Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare life-threatening disorder characterized by hemolysis. The current standard of care (SoC) includes C5 inhibitors, most of which are given intravenously. Pozelimab is a monoclonal antibody that inhibits C5 activation, and cemdisiran is a silencing RNA that reduces circulating C5; the combination of pozelimab and cemdisiran (combo), administered subcutaneously (SC), is being investigated for its ability to achieve complete, durable inhibition of C5. We previously presented results from a phase 3, open-label, active-controlled study (NCT05133531), which demonstrated that combo led to robust control of lactate dehydrogenase (LDH), with more patients (pts) achieving meaningful LDH control versus ravulizumab (rav). Here, we present results from an exploratory arm of a follow-on open-label extension (OLE) study (NCT05744921) where pts who received combo in the parent study continued on combo (legacy-combo) and pts who received rav in the parent study were switched to combo (legacy-rav).

Methods: This study was a phase 3, open-label, 2-arm, multicenter study evaluating the long-term efficacy and safety of combo in pts with PNH who were treated with combo or SoC rav in the parent study. This OLE study consisted of a 108-wk treatment period for all pts, and a 52-wk post-treatment safety follow-up period for any pt who discontinued treatment. All pts who enrolled in the OLE received combo SC every 4 wks (Q4W). Pts who received legacy-combo in the parent study continued to receive combo SC Q4W. Pts entering the OLE who received legacy-rav transitioned to combo therapy over 8 wks following completion of the parent study. The last rav dose was given 8 wks prior to OLE start.

The primary efficacy endpoint was percent change in LDH from baseline to Wk 36. For pts who received legacy-combo, baseline was defined as the last assessment prior to the first dose of treatment in the OLE study; for pts who received legacy-rav, baseline was defined as the last assessment prior to the first dose of cemdisiran. Secondary endpoints included change in CH50, transfusion avoidance (TA), and breakthrough hemolysis events.

Results: Forty-four pts entered the OLE study (n=22 legacy-combo; n=22 legacy-rav), of whom 19 (legacy-combo) and 22 (legacy-rav) received treatment until Wk 36. Mean baseline LDH was 222.1 U/L for pts who received legacy-combo and 312.4 U/L for pts who received legacy-rav. At Wk 36, mean percent change from baseline was +6.4 for pts who received legacy-combo and –19.7 for pts who received legacy-rav, demonstrating improvement in LDH control following crossover treatment. Following the first dose of combo in this OLE study, 21 of 22 pts in each arm maintained adequate control of LDH, defined as ≤1.5x the upper limit of normal, including 3 pts in the legacy-rav arm who had not achieved adequate control of hemolysis in the first transition visit of the parent study. All pts who received legacy-rav achieved and maintained CH50 levels of 0 U/mL from baseline to Wk 24, a mean change from baseline of –15.0 U/mL. TA was defined as not requiring a red blood cell transfusion based on post-baseline hemoglobin values. In the parent study, 29/48 (60.4%) pts achieved TA. Similar numbers were observed in the OLE study at Wk 36, with 27 of 44 (61.4%) achieving TA. Breakthrough hemolysis was experienced by 1 pt in each arm, both associated with a complement-activating condition (infection).

From Day 1 to Wk 36 of this OLE study, 16 (72.7%) and 17 (77.3%) pts experienced an extension-emergent adverse event (AE) in the legacy-combo and legacy-rav arms, respectively; the most comment AE was headache (3 for legacy-combo; 2 for legacy-rav). Serious treatment-emergent AEs were experienced by 2 and 3 pts in the legacy-combo and legacy-rav arms, respectively. No pt in the legacy-rav arm who switched to combo experienced an AE due to large drug-target-drug immune complexes or type III hypersensitivity reactions, suggesting the transition protocol had a favorable safety profile. There were no AEs leading to permanent study discontinuation or death.

Conclusion: In pts with PNH who received prior C5 inhibitor therapy, including rav, the transition to pozelimab 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 type III hypersensitivity reactions.

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2025
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