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Enhancing Hematologic Care: Lorah Perlee from Regeneron in a Riveting Dialogue Exchange with PharmaShots

Shots: 

  • At ASH 2024, Regeneron shared data from the P-III exploratory cohort investigating the pozelimab and cemdisiran combination (poze-cemdi) in patients with paroxysmal nocturnal hemoglobinuria 
  • The novel combination (poze-cemdi) achieved meaningful control of intravascular hemolysis compared to ravulizumab  
  • PharmaShots welcomes Lorah Perlee, Vice President, Global Program Head, Hematology and Translational Sciences at Regeneron, for an illuminating conversation 

Saurabh: Can you elaborate on the study design of ACCESS 1 AND ACCESS-EXTENSION?     

Lorah: ACCESS-1 is a randomized, active-controlled study comprised of two cohorts, evaluating the first-in-class investigational combination of pozelimab and cemdisiran (poze-cemdi) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who are naïve to, or have not recently received, complement inhibitor therapy.  

  • The first cohort (Cohort A) is an exploratory cohort examining the combination administered subcutaneously as a maintenance regimen every four weeks compared to ravulizumab, a standard-of-care complement factor 5 (C5) inhibitor, delivered according to labeled dosing every eight weeks by intravenous infusion (IV).   
  • Cohort B is a registrational cohort examining poze-cemdi every four weeks compared to labelled dosing of eculizumab administered as an IV infusion every two weeks.   

Eligible patients had a confirmed diagnosis of PNH and active disease, characterized by at least one PNH-related sign or symptom, were C5 inhibitor treatment-naïve or had not recently received complement inhibitor therapy, and had an lactate dehydrogenase (LDH) level at screening that was two times the upper limit of normal or higher.​ Patients meeting these criteria were randomly assigned in a one-to-one ratio into one of two treatment arms for the 26-week parent study.​  

The poze-cemdi arm, randomized 25 patients who received a subcutaneous administration of the investigational combination every 4 weeks, after an initial IV pozelimab loading dose on day 1. The active-control treatment arm randomized 23 patients who received ravulizumab via IV administration every 8 weeks, according to the labelled dosing guidelines.  

Patients in both cohorts were offered the option to participate in a follow-on, open label extension (OLE) study (ACCESS-EXTENSION) for up to 108 weeks, which was designed to assess the long-term safety and efficacy of the combination, including in patients switching to poze-cemdi from ravulizumab or eculizumab.  

In the OLE study, all participants received the combination of poze-cemdi, administered subcutaneously every 4 weeks.​ To mitigate risk of potential adverse events due to drug-target-drug (DTD) immune complex deposition during the transition (e.g., type 3 hypersensitivity reactions), patients receiving ravulizumab (or eculizumab) received cemdisiran 4 weeks prior to the first administration of pozelimab during a transition period; this lead-in period served to reduce the levels of C5 prior to the introduction of pozelimab. An initial IV loading dose of pozelimab was provided which also served to reduce the risk of DTD formation.   

Saurabh: What primary and secondary endpoints did you target in patients participating in the ACCESS 1 Cohort A study? 

Lorah: The primary efficacy endpoint of Cohort A was the percent change in LDH from baseline through Week 26​.    

There are several secondary endpoints for Cohort A including other measures of disease control (achievement of LDH ≤1.5 x ULN, LDH normalization, hemoglobin stabilization, transfusion avoidance), quality of life, safety, etc. Full study details can be found on the clinicaltrials.gov listing here: https://clinicaltrials.gov/study/NCT05133531.  

Saurabh: How has poze-cemdi improved the standard of treatment for PNH patients compared to the approved therapies?   

Lorah: Given the investigational nature of the combination, I think it’s important to focus the discussion more broadly on the unmet need for PNH patients. C5 inhibitors are widely considered the mainstay of PNH treatment, but a proportion of patients still do not achieve adequate control and may feel significant treatment burden, as many of these therapies require clinic or home visits for intravenous delivery. We believe there is a strong need for new medicines that can help more patients achieve improved disease control, with the potential for infrequent subcutaneous delivery and self-administration.   

Please note that the potential use of pozelimab and cemdisiran for the treatment of PNH is investigational and has not been fully evaluated by any regulatory authority. At ASH 2024, we shared results from the ACCESS-1 trial, which showed more patients achieved disease control than those treated with standard-of-care. The results for those treated with poze-cemdi (n=25), compared to ravulizumab (n=23), were as follows:  

  • 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.  
  • 93% achieved LDH normalization (≤1 x ULN) across study visits (week 8-26) on average with poze-cemdi compared to 65% with ravulizumab.  
  • 84% decrease in LDH from baseline at week 26 with poze-cemdi compared to 74% with ravulizumab.   

After Week 26, all patients who completed ACCESS-1 could enroll in the follow-on OLE trial to receive poze-cemdi, including those who initially received ravulizumab. At the time of the data cut-off, 19 of the 23 patients treated with ravulizumab had transitioned and were ongoing in the OLE study.   

  • At the start of the OLE, 68% (n=13) of patients treated with ravulizumab had adequate LDH control (≤1.5 x 1ULN). After switching to poze-cemdi, 95% of patients (n=18) achieved LDH control.   
  • 4 of 5 patients who had failed to achieve LDH control while on ravulizumab achieved control after switching to the poze-cemdi combination.  

Saurabh: Can you give us an insight into the safety and tolerability of poze-cemdi?   

Lorah: The safety profile of poze-cemdi was generally consistent with approved C5 inhibitors.   

  • During ACCESS-1, treatment-emergent adverse events (TEAEs) occurred in 84% of patients treated with poze-cemdi, compared to 87% treated with ravulizumab. The most common TEAEs (≥10%) for the combination were headache (28% vs. 17%), upper respiratory tract infection (12% vs. 9%), nausea (12% vs. 4%), anemia (12% vs. 9%), fatigue (8% vs. 13%) and cough (4% vs. 13%). Serious adverse events (SAEs) occurred in two patients receiving the combination that were considered unrelated to treatment by the investigator. This included one patient who had post-traumatic cellulitis that resolved with treatment while continuing the combination. The second patient experienced a fever, seizure and hemolytic crisis within one week of the first dose of the combination that also resolved while continuing the combination; the patient later had a fatal SAE of sepsis and disseminated intravascular coagulation on day 130.  
  • In the OLE, among patients who switched to poze-cemdi from ravulizumab, 68% experienced TEAEs, with the most common being non-serious, mild to moderate injection-site reactions.  
  • No patients discontinued therapy due to an adverse event in either the main study or OLE study.  
  • There were no AEs associated with the development of drug-target-drug immune complexes related to switching from ravulizumab to poze-cemdi or interruption in disease control.  

Saurabh: When can we expect the results of Cohort B of the ACCESS 1 trial?   

Lorah: Results from Cohort B are expected in 2026+.   

Saurabh: Is Poze-Cemdi under investigation for any indication other than PNH?   

Lorah: Poze-cemdi is being evaluated in separate Phase 3 trials for several complement-mediated disorders, including myasthenia gravis (MG), (Phase 3 results expected in the second half of 2025) and geographic atrophy (GA), an advanced form of dry Age-Related Macular Degeneration (Phase 3 pivotal program underway).    

About the Author:

Lorah Perlee

Lorah is a biotechnology professional with 20+ years in translating life science research into robust commercial products. She possesses a broad experience in biomarker discovery, clinical development, companion diagnostic design and predictive algorithm validation. She has a strong communication, organizational and project management skills directing diverse projects across scientific, clinical and commercial groups in a matrix type environment with a solid publication record. 

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