Inhibition of C3 With APL-2 Results in Normalization of Markers of Intravascular and Extravascular Hemolysis in Subjects with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Abstract #2314 Poster #2314

Raymond S.M. Wong, MRCP, FRCP¹; Humphrey W.H. Pullon, FRACP, FRCPA²; Pascal Deschatelets, PhD³; Cedric G. Francois, MD, PhD³; Mohamed Hamdani, MS⁴; Surapol Issaragrisil, MD⁵; Patrick Johnson, PhD⁶; Pimjai Niparuck, MD⁷; Tontanai Numbenjapon, MD⁸; Jameela Sathar, MB, MRCP, MRCPath⁹; Lisa Tan10; Eric Tse, MBBS, PhD, FRCP, FRCPath11; and Federico Grossi, MD, PhD⁴

¹Sir Y.K. Pao Centre for Cancer & Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; ²Waikato Hospital, Hamilton, New Zealand; ³Apellis Pharmaceuticals, Inc, Crestwood, KY; ⁴Apellis Pharmaceuticals, Waltham, MA; ⁵Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand; ⁶JPharma Solutions GmbH, Zurich, Switzerland; Faculty of Medicine; ⁷Ramathibodi Hospital, Bangkok, Thailand; ⁸Phramongkutklao College of Medicine, Bangkok, Thailand; ⁹Department of Hematolgy, Ampang Hospital, Petlaing Jaya, Malaysia; 10Lisa Tan Pharma Consulting Ltd, Cambridge, United Kingdom; 11Department of Medicine, The University of Hong Kong, Hong Kong

Background

Eligibility and Study Design

Demographics and Baseline Characteristics

Results Results Continued

Changes in Hematologic and Blood Chemistry Parameters Quality of Life Assessment

Treatment With APL-2 Has Been Safe and Well-Tolerated

Figure 1. Role of C3 and C5 in hemolysis and site of inhibitory activity of Soliris® and APL-2 in the complement cascade*

PNH is a rare, acquired, potentially life-threatening hematologic disease characterized by bone marrow failure and hemolysis and resulting in debilitating complement-mediated hemolytic anemia and an increased risk of thrombosis¹

Uncontrolled complement activation leads to intravascular hemolysis (IVH) mediated by the membrane attack complex (MAC) and extravascular hemolysis (EVH) mediated by accumulation of C3 fragments, such as C3b, at the cell surface² - IVH is associated with increased lactate dehydrogenase (LDH) and reticulocytosis - EVH is associated with bilirubinemia and reticulocytosis, without significant increases in LDH

The only approved treatment for PNH is Soliris® (eculizumab), a C5 inhibitor which only treats IVH

Up to 75% of patients treated with Soliris® continue to experience ongoing anemia³ and its associated symptoms

APL-2 is a pegylated cyclic peptide that binds to C3, exerting broad inhibition of the complement cascade, preventing both IVH and EVH and helping the body restore normal complement activity (Figure 1)⁴

All 19 subjects responded rapidly after initiating APL-2 therapy, and by day 29 mean baseline Hb increased from 8.0 g/dL to 10.8 g/dLIncreases in Hb were sustained and durable as represented by a mean Hb of 12.2 g/dL at day 85

Aim: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of multiple doses of APL-2, administered by daily subcutaneous injection (SC), in subjects with PNHData is presented from the ongoing study

Decreases in ARC (Figure 4) and total bilirubin (Figure 5) were rapid following initiation of treatment with APL-2

By day 29 mean ARC and total bilirubin were within the normal range: - With the exception of a non-compliant subject, ARC was reduced in all subjects and was within the normal range in 79% subjects at day 29

- With the exception of a non-compliant subject, total bilirubin was reduced in all subjects and was within the normal range in 95% subjects at day 29

Increases in the mean proportion of PNH Type III RBCs (Figure 6) were observed from a baseline value of 32% to 67% at Day 29 and 80% at day 85

Fatigue as measured by the FACIT-Fatigue instrument improved rapidly (within 2 weeks) after initiation of APL-2 therapy, and the mean (SE) change from baseline at day 29 was 6.4 (2.7)The increase in FACIT score was durable and sustained as represented by a mean (SE) change from baseline of 7.86 (2.2) at day 85

No significant infections or thromboembolic events have been observedOne subject was withdrawn due to progression of aplastic anemia related to underlying PNH and one subject was withdrawn due to progression of an underlying malignancy

Reductions in LDH were rapid following initiation of APL-2 therapy, with 95% of subjects achieving an LDH in the normal range by day 29Reductions in LDH have been sustained and durable, with mean LDH maintained within the normal range at all timepoints beyond day 29

References 1. DeZern AE, Dorr D, Brodsky RA. Predictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Eur J Haematol. 2013;90(1):16-24. 2. Mastellos DC, Ricklin D, Yancopoulou D, et al. Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape. Expert Rev Hematol. 2014; 7(5):583–598. 3. McKinley CE, Richards SJ, Munir T, et al. Extravascular hemolysis due to C3-loading in patients with PNH treated with eculizumab: defining the clinical syndrome. Blood. 2017:130 (suppl 1):3471. 4. El Mehdi D, Grossi FV, Deschatelets P, et al. APL-2, a complement C3 inhibitor, may potentially reduce both intravascular and extravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria. Molec Immunol. 2017;89:115.

a ULN = 250 IU/Lb ULN = 100 x 10⁹/L

a Excluding patient with SAA, see Table 3

Treatment with APL-2 in complement-inhibitor-naïve PNHpatients resulted in rapid and durable normalization of Hb, LDH,ARC and total bilirubin

Previously transfusion dependent patients did not require any transfusions during maintenance treatment with APL-2a

Clinically relevant improvement in FACIT-Fatigue scorewas observed

APL-2 was safe and well tolerated

Summary

Figure 2. Increase in Hemoglobin (Hb) in Response to APL-2

Table 1. Demographics and Baseline Characteristics

Figure 3. Decrease in LDH in Response to APL-2

Figure 4. Decrease in Absolute Reticulocyte Count (ARC) in response to APL-2

Table 2. Summary of Laboratory Parameters Before and After Treatment With APL-2

Table 4. Safety of APL-2a Figure 5. Decrease in Serum Total Bilirubin in Response to APL-2

Figure 6. Clonal Distribution of PNH Type III RBCs

Table 5. Disposition

As of November, 2018In the subject requiring 26 units pRBCs all transfusions occurred after day 365 (ie, date of initial thrombocytopenia and severe aplastic anemia [SAA]) and were to treat the SAA. 50% (13/26 units) occurred after discontinuing treatment with APL-2 due to SAA. Prior to Day 364, no transfusions were received in this subject2 of 4 subjects receiving transfusions were prior to APL-2 steady-state (ie, within 2 weeks of starting APL-2 therapy) with 1 of the 2 patients requiring a transfusion to treat an AE of hemolysis during a period when APL-2 was temporarily discontinued; 1 noncompliant subject required a transfusion at day 15 and 1 subject had SAAa

ab

c

Not included in the analysis is one subject who had underlying metastatic ovarian cancer with a chronic low gastrointestinal bleed, unknown at time of screening, resulting in artificially low Hb and high LDH levels determined to be unrelated to PNH

a

a As of November, 2018n = number of subjects that experienced the event, m = number of events

Table 3. Transfusions

Figure 7. Change From Baseline in FACIT Fatigue Score