New Phase III Clinical Trial Enrolling Now

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1 New Phase III Clinical Trial Enrolling Now Paroxysmal Nocturnal Hemoglobinuria (PNH) Designed for Patients 1. At least 18 years of age 2. With a primary diagnosis of PNH confirmed by high-sensitivity flow cytometry 3. On treatment with a stable dose of eculizumab for at least 3 months prior to the screening visit 4. With a hemoglobin <10.5 g/dl, an absolute reticulocyte count > 1.5 ULN, a platelet count of >50,000/mm3, and an absolute neutrophil count >500/mm3 at the screening visit

2 Paroxysmal Nocturnal Hemoglobinuria (PNH) Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, potentially life-threatening blood disorder. PNH can present at any age, in people of any race or gender. However, it is diagnosed most often in people in their early 30s, and it usually continues throughout the life of the patient.1 In PNH, stem cells acquire a gene mutation that results in the production of abnormal blood cells. Defective red blood cells become open to attack by complement, which is part of the immune system.1 This destruction of red blood cells is called hemolysis.2 As a result, the person will suffer from anemia, which is a shortage of healthy red blood cells.2 In addition to suffering from anemia, a patient with PNH may experience a multitude of problems, including renal failure, pulmonary hypertension (high blood pressure in the lungs), thrombosis (blood clots within blood vessels), abdominal pain, dyspnea (shortness of breath), dysphagia (discomfort when swallowing), fatigue, impaired quality of life, and erectile dysfunction in men.3 Thrombosis has a significant impact on survival and is the leading cause of death in patients with PNH.4 Role of Complement in PNH In PNH, stem cells acquire a gene mutation which causes the production of abnormal blood cells that lack two important surface proteins (55 and 59). These proteins protect normal blood cells from attack by the complement system (Figure 1): 55 prevents activation of C3, which can lead to opsonization of the red blood cell, marking it for destruction in the spleen and liver. This process is called extravascular hemolysis.3 C3 activation can also lead to activation of C protects red blood cells and platelets from the membrane attack complexes (MACs) produced by activation of C5.3 MACs cause intravascular hemolysis. The Role of Complement in the Development of PNH Normal blood cells carry 2 surface proteins (55 and 59) that protect them against the complement system. 55 prevents activation of C3, and 59 protects against the membrane attack complexes (MACs) produced by activation of C C3 Convertase C In PNH, many blood cells lack the anchors that would hold 55 and 59 onto their surface. As a result, they can be damaged by activation of any pathway of the complement system. C5 Convertase C5b C5 -mediated extravascular hemolysis C3a coats RBCs and facilitates their destruction in the liver and spleen MAC C5b MAC-mediated intravascular hemolysis C5a MAC is a pore inserted into the RBC membrane, which causes its destruction and release of its contents into blood Thrombosis Figure 1: The complement system is an important part of the immune system. The complement system can be activated through three separate pathways (classical, lectin, and alternative). All 3 eventually lead to the cleavage of C3 (into C3a and ) by C3 convertases. plays a key role in opsonization, which marks a particle or cell for destruction by white blood cells, especially in the liver or spleen. also leads to the cleavage of C5 (into C5a and C5b) by C5 convertases. C5b is a subunit of the membrane attack complex (MAC), which creates a pore that can lead to the death of the cell. Normally, blood cells carry 2 surface proteins that protect them against the complement system. 55 blocks activation of C3. Thus, 55 helps to prevent extravascular hemolysis. 59 protects the cell against MACs, thus preventing intravascular hemolysis. In people with PNH, many of the red blood cells and platelets lack the substance that would normally anchor 55 and 59 onto the cell s surface. The defective red blood cells have an abnormally short life span. The defective platelets can lead to abnormal clotting.3

3 Purpose of PNH Clinical Trial To establish the efficacy and safety of the investigational drug APL-2, as compared to eculizumab, in patients with PNH who continue to have hemoglobin levels <10.5 g/dl despite treatment with eculizumab.5 This study will enroll approximately 70 subjects to compare APL-2 to eculizumab treatment. Through a process known as randomization, roughly ½ of subjects will be assigned to group 1 (APL-2) or group 2 (eculizumab, with a transition to APL-2 at week 17). Key Inclusion Criteria 1. Age 18 years 2. Primary diagnosis of PNH confirmed by high-sensitivity flow cytometry 3. On treatment with eculizumab. Dose of eculizumab must have been stable for 3 months 4. Hemoglobin <10.5 g/dl at the screening visit 5. Absolute reticulocyte count > 1.5x ULN at the screening visit Key Exclusion Criteria 1. Active bacterial infection within 4 weeks prior to day-28 (run-in period) 2. Receiving iron, folic acid, vitamin B12, and erythropoietin, unless the dose is stable 3. Hereditary complement deficiency 4. History of bone marrow transplantation What Is APL-2? APL-2 is a PEGylated cyclic peptide inhibitor of complement C3.6 PEGylation helps keep APL-2 in the body longer, reducing dosing frequency.6 The peptide portion of APL-2 binds to C3, blocking the complement cascade and helping to restore normal complement activity.6

4 Dosing of APL-2 Starting on day-28 (visit 2), subjects will receive self-administered twice-weekly subcutaneous (SC) doses of 1080 mg of APL-2 in addition to their current dose of eculizumab until day 1. Subjects will then be randomized to either group 1 (monotherapy APL-2) or group 2 (monotherapy eculizumab). Subjects in group 1 will receive APL-2 (1080 mg twice a week) each treatment week until the end of week 48. Subjects in group 2 must continue to receive their pre-screening stable dose of eculizumab until the end of week 20. At week 17, subjects will also receive APL-2 (1080 mg twice a week) until the end of week 48. At week 20, subjects will discontinue their eculizumab treatment and remain solely on APL-2 for the remainder of the treatment period of the study. Pegasus Key Endpoints Primary Efficacy Endpoint Week 16 change from baseline in hemoglobin level Secondary Endpoints Week 16 change from baseline in: 0 Reticulocyte count 0 Lactate dehydrogenase (LDH) level 0 FACIT-fatigue scale score Number of packed red blood cell units transfused from week 4 to week 16 (day 28 to day 112) Hemoglobin response (1-g/dL increase from baseline at week 16) in the absence of transfusions (yes/no) Reticulocyte normalization (count being below the upper limit of the normal range) in the absence of transfusions at week 16 (yes/no) Safety Endpoints Incidence and severity of treatment-emergent adverse events (TEAE) Incidence of thromboembolic events Changes from baseline in laboratory parameters Changes from baseline in electrocardiography (ECG) parameters

5 APL-2 Provides Broad Hematologic Improvement in Patients with PNH In a Phase I trial evaluating APL-2 in PNH patients who have never taken eculizumab, clinical markers of hemolysis have shown improvement, such as LDH levels below the upper limit of normal, as well as significant hemoglobin correction within 12 weeks. LDH levels below upper limit of normal (ULN) in 88% of patients6 Mean lactate dehydrogenase (LDH) was reduced from 11.6x ULN to 0.9x ULN by day 28 in 8 eculizumab-naïve patients with PNH that were treated with 270 mg/day of APL x 11.0x 10.0x 9.0x x ULN 8.0x 7.0x 6.0x 5.0x 4.0x 3.0x 2.0x 1.0x 0.0x Week Number Multiple of ULN x 4.8x 2.2x 1.1x 0.9x n=4 0.6x n=4 0.7x Not Taken n=3 0.6x Significant hemoglobin correction within 12 weeks6 The same patients had an average increase in hemoglobin of 4.3 g/dl, from a baseline average of 7.9 g/dl to an average last measurement of 12.2 g/dl (range, g/dl), within the first 12 weeks g/dl Pt. 1 5 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Pt. 7 Pt * Normal 12 g/dl 4 6 Weeks Current PNH treatment blocks the activation of C5, which is the latter part of the complement system.7 However, roughly 70% of patients remain anemic, and 35% to 50% of the patients are still dependent on transfusions due to the early part of the complement system remaining active.6 The activation of C3, which is upstream of C5 in the complement cascade, can also lead to the destruction of the abnormal red blood cells in people with PNH.8 By targeting C3, which is the central protein in the complement cascade and the point where all 3 complement activation pathways meet, APL-2 has the potential to block activation from any pathway and to prevent both intravascular and extravascular hemolysis.7,9

6 To Recommend a Patient for This Trial, apellisclinicaltrials@cherryhcc.com or visit References 1. De Castro C, Rosse W. Paroxysmal nocturnal hemoglobinuria (PNH). National Organization for Rare Disorders Web site. paroxysmal-nocturnal-hemoglobinuria-pnh/. Accessed May 15, Parker CJ. Paroxysmal nocturnal hemoglobinuria. National Organization for Rare Disorders Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18): Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(25): ; quiz Apellis Pharmaceuticals. Study to evaluate the efficacy and safety of APL-2 in patients with PNH. Clinicaltrials.gov Web site. NCT Accessed May 24, Data on file, Apellis Pharmaceuticals. 7. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; Risitano AM, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood. 2009;113(17): 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): Apellis Pharmaceuticals, Inc. All rights reserved.