Voydeya (danicopan) / AstraZeneca - LARVOL DELTA

Low Risk for Meningococcal Infections with Systemically Administered Pegcetacoplan, a Complement C3 and C3b Inhibitor (THSNA 2026) - P3 | "Clinical benefits of the initially available C5 inhibitors that block terminal complement activation (eculizumab, ravulizumab, crovalimab) paved the way for the development of proximal inhibitors, including the C3/C3b inhibitor pegcetacoplan, the factor B inhibitor iptacopan, and the add-on (to C5 inhibitors) factor D inhibitor danicopan. Understanding the safety profile of pegcetacoplan and other complement-targeted therapies will help physicians and patients make informed treatment decisions for individuals with complement-mediated conditions. For over 7 years of total systemic pegcetacoplan exposure, no cases of encapsulated N. meningitidis and consistently low rates of infections by other encapsulated bacteria were observed in patients with PNH, C3G, primary IC-MPGN, or other conditions. These findings may reflect effective risk mitigation strategies."

Complement-mediated Rare Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Infectious Disease • Influenza • Lupus Nephritis • Meningococcal Infections • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Pneumococcal Infections • Pneumonia • Primary Immunodeficiency • Rare Diseases • Respiratory Diseases • Septic Shock

DANICOPAN ADD-ON THERAPY DEMONSTRATES POSITIVE EFFICACY AND SAFETY IN ADVANCED AGE ADULTS WITH PNH AND CLINICALLY SIGNIFICANT EXTRAVASCULAR HEMOLYSIS: PHASE 3 ALPHA TRIAL SUB-ANALYSIS (EBMT 2026) - P3 | "This sub-analysis demonstrates that danicopan add-on to ravulizumab or eculizumab has positive efficacy and safety profile in advanced age patients with PNH and csEVH. During 12 weeks of danicopan therapy, patients reported meaningful improvements in Hb and ARC, maintained transfusion avoidance, and reported low rate of AEs."

Clinical • Metastases • P3 data • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

DANICOPAN ADD-ON THERAPY DEMONSTRATES POSITIVE EFFICACY AND SAFETY IN ADVANCED AGE ADULTS WITH PNH AND CLINICALLY SIGNIFICANT EXTRAVASCULAR HEMOLYSIS: PHASE 3 ALPHA TRIAL SUB-ANALYSIS (EBMT 2026) - P3 | "This sub-analysis demonstrates that danicopan add-on to ravulizumab or eculizumab has positive efficacy and safety profile in advanced age patients with PNH and csEVH. During 12 weeks of danicopan therapy, patients reported meaningful improvements in Hb and ARC, maintained transfusion avoidance, and reported low rate of AEs."

Clinical • Metastases • P3 data • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Danicopan PMS in Korea (clinicaltrials.gov) - P=N/A | N=8 | Not yet recruiting | Sponsor: AstraZeneca

New trial • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Population PK-PD Modeling of Danicopan Add-On Therapy in Participants With Paroxysmal Nocturnal Hemoglobinuria Treated With Ravulizumab or Eculizumab. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Overall, the effects of demographics, baseline, and food status variables were not considered clinically significant. These findings support the approved 150 mg and 200 mg tid dosing regimens for danicopan in patients with PNH."

Journal • PK/PD data • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Renal Disease

Assess Long-Term Safety of Danicopan Add-on Therapy in Participants With Paroxysmal Nocturnal Hemoglobinuria: Analysis of IPIG-Registry Data (clinicaltrials.gov) - P=N/A | N=50 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc.

New trial • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Long-term Safety of Danicopan: IPIG Registry-based Cohort Study (clinicaltrials.gov) - P=N/A | N=50 | Active, not recruiting | Sponsor: Alexion Pharmaceuticals, Inc.

New trial • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Understanding Pharmacokinetic-Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2024 to Better Manage the Risk of Drug Interactions With Concomitant Medications: A Review of Clinical Data From New Drug Applications. (PubMed, Curr Ther Res Clin Exp) - "Of these, 7 drugs were substrates of CYP3A, 3 of CYP2C9, one of CYP1A2, and one of CYP2C8, including the sensitive substrates vanzacaftor (CYP3A) and vorasidenib (CYP1A2). As precipitants, 6 drugs (acoramidis, cefepime/enmetazobactam, givinostat, lazertinib, mavorixafor, and resmetirom) were clinical inhibitors of CYP enzymes (2C8, 2C9, 2D6, 2E1, and 3A), with mavorixafor being a CYP2D6 strong inhibitor. Two drugs (elafibranor and tovorafenib) showed weak induction of CYP3A. Regarding transporter data, 3 drugs were substrates of transporters, including seladelpar (BCRP and OAT3), sulopenem (OAT3), and vadadustat (OAT1/3), and 8 drugs (arimoclomol, danicopan, givinostat, lazertinib, mavorixafor, resmetirom, vadadustat, and vazacaftor/tezacaftor/deutivacaftor) were inhibitors of transporters...Several DDIs with an AUC change <2 also had labeling recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Mechanistic DDI..."

Clinical data • FDA event • Journal • NDA • PK/PD data • Review • CYP1A2 • CYP2C9

Advancing treatment goals for paroxysmal nocturnal hemoglobinuria to align with quality of life improvements in the era of anti-complement therapy (PubMed, Rinsho Ketsueki) - "Eculizumab, a C5 inhibitor introduced in 2010, directly inhibits intravascular hemolysis, and thus not only resolves hemolysis-related symptoms but also prevents organ damage and improves survival...Various drugs have been developed to address these issues, including long-acting C5 inhibitors (ravulizumab and crovalimab) and proximal complement inhibitors capable of blocking extravascular hemolysis, such as a C3 inhibitor (pegcetacoplan), a factor B inhibitor (iptacopan), and a factor D inhibitor (danicopan). In particular, proximal complement inhibitors further enhance QOL because they inhibit both intravascular and extravascular hemolysis, resulting in greater improvement of hemoglobin levels and transfusion independence, and thereby further enhancing of QOL. Today, it is possible to achieve optimal improvement in QOL by appropriately selecting one of the three C5 inhibitors as first-line therapy or one of the three proximal complement inhibitors as second-line..."

HEOR • Journal • Cardiovascular • Chronic Kidney Disease • Complement-mediated Rare Disorders • Hematological Disorders • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Renal Disease • Thrombosis

Systemic medications and their impact on age-related macular degeneration development and progression: a review of current evidence. (PubMed, Curr Opin Ophthalmol) - "Multiple systemic medications have highlighted mixed or stage-dependent benefits on AMD development and progression. Some agents such as metformin and aspirin have shown conflicting findings, having been evaluated in randomized trials and large observational studies. Other medications including GLP-1 agonists, dopamine agonists, statins, fenofibrates, and danicopan show early promise in more limited studies, but require further clinical validation."

Journal • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

Ravulizumab-danicopan combination therapy in PNH management. (PubMed, Clin Adv Hematol Oncol) - No abstract available

Journal

Optimizing PNH treatment with the complement inhibitor pegcetacoplan: A case report (ASH 2025) - "The current treatment landscape includes 6 approved complement cascade inhibitors: 3 C5 inhibitors (eculizumab, ravulizumab, crovalimab), 1 C3/C3b inhibitor (pegcetacoplan), 1 factor B inhibitor (iptacopan), and 1 factor D inhibitor used as add-on treatment (danicopan)...Concomitant medications included apixaban, penicillin, and folic acid. In November 2020, her platelets count declined, and a bone marrow evaluation was diagnostic for moderate aplastic anemia (55-65% cellularity for age) and she was started on eltrombopag and cyclosporin. Despite ravulizumab and eltrombopag treatments, the patient developed significant anemia related to extravascular hemolysis (hemoglobin, 5.7 g/dL; LDH, 495 U/L; C5, 26.1 mg/dL [high]; complement hemolytic activity 50 [CH50], 7 U/mL [low])...After receiving both pegcetacoplan and iptacopan for 1 week and rivaroxaban 10 mg once daily for 48 hours, pegcetacoplan treatment ended on May 16, 2024... For this patient with PNH, the..."

Case report • Clinical • Anorexia • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Meningococcal Infections • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Successful retreatment of PNH with switch to ravulizumab and add-on danicopan after experiencing breakthrough hemolysis on pegcetacoplan: A case report (ASH 2025) - "Terminal complement inhibition with C5 inhibitors ravulizumab (Rav), the standard of care for PNH treatment, and eculizumab (Ecu) have provided effective control of terminal complement activity and IVH and decreased rates of thrombosis...The patient was treated intermittently with antithymocyte globulin and/or cyclosporine for ~5 years while receiving red blood cell transfusions... Hb, 11.8 g/dL; LDH, 351 U/L). The patient restarted Rav with 2 loading doses 2 weeks apart. The patient experienced 1 mild episode of BTH ~4 months after restarting Rav (Hb, 9.9 g/dL; LDH, 382 U/L), resolving rapidly with her scheduled dose of Rav."

Case report • Clinical • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Overview of treatment advances with complement inhibitors in patients with paroxysmal nocturnal hemoglobinuria (ASH 2025) - P3 | "The success of terminal C5 inhibitors emboldened researchers to investigate proximal complement inhibitors that have the potential to control both IVH and EVH, such as pegcetacoplan (C3/C3b inhibitor) and iptacopan (factor B inhibitor), as well as danicopan (factor D inhibitor) used as an add-on to C5 inhibitors...In the most recent analysis of the phase 3 ALPHA trial (NCT04469465), 57 patients (mean age 53 years) with PNH and residual clinically significant EVH (Hb ≤9.5 g/dL with ARC ≥120 × 10 9 /L) while receiving ravulizumab (63%) or eculizumab (37%) for a mean of 5 years were given danicopan in addition to their current C5 inhibitor for 12 weeks.[Kulasekararaj A, et al... Across clinical studies that included patients with PNH and Hb ≥10 g/dL after C5 inhibition, proximal complement inhibitors improved measures of residual anemia and quality of life to clinically significant degrees (increases of ≥2 g/dL in Hb levels and ≥3–5 points in FACIT-Fatigue..."

Clinical • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Meningococcal Infections • Otorhinolaryngology • Paroxysmal Nocturnal Hemoglobinuria • Pneumonia • Rare Diseases • Respiratory Diseases • Thrombosis

Low risk for meningococcal and other encapsulated bacteria infections with systemically administered pegcetacoplan in paroxysmal nocturnal hemoglobinuria and C3 glomerulopathies (ASH 2025) - P3 | "Clinical benefits of the initially available C5 inhibitors that blocked terminal complement activation (eculizumab, ravulizumab, crovalimab) paved the way for the development of proximal inhibitors, including the C3/C3b inhibitor pegcetacoplan, the factor B inhibitor iptacopan, and the add-on (to C5 inhibitors) factor D inhibitor danicopan. Understanding the safety profile of pegcetacoplan and other complement-targeted therapies, especially the risk for meningococcal and other encapsulated bacteria infections, will help physicians and patients make informed treatment decisions for individuals with complement-mediated conditions. For nearly over 7 years, systemically administered pegcetacoplan has had a consistently low rate of encapsulated bacteria infections in patients with PNH, C3G, or primary IC-MPGN. These findings may reflect effective risk mitigation strategies."

CNS Disorders • Complement-mediated Rare Disorders • Glomerulonephritis • Hematological Disorders • Immunology • Infectious Disease • Influenza • Lupus Nephritis • Meningococcal Infections • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Pneumococcal Infections • Pneumonia • Primary Immunodeficiency • Rare Diseases • Respiratory Diseases • Septic Shock

Rapidly progressive acute chest syndrome is associated with complement-mediated cell injury in adults with sickle cell disease (ASH 2025) - "Additional testing on a single sample by flow cytometry showed that C5b9 deposition was fully blocked by adding eculizumab but only partially blocked by danicopan, suggesting a contribution of the classical complement pathway as a driver. However, due to the small sample size, our results should be considered as hypothesis-generating. Future studies with larger cohorts and newer functional complement assays, like the mHAM 2.0, should be considered to obtain definitive results."

Clinical • Cough • Genetic Disorders • Hematological Disorders • Pulmonary Disease • Respiratory Diseases • Sickle Cell Disease • Thrombocytopenia • CD55 • CD59

The use of danicopan as an add-on therapy in a ravulizumab-treated adult patient with paroxysmal nocturnal hemoglobinuria (PNH) and concomitant stage IV renal failure has induced a marked improvement of anemia and of clinically significant extravascular hemolysis in absence of deterioration of renal function (ASH 2025) - "In 2019, this patient was treated with biosimilar eculizumab (phase 3 trial- ABP959-Amgen) till spring 2022. In conclusion, danicopan has demonstrated high efficacy in increasing hemoglobin level (range 2.3-3 g/dL), and reducing markers of hemolysis in a PNH patient with concomitant stage IV renal failure, having an inadequate hematological response to either eculizumab or ravulizumab (hemoglobin <9•5 g/dL). Interestingly, renal function was not affected by the combined use of ravulizumab and danicopan, during a 11 months- follow-up observation period."

Clinical • Metastases • Anemia • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Endocrine Disorders • Hematological Disorders • Hypertension • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Renal Disease • Thrombosis

Early access program for danicopan (ALXN2040) as add-on treatment to eculizumab or ravulizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH): Preliminary data from the Italian real-world survey. (ASH 2025) - "Antithrombotic prophylaxis was reported in 4 patients (2warfarin and 2 low molecular weight heparin (LMWH)). to date, data from 10 of the treated patients are available (4 females, median age 41.5ys, range22-49, and 6 males, median age 58ys, range 33-86). Patients mainly suffered from classical PNH (80%),followed by PNH/aplastic anemia (PNH/AA, 20%). Median laboratory tests at the beginning of the C5iwere as follows: hemoglobin level (Hgb) 8.9 g/dl (range, 7.0-9.8), reticulocytes (Ret) count 180*10^6/L(range, 20-341), LDH value 5 x upper limit of normality (ULN) (range, 1.5-28)."

Clinical • Real-world • Real-world evidence • Anemia • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Real-world data on breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with proximal and terminal complement inhibitors. (ASH 2025) - "Four patients were treated with factor D inhibitor danicopan(n=3) or iptacopan (n=1) concurrently with ravulizumab.A total of 49 BTH events were identified; while on eculizumab (26 events, 12 patients), ravulizumab (14events, 7 patients), ravulizumab and danicopan (6 events, 3 patients), pegcetacoplan (1 event, 1 patient),zilucoplan (2 events, 2 patients), and no events while on iptacopan. Twelve BTH events were incidentally detected during routine CIadministration; more frequent lab draws may be beneficial for patients with chronic hemolysis. Moredata is needed to understand the BTH rates of different CIs and guide clinicians in BTH management."

Clinical • Real-world • Real-world evidence • Anemia • Aplastic Anemia • Breast Cancer • Complement-mediated Rare Disorders • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Solid Tumor • CD55 • CD59 • HP

Danicopan add-on therapy demonstrates positive efficacy and safety outcomes in advanced age adults with paroxysmal nocturnal hemoglobinuria and clinically significant extravascular hemolysis: A sub-analysis of the phase 3 ALPHA trial (ASH 2025) - P3 | "During 12 weeks ofdanicopan add-on therapy, these patients reported meaningful improvements in Hb concentration andARC, while maintaining transfusion avoidance and a low rate of AEs. Overall, this analysis supports theuse of danicopan add-on therapy in patients with advanced age with PNH and csEVH treated withravulizumab or eculizumab, with no new safety signals."

Clinical • Metastases • P3 data • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

Iptacopan monotherapy demonstrated improved clinical outcomes in a real-world cohort with paroxysmal nocturnal hemoglobinuria: Evidence from a managed access program (ASH 2025) - "The proportion of pts previously treated witheculizumab, ravulizumab, pegcetacoplan, and danicopan was 71.6%, 37.9%, 13.7%, and 6.3%,respectively. The updated data from this MAP confirm hematological and clinical improvements withiptacopan in Ci-naive and Ci-experienced pts with PNH, with approximately 6 months of iptacopantherapy. Oral iptacopan monotherapy led to normalization of Hb and LDH level, and RLC, along with ahigher proportion of pts achieving transfusion avoidance at retreatment visits compared to BL. Pts alsoreported notable improvements in fatigue and tx satisfaction."

Clinical • Clinical data • Monotherapy • Real-world • Real-world evidence • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • CFB

Treatment-requiring paroxysmal nocturnal hemoglobinuria in association with myeloproliferative neoplasms (MPNs): Clinical correlations and outcomes (ASH 2025) - "Cytogeneticanalysis (n =10) demonstrated an abnormal karyotype in 3 patients (30%), all of which were categorizedas favorable risk.First-line treatment for PNH included complement inhibitors in 9 patients (82%), with eculizumab (n=8), orravulizumab (n=1)...Notably, one patient with PNH clone size of 91.19 % in granulocytes, had ongoing hemolysisdespite dual complement blockade with ravulizumab and danicopan.Treatment for MPN included hydroxyurea (n=5), ruxolitinib (n=4), pacritinib (n=1), and erythropoiesisstimulating agents (n=4)...The current study represents the largest series of patients with treatment-requiring PNH and MPN. Itreveals a predominance of MF patients, particularly among those harboring CALR mutations, andunderlines suboptimal efficacy of complement inhibitor therapy in this patient population."

Clinical • Cardiovascular • Complement-mediated Rare Disorders • Hematological Malignancies • Infectious Disease • Myelodysplastic Syndrome • Myelofibrosis • Paroxysmal Nocturnal Hemoglobinuria • Polycythemia Vera • Rare Diseases • Septic Shock • Thrombocytosis • Thrombosis • ASXL1 • CALR • JAK2 • SF3B1 • ZRSR2

Complement-induced procoagulant platelets in patients with antiphospholipid antibodies (ASH 2025) - "On certain occasions sera were heat inactivated at 56º C for30 min or pre-treated with IdeS (IgG cleaving enzyme) (10000 U/ml at 37º C for 30 min), eculizumab (1mg/ml), sutimlimab (C1s inhibitor) (1.5 mg/ml) and/or danicopan (Factor D inhibitor) (100 µM). Also, onother occasions platelets were pre-incubated with antagonists of C3aR (SB290157), FcgRIIa (IV.3) or C5aR1(Avacopan) (10 µM) before serum.ResultsWe found that although activation and responsiveness to agonists of platelets from aPL+/APS patientswere like those from healthy individuals, unstimulated platelets from APS patients exhibited higherphosphatidylserine (PS) exposure (19.6±3.9% vs 4.0±1.0% controls) and P-selectin expression (15.9±2.3%vs 8.6±1.8% controls) than controls suggesting induction of procoagulant activity...Pre-incubating platelets with FcgRIIa, C3aR or C5aR1 antagonistsdid not reverse the procoagulant activity induced by APS serum.ConclusionWe demonstrate..."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Thrombosis • ANXA5 • CASP3 • CASP7 • SELP

Management of a real-world cohort of patients with paroxysmal nocturnal hemoglobinuria treated with iptacopan: A multi-institutional analysis (ASH 2025) - "In the 50 patients who switched, 60%transitioned from ravulizumab, 30% from pegcetacoplan, 8% from eculizumab, and 2% fromravulizumab and danicopan. In this real-world cohort, iptacopan provided substantial and durable hemoglobinimprovement across naive and previously treated patients with PNH, with meaningful reduction inhemolytic parameters, absence of thrombosis, and low BTH rate predominantly linked to infection.Patients with previous satisfactory responses also showed improved Hgb levels. The favorable safetyprofile and high treatment persistence underscore iptacopan's role as an effective first-line or switchtherapy and support its incorporation into evidence-based sequencing algorithms in the evolving PNHtreatment landscape."

Clinical • Real-world • Real-world evidence • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Congestive Heart Failure • Heart Failure • Hematological Disorders • Infectious Disease • Pancreatitis • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis • Vascular Neurology

Switching between complement inhibitors in patients with PNH: A real-world analysis of strategy, efficacy, and safety. (ASH 2025) - "In 2025, 3 C5 inhibitors (C5i) are approved (eculizumab (ECU), ravulizumab (RAV), crovalimab) & 3proximal inhibitors (PI) (pegcetacoplan (PEG), ipatacopan (IPTA), danicopan (DAN) plus C5i). Some clinicaltrial therapies have not continued development (vermicopan (VERM), BCX9930 (BCX), other C5i).PI clinical trials have protocols for changing from terminal to PI, based on drug half-life... Sixty-two pts from 8 countries were included with mean age at diagnosis 38.4 years (range 16-79)& mean Hb 87.8 g/L (missing data, n=17). Where reported indications for CI were hemolysis (49/62),hemolysis and thrombosis (5/62), thrombosis (3/62). Mean time on CI was 103.6 months (range 23-276; missing n=3) & mean granulocyte clone 86% (range 31-99; missing n=9).First-line CI were ECU/RAV (50/62), VERM (9/62) & investigational C5i (3/62)."

Clinical • Real-world • Real-world evidence • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis