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TEMPLATE DESIGN © 2008 www.PosterPresentations.com APL-2, a Complement C3 Inhibitor for the Potential Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH): Phase I Data from Two Completed Studies in Healthy Volunteers Background Aims To assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of APL-2 administered by subcutaneous injection (SC) in healthy adult volunteers. Conclusions • PNH is a rare, acquired, potentially life- threatening disease characterized by complement-mediated hemolytic anemia. • PNH arises from a somatic mutation resulting in impairment of an anchor protein responsible for the expression of numerous proteins at the cell surface of the red blood cells. • Subsequent uncontrolled activation of the complement system leads to both intravascular hemolysis triggered by the membrane attack complex (MAC) and extravascular hemolysis, mediated by complement C3b accumulation at the cell surface (opsonization). • Due to the key position of C3 in the complement cascade, APL-2, a PEGylated cyclic peptide inhibitor of C3, may prevent both intravascular and extravascular hemolysis and be a potential treatment for PNH. • Single SC doses of APL-2 up to a dose of 1440 mg and multiple doses up to 270 mg/d for 28 days were safe and well tolerated • PK and complement C3 data from these studies have been used to develop a predictive TMDD model which has been used for dose selection in PNH patients. • APL-2’s PK/PD profile supports daily SC administration. • APL-2 doses of 180 mg and 270 mg reduced hemolytic activity as early as eight days after the start of dosing, and this inhibition was maintained through the dosing period. Subject Disposition Federico V Grossi, MD PhD 1 *, Pauline Bedwell 2 *, Pascal Deschatelets, PhD 1 *, Lil Edis, PhD 3 *, Cedric G Francois, MD, PhD 1 *, Patrick J Johnson, PhD 4 *, Helen J Richardson 5 *, Lisa Tan 6 *, Carolina A Vega 1 * and Jason Lickliter, MBBS, PhD 7 * 1 Apellis Pharmaceuticals Inc, Crestwood, KY; 2 PB Clinical Services Ltd, UK; 3 Apellis Australia Pty Ltd, Brisbane, Australia; 4 JPharma Solutions GmbH, Switzerland; 5 Paramstat Ltd, UK; 6 Lisa Tan Pharma Consulting, UK; 7 Nucleus Network Ltd, Victoria, Australia Study Design Two parallel group, placebo controlled studies: Study 1: Single Ascending Dose (SAD) Study at single SC doses of 45, 90, 180, 360, 720, 1440 mg. Study 2: Multiple Ascending Dose (MAD) Study at SC doses of 30, 90, 180 and 270 mg/day for 28 days. Pharmacokinetics Pharmacokinetics Figure 3 Summary APL-2 PK concentrations over nominal time post first dose split by single SC dosing cohort overlaid with the model fit. The closed circles represent the mean observed PK concentration at respective time points and solid lines the PK model fit. Study 1: single-dose Study 2: multiple-dose Figure 4 Summary APL-2 PK concentrations over nominal time post first dose split by multiple SC OD dosing cohort overlaid with the model fit. The closed circles represent the mean observed PK concentration at respective time points and solid lines the PK model fit. Figure 5 Summary complement AP50 change from baseline (CFB) over nominal time post first dose split by single SC dosing cohort. The solid lines represent the complement AP50 adjusted CFB mean at respective time points. Figure 6 Summary complement AP50 change from baseline (CFB) over nominal time post first dose split by multiple SC OD dosing cohort. The solid lines represent the complement AP50 adjusted CFB mean at respective time points. Figure 1 TMDD model schematic illustrating main mechanisms that describe the PK response of APL-2 and its interdependence with its target, complement C3. Figure 2 Predicted free complement C3 over nominal time post first-dose split by Study 2 SC MD doses. Solid lines represent predicted complement free C3 concentration at respective time points. PKPD Summary: •Figure 3 shows the long absorption following a single SC dose (T max 5-8 days) •Both studies (Figures 3 and 4) demonstrate a slow terminal elimination (t½ 8-10 days) •Long absorption and half-life support daily SC dosing (or even longer dosing interval). •There was a dose-dependent reduction in complement AP50 (Figures 5 and 6) confirming inhibition of C3. RESULTS PKPD Model Summary: •APL-2 is a potent and selective inhibitor of complement C3. The binding fraction is so high that it influences both the disposition of APL-2 PK and its target, C3. A PK model that describes this interdependence between drug and its target was first proposed by Mager & Jusko 1 and known as Target Mediated Drug Disposition (TMDD). •APL-2 PK together with the impact of binding to complement C3 was successfully modelled using TMDD. A schematic is present in Figure 1. •Presented in Figures 3 & 4 are the summary observed PK concentrations overlaid with the TMDD model fit for the SAD and MAD studies, respectively. •Figure 2 presents the decrease in free complement C3 concentration predicted for the MAD study dosing levels. At the highest dose level (270 mg/day) the free complement C3 levels dropped from a baseline concentration of 1.07 g/L to under 0.15 g/L after 14 days OD dosing. Reference: 1 Mager DE, JuskoWJ: General pharmacokinetic model for drugs exhibiting target mediated drug disposition. J. Pharmacokinet Pharmacodyn (2001) 28: 507-532. Pharmacodynamics Entry Criteria Healthy male or female aged 18-55 years. In Study 2 (MD) all subjects received vaccination against Neisseria Meningitides, Streptococcus pneumoniae and Haemoplilus influenza. Study 1: single-dose APL-2 (mg) Placebo 30 45 90 180 270 360 720 1440 Total Enrolled 11 4 4 8 8 4 4 4 4 51 Completed 9 4 3 7 7 4 2 4 4 44 Withdrawn 2 - 1 1 1 - 2 - - 7 Table 1 Number of enrolled, completed and withdrawn subjects across both studies. All 7 subjects withdrew for personal reasons during the follow up period. All 51 subjects were included in the safety, PK and PD analysis populations. Table 2 Summary of Treatment-Emergent Adverse Events (TEAEs) occurring in >1 APL-2 treated subject across both studies. Safety Safety Summary: •The most commonly reported TEAE across both studies was headache and the frequency was similar across both treated and placebo subjects. •Of the 10 infections and infestations reported in APL-2 treated subjects only the viral infection was considered to be possibly related to APL-2 treatment – All infections resolved spontaneously with supportive treatment only with the exception of the herpes zoster infection which was successfully treated with valaciclovir. •The majority (9) of injection site reactions occurred in 3 of 4 subjects who received the highest dose (270 mg/d for 28 days). They were reported as pain, pruritus, erythema, bruising and swelling. All were mild in severity, not reported at every injection, and symptoms lasted between 1 and 6 days. •There were no clinically relevant changes in vital signs, ECGs or safety lab parameters System Organ Class Preferred Term Placebo (N=11) APL-2 (N=40) Total (N=51) Subjects with at least 1 TEAE 5 (45%) 27 (67%) 32 (62%) Gastrointestinal disorders 1 (9%) 4 (10%) 5 (10%) Constipation - 1 1 Diarrhoea/soft faeces 1 1 2 Nausea - 1 1 Abdominal pain - 1 1 Infections and infestations 2 (18%) 10 (25%) 12 (48%) Ear infection - 1 1 Herpes zoster - 1 1 RTI/Nasopharyngitis/Pharyngitis 2 6 8 Viral infection - 2 2 Nervous system disorders 4 (36%) 14 (35%) 18 (35%) Abnormal dreams 1 2 3 Headache 3 (27%) 12 (30%) 15 (29%) General disorders and administration site conditions 1 (9%) 11 (27%) 12 (23%) Injection site bruising - 3 3 Injection site erythema 1 8 9 Injection site pain - 2 2 Injection site pruritus - 5 5 Injection site oedema - 1 1 Study 2: multiple-dose Conflict of interest: Employees of Apellis with equity (FG, PD, LE, CF, CV); Membership on entity’s Board of Directors (CG); Consultants to Apellis (PB, PJ, HR, LT)
