Inhibiting Complement C3 with APL-2 Controls Haemolysis and Increases Haemoglobin Levels in

Patients With Autoimmune Haemolytic Anemia (AIHA)

Interim Results From the PLAUDIT Clinical Trial Dr Bruno Fattizzo, MD

Fondazione IRCCS Ca’ Granda Policlinico Hospital Milan, Italy

Updates to slide 13 were made on 06/17/19

DisclosuresBruno Fattizzo, MD

Consultation on AIHA for Apellis

2

AIHA Is A Rare and Heterogeneous Disease

1. Anemia, hemolytic, acquired autoimmune. National Organization for Rare Disorders Web site. https://rarediseases.org/rare-diseases/anemia-hemolytic-acquired-autoimmune/. Accessed March 1, 2018. 2. Berentsen S. Role of complement in autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):303-310. 3. Sonikpreet S, Oberoi G, Kumar S. Case report: autoimmune hemolytic anemia with venous thromboembolism, a common complication of a rare disease. Blood. 2014;123:4869. 4. Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev. 2014;13(4-5):560-564. 5. Barcellini W. Pitfalls in the diagnosis of autoimmune haemolytic anaemia. Blood Transfus. 2015;13(1):3-5.

• Incidence in adults of 0.8–3 per 100.000/year

• Middle-age female predominance• Pathogenesis autoantibodies

against erythrocytes• Diagnosis DAT test (I,II,III level),

steroid response

Characterized by the premature haemolysis of red blood cells (RBCs) by autoantibodies.1

3

Complement C3 Is Central in the Disease Pathology of AIHA

Extravascular Haemolysis is Reported To Be The Unique Route of Haemolysis in wAIHA2

Haemolysis in CAD Appears To Be Complement-Mediated1-3

4

Steroids

Rituximab

Splenectomy

Immune-suppression

5

Current Treatment Options

Rituximab

Alone or in association

W. Barcellini, Current treatment strategies in autoimmune hemolytic disorders. Expert Rev Hematol. 2015S. Berentsen, Bendamustine plus rituximab for chronic cold agglutinin disease (...). Blood. 2017

EPO, PEX, ECULIZUMAB, ANTI-C3, BORTEZOMIB, BMT…

APL-2 Inhibits C3, The Central Complement Protein

Lectin Pathway

C5aC3b

C5b MAC

Inflammation

Cell removal, Antigen uptake

by APCs

C5

C3a Inflammation

Classical Pathway

Alternative Pathway

APL-2

C3

6

Cell death, secretion, lysis, or

proliferation

Central inhibition of complement

Update From PLAUDIT: A Phase 2 Clinical Study of APL-2 for the Treatment of AIHA

Abstract Code: S899

Randomized 1:1

Randomized 1:1

Key Eligibility Criteria

• Haemoglobin (Hb) levels <11 g/dL• Signs of haemolysis• Positive direct antiglobulin test (DAT) for IgG and/or complement C3

Study Design – Open Label

APL-2 Daily 270mg (N=6)

APL-2 Daily 360mg (N=6)

APL-2 Daily 270mg (N=6)

APL-2 Daily 360mg (N=6)

Cohort 1Warm AIHA

(N=12)

Cohort 2Cold AIHA

(N=12)

Efficacy assessed by change from baseline in

haematologic and blood chemistry parameters and

FACIT

Treat for 48 Weeks

Eligibility & Study Design

8

Demographics and Baseline CharacteristicsCAD wAIHA C3+

270 mg(n=7)

360 mg(n=6)

All(n=13)

270 mg(n=3)

360 mg(n=5)

C3+(n=8)

Age, years, mean (SD) 68.9(8.5)

75.7(7.5)

72.0(8.5)

50.7(15.0)

51.6(23.6)

51.3(19.6)

Sex, n (%)MaleFemale

3 (42.9)4 (57.1)

1 (16.7)5 (83.3)

4 (30.8)9 (69.2)

0 (0.0)3 (100.0)

2 (40.0)3 (60.0)

2 (25.0)6 (75.0)

Ethnicity, n (%)Hispanic or LatinoNot Hispanic or Latino

1 (14.3)6 (85.7)

1 (16.7)5 (83.3)

2 (15.4)11 (84.6)

3 (100.0)0 (0.0)

3 (60.0) 2 (40.0)

6 (75.0)2 (25.0)

Race, n (%)WhiteNon-whiteOther

7 (100.0)0 (0.0)0 (0.0)

5 (83.3)1 (16.7)1 (16.7)

12 (92.3)1 (7.7)1 (7.7)

3 (100.0) 5 (100.0) 8 (100.0)

Weight, kg, mean (SD) 83.6(19.2)

71.0(10.6)

77.8(16.5)

70.4(7.0)

93.8(18.4)

85.1(18.8)

CAD= cold agglutinin disease; n=number of subjects; SD=standard deviation; wAIHA=warm antibody autoimmune hemolytic anemia9

Results: Haematologic Parameters – All SubjectsBaseline Day 28 Day 168 Day 336

CAD Cohort: Mean (SD)Hb, g/dL 8.9 (0.4)

n=1311.2 (0.5)

n=1111.2 (0.6)

n=1012.6 (0.1)

n=2LDH, U/L 486.5 (142.1)

n=13267.1 (60.6)

n=12183.2 (22.2)

n=10155.5 (0.5)

n=2Bilirubin, mg/dL 1.9 (0.3)

n=130.7 (0.2)

n=120.4 (0.1)

n=100.7 (0.5)

n=2Haptoglobin, mg/dL 24.1 (10.2)

n=1347.7 (14.2)

n=1244.4 (13.8)

n=825.0 (15.0)

n=2ARC, 109/L 138.6 (18.5)

n=12101.5 (19.9)

n=1163.6 (6.0)

n=1079.7 (5.2)

n=2BMRI 94.0 (65.5)

n=1187.6 (63.5)

n=1148.7 (33.9)

n=1076.7 (8.7)

n=2wAIHA C3+ Cohort: Mean (SD)

Hb, g/dL 9.2 (0.3)n=8

10.5 (0.4)n=8

11.0 (0.7)n=5

11.0 ()n=1

LDH, U/L 337.4 (62.6)n=8

207.0 (22.1)n=7

142.2 (6.0)n=5

147.0 ()n=1

Bilirubin, mg/dL 0.8 (0.1)n=8

0.4 (0.1)n=7

0.3 (0.1)n=5

0.1 ()n=1

Haptoglobin, mg/dL 22.5 (8.3)n=8

66.1 (19.2)n=8

103.0 (30.6)n=5

195.0 ()n=1

ARC, 109/L 193.0 (21.8)n=8

112.7 (32.8)n=8

92.2 (19.3)n=5

42.0 ()n=1

BMRI 144.2 (48.1)n=8

93.2 (77.3)n=8

79.7 (32.1)n=5

38.5 ()n=1

ARC = absolute reticulocyte count; BMRI = bone marrow responsiveness index [(absolute reticulocyte count) X (subject’s Hb/normal Hb)]; CAD = cold agglutinin disease; Hb = hemoglobin; LDH = lactate dehydrogenase; n = number of subjects reporting data at this timepoint; SD = standard deviation; wAIHA = warm antibody autoimmune hemolytic anemia

10

AIHA is A Puzzle!!

B-cellproliferation

Macrophagesystem

activation

Bone marrow

responseflogosis

Auto-immunity

Complement

11

Reticulocytes in wAIHA and CAD in Response to APL-2

• Mean reticulocyte count decreased from 138.6´ 109/L at baseline to 63.6 ´ 109/L at day 168.

• Mean reticulocyte count decreased from 193.0 ´ 109/L at baseline to 92.2 ´ 109/L at day 168.

ARC in wAIHAARC in CAD

12

Results: Transfusion and FACITTransfusions

FACIT Fatigue Score*

CAD wAIHA C3+Subjects with Transfusions (within 168 days before study entry) 6/13 2/8

Subjects with Transfusions(within 14 days on study) 2/13 0/8

Subjects with Transfusions(between 15-168 days on study)

2/13(both subjects discontinued

before day 168)

2/8(both subjects discontinued

before day 168)

Subjects at Day 168 with Transfusions after Day 14 0/10 2/5

CAD wAIHA C3+Mean (SD) Change from Baseline at Day 168

9.7 (2.3)n=10

2.4 (4.1)n=5

*FACIT- Clinically significant increase is 3 or more points

• CAD: Two heavily transfusion dependent patients did not respond to APL-2 and left the study at Day 56 and 108 respectively and one patient is still participating in the study and has not yet reached Day 168

• wAIHA C3+: Two of the eight enrolled C3+ wAIHA patients left the study due to lack of response prior to day 168; one of the eight enrolled C3+ wAIHA subjects is still participating in the study and has not yet reached Day 168

13

Results: Safety

• All 13 CAD subjects and 10 of 11 wAIHA (C3+ and C3-) experienced ≥1 treatment-emergent adverse event (TEAE), mainly Grade 1-2.

• Ten subjects reported 13 unrelated serious adverse events (SAEs).

• Ten subjects experienced 26 unrelated/unlikely related Grade 3 TEAEs (haemolytic flare, pneumonia, dyspnoea, hypertension, acute cholecystitis, squamous cell carcinoma, purpura, hypokalaemia, acute kidney injury, dizziness, nausea, pain in extremity).

• 1 subject reported 2 unrelated Grade 4 TEAEs (high calcium, high creatinine) and withdrew.

• No grade 3 or 4 AEs were considered to be treatment related.

n = number of subjects with AEs in that category; m = number of AEs in that category.

14

CategoryCAD

(n=13)wAIHA(n=11)

n (%) m n (%) m

Any TEAE 13 (100) 142 10 (90.9) 120

SAE 5 (38.5) 8 5 (45.5) 5

TEAEs Related to APL-2 7 (53.8) 26 8 (72.7) 25

TEAEs Leading to Discontinuation 2 (15.4) 3 2 (18.2) 4

Severe TEAEs (≥ Grade 3) 6 (46.2) 7 5 (45.5) 21

Treatment With APL-2 Has Been Well-Tolerated

Mainly grade 1-2

Grade 3-4 not related to APL-2Infections not related

Summary

• APL-2 rapidly increases Hb values both in CAD and in wAIHA (C3+) within the first weeks of treatment

• APL-2 reduces both intra- and extravascular hemolysis, as shown by reductions in LDH, bilirubin and reticulocytes

• APL-2 effect seems linked to C3+ in wAIHA, but further testing in DATmono C3− subjects is required

• APL-2 appears to be well tolerated in patients with AIHA

Disposition

15

CAD wAIHA C3+ Overall n(%)

DATmono C3- DATmono C3+

Screened Subjects 15 15 30

Enrolled Subjects 13 3 8 24

Study Drug Discontinuation 2 2 2 6

Did Not Complete Study 2 2 1 5

Early Withdrawal 2 2 1 5

Thank you for the kind attention

Abstract Code: S899

Results CAD: Haemoglobin ResponseRapid, Sustained and Durable Increase in Haemoglobin (Hb) in Response to APL-2

Normal range, 12-17.5 g/dL17

Results CAD: Lactate Dehydrogenase (LDH) ResponseRapid, Sustained and Durable Decrease in LDH in Response to APL-2

Normal range, 87-252 U/L18

Results CAD: ARC and Indirect Bilirubin Response

Normal range, 0.1-0.75 mg/dLNormal range, 30-100 ´ 109/L

Sustained and durable decrease in Absolute Reticulocyte Count (ARC) in Response to APL-2 Sustained and durable decrease in Indirect Bilirubin in Response to APL-2

• Mean reticulocyte count decreased from 138.6 ´109/L at baseline to 63.6 ´ 109/L at day 168.

• Mean indirect bilirubin decreased from 1.9 mg/dL at baseline to 0.4 mg/dL at day 168.

19

Results wAIHA C3+: Haemoglobin and LDH Response

Normal range, 12-17.5 g/dL

• Mean haemoglobin (Hb) increased from 9.2 g/dL at baseline to 11.0 g/dL at day 168.

• Mean LDH decreased from 337.4 U/L at baseline to 142.2 U/L at day 168.

20

APL-2improves anaemia (2 g/dL average)

Normalizes LDH

Increase in Hb in Response to APL-2 Decrease in LDH in Response to APL-2

Results wAIHA C3+: ARC and Indirect Bilirubin Response

Normal range, 0.1-0.75 mg/dLNormal range, 30-100 ´ 109/L

Sustained and durable decrease in ARC in Response to APL-2 Sustained and durable decrease in Indirect Bilirubin in Response to APL-2

• Mean reticulocyte count decreased from 193.0 ´109/L at baseline to 92.2 ´ 109/L at day 168.

• Mean indirect bilirubin decreased from 0.8 mg/dL at baseline to 0.3 mg/dL at day 168.

21

APL-2Normalizes ALL haemolytic markers…

Why is anaemia still there?