Garetosmab, an inhibitor of activin A, reduces heterotopic ossification and flare-ups in adults with fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial
Notice bibliographique
Résumé
ABSTRACT Background Fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 ( ACVR1) , is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. Methods LUMINA-1 ( NCT03188666 ) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period_1), followed by an open-label period (Period_2). After Period_2, patients were allowed to stay on garetosmab in an open-label extension. For Period_1, primary endpoints were HO total lesion activity (HO-TLA) by 18 F-sodium fluoride positron emission tomography ( 18 F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period_2 primary endpoint compared the number of new lesions in Period_2 versus Period_1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. Findings Patients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P =0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18 F-NaF PET, post-hoc P =0.009; 90% relative reduction by CT, post-hoc P =0.017); flare-ups were significantly reduced ( P =0.0005). For placebo patients transitioning to garetosmab in Period_2, no patients developed new HO lesions (0% in Period_2 versus 40.9% in Period_1; P =0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients’ ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period_2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Interpretation Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab. Funding Regeneron Pharmaceuticals, Inc.
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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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».