et al. IOVS, 2020.

83

AVORALSTAT HAS POTENTIAL TO BE LEADING SECOND-LINE
THERAPY IN A GROWING DME MARKET$2B US VEGF inhibitor sales in 2022 expected to grow to $4B by 2028, driven by expanded patient
identification and treatment1
Competitor2

MoA2

Avastin, Eyelea,
Lucentis,
Vabysmo, Beovu

VEGF inh

Illuvien®,
Ozurdex®

Dosing/Administration2

Development
Stage

How Avoralstat Will beBest-in-Class

Intravitreal injections
every 1-4 months

Approved• Head-to-head superiority data vs
VEGF inh inadequate responders

Glucocorticoids

Implants every
3 months to 3 years

Approved• Better safety• Better efficacy

THR-149(Oxurion)

KKI

Monthly intravitreal
injections

Phase 2

• Less frequent dosing• Potentially superior efficacy
based on suprachoroidal delivery

RZ-402 (Rezolute)

KKI

QD OralPhase 2• Potentially superior efficacy
based on suprachoroidal delivery

Inh, inhibitor; KKI, plasma kallikrein inhibitor; QD, once daily; VEGF, vascular endothelial growth factor; 1. Evaluate
Pharma. 2. www.clinicaltrials.gov.

84

KEY TAKEAWAYS: AVORALSTAT FOR DME
Plasma kallikrein inhibition is a promising approach for DME treatment

Slow dissolution and high potency of avoralstat are ideal
characteristics for local depot delivery

Clearside partnership allows for suprachoroidal delivery of avoralstat
for patients with DME

Potential to be a leading 2L therapy for DME in a growing market

85
2L, second-line; DME, diabetic macular edema.

ORLADEYO PEDIATRIC INDICATION86

OUR BROAD AND DIVERSIFIED PIPELINEASSETPROGRAMORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor

Hereditary Angioedema (HAE)

ORLADEYO® (berotralstat)
Oral Plasma
Kallikrein Inhibitor in Pediatrics

Hereditary Angioedema (HAE)

BCX10013
Oral Factor D Inhibitor

Complement-Mediated Diseases

BCX17725
Protein Therapeutic

Netherton Syndrome

Avoralstat
Ocular Plasma Kallikrein Inhibitor

Diabetic Macular Edema (DME)

Oral C5 Inhibitor

Complement-Mediated Diseases

Oral C2 Inhibitor

Complement-Mediated Diseases

Bifunctional Complement Inhibitor
CP, LP, AP Inhibition

Complement-Mediated Diseases

LEAD
OPTIMIZATIONPRECLINICAL

PROOF OFCONCEPT*

PIVOTAL†APPROVED /COMMERCIAL*Typically Phase 1-2 studies.
†Typically Phase 3 studies.
C5, complement component 5; C2, complement component 2; CP, classical pathway; LP, lectin pathway, AP, alternative pathway.

87

ORLADEYO® CAN ADDRESS UNMET NEED IN CHILDREN WITH
HEREDITARY ANGIOEDEMA (HAE)
HAE is a rare, potentially life-threatening,
and lifelong disease that typically begins in childhood1

1 in 10,000 to 1 in 50,000

people affected2

Current Prophylaxis Options for Kids
TAKHZYRO(ages 2+)6*:
SC injection

2 out of 5 patients have theirfirst attack by 5 years of age1

HAEGARDA(ages 6+)7:
SC injection

CINRYZE(ages 6+)8:
IV infusion

TREATMENTSCHEDULESCHEDULE
TREATMENT
Week 1Children have smaller airway
diameters, which can increase riskof fatal laryngeal attacks3

Week 2
Week 3
Week 4

There is a desire for oral treatments for children with HAE
as injectable therapy can be difficult to sustain over time1,4

There are no current targeted oral therapies
available for prophylaxis in children < 12 years old5*The dosing frequency in patients aged 2 to <6 years is every 4 weeks, and in patients 6 to 12 years old, every 2 weeks, with every 4 weeks considered in some.
SC, subcutaneous; IV, intravenous.
1. Tachdjian R, et al. Clin Pediatr (Phila). 2023;99228231155703. 2. Bernstein JA. Allergy Asthma Proc. 2013;34(1):3-6. 3. Betschel SD, et al. J Allergy Clin Immunol
Pract. 2023;11:2315-25. 4. Wahn V, et al. Pediatric Allergy and Immunology. 2020;31:974-989. 5. Tachdjian R, et al. J Allergy Clin Immunol.
2023;151(2 suppl):AB136. 6. Takhzyro [package insert]. Takeda Pharmaceuticals. 2023. 7. Haegarda [package insert]. CSL Behring. 2020. 8. Cinryze[package insert]. ViroPharma Biologics LLC, Takeda Pharmaceuticals. 2022.

88

ORLADEYO® ADMINISTERED VIA GRANULES
New dosage form
Pediatric Granules(~ 2 x 3 mm)

Dosage instructions

Sprinkle granules on tongue
and swallow with water or milkOR
Sprinkle granules over 1 tablespoon of soft
non-acidic food and consume immediately•

Chocolate pudding, baby food (peas, banana,carrot), mashed potatoes or sweet creamed corn

89

APEX-P: ORLADEYO® FOR THE TREATMENT OF HAE IN
CHILDREN 2 TO < 12 YEARS OLD
Open-label trial across North America, Israel, UK andEurope (~15 sites) designed to evaluate thepharmacokinetics (PK) and safety of ORLADEYO in
pediatric patients with HAE (ages 2 to < 12 years old)
• Goal is to determine the dosage that matches the
exposure in adults

Submit US sNDA

• 4 cohorts (N = 30) grouped by patient body weight

SOC Therapy
Screening/
Enrollment

2025

ORLADEYO QD
Day 1 (BL)Start
berotralstat

Week 12

Collect PK andsafety data

Week 48*

Collect long-term
safety data to support
sNDA*Patients may continue to receive Orladeyo on study beyond 48 weeks. BL, baseline; HAE, hereditary angioedema; QD, once daily; PK, pharmacokinetics;
sNDA, supplemental new drug application; SOC, standard of care; UK, United Kingdom; US, United States.

90

KEY TAKEAWAYS: ORLADEYO FOR PEDIATRICS
Critical unmet need for oral treatment for children with HAE

ORLADEYO can be administered via granules, making it easier todose for children

APEX-P is a pivotal, ongoing trial for ORLADEYO treatment inchildren with HAE

On track to submit US sNDA in 2025

91
HAE, hereditary angioedema; sNDA, supplemental new drug application; US, United States.

PIPELINE PROGRAMS PAVE WAY FOR POTENTIAL
THERAPEUTIC AREA GROWTH
Therapeutic area

Potential initial indications

Potential portfolio expansion

Allergy / Immunology

ORLADEYO® for HAE•

ORLADEYO pediatric••

Oral C5i + C2i combo for hidradenitis
suppurativa (HS)Bifunctional for bullous pemphigoid (BP)••Bifunctional for lupus nephritis (LN)
BCX10013 + C2i oral combo for IgAN
Oral C5i for neuromyelitis optica (NMO)
Oral C2i for multifocal motor neuropathy(MMN)

Dermatology

BCX17725 for NS

Nephrology

BCX10013 for IgAN or C3G

Neurology

Oral C5i for gMG••

Hematology

Oral C2i for CAD•

Oral C2i for wAIHA

Ophthalmology

Avoralstat for DME•

Complement inhibitor for AMD and GA
Non-complement inhibitor programs

AMD, age-related macular degeneration; C2i, complement 2 inhibitor; C5i, complement 5 inhibitor; C3G, C3 glomerulopathy; CAD, cold agglutinin
disease; DME, diabetic macular edema; GA, geographic atrophy; HAE, hereditary angioedema; IgAN, Immunoglobulin A nephropathy;
gMG, generalized myasthenia gravis; NS, netherton syndrome; wAIHA, warm autoimmune hemolytic anemia.

92

DISCIPLINED CAPITAL ALLOCATION APPROACH
Anthony Doyle, Chief Financial Officer

93

DISCIPLINED CAPITAL ALLOCATION

Strategic discovery process

Disciplined approach to stage-gate investment

Financial strength and future optionality

94

THANK YOU

95