Treatment with APL-2 in patients who remain anemic despite treatment with Soliris® leads to increases in hemoglobin, transfusion avoidance and broad control of hemolysis Carlos de Castro, MD¹, Ilene Weitz, MD², Pascal Deschatelets, PhD³, Cedric François, MD, PhD³, Jaroslaw Maciejewski, MD, PhD⁴, Eloy Roman, MD⁵, Vivek Sharma, MD⁶, Lisa Tan⁷, Federico Grossi, MD, PhD⁸ ¹Duke University School of Medicine, Durham, NC, USA, ²Keck-USC School of Medicine, Los Angeles, CA, USA, ³Apellis Pharmaceucals, Crestwood, KY, USA, ⁴Taussig Cancer Instute, Translaonal Hematology and Oncology Research, Cleveland, OH, USA, ⁵Lakes Research, Miami Lakes, FL, USA, ⁶University of Louisville, Louisville, KY, USA, ⁷Lisa Tan Pharma Consulng, Cambridge, UK, ⁸Apellis Pharmaceucals, Waltham, MA Aim Assess the response to SC APL-2 as an add-on to standard-of-care in paents with PNH who connue to be anemic despite treatment with eculizumab (Soliris®). Methods Study CP-0514, an open-label study conducted in the USA, was designed to assess safety, tolerability, pharmacokinecs and pharmacodynamics of APL-2 administered daily by SC injecons as an add-on to standard of care (Soliris®). Key Eligibility Criteria Figure 1. Role of C3 and C5 in hemolysis and site of inhibitory acvity of Soliris® and APL-2 in the complement cascade * PNH is a rare, acquired, potenally life-threatening hematologic disease characterized by bone marrow failure and hemolysis and resulng in debilitang complement-mediated hemolyc anemia and an increased risk of thrombosis¹ Uncontrolled complement acvaon leads to intravascular hemolysis (IVH) mediated by the membrane aack complex (MAC) and extravascular hemolysis (EVH) mediated by accumulaon of C3 fragments, such as C3b, at the cell surface² - IVH is associated with increased lactate dehydrogenase (LDH) and reculocytosis - EVH is associated with bilirubinemia and reculocytosis, 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 paents treated with Soliris® connue to experience ongoing anemia³ and its associated symptoms APL-2 is a pegylated cyclic pepde that binds to C3, exerng broad inhibion of the complement cascade, prevenng both IVH and EVH and helping the body restore normal complement acvity (Figure 1)⁴ PNH (WBC clone >10%) and persistent anemia On treatment with Soliris® (IV) for ≥3 months prior to screening Hb < 10 g/dL at screening OR have received ≥1 transfusion within 12 months prior to screening Platelet count >30,000/μL Absolute neutrophil count >500 x10⁹/L Note: During the course of the study, the dose of APL-2 was increased to 360 mg/d for 3 subjects then further increased for 1 subject to 440 mg/d. Subjects received APL-2 (270 mg/d) SC injecons for 28 days. Aſter the inial assessment, subjects in this cohort were allowed to connue treatment with APL-2 for up to 2 years Baseline Three of 4 subjects were receiving higher than label doses of Soliris® Despite treatment with Soliris®, hemoglobin was significantly lower than normal limits, while bilirubin and absolute reculocyte count (ARC) were nearly 2x and 3x upper limits of normal, respecvely, resulng in an average of 6 pRBC transfusions per subject in the prior year Gradual Soliris® Dose Disconnuaon In 4 subjects who connued treatment beyond 8 months - Soliris® dose was reduced to label-approved dose of 900 mg bi-weekly between months 6 and 12 of APL-2 therapy - Soliris® was disconnued between months 14 and 22 of APL-2 therapy and subjects connue to be maintained with APL-2 monotherapy All 4 subjects responded rapidly to treatment with APL-2, with an absolute reculocyte count (ARC) of 56.0 x 10⁹/L and mean total bilirubin of 0.58 mg/dL at day 29 (an 83% and 72.6% improvement from baseline, respecvely) The decrease in ARC and total bilirubin was durable, as represented by a mean ARC of 109.3 x 10⁹/L and mean bilirubin of 0.53 mg/dL on Day 561, respecvely Six subjects entered the cohort and 2 were withdrawn aſter approximately 8 months; 1 due to significant co-morbidies and 1 who became pregnant during the study. The results from the 4 subjects who have completed an average 21.2 months of dosing with APL-2 are presented. Complement inhibion leads to protecon against complement mediated hemolysis and an increase in the relave fracon PNH Type III RBCs A reducon from baseline values in C3 deposion on PNH cells was observed for all subjects Background Aim, Methods, Eligibility Results Table 1. Key Baseline Characteriscs of 4 Ongoing Paents * Table 2. Summary of Key Parameters Before and Aſter Treatment with APL-2 Figure 4. Decrease in Serum Total Bilirubin in Response to APL-2 * Figure 6. C3d Deposion on Pooled Type II (CD59-diminished) and Type III (CD59-negave) Red Blood Cells * During this two-year study, all subjects experienced durable and significant: - Increases in hemoglobin - Decreases in absolute reculocyte count - Decreases in serum total bilirubin - Transfusion independence The effects observed when APL-2 was co-administered with Soliris® were maintained when subjects were switched and treated with APL-2 monotherapy Treatment with APL-2 prevents extravascular and intravascular hemolysis Conclusions Table 3. Safety of APL-2 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; exploing 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 paents with PNH treated with eculizumab: defining the clinical syndrome. Blood. 2017;130:3471. 4. El Mehdi D, Grossi FV, Deschatelets P, et al. APL-2, a complement C3 inhibitor, may potenally reduce both intravascular and extravascular hemolysis in paents with paroxysmal nocturnal hemoglobinuria [abstract 001]. Mol Immunol. 2017;89:115. Figure 2. Increase in Hemoglobin (Hb) in Response to APL-2 * All 4 subjects responded rapidly aſter iniang APL-2 therapy, with a mean Hb of 11.4 g/dL at day 15 and 12.1 g/dL at day 29 The increase in Hb was durable, as represented by a mean Hb of 11.2 g/dL on day 561 Figure 3. Decrease in Reculocytes in Response to APL-2 * Figure 5. Clonal Distribuon of PNH Type III RBCs * * n = 4 for each mepoint except where indicated as (a) n = 3; (b) n = 2 a Last reading during eculizumab monotherapy prior to co-treatment with APL-2 b Last reading during co-treatment and prior to APL-2 monotherapy c Last reading while on APL-2 monotherapy d Average last available reading for all 4 paents on each dosing regimen % based on the 4 subjects in the analysis set n = number of subjects who experienced the event m = number of events
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Treatment with APL-2 in patients who remain anemic despite treatment with Soliris® leads to increases in hemoglobin, transfusion avoidance and broad control of hemolysis
Carlos de Castro, MD¹, Ilene Weitz, MD², Pascal Deschatelets, PhD³, Cedric François, MD, PhD³, Jaroslaw Maciejewski, MD, PhD⁴, Eloy Roman, MD⁵, Vivek Sharma, MD⁶, Lisa Tan⁷, Federico Grossi, MD, PhD⁸ ¹Duke University School of Medicine, Durham, NC, USA, ²Keck-USC School of Medicine, Los Angeles, CA, USA, ³Apellis Pharmaceuticals, Crestwood, KY, USA, ⁴Taussig Cancer Institute, Translational Hematology and
Oncology Research, Cleveland, OH, USA, ⁵Lakes Research, Miami Lakes, FL, USA, ⁶University of Louisville, Louisville, KY, USA, ⁷Lisa Tan Pharma Consulting, Cambridge, UK, ⁸Apellis Pharmaceuticals, Waltham, MA
AimAssess the response to SC APL-2 as an add-on to standard-of-care in patients with PNH who continue to be anemic despite treatment with eculizumab (Soliris®).
MethodsStudy CP-0514, an open-label study conducted in the USA, was designed to assess safety, tolerability, pharmacokinetics and pharmacodynamics of APL-2 administered daily by SC injections as an add-on to standard of care (Soliris®).
Key Eligibility Criteria
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 thrombosis¹Uncontrolled 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 IVHUp to 75% of patients treated with Soliris® continue toexperience ongoing anemia³ and its associated symptomsAPL-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
PNH (WBC clone >10%) and persistent anemia On treatment with Soliris® (IV) for ≥3 months prior to screeningHb < 10 g/dL at screening OR have received ≥1 transfusion within 12 months prior to screeningPlatelet count >30,000/μLAbsolute neutrophil count >500 x10⁹/L
Note: During the course of the study, the dose of APL-2 was increased to 360 mg/d for 3 subjects then further increased for 1 subject to 440 mg/d.
Subjects received APL-2 (270 mg/d) SC injections for 28 days. After the initial assessment, subjects in this cohort were allowed to continue treatment with APL-2 for up to 2 years
BaselineThree of 4 subjects were receiving higher than label doses of Soliris® Despite treatment with Soliris®, hemoglobin was significantly lower than normal limits, while bilirubin and absolute reticulocyte count (ARC) were nearly 2x and 3x upper limits of normal, respectively, resulting in an average of 6 pRBC transfusions per subject in the prior year
Gradual Soliris® Dose Discontinuation In 4 subjects who continued treatment beyond 8 months - Soliris® dose was reduced to label-approved dose of 900 mg bi-weekly between months 6 and 12 of APL-2 therapy - Soliris® was discontinued between months 14 and 22 of APL-2 therapy and subjects continue to be maintained with APL-2 monotherapy
All 4 subjects responded rapidly to treatment with APL-2, with an absolute reticulocyte count (ARC) of 56.0 x 10⁹/L and mean total bilirubin of 0.58 mg/dL at day 29 (an 83% and 72.6% improvement from baseline, respectively)
The decrease in ARC and total bilirubin was durable, as represented by a mean ARC of 109.3 x 10⁹/L and mean bilirubin of 0.53 mg/dL on Day 561, respectively
Six subjects entered the cohort and 2 were withdrawn after approximately 8 months; 1 due to significant co-morbidities and 1 who became pregnant during the study. The results from the 4 subjects who have completed an average 21.2 months of dosing with APL-2 are presented.
Complement inhibition leads to protection against complement mediated hemolysis and an increase in the relative fraction PNH Type III RBCsA reduction from baseline values in C3 deposition on PNH cells was observed for all subjects
Background Aim, Methods, Eligibility
Results
Table 1. Key Baseline Characteristics of 4 Ongoing Patients*
Table 2. Summary of Key Parameters Before and After Treatment with APL-2
Figure 4. Decrease in Serum Total Bilirubin in Response to APL-2* Figure 6. C3d Deposition on Pooled Type II (CD59-diminished) and Type III (CD59-negative) Red Blood Cells*
During this two-year study, all subjects experienced durable and significant: - Increases in hemoglobin - Decreases in absolute reticulocyte count - Decreases in serum total bilirubin - Transfusion independence
The effects observed when APL-2 was co-administered with Soliris® were maintained when subjects were switched and treated with APL-2 monotherapyTreatment with APL-2 prevents extravascular and intravascular hemolysis
Conclusions
Table 3. Safety of APL-2
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;130:3471. 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 [abstract 001]. Mol Immunol. 2017;89:115.
Figure 2. Increase in Hemoglobin (Hb) in Response to APL-2*
All 4 subjects responded rapidly after initiating APL-2 therapy, with a mean Hb of 11.4 g/dL at day 15 and 12.1 g/dL at day 29
The increase in Hb was durable, as represented by a mean Hb of 11.2 g/dL on day 561
Figure 3. Decrease in Reticulocytes in Response to APL-2* Figure 5. Clonal Distribution of PNH Type III RBCs*
* n = 4 for each timepoint except where indicated as (a) n = 3; (b) n = 2
a Last reading during eculizumab monotherapy prior to co-treatment with APL-2b Last reading during co-treatment and prior to APL-2 monotherapyc Last reading while on APL-2 monotherapyd Average last available reading for all 4 patients on each dosing regimen
% based on the 4 subjects in the analysis setn = number of subjects who experienced the eventm = number of events
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