cemdisiran (ALN-CC5) / Alnylam, Regeneron - LARVOL DELTA

Study design of A phase 3, open-label trial for pozelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria with inadequate control of intravascular hemolysis (ASH 2025) - "Treatment for PNH includes C5 inhibitorssuch as eculizumab/biosimilar, ravulizumab, and crovalimab, however, patients under terminalcomplement inhibition can experience residual intravascular hemolysis due to incomplete C5 blockade.The combination of pozelimab (a monoclonal antibody that prevents activation of C5) and cemdisiran (asilencing RNA that reduces production of circulating C5) is a novel approach being investigated for itsability to achieve durable inhibition of the terminal complement pathway. During the ext period, the secondary endpoints willinclude percent change in LDH from baseline to ext week 24 and ext week 52, normalization of LDH ateach visit through ext week 52, inclusive, and adequate control of hemolysis at each visit through extweek 52. Recruitment for this study is expected to begin around November 2025."

Clinical • Combination therapy • P3 data • Bone Marrow Transplantation • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Efficacy and safety of pozelimab plus cemdisiran versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria who received prior C5 therapy (ASH 2025) - P3 | "In pts with PNH who received prior C5 inhibitor therapy, including rav, the transition topozelimab and cemdisiran combo led to robust control of LDH. The combo was generally well-tolerated,with a favorable safety profile and no AEs related to the development of large immune complexes or typeIII hypersensitivity reactions."

Clinical • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Characteristics and Long-Term Efficacy of 25 Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Eculizumab or Ravulizumab in Taiwan (ASH 2024) - "The median LDH level was 6.9 (range 1.67-14.74) times the upper limit of normal (ULN) at baseline.Before receiving eculizumab or ravulizumab, thirteen patients (52%) had previously received other therapies, including steroids in nine patients (36%), cyclosporine and/or anti-thymocyte globulin (ATG) in five (20%), danazol in five (20%), and crovalimab in one (4%) who had been enrolled in a trial...Except for one patient who achieved remission of PNH and three patients who crossed over to clinical trials of iptacopan or pozelimab/cemdisiran, seven patients discontinued eculizumab...Eculizumab and ravulizumab were well-tolerated, and no cases of meningococcal disease were reported.Conclusion : Our experiences demonstrated the clinical characteristics and long-term efficacy and safety of eculizumab and ravulizumab in Taiwanese PNH patients with high disease burdens. However, a major reason for discontinuing treatment was the need for frequent transfusions, which did not meet..."

Clinical • Anemia • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Hematological Malignancies • Infectious Disease • Meningococcal Infections • Myelodysplastic Syndrome • Oncology • Paroxysmal Nocturnal Hemoglobinuria • Pulmonary Disease • Rare Diseases • Renal Disease

Efficacy and Safety of Pozelimab Plus Cemdisiran Vs Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Are Naïve to Complement Inhibition (ASH 2024) - P3 | "The potential transition regimen using cemdisiran to reduce C5 prior to administering a different C5 antibody appears effective at mitigating DTD reactions. Results support development of the combination of pozelimab and cemdisiran in PNH and other complement-mediated diseases."

Clinical • Cardiovascular • CNS Disorders • Complement-mediated Rare Disorders • Dermatology • Epilepsy • Hematological Disorders • Immunology • Infectious Disease • Nephrology • Paroxysmal Nocturnal Hemoglobinuria • Pneumonia • Rare Diseases • Respiratory Diseases • Septic Shock • Thrombosis

A Study to Evaluate How Pozelimab + Cemdisiran Combination Therapy Works in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Whose Current Treatment is Not Working Efficiently (clinicaltrials.gov) - P3 | N=35 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Jan 2031 ➔ Jun 2031 | Trial primary completion date: Jan 2031 ➔ Jul 2029

Trial completion date • Trial primary completion date • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Regeneron Highlights Progress at American Society of Hematology (ASH), with Updated Data in…Paroxysmal Nocturnal Hemoglobinuria Programs (GlobeNewswire) - "Additional presentations include updated results for the novel combination of cemdisiran with pozelimab (cemdi-poze) compared to ravulizumab in paroxysmal nocturnal hemoglobinuria as well as the first-in-human evaluation of REGN7257 in severe aplastic anemia."

Clinical data • First-in-human • Aplastic Anemia • Paroxysmal Nocturnal Hemoglobinuria

52-Week Open-Label Extension Data from a Phase 2 Study Evaluating the Safety and Efficacy of Pozelimab and Cemdisiran Combination Therapy in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Switched from Eculizumab (ASH 2023) - P2 | "Results suggest that, in patients with PNH transitioning from eculizumab treatment, the combination of pozelimab and cemdisiran was generally well tolerated and provided long term sustained control of intravascular hemolysis without any breakthrough hemolysis events. Findings support the ongoing development of pozelimab and cemdisiran combination therapy."

Clinical • Combination therapy • P2 data • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Meningococcal Infections • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Respiratory Diseases

Psychometric Evaluation of the PNH Symptom Questionnaire (PNH-SQ) Among Patients with Paroxysmal Nocturnal Hemoglobinuria from Three Phase 2 Clinical Trials with Pozelimab Monotherapy or in Combination with Cemdisiran (ASH 2023) - P2 | "Our analyses documented the PNH-SQ as an instrument to capture symptoms of PNH. The most frequent symptoms reported in our sample using the PNH-SQ, fatigue, dyspnea, and headaches, were aligned with observational study data. The sample of observations from the three trials was strongly skewed towards absence of symptoms, probably reflecting the low symptomatic severity of patients included in the study."

Clinical • Combination therapy • Monotherapy • P2 data • Complement-mediated Rare Disorders • Fatigue • Hematological Disorders • Musculoskeletal Pain • Pain • Paroxysmal Nocturnal Hemoglobinuria • Pulmonary Disease • Rare Diseases

Regeneron is planning a U.S. regulatory submission for cemdisiran monotherapy in the first quarter of 2026, pending discussions with the FDA. (Businesswire)

FDA filing • Myasthenia Gravis

Pharmacological Therapies in Paroxysmal Nocturnal Haemoglobinuria: Focus on Complement Inhibition. (PubMed, Drugs) - "This has been largely supplanted by a longer-acting antibody, ravulizumab, targeting the same binding site on C5...Other terminal inhibitors available include eculizumab biosimilars, crovalimab, pozelimab and cemdisiran (combination)...Currently available proximal inhibitors (and their targets) are pegcetacoplan (C3), danicopan (Factor D) and iptacopan (Factor B). While effective, as with all other complement inhibitors, there is a risk of breakthrough IVH with their use and approaches to manage this complication are being developed."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Thrombosis

A Study to Evaluate How Pozelimab + Cemdisiran Combination Therapy Works in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Whose Current Treatment is Not Working Efficiently (clinicaltrials.gov) - P3 | N=35 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P3 trial • Complement-mediated Rare Disorders • Hematological Disorders • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

Regeneron Announces Positive Results from Phase 3 Trial in Generalized Myasthenia Gravis (Regeneron Pharmaceuticals Press Release) - "Historical clinical trial data report that currently approved C5 inhibitor therapies have shown a placebo-adjusted treatment difference in MG-ADL total scores ranging from ­-1.6 to -2.1 at 12 to 26 weeks...Both cemdisiran and cemdi-poze demonstrated improvements in activities of daily functioning at week 24, with cemdisiran showing numerically better results across all gMG-specific outcomes. In the MG-ADL and QMG, greater reductions in total scores indicate greater improvement in disease symptoms and better treatment effect....Detailed results from the NIMBLE trial will be presented at an upcoming medical meeting. The U.S. regulatory application for cemdisiran is planned for the first quarter of 2026, pending discussions with the FDA."

FDA filing • P3 data • Myasthenia Gravis

NIMBLE: A Study to Test How Safe Pozelimab and Cemdisiran Combination Therapy and Cemdisiran Alone Are and How Well They Work in Adult Patients With Generalized Myasthenia Gravis (clinicaltrials.gov) - P3 | N=288 | Active, not recruiting | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: Mar 2029 ➔ Nov 2028

Enrollment closed • Monotherapy • Trial completion date • CNS Disorders • Myasthenia Gravis

Key Upcoming Events (Businesswire) - "Alnylam announces today that it will present results from the KARDIA-3 Phase 2 trial of zilebesiran in patients with hypertension during a Hot Line Session at the European Society of Cardiology (ESC) Congress in Madrid, Spain on August 30, 2025...In addition, in the second half of 2025, Alnylam expects to: Initiate a Phase 3 cardiovascular outcomes trial of zilebesiran, in collaboration with its partner Roche; Initiate the TRITON-PN Phase 3 trial of nucresiran in hATTR-PN; Initiate a Phase 2 trial of mivelsiran in Alzheimer’s disease....In addition, Alnylam's partner, Regeneron Pharmaceuticals, plans to share results from the Phase 3 trial of cemdisiran tested as a monotherapy and in combination with pozelimab in patients with myasthenia gravis in the second half of 2025."

Clinical data • New P2 trial • New P3 trial • Alzheimer's Disease • Amyloidosis • Cardiovascular • Hypertension • Myasthenia Gravis

Safety, Efficacy, and Patient-Reported Outcomes From a Phase 2 Randomized Trial of Pozelimab and Cemdisiran Combination in Patients With Paroxysmal Nocturnal Hemoglobinuria. (PubMed, EJHaem) - P2 | "Administration of pozelimab Q2W did not improve disease control as compared to pozelimab Q4W. ClinicalTrials.gov/NCT04811716."

Journal • P2 data • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hematological Disorders • Infectious Disease • Meningococcal Infections • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Thrombosis

SIENNA: A Study Investigating Subcutaneously Administered Pozelimab in Combination With Cemdisiran or Cemdisiran Alone in Adult Participants With Geographic Atrophy (clinicaltrials.gov) - P3 | N=975 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=750 ➔ 975

Enrollment change • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

Neuromuscular junction and the complement system. (PubMed, Int Rev Neurobiol) - "The currently studied anti-complement therapies for MG include eculizumab, zilucoplan, ravulizumab, pozelimab, cemdisiran, gefurilimab, danicopan and few others in the pipeline. Given the risk of Gram-negative septicaemia (especially by meningococcus), patients would need vaccination prior to initiation of treatment and in some countries prophylactic antibiotics during treatment is recommended, although no major safety signatures have been noted in the studies so far. Future studies identifying specific biomarkers might help clinicians select the most appropriate patients who are more likely to respond to complement inhibitory therapies."

Journal • Review • CNS Disorders • Infectious Disease • Meningococcal Infections • Myasthenia Gravis

CLINICAL FEATURES AND OUTCOMES OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PATIENTS TREATED WITH ECULIZUMAB IN TAIWAN: A MULTICENTER RETROSPECTIVE ANALYSIS (EHA 2025) - "Prior treatments included steroids (29.4%), cyclosporine (18.9%), anti-thymocyte globulin (10.8%), danazol (24.2%), and one crovalimab trial participant...Adjuvant therapies for EVH associated with symptomatic anemia included rituximab (n=2), steroids (n=14), cyclosporine (n=6), and danazol (n=5)... Eculizumab effectively reduces intravascular hemolysis and improves survival in Taiwanese PNH patients, though BTH and transfusion-dependent treatment discontinuation remain challenges."

Retrospective data • Anemia • Aplastic Anemia • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Paroxysmal Nocturnal Hemoglobinuria • Pulmonary Disease • Rare Diseases • Renal Disease • Thrombosis

PATIENT-REPORTED OUTCOMES FROM A PHASE 3, RANDOMIZED TRIAL EVALUATING THE COMBINATION OF POZELIMAB AND CEMDISIRAN IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (EHA 2025) - P3 | "Improvements were observed for FACIT-fatigue, GHS/QoL, and physical function scores for both pozelimab + cemdisiran and ravulizumab arms. Though Cohort A was not sized to achieve statistical significance for these endpoints, numerically greater improvements were observed with pozelimab + cemdisiran therapy compared with ravulizumab."

Clinical • P3 data • Patient reported outcomes • Complement-mediated Rare Disorders • Fatigue • Oncology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

EFFICACY AND SAFETY OF POZELIMAB PLUS CEMDISIRAN VERSUS RAVULIZUMAB IN PATIENTS WITH PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA WHO ARE NAÏVE TO COMPLEMENT INHIBITION (EHA 2025) - P3 | "Pozelimab plus cemdisiran led to robust control of LDH, with more pts achieving meaningful LDH control versus ravu. The safety profile was generally consistent with approved C5 inhibitors. Reducing C5 with cemdisiran prior to administering pozelimab appears effective at mitigating DTD reactions in patients who transitioned from ravu."

Clinical • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Pain • Paroxysmal Nocturnal Hemoglobinuria • Septic Shock

The Role of Complement in the Pathogenesis and Treatment of Myasthenia Gravis. (PubMed, Cells) - "This has led to the development of the first C5 inhibitors approved for myasthenia gravis with AchR antibodies: eculizumab, ravulizumab, and zilucoplan. Other clinical trials are currently in progress, investigating the potential therapeutic role of other targets, including the Factor B inhibition or hepatic synthesis of the C5 protein. Other proposed potential targets that have not yet been clinically tested are also discussed in this review article."

Journal • Review • CNS Disorders • Immunology • Myasthenia Gravis

NIMBLE: A Study to Test How Safe Pozelimab and Cemdisiran Combination Therapy and Cemdisiran Alone Are and How Well They Work in Adult Patients With Generalized Myasthenia Gravis (clinicaltrials.gov) - P3 | N=335 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial primary completion date: May 2026 ➔ Jul 2025

Monotherapy • Trial primary completion date • CNS Disorders • Myasthenia Gravis

NIMBLE: A Study to Test How Safe Pozelimab and Cemdisiran Combination Therapy and Cemdisiran Alone Are and How Well They Work in Adult Patients With Generalized Myasthenia Gravis (clinicaltrials.gov) - P3 | N=335 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=235 ➔ 335 | Trial completion date: Mar 2028 ➔ Mar 2029 | Trial primary completion date: May 2025 ➔ May 2026

Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • CNS Disorders • Myasthenia Gravis

The road ahead: emerging therapies for primary IgA nephropathy. (PubMed, Front Nephrol) - "Sparsentan is indicated for persisting proteinuria...To reduce Gd-IgA1 production, targeted-release budesonide is approved...The terminal pathway inhibitors cemdisiran and ravulizumab show promise in phase 2 studies. Our current approach for those requiring immunosuppression involves combining the reduction of Gd-IgA1 (nefecon) with suppressing the effects of inflammation (iptacopan). The optimal duration of such therapy is uncertain. Clearly, there is more to be learned with many trials underway."

Journal • Review • Chronic Kidney Disease • Glomerulonephritis • IgA Nephropathy • Inflammation • Nephrology • Renal Disease

Novel Combination of Pozelimab and Cemdisiran (Poze-Cemdi) Achieved Greater Control of Intravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria Compared to Ravulizumab (GlobeNewswire) - P3 | N=190 | ACCESS-1 (NCT05133531) | Sponsor: Regeneron Pharmaceuticals | "Results for those treated with poze-cemdi (n=25), compared to ravulizumab (n=23), were as follows: i) 96% achieved adequate LDH control (≤1.5 x ULN) across study visits (weeks 8-26) on average with poze-cemdi, compared to 80% with ravulizumab. At 26 weeks, 5 patients receiving ravulizumab, compared with 1 patient receiving poze-cemdi, did not achieve meaningful LDH control. ii) 93% achieved LDH normalization (≤1 x ULN) across study visits (week 8-26) on average with poze-cemdi, compared to 65% with ravulizumab. iii) 84% decrease in LDH from baseline at week 26 with poze-cemdi compared to 74% with ravulizumab. iv) The CH50 profile observed with poze-cemdi demonstrated complete and uninterrupted inhibition of terminal complement, compared to the profile for ravulizumab showing loss of inhibition at the end of the dosing interval."

P3 data • Paroxysmal Nocturnal Hemoglobinuria