International PNH Interest Group Meeting Dec 8, 2017
APL-2 is a C3 inhibitor APL-2 Subcutaneous for PNH, AIHA & CDN Intravitreal for GA Peptides of the APL-2 family bind to a pocket of C3 and inhibit activation* APL-1 Ac-IC*V(Me)WQDWGAHRC*T-NH2 APL-2 * Janssen, J. Biol. Chem., 282(40), 29241-29247, 2007 2
APL-2 may prevent both intra- and extravascular hemolysis Lectin Pathway Classical Pathway Alternative Pathway C3 Amplification loop C3b$on$RBC Inflammation C3a C3b EXTRAVASCULAR HEMOLYSIS C5 Eculizumab (C5, Alexion) C5 Inflammation C5a C5b MAC 3 INTRAVASCULAR HEMOLYSIS
APL-2 may prevent both intra- and extravascular hemolysis Lectin Pathway Classical Pathway Alternative Pathway APL-2 Reduced anemia and transfusion dependency C3 Amplification loop C3b$on$RBC Inflammation C3a C3b EXTRAVASCULAR HEMOLYSIS C5 Eculizumab (C5, Alexion) C5 Inflammation C5a C5b MAC 4 INTRAVASCULAR HEMOLYSIS
Many PNH patients on Soliris remain anemic due to extravascular hemolysis (g/dl) in 141 random PNH Patients on Soliris < 10 g/dl > 12 g/dl Severely Anemic 26% Normal Hb 29% 10 g/dl 12 g/dl Anemic 45% 5 *10.9 g/dl *Note: 10.9 g/dl is the median Hb measure for the 141 patient sample Data courtesy of Dr. Pete Hillmen and Dr. Anita Hill in Apellis sponsored research collaboration
Two ongoing trials to evaluate APL-2 safety and efficacy APL-2 Monotherapy (Phase 1b) PNH subjects never exposed to Soliris n=3 (270 mg/day) Expansion of high dose cohort planned APL-2 add-on to Soliris (Phase 1b) Hb < 10 g/dl or at least one transfusion in previous year n=6 (270 mg/day) Soliris dose normalization & weaning 6
APL-2 monotherapy - 270 mg/d Subject 1 of 3 NOTES Subject stopped dosing after week 4 due to personal reasons 3250 3000 2750 2500 2250 2000 LDH LDH U/L 1750 1500 1250 1000 750 500 250 Normal 120-250 0-4 0 4 8 12 16 20 24 28 32 160 140 120 Normal 120-160 100 g/l 80 60 40 20 APL-2 subq 270 mg / day 0-4 0 4 8 12 16 20 24 28 32 STOP 7
APL-2 monotherapy - 270 mg/d Subject 2 of 3 NOTES APL-2 dose increased to 360 mg/d at Week 24 LDH increase (unexpected) Hb increase (expected) Metastatic ovarian carcinoma Tumor lysis may have elevated LDH GI bleeding due to cancer metastases may have contributed to low Hb U/L 3250 3000 2750 2500 2250 2000 1750 1500 1250 1000 750 500 250 0-4 0 4 8 12 16 20 24 28 32 160 140 LDH LDH Normal 120-250 Normal 120-160 120 g/l 100 80 60 40 APL-2 subq 20 Transfusion 0-4 0 4 8 12 16 20 24 28 32 270 mg / day 360 mg / day STOP 8
APL-2 monotherapy - 270 mg/d Subject 3 of 3 NOTES APL-2 subcutaneous pump infusion Iron supplementation in Month 1 1500 1250 1000 LDH LDH U/L 750 500 250 Normal 120-250 0-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 160 140 120 Normal 120-160 100 g/l 80 60 40 20 APL-2 subq 270 mg / day 0-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 9
APL-2 add-on to Soliris (n=6) 14 Mean 13 12 Lower Limit of Normal g/dl 11 10 9 Transfusions 8 7 6-28 -24-20 -16-12 -8-4 0 4 8 12 16 20 24 28 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 Months Dosing Mean LDH Each is a transfusion color-coded by patient 400 350 LDH 300 U/L 250 200 Soliris IV: 900 mg / 2 weeks (n=1) 900 mg / 1 week (n=3) 1,200 mg / 2 weeks (n=2) + APL-2 subq: 270 mg / day 150 Normal 100 50-4 -2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 1 2 3 4 5 6 7 10
Two patients ceased dosing within first 12 months Patient 1 Unexpected pregnancy SMC decision to cease dosing after ~8 months of dosing Patient 2 BMI: 55 - possibly underdosed Responder but Hb ~8 g/dl Issues with pre-existing kidney stones and UTIs Company decision to cease dosing after ~6 months of dosing 11
APL-2 add-on to Soliris four patients >1 year 14 13 Normal 12 g/dl 11 10 9 8 7 6-52 -48-44 -40-36 -32-28 -24-20 -16-12 -8-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 500 Reticulocyte Count Reticulocyte Count 450 400 350 300 10 3 /ul 250 200 150 100 50 Normal 12 Soliris APL-2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Therapeutic objective APL-2 in PNH: normalization Soliris ALXN-1210 APL-2 Dosing q 2 weeks IV q 8 weeks IV twice weekly subq Low Low Normal Reticulocytes Elevated Elevated Normal PNH visits / year >3 >3 <2 APL-2 Twice per Week * Shasha, D. et al. JNCCN 2004;2:509-517 LASA Quality of Life (QoL) scores associated with Levels in patients on treatment with erythropoietin alfa 13
Recap 2017 2018 2019+ H2 H1 H2 Hematology Phase 1b PNH Add-on Soliris Phase 1b PNH Monotherapy Soliris weaning Mono expansion Phase 2 AIHA 1 Phase 3 PNH (H:H vs Soliris) Note: Study start dates are estimates by management (+/- 3 months). Study end dates are not projected with the exception of the Phase 2 GA 18 month data 1 APL-2 study in AIHA will include the common sub-types Cold Agglutinin Disease & warm-anti-body AIHA 2 APL-2 study in CDN will include the common sub-types IgA nephropathy, lupus nephritis, idiopathic membranous nephropathy and C3 glomerulopathy 14
Phase 3 Enrollment sharon@apellis.com 15