Treatment Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Monoclonal Antibodies Capable of Inhibiting Complement Downstream of C5 in Multiple Species

Better understanding of roles of complement in pathology has fuelled an explosion of interest in complement-targeted therapeutics. The C5-blocking monoclonal antibody (mAb) eculizumab, the first of the new wave of complement blocking drugs, was FDA approved for treatment of Paroxysmal Nocturnal Hemoglobinuria in 2007; its expansion into other diseases has been slow and remains restricted to rare and ultra-rare diseases such as atypical hemolytic uremic syndrome. The success of eculizumab has provoked other Pharma to follow this well-trodden track and made C5 blockade the busiest area of complement drug development. C5 blockade inhibits generation of C5a and C5b, the former an anaphylatoxin, the latter the nidus for formation of the pro-inflammatory membrane attack complex. In order to use anti-complement drugs in common complement-driven diseases, more affordable and equally effective therapeutics are needed. To address this, we explored complement inhibition downstream of C5. Novel blocking mAbs targeting C7 and/or the C5b-7 complex were generated, identified using high throughput functional assays and specificity confirmed by immunochemical assays and surface plasmon resonance (SPR). Selected mAbs were tested in rodents to characterize pharmacokinetics, and therapeutic capacity. Administration of a mouse C7-selective mAb to wildtype mice, or a human C7 specific mAb to C7-deficient mice reconstituted with human C7, completely inhibited serum lytic activity for >48 h. The C5b-7 complex selective mAb 2H2, most active in rat serum, efficiently inhibited serum lytic activity in vivo for over a week from a single low dose (10 mg/kg); this mAb effectively blocked disease and protected muscle endplates from destruction in a rat myasthenia model. Targeting C7 and C7-containing terminal pathway intermediates is an innovative therapeutic approach, allowing lower drug dose and lower product cost, that will facilitate the expansion of complement therapeutics to common diseases.

Paroxysmal nocturnal hemoglobinuria: current treatments and unmet needs.

The current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) are the C5 inhibitors eculizumab and ravulizumab, both monoclonal antibodies designed to target the complement protein C5, thereby preventing its cleavage and the formation of the terminal attack complex. C5 inhibitors have yielded substantial improvements in the treatment of PNH and changed the mortality and morbidity, as well as health-related quality of life of patients with the disease. These treatments target underlying intravascular hemolysis; however, they do not address extravascular hemolysis, resulting in incomplete response and remaining symptoms in some patients. Therefore, despite treatment with a C5 inhibitor, some patients still experience anemia with associated fatigue, transfusion needs, and impaired health-related quality of life. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.

PRO27 Pharmacoeconomic Prospects for the Use of Ravulizumab in the Treatment of Paroxysmal Nocturnal Hemoglobinuria

PRO27 Pharmacoeconomic Prospects for the Use of Ravulizumab in the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Current global scenario of guidelines on the management of paroxysmal nocturnal hemoglobinuria: a systematic literature review

Objective: To report the outcomes of a systematic literature review of guidelines and consensus on the management of paroxysmal nocturnal hemoglobinuria (PNH) and describe the main therapeutic options available worldwide. Methods: A systematic literature review was conducted in April 2018 with no time limit and reported in line with the PRISMA statement. The AGREE II instrument was used to determine the quality of each guideline included in the systematic review. Results: Eight guidelines/consensus were eligible, one developed by an international group, two in Spain, and one each in Turkey, Germany, Argentina, Australia and the United Kingdom. Supportive treatment with erythrocyte transfusion, anticoagulants and steroids is indicated by all guidelines and consensus. The use of erythropoietin is suggested by three of them. Recommendations for the prescription of eculizumab were consistent in all but one guideline, published in 2005. Allogeneic hematopoietic stem cell transplantation is reported as the only potentially curative treatment for PNH, although its association with high mortality and morbidity rates is emphasized, being indicated for a selected group of patients. The AGREE II scores applied for each domain showed in general a low and heterogeneous methodological quality among guidelines. Conclusion: Despite the low and heterogeneous methodological quality, in general the comparison of guidelines and consensus for PNH management showed consistent recommendations regarding supportive care, eculizumab and hematopoietic stem cell transplantation.

Paroxysmal nocturnal hemoglobinuria: role of the complement system, pathogenesis, and pathophysiology.

The complement system is part of the innate immune response system, which comprises more than 50 distinct plasma and serum proteins that interact to opsonize pathogens (i.e., mark pathogens for destruction) and induce inflammatory responses to fight infection. The role of the complement system is 2-fold: immune surveillance and host defense. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic disease caused by somatic mutations in the gene PIGA in the hematopoietic stem cells. These stem cells produce abnormal clone blood cells that lack the complement regulatory proteins CD55 and CD59, causing the body to recognize these otherwise healthy red blood cells as damaged. The complement system destroys cells without these protective proteins, resulting in general hemolysis. PNH is characterized by fatigue; hemolytic anemia that can be severe and debilitating; increased lactic dehydrogenase level, reticulocyte count, and bilirubin level; propensity for thrombotic events; and renal dysfunction. Epidemiologic data, while sparse, suggest that an estimated 5,000-6,000 individuals in the United States are affected by PNH. If left untreated, PNH has a 10-year mortality rate of 29%, although the natural history of this disease has been recently altered by the introduction of complement inhibitors for the treatment of PNH. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.

Is Allogeneic Stem Cell Transplantation a Good Option for Paroxysmal Nocturnal Haemoglobinuria?

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, nonmalignant, haematopoietic clonal disorder that manifests with haemolytic anaemia, thrombosis, and peripheral blood cytopenias. The diagnosis is based on laboratory findings of intravascular haemolysis and flow cytometry. Clinical findings in PNH include haemolytic anaemia, thrombosis in atypical sites, or nonspecific symptoms attributable to the consequences of haemolysis. Thrombosis is the leading cause of death in PNH. Terminal complement pathway inhibition with eculizumab controls most of the symptoms of haemolysis and the life-threatening complications of PNH. However, there is still no consensus about haematopoietic stem cell transplantation (HSCT) in the management of PNH; it is the only potentially curative therapy for PNH. There are limited data and few case series about both the long-term outcomes of HSCT for PNH and the impacts of conditioning regimens on PNH clones. The authors have reviewed the findings of these studies which report on HSCT for the treatment of PNH.

C3 Inhibition with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Paddock and Palomino Trials

C3 Inhibition with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Paddock and Palomino Trials

Management of Meningococcal Disease Risk in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) on Complement Inhibitors: 18 Years' Experience from the UK National PNH Service in Leeds

Management of Meningococcal Disease Risk in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) on Complement Inhibitors: 18 Years' Experience from the UK National PNH Service in Leeds

Results of the Pegasus Phase 3 Randomized Trial Demonstrating Superiority of the C3 Inhibitor, Pegcetacoplan, Compared to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria

Results of the Pegasus Phase 3 Randomized Trial Demonstrating Superiority of the C3 Inhibitor, Pegcetacoplan, Compared to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria

Effect of Pegcetacoplan on Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria from the Pegasus Phase 3 Trial Comparing Pegcetacoplan to Eculizumab

Effect of Pegcetacoplan on Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria from the Pegasus Phase 3 Trial Comparing Pegcetacoplan to Eculizumab

Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Previously Treated with Eculizumab: A Matching-Adjusted Indirect Comparison

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disease characterized by complement-mediated hemolysis, resulting in anemia, thrombosis, and bone marrow failure. Currently available treatment options for PNH include the C5 inhibitors eculizumab and ravulizumab, which target intravascular hemolysis through terminal complement inhibition. Pegcetacoplan is a targeted C3 inhibitor being developed to control both intravascular and extravascular hemolysis, to improve hematologic and clinical outcomes. There is no head-to-head study of pegcetacoplan vs ravulizumab in patients with PNH. We assessed the comparative effectiveness of pegcetacoplan to ravulizumab through comparison of phase 3 study results, using matching-adjusted indirect comparison (MAIC) methodology, anchoring on the common comparator arm in the studies, eculizumab. We also acknowledge inherent limitations to MAIC (eg, lack of generalizability beyond the analyzed population). METHODS Individual patient data from PEGASUS, an ongoing, randomized, phase 3 study comparing pegcetacoplan and eculizumab among patients with PNH previously treated with eculizumab, were used to adjust for baseline differences compared to aggregate, published results from the randomized 302 study (Kulasekararaj AG, et al. Blood. 2019;133(6):540-549), which compared ravulizumab and eculizumab among patients with PNH with previous eculizumab. Both studies had similar eligibility criteria. However, PEGASUS also required hemoglobin <10.5 g/dL and absolute reticulocyte count >1.0× the upper limit of normal; these criteria were not applicable in the 302 study. To adjust for cross-study differences in baseline characteristics, propensity score weighting was used to balance demographic and clinical characteristics. Outcomes assessed included transfusion avoidance, total number of units of packed red blood cells (PRBCs) transfused, hemoglobin stabilization, and change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Outcomes were assessed from PEGASUS at week 16 and from the 302 study at week 26. Unadjusted mean and least-squares mean change in FACIT-Fatigue score were compared for PEGASUS and the 302 study, respectively. Weighted Wald tests and 95% confidence intervals (CIs) were computed for comparisons of categorical and continuous outcomes (ie, chi-square and z tests, respectively). RESULTS Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from the 302 study (97 ravulizumab; 98 eculizumab) were included. Among pegcetacoplan and ravulizumab patients, mean age was 46.4 years, 48.5% were female, and 51.5% were white. Overall, 51.5% received ≥4 transfusions in the 12 months before screening in PEGASUS. The adjusted difference in proportion of transfusion avoidance was 71.4% (95% CI, 53.5-89.3%; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 71.4% more transfusion avoidance than ravulizumab. The difference in mean number of units of PRBCs transfused during follow-up was -5.7 units (95% CI, -7.2 to -4.2; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 5.7 fewer units of PRBCs transfused during treatment than ravulizumab. The adjusted difference in proportion of hemoglobin stabilization was 75.5% (95% CI, 56.4-94.6%; P < 0.0001), suggesting that pegcetacoplan is associated with 75.5% more patients who achieved hemoglobin stabilization than ravulizumab. The adjusted difference in mean change from baseline in FACIT-Fatigue score was 8.8 points (95% CI, 4.2-13.3; P < 0.0001), suggesting that pegcetacoplan is associated with an improvement ~3 times greater than the clinically meaningful improvement of 3 points than ravulizumab. See the Figure for additional details. CONCLUSIONS MAIC methodology allowed the examination of the comparative effectiveness of pegcetacoplan vs ravulizumab in the absence of a head-to-head trial. Results suggest an improvement in transfusion avoidance, hemoglobin stabilization, and fatigue and a reduction in the total number of units of PRBCs transfused for patients who received pegcetacoplan, a C3 inhibitor, in PEGASUS, vs patients who received ravulizumab, a C5 inhibitor, in the 302 study. As PEGASUS progresses, week 26 data will be used to refresh these analyses. Disclosures Bhak: Apellis: Research Funding. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Yee:Apellis: Research Funding. Sundaresan:Apellis: Research Funding. Swartz:Apellis: Research Funding. Duh:Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding; Merck: Research Funding. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Improvements in Fatigue Correlate with Changes in Clinical and Hematological Outcomes: Post Hoc Analyses from the Pegasus Study

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematologic disease characterized by complement-mediated hemolysis resulting in anemia, thrombosis, and bone marrow failure. The PEGASUS phase 3 randomized study demonstrated superiority of pegcetacoplan vs. eculizumab on improvements in hemoglobin, and pegcetacoplan improved clinical and hematological outcomes such as fatigue in patients with partial response to eculizumab after treatment for at least 3 months (Hb <10.5 g/dL). The objectives of these post-hoc analyses were to explore relationships among effect modifiers, including fatigue and hemoglobin, reticulocyte count, indirect bilirubin, and physical functioning. Also, this study assessed further detail on the treatment effects of pegcetacoplan on fatigue in patients. METHODS Patients ≥18 years of age with PNH and hemoglobin concentration <10.5 g/dL despite receiving treatment with eculizumab for ≥3 months were eligible for inclusion. Patients entered a 4-week run-in period in which they received eculizumab plus twice-weekly pegcetacoplan (1080 mg, self-administered subcutaneously) and were then randomized 1:1 to monotherapy with pegcetacoplan or eculizumab for 16 weeks. Fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue scale, and a variety of symptoms (including fatigue and physical functioning) were evaluated with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) scale. Convergent validity was assessed using Spearman correlations and known groups validity was assessed using analysis of covariance (ANCOVA), as suggested by the FDA Guidance on patient-reported outcomes (US Food Drug Administration.Fed Regist. 2009;74(235):65132-65133). Subjects were grouped based on hemoglobin level (<10 g/dL, 10 to ≤12 g/dL, >12 g/dL), and by degree of hemoglobin improvement: <1 g/dL, ≥1 to <2 g/dL, and ≥2 g/dL. RESULTS At Week 16, in the overall sample (n = 80; intent-to-treat), the FACIT-Fatigue total score was significantly correlated with hemoglobin (r = 0.47, p < 0.0001; Figure 1), reticulocyte count (r = -0.37, p < 0.01), indirect bilirubin (r = -0.25, p < 0.05), and with multiple EORTC domains including fatigue and physical function (r = -0.88, p < 0.0001 and r = 0.82, p < 0.0001 respectively). In a responsiveness analysis, groups with greater improvement in hemoglobin over 16 weeks showed the most improvement in fatigue (F = 9.03, p < 0.0001), with the largest reduction in fatigue in the group with an increase in hemoglobin of ≥2 g/dL (11.3-point improvement in FACIT-F total score). In contrast, individuals with little to no hemoglobin improvement (<1 g/dL) reported slightly more fatigue (-1.2 worsening in FACIT-F total score). The FACIT-F also distinguished between groups with different levels of hemoglobin (<10 g/dL, 10 to ≤12 g/dL, >12 g/dL) at Week 16 (F = 4.78, p = 0.0019). An analysis of the correlation of change scores indicates a clear separation between pegcetacoplan and eculizumab, showing a greater effect of pegcetacoplan on change in hemoglobin and improvement in fatigue (Figure 2). CONCLUSION In PNH, hemoglobin level and positive change in hemoglobin were significantly related to reduced fatigue. Pegcetacoplan resulted in significantly lower fatigue and hemoglobin scores at Week 16 compared to eculizumab. Disclosures Cella: Novartis:Consultancy;Kiniksa:Consultancy;IDDI:Consultancy;BMS:Consultancy, Research Funding;Oncoquest:Consultancy;ASAHI KASEI PHARMA CORP.:Consultancy;Mei Pharma:Consultancy;Ipsen:Consultancy, Research Funding;Evidera:Consultancy;DSI:Consultancy, Research Funding;BlueNote:Consultancy;Abbvie:Consultancy, Research Funding;Astellas:Consultancy, Honoraria;FACIT.org:Membership on an entity's Board of Directors or advisory committees, Other: President;PROMIS Health Org:Membership on an entity's Board of Directors or advisory committees, Other;Pled Pharma:Research Funding;Janssen:Research Funding;Clovis:Research Funding;Alexion:Research Funding;Apellis:Consultancy;Pfizer:Consultancy, Research Funding.Lenderking:Evidera:Current Employment.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.Hamdani:Apellis Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Hsieh:Evidera/PPD:Current Employment.Shaffer:Evidera:Current Employment.Röth:Sanofi:Consultancy, Honoraria;Roche:Consultancy, Honoraria, Research Funding;Novartis:Consultancy, Honoraria;Biocryst:Consultancy, Honoraria;Apellis:Consultancy, Honoraria;Alexion Pharmaceuticals Inc.:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Pegcetacoplan Is Superior to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Regardless of Prior Transfusion Requirement

Pegcetacoplan Is Superior to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Regardless of Prior Transfusion Requirement

Real-World Treatment Patterns and Healthcare Resource Utilization (HRU) of Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) Receiving Eculizumab in a US Population

INTRODUCTION The C5 inhibitor eculizumab is the current standard of care for the treatment of PNH. However, some pts receiving eculizumab to treat PNH continue to experience ongoing hemolysis and anemia, resulting in red blood cell transfusion dependence, substantial unmet clinical needs, and considerable health economic burden. This study evaluated the treatment patterns of pts with PNH receiving eculizumab and compared HRU among blood transfusion-dependent (TD) pts versus blood transfusion-free (TF) pts in real-world clinical practice in the United States. METHODS Pts aged ≥12 years with ≥2 claims for eculizumab infusion between April 1, 2014, and September 30, 2019, were identified from the IBM® MarketScan® Research Databases. The index date was the first observed claim for eculizumab infusion with ≥3 months of continuous eligibility prior (baseline period). Pts with ≥1 diagnosis of indications other than PNH for eculizumab (ie, atypical hemolytic uremic syndrome, generalized myasthenia gravis, neuromyelitis optica spectrum disorder) during the baseline period or on the index date were excluded to identify pts with PNH. The full cohort of PNH pts treated with eculizumab were then stratified into the TD cohort (≥1 claim for blood transfusion within 6 months following any eculizumab infusion) or TF cohort. Patient demographic and clinical characteristics in the baseline period were compared between TD and TF cohorts using standardized differences (std diff), with >20% indicating substantial differences. Treatment patterns and HRU (all-cause and PNH-related) were evaluated during the observation period (ie, from index date to earliest date between end of continuous healthcare plan enrollment and end of data availability). Time from index date to treatment discontinuation among pts in the full cohort was assessed using Kaplan-Meier analysis. HRU was compared between TD and TF cohorts using incidence rate ratios (IRRs) adjusted for baseline covariates. RESULTS A total of 151 eculizumab users with PNH were identified as the full cohort; 55 (36%) were TD and 96 (64%) were TF. Mean (range) age was 36.7 (12-74) years among all pts (TD: 35.1 years; TF: 37.6 years). Overall, 56% of pts were female, with a higher proportion in the TD vs TF cohort (67% vs 49%; std diff = 38%). More pts in the TD vs TF cohort had blood transfusions (71% vs 18%; std diff = 127%) and use of corticosteroid therapy (46% vs 32%; std diff = 27%) during baseline. Baseline coagulopathy and aplastic anemia were more common in the TD vs TF cohort (coagulopathy: 49% vs 30%; std diff = 39%; aplastic anemia: 64% vs 43%; std diff = 43%). Myelodysplastic syndrome was present in 10% of the full cohort (TD: 13%; TF: 8%; std diff = 14%). During a mean observation period of 19 months for the overall sample (TD: 20 months; TF: 19 months), pts had a median (interquartile range) of 8 (3-30) eculizumab infusions (TD: 5 infusions; TF: 8 infusions) during maintenance phase; 29% of pts (TD: 21%; TF: 33%) had on average 14 days between maintenance eculizumab infusions; 61% of pts (TD: 66%; TF: 58%) discontinued eculizumab treatment (ie, gap of >42 days between 2 infusions) and the median time to treatment discontinuation was 254 days (TD: 180 days; TF: 337 days). Mean (range) number of blood transfusions among TD pts was 8.5 (1-54). During the observation period, pts in the TD cohort had 2.95 times more all-cause hospitalizations and 4.58 times more hospitalization days compared to pts in the TF cohort (all P < 0.05). Similar trends were observed for PNH-related hospitalizations. Results for all-cause and PNH-related HRU are presented in the Table. CONCLUSIONS This study demonstrated a considerable economic burden among pts with PNH treated with eculizumab, particularly among pts dependent on blood transfusions. TD eculizumab users comprised >36% of the overall sample, indicating that disease activity may not be well controlled. These pts had >4 times the number of hospitalization days compared to TF pts, emphasizing the substantial unmet clinical need despite treatment with eculizumab. These findings suggest that the current PNH standard of care may be insufficient for TD pts. Based on time between dosing intervals, >70% of PNH pts in this study were not dosed per label, and two-thirds of pts discontinued eculizumab within an average of a 1.5-year timeframe. New therapies are needed to reduce the considerable burden of pts with PNH. Disclosures Cheng: Apellis: Research Funding. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Yenikomshian:Apellis: Research Funding. Scoble:Apellis: Current Employment, Current equity holder in publicly-traded company. Mahendran:Apellis: Research Funding. Lejeune:Apellis: Research Funding. Yu:Apellis: Research Funding. Duh:Apellis: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding.

BCX9930, an Oral Factor D Inhibitor, for the Potential Treatment of Alternative Pathway Mediated Diseases: Interim Results of a Phase 1 Study in Healthy Subjects

INTRODUCTION: Complement factor D is the rate-limiting enzyme for activation of the complement alternative pathway (AP). Targeting factor D is therefore an attractive therapeutic strategy for treatment of AP-mediated diseases including paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy, and atypical hemolytic uremic syndrome. BCX9930 is a potent and selective orally bioavailable inhibitor of factor D in development for the treatment of PNH and other complement-mediated diseases. PNH is an acquired, chronic, non-malignant disorder of hematopoietic stem cells that is characterized by clonal deficiency of AP regulatory proteins CD55 and CD59, resulting in dysregulated AP amplification, opsonization, membrane attack complex (MAC) formation, and hemolysis. The approved intravenously (IV) administered C5 inhibitors eculizumab and ravulizumab inhibit MAC formation and intravascular hemolysis, but do not inhibit opsonization, leading to extravascular hemolysis and potentially incomplete treatment response. Inhibition of factor D is expected to prevent both intravascular and extravascular hemolysis in PNH, a distinct advantage over currently available parenteral therapies. METHODS: This abstract describes preliminary data in healthy subjects enrolled in the single ascending dose (SAD) and multiple ascending dose (MAD) evaluations of Study BCX9930-101 (NCT04330534), an ongoing first in human (FIH) study that includes randomized, double-blind, placebo-controlled evaluations of the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy subjects. Safety and tolerability are evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 are measured using a validated liquid chromatography-dual mass spectrometry (LC/MS/MS) assay; PD effects are assessed using multiple assays, including inhibition of AP activity in the AP-specific Wieslab (AP-W) and AP Hemolysis ([AP-H], lysis of rabbit red blood cells [RBCs] by human serum) assays. RESULTS: To date, 48 subjects have been enrolled into 6 SAD cohorts (n = 6 BCX9930, n = 2 placebo per cohort), with doses ranging from 10 to 1200 mg. Sixty subjects have been enrolled into 5 MAD cohorts (n = 10 BCX9930, n = 2 placebo per cohort), with doses ranging from 50 mg every 12 hours (Q12h) to 400 mg Q12h. The mean age of all enrolled subjects was 34.3 years and 50.9% were male. BCX9930 was safe and generally well-tolerated at all doses evaluated. There were no serious adverse events or dose-related safety signals. Mild headache was the most frequent treatment-emergent adverse event and showed no correlation with dose. A benign maculopapular exanthem attributed to study drug was observed following MAD administration. These events were mild or moderate in severity and resolved in a median of 5 days. BCX9930 exposure was approximately linear and dose-proportional across all evaluated SAD and MAD doses. Mean BCX9930 concentrations at 12 hours post dose were ≥ 8 to 10 times the factor D half-maximal effective concentration (EC50) for SAD doses ≥ 300 mg and for MAD doses ≥ 100 mg Q12h at steady-state. Rapid, dose-dependent AP suppression was observed following SAD and MAD, as measured by the AP-W and AP-H assays (Figure 1). AP suppression > 98% was observed in both assays at steady state for MAD doses ≥ 200 mg Q12h. Duration of complete suppression increased with dose and was ≥ 12 hours for MAD doses ≥ 200 mg Q12h. Doses ≥ 200 mg Q12h showed greater, more durable, and more consistent inhibition across subjects compared with doses ≤ 100 mg Q12h. PK/PD modeling of AP-H and AP-W demonstrates a clear concentration-response, with estimated EC50 values between 21.7 and 40.7 nM. These estimates are consistent with the in vitro IC50 for inhibition of proteolytic activity against the natural substrate C3bB of 28.1 nM. CONCLUSIONS: BCX9930 is a potent and selective orally bioavailable inhibitor of human complement factor D. In this preliminary analysis of an ongoing FIH study, BCX9930 displayed a promising safety and tolerability profile. Exposure was approximately linear and dose-proportional across a wide dose range, and complete and durable suppression of the AP was achieved. Together, these findings support further evaluation of BCX9930 in patients with PNH and other AP-mediated diseases. Disclosures Davidson: BioCryst Pharmaceuticals, Inc.:Current Employment.Mathis:BioCryst Pharmaceuticals, Inc.:Current Employment.Mair:Quotient Sciences:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Reynolds:BioCryst Pharmaceuticals, Inc.:Current Employment.Parker:BioCryst Pharmaceuticals, Inc.:Current Employment.Babu:BioCryst Pharmaceuticals, Inc.:Current Employment.

Biotechnological products for the treatment of complement system disorders including paroxysmal nocturnal hemoglobinuria: currently available and in development

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder caused by somatic mutations in phosphatidylinositol glycan, class A gene (PIG-A) in hematopoietic stem cells which manifests as haemolytic anemia, bone marrow failure, thromboses, impaired renal function, and other severe clinical symptoms. The management of PNH is a clinical challenge requiring a comprehensive approach. Over the past decade, target therapy with eculizumab, an antibody inhibitor of terminal complement activation, has played a key role in the treatment of PNH. Eculizumab is the first humanized anti-C5 monoclonal antibody that was proven effective in inhibiting the complement system and was approved as a standard treatment for PNH in many countries. Elizaria, the first biosimilar version of eculizumab, whose similarity to the original drug in terms of efficacy and safety was demonstrated in clinical trials, has been widely used in Russia since 2019. New complement inhibitors classified by their mechanism of action into inhibitors targeting complement component C5 (the terminal pathway) and those targeting early phases of complement activation cascade (the proximal pathway) are currently in development. These new drugs include monoclonal antibodies, small molecules, small peptide inhibitors, small interfering RNA, and recombinant proteins based on endogenous regulators of complement activation.

Ravulizumab in the treatment of paroxysmal nocturnal hemoglobinuria

ABSTRACT Introduction Eculizumab, the anti-C5 monoclonal antibody therapeutic, has revolutionized the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) and has shown efficacy in other complement-mediated disorders including atypical Hemolytic Uremic Syndrome (aHUS) and Myasthenia Gravis (MG). Despite the effectiveness of eculizumab, challenges remain in the treatment of these diseases, including breakthrough hemolysis, frequent intravenous infusions, and cost; in an effort to mitigate these challenges, the new monoclonal therapeutic ravulizumab has been developed. Areas covered In this paper, we review the characteristics and clinical performance of ravulizumab and assess its potential utility in the treatment of PNH, and its position in this rapidly-developing therapeutic landscape. A review of published data up to Phase III of ravulizumab had been performed. Studies were identified via Google Scholar, PubMed, the United States National Library of Medicine Clinical Trials, citation chasing, and topic knowledge of the authors. Expert opinion Ravulizumab represents an important advance in the clinical care of complement-mediated disorders. Clinical trials demonstrate non-inferior efficacy and indistinguishable safety and tolerability to eculizumab, with added patient-preferred benefits including longer intervals between infusions. Though improved, physicians should be aware of the limitations of ravulizumab, including the need for intravenous infusions and possible breakthrough hemolysis.

Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a chronic, multi-systemic, progressive and life-threatening disease characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. Paroxysmal nocturnal hemoglobinuria results from the expansion of a clone of hematopoietic cells that due to an inactivating mutation of the X-linked gene PIG-A are deficient in glycosylphosphatidylinositol-linked proteins. Early diagnosis, using flow cytometry performed on peripheral blood, the gold standard test to confirm the diagnosis of paroxysmal nocturnal hemoglobinuria, is essential for improved patient management and prognosis. The traditional therapy for paroxysmal nocturnal hemoglobinuria includes blood transfusion, anti-thrombosis prophylaxis or allogeneic bone marrow transplantation. The treatment that has recently become available is the complement blockade by the anti-C5 monoclonal antibody eculizumab. In this consensus, we are aiming to review the diagnosis and treatment of the paroxysmal nocturnal hemoglobinuria patients, as well as the early recognition of its systemic complications. These procedures express the opinions of experts and have been based on the best available evidence and international guidelines, with the purpose of increasing benefits and reducing harm to patients.

Kinetic parameters of complement activation in patients with paroxysmal nocturnal hemoglobinuria during eculizumab therapy

Introduction. Eculizumab inhibits the terminal steps of complement activation and is the standard treatment for paroxysmal nocturnal hemoglobinuria (PNH). Unstable complement inhibition causes “breakthrough” intravascular hemolysis and a suboptimal response to eculizumab therapy in some patients with PNH.Aim: to evaluate the stability of complement inhibition in eculizumab treatment by testing the kinetic parameters of complement activation.Materials and methods. The study included 12 PNH patients receiving long-term eculizumab therapy (median 54 months, range 4–66 months). The median age was 35 years (from 22 to 68 years), 92 % of patients were female. The median PNH clone size was 96 % of the granulocytes. The control group consisted of 12 healthy donors (age 25–60 years, women 75 %). Complement activation was evaluated immediately prior to the next eculizumab infusion, and then again after 5 and 10 days. Kinetic parameters (induction period, hemolysis rate, T50-the time required to achieve 50 % hemolysis) were recorded separately for the total complement activity and an alternative activation pathway using rabbit red blood cells (rRBC).Results. The parameters of complement activation directly before the next eculizumab administration corresponded to a marked inhibition of the overall activity of the system. The induction period was extended by 7 times compared to the control (median 180 vs 25 seconds, p < 0.0001), and the hemolysis rate was 28 times less (median 1.6 vs 45.1 × 106 rRBC/min, p < 0.0001). The T50 value exceeded the control value by 20 times (median 690 vs 35 seconds, p < 0.0001). The parameters of the alternative complement activation pathway were reduced by 2–3 times compared to the control. In one case, repeated tests revealed insuffi cient complement inhibition, which was associated with pharmacokinetic “breakthrough” hemolysis. The degree of further complement inhibition and the tendency to restore activity varied signifi cantly during dynamic testing on days 5 and 10 after eculizumab infusion.Conclusion. The results of this study demonstrate individual differences in the residual activity of complement in PNH patients receiving long-term eculizumab therapy. Testing of complement activity is necessary with a suboptimal response to eculizumab therapy and when considering therapy correction. Kinetic registration of residual complement-dependent lysis of rabbit red blood cells demonstrates a higher sensitivity than the traditional CH50 study.Conflict of interest: the authors declare no conflict of interest.Financial disclosure: the study had no sponsorship.