Efficacy and safety of pozelimab plus cemdisiran versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria who received prior C5 therapy
Notice bibliographique
Résumé
Abstract 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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».