Yasutaka Ueda

Warm autoimmune hemolytic anemia (wAIHA) is a rare, life-threatening disease characterized by autoantibody-mediated destruction of red blood cells with no approved treatments. Nipocalimab, an immunoselective neonatal Fc receptor blocker, reduces circulating IgG levels, including autoantibodies implicated in wAIHA. The phase 2/3, randomized, 24-week, double-blind ENERGY study in participants with wAIHA evaluated nipocalimab 30 mg/kg IV q4w (n=38), 15 mg/kg IV q2w (n=38), and placebo (n=39). The primary endpoint, durable hemoglobin response (hemoglobin ≥10 g/dL and a ≥2 g/dL increase from baseline at 3 consecutive visits [≥28 days] starting by Week 16, without rescue therapy), achieved statistical significance for nipocalimab 30 mg/kg IV q4w (23.7% [9/38]; 1-sided P=0.015) but not 15 mg/kg IV q2w (21.1% [8/38]; P=0.044; not significant) versus placebo (7.7% [3/39]). Improvement in FACIT-Fatigue score at Week 24 (key secondary endpoint) was observed with nipocalimab, with mean (SD) improvement of 3.4 (7.29) points (nominal P=0.007) for 30 mg/kg IV q4w and 1.2 (6.07) (nominal P=0.267) for 15 mg/kg IV q2w versus 0.6 (3.42) for placebo. Mean percent (SD) reduction in average daily prednisone dose (key secondary endpoint) was 15.1% (28.2) for nipocalimab 30 mg/kg IV q4w (nominal P=0.039) and 14.0% (30.4) for 15 mg/kg IV q2w (nominal P=0.055) versus 3.9% (16.33) for placebo. The safety profile was consistent with the known safety profile of nipocalimab and with wAIHA-associated risks. Overall, in the double-blind ENERGY study, nipocalimab demonstrated rapid hemoglobin response and nominal improvements in fatigue that were maintained over 24 weeks, with no new safety findings in wAIHA. NCT04119050

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening hematologic disease, often misdiagnosed because of its non-specific symptoms. PNH is characterized by terminal complement activity and intravascular hemolysis, potentially leading to thrombosis, kidney failure, and premature mortality. Early identification remains challenging, necessitating improved diagnostic strategies. In this retrospective JMDC Claims Database analysis, we evaluated the PNH patient journey, including the time from PNH-related symptom onset to first diagnosis and the association of this interval with outcomes. Overall, 160 patients were definitively diagnosed with PNH between July 2010 and April 2022. Flow cytometry (diagnostic standard to detect PNH-type blood cells) was performed in 99 of 160 patients. Ninety-two of 160 patients (57.5%) had PNH-related symptoms before first diagnosis. The median time from PNH-related symptom onset to diagnosis was 26.5 (range, 1–146) months. The incidence of PNH-related complications (kidney failure, thrombosis [including venous thromboembolism]) per 1000 patient-years increased with time from symptom onset to diagnosis. Considerable time elapsed between symptom onset and definitive PNH diagnosis. Longer intervals from symptom onset to diagnosis were descriptively associated with higher rates of complications, including kidney failure and thrombosis, highlighting the potential importance of improved awareness and earlier diagnostic testing for improving PNH outcomes.

Objective: This study aimed to assess the burden of warm autoimmune haemolytic anaemia (wAIHA) and treatment practices in the Asia‐Pacific (APAC) region. Methods: A systematic literature review (SLR) of observational studies in adult patients with wAIHA was conducted. Based on these findings, a Delphi panel was convened to develop consensus recommendations on diagnosis, treatment goals and algorithms by subtypes, unmet needs and research priorities. Results: The SLR included 37 publications. Clinical guidelines consistently recommend direct antiglobulin testing for diagnosis and corticosteroids as first‐line treatment. Real‐world data showed corticosteroid use in over 80% of patients, with response rates of 81%–96%, and relapse rates of 18%–45%. The Delphi panel recommended routine screening for underlying conditions and early therapeutic interventions. Key challenges identified included restricted access to rituximab in parts of the APAC region and gaps in physician awareness. Research priorities included optimising therapy, assessing long‐term outcomes and improving disease awareness. Conclusion: This research emphasises the need for evidence‐based, regionally adaptable treatment algorithms for wAIHA in the APAC region. Ongoing data gaps related to epidemiology, outcomes and quality of life must be addressed to enhance patient care. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Thromboembolism (TE) is a major cause of morbidity and mortality in patients with paroxysmal nocturnal hemoglobinuria (PNH). This narrative review summarizes available evidence on TE in Asian patients with PNH and discusses practical considerations and challenges for preventing and managing PNH-associated TE in Asian populations. Evidence suggests that, compared with non-Asians, fewer Asian patients have a history of TE (3.6% vs. 8.9%, p < 0.01), receive anticoagulants (8.5% vs. 16.2%, p = 0.002), or die from TE (6.9% vs. 43.7%, p = 0.000). Independent predictors of TE include lactate dehydrogenase ≥ 1.5 × upper limit of normal, pain, and male sex. Clone size alone does not appear to be a reliable estimate of TE risk. D-dimer levels are a useful marker of hemostatic activation, although they are not specific to PNH. Complement inhibition reduces the incidence of TE, although it does not wholly eliminate TE risk. Eligibility criteria and access to complement inhibitors vary across Asia, with limited availability in some countries. Anticoagulation is required to treat acute TE events and for primary or secondary prophylaxis in selected patients. Physicians and patients must stay alert to the signs and symptoms of TE to ensure prompt and appropriate treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) clones can be identified in a significant proportion of patients with aplastic anemia (AA). Screening for PNH clones at the time of an AA diagnosis is recommended by national and international guidelines. In this report, an expert panel of physicians discusses current best practices and provides recommendations for managing PNH in patients with AA in the Asia–Pacific region. Plasma/serum lactate dehydrogenase (LDH) levels and reticulocyte count should be measured with every blood test. PNH clone size should be monitored regularly by flow cytometry, with on-demand testing in the event of a rise in LDH level ± reticulocyte count or development of symptoms such as thrombosis. Monitoring for PNH clones can guide the choice of initial AA treatment, although flow cytometry has resource implications which may present a challenge in some Asia–Pacific countries. The treatment of patients with both PNH and AA depends on which condition predominates; following PNH treatment guidelines if hemolysis is the main symptom and AA treatment guidelines if bone marrow failure is severe (regardless of whether hemolysis is mild or moderate). The expert panel’s recommendations on the monitoring and treatment of PNH in patients with AA are practical for healthcare systems in the Asia–Pacific region.

The advent of recycling antibodies, leveraging pH-dependent antigen binding and optimized FcRn interaction, has advanced the field of antibody therapies, enabling extended durability and reduced dosages. Eculizumab (Soliris^®) demonstrated the efficacy of C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH), while its derivative, ravulizumab (Ultomiris^®), recognized as a recycling antibody, extended the dosing intervals. However, limitations including intravenous administration and inefficacy in patients with the R885H single-nucleotide polymorphism (SNP) in C5 could necessitate alternative solutions. Crovalimab (PiaSky^®), a next-generation recycling antibody, overcomes these challenges with innovative charge engineering, achieving the enhanced cellular uptake of C5–crovalimab complexes and targeting a unique C5 epitope, allowing for efficacy regardless of the R885H SNP. This study highlights crovalimab’s distinctive molecular features, showing its eliminated binding to Fcγ receptors and C1q, alongside its optimized antigen binding characteristics. The impact of charge engineering was reconfirmed in mice, demonstrating faster C5 clearance than recycling antibodies. Notably, in the maintenance dosing regimen, crovalimab neutralizes approximately seven C5 molecules per antibody on average. Furthermore, its design also reduces the viscosity to facilitate high-concentration formulations suitable for subcutaneous delivery. Consequently, crovalimab offers a four-weekly subcutaneous injection regimen for PNH, marking a substantial improvement in treatment convenience and potentially transforming patients’ quality of life.

Introduction Crovalimab is a novel anti-complement component 5 (C5) monoclonal antibody engineered with the Sequential Monoclonal Antibody Recycling Technology (SMART-Ig; Fukuzawa et al, Sci Rep. 2017) to extend half-life and enable infrequent, subcutaneous (SC) self-administration in C5-mediated diseases. Crovalimab is being investigated as a therapy for paroxysmal nocturnal hemoglobinuria (PNH), a disease for which C5 inhibition is the standard of care. The Phase I/II COMPOSER trial (NCT03157635; Röth, et al. Blood. 2020) is a global, open-label, multicenter study of crovalimab consisting of 4 sequential parts. Parts 1, 2, and 3 assessed the pharmacokinetics (PK) and safety of crovalimab in healthy volunteers, C5 inhibitor-naive patients, and patients switched from eculizumab, respectively. Part 4 assessed an optimized crovalimab dose and regimen in naive and switched patients with PNH. Because eculizumab and crovalimab bind to different C5 epitopes, drug-target-drug complexes (DTDCs) consisting of eculizumab, C5, and crovalimab motifs can temporarily form in the circulation of patients who switch treatments. DTDCs can form in a range of sizes, from single crovalimab-C5-eculizumab motif to larger complexes with multiple motifs. Larger DTDCs are a concern because they take longer to clear and may be more likely to induce type III hypersensitivity reactions. Objectives Describe the impact of DTDC formation on the safety, PK, and pharmacodynamics of crovalimab in patients with PNH who switched from eculizumab to crovalimab and to describe the effect of crovalimab dose on DTDC size distribution and kinetics. Study Design and Methods Using data from COMPOSER Parts 1-3, a biochemical mathematical model was developed to investigate the kinetics of the formation and dissociation of DTDCs under the assumption that larger complexes are formed by the reversible binding of smaller complexes. The model was calibrated using concentration-time profiles of total C5, total crovalimab, and the concentration of eculizumab at the time of crovalimab initiation. DTDC size distributions were measured using size-exclusion chromatography coupled to enzyme-linked immunosorbent assay. Using model-based simulations, an optimized crovalimab dosing strategy was identified to reduce the formation of large DTDCs while maintaining serum concentration of crovalimab above the target level of ≈ 100 μg/mL. The optimized dose and regimen were a loading series of 1000 mg intravenously on day 1 and 340 mg SC on days 2, 8, 15, and 22, followed by maintenance dosing of 680 mg SC every 4 weeks starting on day 29. The loading dose series increased the total crovalimab dose received during the first month of treatment to reduce the formation of larger DTDCs, in line with the lattice theory of complex formation. This optimized dosing strategy was investigated in Part 4 patients who switched from eculizumab. Results In COMPOSER, 19 patients with PNH were enrolled in Part 3 and switched from eculizumab to crovalimab. DTDCs were observed in all patients from Part 3 (Figure; larger DTDCs are found in fractions 1-4 and smaller crovalimab-containing complexes, such as single motifs and single crovalimab molecules, are found in fractions 5 and 6). Two Part 3 patients experienced clinical manifestations compatible with type III hypersensitivity reactions that were ascribed to DTDCs. The DTDC size distribution in Part 4 patients, who received the optimized dosing strategy, evolved differently than in Part 3 patients, consistent with model predictions. In the switched patients from Part 4, large DTDC levels started to decrease on day 8 and continued to decrease, in contrast to Part 3, in which they started to decrease on day 15. On day 22, the mean percentage of the largest DTDCs was reduced by 56% in patients in Part 4 relative to patients in Part 3. Part 4 patients achieved and maintained serum crovalimab concentrations above ≈ 100 µg/mL throughout follow-up. Despite DTDCs being observed in all Part 4 patients who switched from eculizumab, no adverse events suggestive of a type III hypersensitivity reaction occurred. Conclusions The optimized crovalimab regimen resulted in lower concentrations of large DTDCs than in patients who received the Part 3 regimen and reduced the persistence of DTDCs in patients who switched treatment. This regimen is now being evaluated in the Phase III COMMODORE 1 (NCT04432584) and COMMODORE 2 (NCT04434092) studies.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol (GPI)-anchored proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent auto-inflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients’ leukocytes and of PIGT-knockout THP-1 cells we show that, through increased IL-1β secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of auto-inflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also auto-inflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.