PB2554: DESIGN OF A PHASE 1B OPEN-LABEL STUDY TO ASSESS THE SAFETY, EFFICACY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF POVETACICEPT (ALPN-303) IN SUBJECTS WITH AUTOIMMUNE CYTOPENIAS (RUBY-4)
Notice bibliographique
Résumé
Topic: 28. Enzymopathies, membranopathies and other anemias Background: B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) play key roles in B cell development, survival, and differentiation into antibody-secreting cells (ASC). Given their importance in ASC survival and antibody production, inhibition of BAFF and/or APRIL (particularly in combination), is a promising approach for the treatment of a variety of autoimmune or autoantibody-related diseases including autoimmune cytopenias. Significantly higher levels of both BAFF and APRIL have been observed in the serum of patients with autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) compared to healthy subjects.1,2 An inhibitor of BAFF, belimumab, has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus and in combination with rituximab in patients with ITP.3-5 Currently, there are no BAFF and/or APRIL inhibitors approved to treat AIHA or ITP. Povetacicept (ALPN-303) is an engineered dual BAFF/APRIL antagonist with the potential to improve outcomes for patients with autoimmune cytopenias. In a mouse AIHA model, povetacicept treatment suppressed anti-erythrocyte antibodies and increased hematocrit. Povetacicept has been well tolerated in adult healthy volunteers and exhibits dose-dependent pharmacokinetic (PK) and pharmacodynamic (PD) effects corresponding to reductions in circulating ASC and immunoglobulins. We present here the design of a Phase 1b clinical trial of povetacicept in adults with autoimmune cytopenias. Aims: This is an open-label, group-sequential study to evaluate the safety, efficacy, PK, and PD of povetacicept in subjects with ITP, warm AIHA (wAIHA), or cold agglutinin disease (CAD). Methods: Subjects must have primary cytopenia for at least 12 weeks duration, confirmation of sustained thrombocytopenia (ITP, platelet count <30 × 109/L) or symptomatic anemia (AIHA, Hb ≤10 g/dL) on 2 occasions during the screening, and a history of failure or relapse to at least 2 prior treatment regimens. Subjects are allowed to use some background treatments including corticosteroids if the doses are stable for the durations specified by the protocol. Exclusion criteria include secondary autoimmune cytopenias, Evans syndrome, rituximab or splenectomy within 12 weeks. The study will include 3 parallel cohorts of subjects grouped by diagnosis (ITP, wAIHA, CAD). Seven to 14 subjects will be enrolled in each cohort and begin subcutaneous once every 4 weeks week dosing of povetacicept for 6 cycles (24 weeks). When the first 7 subjects in each cohort have been enrolled and treated with povetacicept for 12 weeks, an interim analysis will be conducted to determine if the disease cohort should stop enrolment for futility or lack of efficacy. Subjects who are experiencing treatment benefit at week 24 may continue with study treatment. Upon completion of their last treatment cycle, all subjects will be followed for safety for 8 weeks (Figure 1). The efficacy endpoints will be disease specific response criteria for platelet counts or Hb levels. Other endpoints will include safety, PK/PD, and immunogenicity. References: 1. Blair HA, Duggan ST. Drugs. 2018;78(3):355-366. 2. Mahevas M, Azzaoui I, Crickx E, et al. Haematologica. 2021;106(9):2449-2457. 3. Gu D, Ge J, Du W, et al. Autoimmunity. 2009;42(8):692-8. 4. Emmerich F, Bal G, Barakat A, et al. Br J Haematol. 2007;136(2):309-14. 5. Xu Z, Zhao B, Xiong H, et al. Int J Hematol. 2015;102(4):394-400. Results: NA Summary/Conclusion: NAKeywords: BAFF, Immune thrombocytopenia (ITP), Autoimmune hemolytic anemia (AIHA), Autoantibody
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,002 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| 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 ».