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

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

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 • Pain • Paroxysmal Nocturnal Hemoglobinuria • Pneumonia • Rare Diseases • Respiratory Diseases • Septic Shock • Thrombosis

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

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

SIENNA: A Study Investigating Subcutaneously Administered Pozelimab in Combination With Cemdisiran or Cemdisiran Alone in Adult Participants With Geographic Atrophy (clinicaltrials.gov) - P3 | N=750 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Not yet recruiting ➔ Recruiting | Trial completion date: Jan 2032 ➔ May 2032 | Trial primary completion date: Jul 2027 ➔ Nov 2027

Combination therapy • Enrollment open • Trial completion date • Trial primary completion date • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Sporadic Inclusion Body Myositis (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: Austin Neuromuscular Center | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Immunology • Myositis

SIENNA: A Study Investigating Subcutaneously Administered Pozelimab in Combination With Cemdisiran or Cemdisiran Alone in Adult Participants With Geographic Atrophy (clinicaltrials.gov) - P3 | N=750 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

Combination therapy • New P3 trial • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

Pozelimab and cemdisiran combination therapy in patients with myasthenia gravis: Phase 3 NIMBLE trial design (EAN 2024) - P3 | "This ongoing study (open for recruitment) is designed to evaluate the effect of pozelimab plus cemdisiran on daily functioning and other MG efficacy measures (including quality of life), as well as safety in patients with symptomatic gMG. TABLE 2. Outcomes in patients switched from eculizumab to ravulizumab."

Clinical • Combination therapy • P3 data • CNS Disorders • Immunology • Myasthenia Gravis • LRP4

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=235 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial primary completion date: Aug 2025 ➔ May 2025

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

Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Patients With Sporadic Inclusion Body Myositis (clinicaltrials.gov) - P1 | N=10 | Not yet recruiting | Sponsor: Austin Neuromuscular Center

Combination therapy • New P1 trial • Immunology • Myositis

Complement inhibition in PHN: from biology to therapy (ISLH 2024) - "The anti-C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life-long intravenous fortnightly drug...Ravulizumab, a longer half-life anti-C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti-C5 concentrations. More recently, several other anti-C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti-C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti-factor B) and danicopan (anti-factor D)...Additionally, both anti-C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review,..."

Anemia • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

EVALUATING THE SAFETY AND EFFICACY OF POZELIMAB AND CEMDISIRAN IN PATIENTS WITH PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA: PATIENT-REPORTED OUTCOMES FROM THE PHASE 2 OPEN-LABEL EXTENSION STUDY (EHA 2024) - P2 | "Patients with PNH who were treated with pozelimab and cemdisiran combination therapy during the OLTP andwho continued on the combination therapy Q4W in the OLEP maintained improvement in fatigue, physicalfunctioning and QoL."

Clinical • P2 data • Patient reported outcomes • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Genetic Disorders • Hematological Disorders • Oncology • Pain • Paroxysmal Nocturnal Hemoglobinuria • Pulmonary Disease • Thrombosis

EFFICACY AND SAFETY OF POZELIMAB PLUS CEMDISIRAN IN PATIENTS WITH PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA WHO ARE NAÏVE TO COMPLEMENT INHIBITION (EHA 2024) - P3 | "Standard of care includescomplement component C5 inhibitors (e. g. eculizumab, ravulizumab). Based on interim data, in treatment-naïve patients with PNH the combination of pozelimab and cemdisiran wasgenerally well tolerated and provided robust control of LDH through 26 weeks, with mean LDH below the lowerlimit of normal. Results support the ongoing development of pozelimab and cemdisiran combination therapyin PNH and other complement-mediated diseases."

Clinical • CNS Disorders • Complement-mediated Rare Disorders • Dermatology • Epilepsy • Hematological Disorders • Mood Disorders • Pain • Paroxysmal Nocturnal Hemoglobinuria

RESULTS FROM THE OPEN-LABEL EXTENSION PERIOD OF A PHASE 2 TRIAL EVALUATING THE SAFETY AND EFFICACY OF POZELIMAB AND CEMDISIRAN COMBINATION IN PATIENTS WITH PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (EHA 2024) - P2 | "During the OLEP, the combination of pozelimab and cemdisiran was generally well tolerated in patients withPNH. All patients maintained adequate control of haemolysis for the duration of the OLEP on a Q4W dosingregimen of pozelimab and cemdisiran. Most patients (69."

Clinical • P2 data • Complement-mediated Rare Disorders • Gastrointestinal Disorder • Hematological Disorders • Infectious Disease • Meningococcal Infections • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

ACCESS-EXT: A Study in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) to Evaluate How Safe Long-term Treatment With Pozelimab + Cemdisiran Combination Therapy is and How Well it Works. (clinicaltrials.gov) - P3 | N=202 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: May 2029 ➔ Feb 2029 | Trial primary completion date: May 2029 ➔ Feb 2029

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

Complement inhibition in paroxysmal nocturnal hemoglobinuria: From biology to therapy. (PubMed, Int J Lab Hematol) - "The anti-C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life-long intravenous fortnightly drug...Ravulizumab, a longer half-life anti-C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti-C5 concentrations. More recently, several other anti-C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti-C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti-factor B) and danicopan (anti-factor D)...Additionally, both anti-C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review,..."

Journal • Review • Aplastic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Infectious Disease • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases

NIMBLE: A Study to Examine the Efficacy and Safety of Pozelimab and Cemdisiran Combination Therapy in Adult Patients With Symptomatic Generalized Myasthenia Gravis (clinicaltrials.gov) - P3 | N=235 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: May 2027 ➔ Mar 2028 | Trial primary completion date: Aug 2024 ➔ Aug 2025

Combination therapy • Trial completion date • Trial primary completion date • CNS Disorders • Myasthenia Gravis

Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial. (PubMed, Clin J Am Soc Nephrol) - "These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated."

Journal • P2 data • Glomerulonephritis • IgA Nephropathy • Inflammation • Nephrology • Renal Disease

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