APL-2 and complement inhibition; a potential treatment of ... · Apellis Highlights Mission: to...

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September 27, 2016 APL-2 and complement inhibition; a potential treatment of PNH and other complement- mediated diseases Carolina Vega, MS Director of Pharmaceutical Development Boulder Peptide Symposium 1

Transcript of APL-2 and complement inhibition; a potential treatment of ... · Apellis Highlights Mission: to...

Page 1: APL-2 and complement inhibition; a potential treatment of ... · Apellis Highlights Mission: to create disease-modifying therapies in chronic inflammatory and orphan disease indications

September 27, 2016

APL-2 and complement inhibition; a potential treatment of PNH and other complement-

mediated diseases

Carolina Vega, MSDirector of Pharmaceutical Development

Boulder Peptide Symposium

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Apellis Highlights

�Mission: to create disease-modifying therapies in chronic inflammatory and

orphan disease indications via complement inhibition

�Lead product candidates APL-1 and APL-2

§ Potent and selective C3 inhibitors of the compstatin family

�Clinical pipeline targets autoimmune and inflammatory diseases

§ Initially PNH, AMD and COPD

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APL$1APL$2

Activation.Pathways

Classical.pathwayActivated)by)antibody.antigen)complex

Lectin.pathwayActivated)by)lectin)and)mannose)complex

Alternative.pathwaySpontaneous)C3)

convertase)activation

C3

C3bC3a

C5

C5bC5a MACInflammation

Inflammation Cell.removal

Cell.destruction

Lead candidates target C3 central in the complement cascade

Broad inhibition of complement

cascade

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Evidence of safety of C3 inhibition

� A small population of individuals lack functional levels of C3 and C5*.These individuals are susceptible to infection by certain bacterial species

� No cases of drug-related infections following experiments involving >300 non-human primates§ Multiple compounds (APL-1, APL-2 and others)§ Acute and chronic exposure

� No cases of infections with subcutaneous APL-2 to date – triple vaccination� No cases of infections with intravitreal APL-2 to date – no vaccination� Two cases of fever with nebulized APL-1 (resolved with antibiotics) – single vaccination

C5-deficient individuals Neisseria meningitidis

C3-deficient individuals Neisseria meningitidis,

Streptococcus pneumoniaeHaemophilus influenzae

INFECTION RISK MANAGEABLE WITH

VACCINATION

4*Figueroa,J.E.etalClin.Microb.Rev.4(3),359-395,1991

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� HaematologicalParoxysmal nocturnal haemoglobinuria, cold agglutinin disease, and warm antibody autoimmune hemolytic anemia

� OphthalmologyAge-related macular degeneration, dry eye, glaucoma, uveitis, and diabetic retinopathy

� Respiratorychronic obstructive pulmonary disease, idiopatic pulmonary fibrosis, acute respiratory distress syndrome, asthma, bronchiolitis obliterans syndrome and cystic fibrosis

� NeurologicalMyasthenia gravis, neuromyelitis optica, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Guillain-Barré syndrome, cerebral lupus, multifocal motor neuropathy, and stroke

� RenalLupus nephritis, membranoproliferative glomerulonephritis, membranous nephritis, immunoglobulin A nephropathy, goodpasture syndrome, post-streptococcal glomerulonephritis, dense deposit disease, C3 glomerulonephritis, and atypical haemolytic uraemic syndrome

� RheumatologicalSystemic lupus erythematosus, lupus arthritis, rheumatoid arthritis, Sjögren’s syndrome, Behçet’s syndrome, cryopyrin-associated autoinflammatory syndrome and systemic sclerosis

� VascularMyocardial infarction and atherosclerosis

� AllergicAnaphylactic shock, allergy and asthma

� DermatologyVasculitis, pemphigus, bullous pemphigoid, phototoxic reactions and psoriasis

� OtherInflammatory bowel disease, thyroiditis, Crohn’s disease, cryoglobulinaemia, foetal loss, organ graft rejection, sepsis and trauma (including spinal cord injury)

Overview of complement-related indications

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Apellis Broad Pipeline

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2016 2017

1H 2H

COPD (Pulmonary)

PNH – rMG - NMO (Rare Indications)

GA (Ophthalmology)

Preclinical StudiesPh 1b Soliris (USA; n=8-16)Ph 1b Tx NZ; n=6)Ph 3 (PNH; TBNaïve (D)Ph 3 (rMG; TBD)Ph 3 (NMO; TBD)

Ph 2 (Aus, USA; n=240)

Ph 1 HV (n=18)

2018

1H 2H 1H 2H

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Compstatin-based Peptides

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Discovery of CompstatinThe sequence of compstatin was identified from a phage library experiment using a 27-mer library.

Summary

� Compstatin was first identified from a phage display experiment by Prof. John Lambris at the University of Pennsylvania

� A pIII phage 27-mer library of 2 x 108 recombinants expressing the peptide sequence SR X12 (S, P, T, or A) A (V, A, D, E, or G) X12 SR was screened against human C3b.

� One clone (Clone 9) was isolated that was shown to bind selectively to C3, C3b, and C3c.

Sahu, J. Immunol., 1996, vol. 157, p.884

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A 13-mer complement inhibiting domain of Clone 9 was identified and named Compstatin.

The complement inhibitory domain was identified as a 13-mer cyclic subsequence (peptide IV) using standard hemolysis-based classical and alternative complement inhibition assay (with an IC50 of 63 µM and 12 µM respectively) and was named Compstatin.

Identification of Compstatin

Sahu, J. Immunol., 1996, vol. 157, p.884

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Cyclization and acetylation were shown to slow the degradation and enhance the activity

Summary

� Compstatin was shown to be active only against primate C3 (above).

� Non acetylated and linear compstatin degrades very quickly by cleavage at the N- terminus and has reduced activity (right)

Properties of Compstatin

Sahu, Mol. Immunol,. 39, 557-566, 2003

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Compstatin binds to a pocket of C3 and sterically hinders its binding.

Summary

� Crystal structure of compstatin and C3c was elucidated in 2007.

� Compstatin was shown not to induce significant structural changes to C3 upon binding.

� Compstatin is believed to sterically interfere with C3 binding to C3-convertase complexes of the complement cascade.

Mechanism of Action of Compstatin

Janssen, J. Biol. Chem., 282(40), 29241-29247, 2007

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APL-1 is an improved compstatin derivative.

Overview

� APL-1§ 3rd generation compstatin derivative optimized using

rational design and peptide library screening.§ At least 250x more potent than the original compstatin

APL-1 Structure

Ac-Ile-Cys-Val-MeTrp-Gln-Asp-Trp-Gly-Ala-His-Arg-Cys-Thr-NH2|___________________________________|

Ac-Ile-Cys-Val-Val-Gln-Asp-Trp-Gly-His-His-Arg-Cys-Thr-NH2|________________________________|

APL-1

Compstatin

Kd(usingSPR)

C3 C3(H2O) C3b iC3b C3c

Compstatin 0.13µM 0.06µM 2.6µM ND 9.6µMAPL-1 260pM ND 174pM 435pM ND

APL-1

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APL-2 Program

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APL-2 ProgramThis program aims to extend the circulating half-life of APL-1 and improve its solubility in serum in order to address chronic, systemic complement-mediated indications.

Design of New APL-1 Conjugates with Extended Serum Half-Life

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� Several life extensions technologies were tested, among them were PEGylation, albumin conjugation and some proprietary technologies.

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Extended Half-Life Candidates PharmacokineticsExtended half-life candidates have a terminal half-life 10x higher and a significantly higher Cmaxthan APL-1 in Cynomolgus monkeys at comparable dose

A P L - 2 C a n d id a t e s C o m p a r a t iv e T 1 /2 A f te r IV In je c t io n

T Im e (d a y s )

Co

nc

en

tra

tio

n

(ug

/mL

)

0 5 10 151

10

100

1000

10000

A P L -1 ( IV 2 0 0 m g /k g )

C a n d id a te 3 ( IV 5 0 m g /k g )

C a n d id a te 2 ( IV 5 0 m g /k g )

C a n d id a te 1 ( IV 7 0 m g /k g )A P L -8 ( IV 5 0 m g /k g )

C a n d id a te 4 ( IV 3 2 m g /k g )

A P L -7 (s in g le IV 7 m g /k g )

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PK vs Conjugate Size in CynoLarger conjugates have longer half-life as expected. Balance between size and half-life is important.

D i f f e r e n t C a n d id a t e s v s A P L -1 P h a r m a c o k in e t ic s

T Im e (d a y s )

Co

nc

en

tra

tio

n

( µg

/mL

)

0 5 10 150 .1

1

10

100

1000

A P L -1 ( IV 2 0 0 m g /k g )

A P L -9 (7 m g /k g S C )

A P L -1 0 (7 m g /k g S C )

A P L -1 1 (7 m g /k g S C )

A P L -2 (7 m g /k g S C )

A P L -1 2 (7 m g /k g S C )

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Simple stability experiment outlines very significant differences between coupling chemistry.

Coupling Chemistry Stability

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APL-2 Coupling ChemistriesDifferent coupling chemistries are available during conjugation. Some of these chemistries are more stable in vivo than others.

C o m p a r a t iv e P K ( C o u p l in g C h e m is t r ie s C o m p a r is o n )

T Im e (d a y s )

Co

nc

en

tra

tio

n

(ug

/mL

)

0 5 10 151

10

100

1000

C h e m is t r y A ( IV 5 0 m g /k g )C h e m is t r y B ( IV 3 2 m g /k g )

A P L -1 ( IV 2 0 0 m g /k g )T1/2 ≈ 4-5 days

T1/2 ≈ 7-8 days

T1/2 ≈ 6-8 hours

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Careful Design (Geometry, Linker, Chemistry)Preserved Conjugate Activity

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0 .0 0 0 1 0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 0

0

1

2

A lte r n a t iv e C o m p le m e n t In h ib it io n A s s a y

C o n c e n tra t io n (u M )

Co

mp

lem

en

t A

cti

vit

y (

Ab

so

rba

nc

e

Un

its

)

A P L -1A P L -2

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APL-2:Preclinical Data

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APL-2 Preclinical Summary

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� APL-2 SC preclinical work conducted in cynomolgus monkeys, New Zealand white rabbits, or CD rats

� Safety Pharmacology (monkeys)

§ hERG assay: no significant drug-related hERG current amplitude change over the concentrations used (1 to 300 µM)

§ Cardiopulmonary telemetry: no drug-related observations (highest dose tested: 140 mg/kg)

� APL-2 non-genotoxic (AMES, In vitro TK6 micronucleus, In Vivo mouse micronucleus)

� Reproductive SC studies (rats and rabbits)

§ Pilot prenatal studies conducted (1, 3.5, 7, 28 mg/kg/d)

§ No drug-related findings at any dose in either species

� Chronic IVT repeated-dose studies (monkeys only)

§ Monkeys: 9-month study with 3-month peel-off

§ IVT"3.1, 12.4, 24.8 mg/eye (every 4 weeks)

§ No significant drug-related observation at any doses tested (NOEL ≥24.8 mg/eye)

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APL-2 Preclinical Summary (cont.)

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� 28-day SC/IV repeated-dose studies (monkeys and rabbits)

§ Doses tested: SC"0.25, 1, 3, 7, 28, 140 mg/kg/d; IV"2 x 42 mg/kg

§ SC: Macrophage vacuolation at ≥3 mg/kg/d (NOEL ~3 mg/kg/d)

§ SC: Minimal kidney tubule degeneration at ≥28 mg/kg/d (NOAEL between 7 and 28 mg/kg/d)

§ IV: No drug-related observation at 2 x 42 mg/kg (doses on Day 1 and Day 15)

§ PEG and APL-2 mildly antigenic in rabbits and not antigenic in monkeys

� Chronic SC repeated-dose studies (monkeys and rabbits)

§ Monkeys: 9-month study with 3-month peel-off

– After 3 months of treatment the same effects than the 28-day dosing study were observed.

§ Rabbits: 6-month study with no peel-off

– Doses tested: SC"1, 7, 28 mg/kg/d

– No drug-related findings after 6 months of treatment.

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T im e (d a y s )

Co

nc

en

tra

tio

n

( µg

/mL

)

0 20 40 601

10

100

1000

10000

7 m g /k g /d in m o n k e y s2 8 m g /k g /d in m o n k e y s1 4 0 m g /k g /d in m o n k e y s

0 .2 5 m g /k g /d in m o n k e y s

1 m g /k g /d in m o n k e y s

3 m g /k g /d in m o n k e y s

4 2 m g /k g e v e r y 2 w e e k s ( IV ) in m o n k e y s

APL-2 PK: Subcutaneous Injections

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APL-2 PK after daily SC injections in Cynos

Last SC dose

APL-2 demonstrates well-behaved pharmacokinetic behavior in monkeys. T½ of approximately 7.5 days.

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APL-2 PK: Intravitreal Injections

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T im e (d a y s )

Co

nc

en

tra

tio

n

(ug

/mL

)

0 1 0 0 2 0 0 3 0 01

1 0

1 0 0

1 0 0 0

1 0 0 0 0

A P L -2 (9 .6 m g ) - s e r u m

A P L -2 (9 .6 m g ) - v i t r e o u s h u m o r

A P L -2 (3 .1 m g ) - s e r u m

A P L -2 (1 2 .4 m g ) - s e r u mA P L -2 (2 4 .8 m g ) - s e r u m

A P L -2 (2 4 .8 m g ) - v i t r e o u s h u m o r

APL-2 PK after intravitreal injections in Cynos (every 4 wks)

ITV Dose

APL-2 T½ in monkeys was 3.2 days in vitreous and 10.4 days in serum.

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APL-2 (subcutaneous):Paroxysmal Nocturnal Hemoglobinuria

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Unmet need in paroxysmal nocturnal hemoglobinuria DISEASE� ~4,700 patients in the US� Severe anemia, thrombotic risk, impaired bone marrow

functions� ~35% 5-year mortality if left untreated (main cause:

thrombosis)

STANDARD OF CARE� Soliris® only approved therapy

§ Controls intravascular hemolysis§ ~$583,000 / year / adult patient

UNMET NEED � 35-40% of patients on Soliris continued to be

transfusion-dependent for 30 months following the beginning of treatment*

§ Soliris® does not prevent C3b-mediated extravascular hemolysis

*Hillmen,P.etal.Br.J.Haematology,2013,162(1):62–73(Dr.Hillmen isanadvisortoApellis)

35-40% of Solirispatients continue to be transfusion

dependent*

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Intravascular vs extravascular hemolysis

Rother R,RollinsSA,Mojcik C,BrodskyRAandBellL. Discoveryanddevelopmentofthecomplementinhibitoreculizumab forthetreatmentofparoxysmalnocturnalhemoglobinuria.NatureBiotechnology.2007.25(11):1256-1264.

No#Complement+mediated#

hemolysisC5/MAC+mediated

Intravascular#hemolysisC3b+mediated

Extravascular#hemolysis

HEALTHY PNH)PatientsC3b#on#RBC

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Activation)Pathways

Classical)pathwayActivated)by)antibody.antigen)complex

Lectin)pathwayActivated)by)lectin)and)mannose)complex

Alternative)pathwaySpontaneous)C3)

convertase)activation

C5

C5bC5a MACInflammation

Inflammation Cell)removal

Cell)destruction

Eculizumab

C3

C3bC3a

Inhibition of C5 prevents C5a and MAC but not C3a-mediated inflammation and C3b deposition

C3b$on$RBC

INTRAVASCULAR

EXTRAVASCULAR

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Activation)Pathways

Classical)pathwayActivated)by)antibody.antigen)complex

Lectin)pathwayActivated)by)lectin)and)mannose)complex

Alternative)pathwaySpontaneous)C3)

convertase)activation

C5

C5bC5a MACInflammation

Inflammation Cell)removal

Cell)destruction

Eculizumab

C3

C3bC3a

Broader inhibition of complement at C3 may overcome limitations of C5 inhibition

C3b$on$RBC

INTRAVASCULAR

EXTRAVASCULAR

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Potential Benefits APL-2 • Prevention of blood clot formation• Reduced anemia and transfusion dependency• Ease of use (self-administered once daily)• Disease modifying potential

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In PNH blood APL-2 prevents C3 deposition and should prevent extravascular hemolysis*

*AbstractatASHConference2013byDr.PeterHillmen,LeedsTeachingHospitals,NHSTrust,UnitedKingdom(Dr.Hillmen isanadvisortoApellis)

MimicsEXTRAVASCULAR

Hemolysis

PNH$patient

C3b.coated$RBCs

Complement$activationAPL.2

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Phase 1 Studies

Trial N Doses & dosing period Endpoints Preliminary Results

Phase 1HealthySAD

3124 active 7 placebo

• 45-1440 mg/day• Safety/tolerability• PK/PD• Hemolytic activity

No SAEs. Well toleratedC max 3 days/ half life 10 daysReduced hemolytic activity

Phase 1HealthyMAD

2016 active 4 placebo

• 30 – 270 mg/day• 28 days

• Safety/tolerability• PK/PD• Hemolytic activity

No SAEs. Well toleratedPK profile supports daily subcutaneous injectionReduced hemolytic activity

Design: randomized, double-blind, placebo-controlled, single and multiple ascending dose studies toassess the safety, tolerability, PK and PD of subcutaneous APL-2 in healthy adult subjects who havereceived the triple vaccination.

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APL-2 demonstrates well-behaved pharmacokinetic behavior in human subjects. Tmax of approximately 4-5 days and long T½ of approximately 9 to 10 days.

Phase 1 healthy SAD trial PK data

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Phase 1 healthy MAD trial PK data (28-day)

Cohort 1 – 30 mg/dayCohort 2 – 90 mg/dayCohort 3 – 180 mg/dayCohort 4 – 270 mg/day

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Normal hemolytic activity in placebo subject

0 1 0 2 0 3 0 4 00

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

1 1 0

H e m o ly s is o f R e d B lo o d C e lls b y th e A lte rn a tiv e P a th w a y(1 :4 P la s m a D ilu tio n )

D a y s

%

He

mo

lys

is (

Alt

ern

ati

ve

P

ath

wa

y)

H e a lth y S u b je c t (p la c e b o )

Treatment Period

Effective complement inhibition by Soliris (≤20% hemolytic activity)**,***

**P Hillmen, N Engl J Med 2004;350:552-9***Hemolyticactivityassaysusedmayvary

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APL-2 reduces hemolytic activity - 180 mg

0 1 0 2 0 3 0 4 00

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

1 1 0

H e m o ly s is o f R e d B lo o d C e lls b y th e A lte rn a tiv e P a th w a y

D a y s

%

He

mo

lys

is (

Alt

ern

ati

ve

P

ath

wa

y)

H e a lth y S u b je c t(p la c e b o )

H e a lth y S u b je c ts(A P L -2 tre a te d )

Treatment Period

Effective complement inhibition by Soliris (≤20% hemolytic activity)**,***

**P Hillmen, N Engl J Med 2004;350:552-9***Hemolyticactivityassaysusedmayvary

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APL-2 reduces hemolytic activity - 270 mg

0 1 0 2 0 3 0 4 00

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

1 1 0

1 2 0

1 3 0

R a b b it R e d B lo o d C e ll A lte rn a tiv e P a th w a y H e m o ly s is

D a y s

%

He

mo

lys

is (

Alt

ern

ati

ve

P

ath

wa

y)

H e a lth y S u b je c t(p la c e b o )

H e a lth y S u b je c ts (A P L -2 tr e a te d )

Treatment Period

Effective complement inhibition by Soliris (≤20% hemolytic activity)**,***

**P Hillmen, N Engl J Med 2004;350:552-9***Hemolyticactivityassaysusedmayvary

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Phase 1b studies in PNH patients

The Paddock study

The Pharoah study

• Primary Endpoints: number and severity of TEAEs and pharmacokinetics parametersof APL-2 following administration of multiple SC doses

• Secondary Endpoints: Lactate dehydrogenase (LD), Hemoglobin, Haptoglobin, PNHclones

• Subjects with Paroxysmal Nocturnal Hemoglobinuria (PNH) that have not been treated with Eculizumab in the past

• Total of 6 subjects in 2 Cohorts• Two doses: 180 and 270 mg/d of APL-2 for 28 days

• Subjects with PNH currently receiving Eculizumab• Total of 8 subjects in 4 Cohorts• Doses ranging for 30mg/d to 270 mg/d of APL-2 for 28 days

Both Studies

To assess the safety, preliminary efficacy and pharmacokinetics of subcutaneouslyadministered APL-2

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APL-1 Conjugate with Extended Half-Life was Successfully Developed, Optimized, and Is Now Being Tested in Multiple Clinical Trials

Conclusion

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APL-2 Development

� Numerous half-life extension technologies were tested.� The most promising technology was chosen for optimization.

APL-2 Optimization

� The optimal size was determined as the best compromise between serum half-life and molecular weight.

� The most stable coupling chemistry was used.

� The resulting optimized molecule has a half-life that is about 30x the half-life of APL-1 with an activity that is at least 50% higher on a molar basis.

APL-2 Preclinical Testing

� Up to date APL-2 has proven to be safe when administered chronically by SC and IVT administration.

APL-2 Clinical Testing

� APL-2 was tested in healthy volunteers to confirm subcutaneous PK parameters.� It was confirmed that APL-2 could reduce the hemolytic activity via the Alternative Pathway at doses of 180 and 270

mg/day. � Testing in PNH patients is ongoing using subcutaneous injections.

� Testing in AMD patients is ongoing using intravitreal injections.

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Thank you

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