Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

Adult Humans Myositis Ossificans / drug therapy Positron Emission Tomography Computed Tomography Ossification, Heterotopic / pathology

Journal

Nature medicine

ISSN: 1546-170X

Titre abrégé: Nat Med

Pays: United States

ID NLM: 9502015

Informations de publication

Date de publication:
10 2023

Historique:

received: 26 09 2022

accepted: 23 08 2023

medline: 23 10 2023

pubmed: 29 9 2023

entrez: 28 9 2023

Statut: ppublish

Résumé

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .

Identifiants

DOI: 10.1038/s41591-023-02561-8 PMID: 37770652 PMC: PMC10579054

pubmed: 37770652

doi: 10.1038/s41591-023-02561-8

pii: 10.1038/s41591-023-02561-8

pmc: PMC10579054

doi:

Banques de données

ClinicalTrials.gov

['NCT03188666']

Types de publication

Randomized Controlled Trial Clinical Trial, Phase II Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2615-2624

Informations de copyright

Références

Pignolo, R. J., Shore, E. M. & Kaplan, F. S. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J. Rare Dis. 6, 80 (2011).

doi: 10.1186/1750-1172-6-80 pubmed: 22133093 pmcid: 3253727

Baujat, G. et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J. Rare Dis. 12, 123 (2017).

doi: 10.1186/s13023-017-0674-5 pubmed: 28666455 pmcid: 5493013

Liljesthrom, M., Pignolo, R. J. & Kaplan, F. S. Epidemiology of the global fibrodysplasia ossificans progressiva (FOP) community. J. Rare Dis. Res Treat. 5, 31–36 (2020).

doi: 10.29245/2572-9411/2020/2.1196

Morales-Piga, A. et al. Fibrodysplasia ossificans progressiva in Spain: epidemiological, clinical, and genetic aspects. Bone 51, 748–755 (2012).

doi: 10.1016/j.bone.2012.07.002 pubmed: 22796417

Pignolo, R. J. et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization. Orphanet J. Rare Dis. 16, 350 (2021).

doi: 10.1186/s13023-021-01983-2 pubmed: 34353327 pmcid: 8340531

Pignolo, R. J. et al. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J. Rare Dis. 14, 98 (2019).

doi: 10.1186/s13023-019-1068-7 pubmed: 31053156 pmcid: 6499994

Kaplan, F. S. et al. Fibrodysplasia ossificans progressiva. Best. Pr. Res Clin. Rheumatol. 22, 191–205 (2008).

doi: 10.1016/j.berh.2007.11.007

Ortiz-Agapito, F. & Colmenares-Bonilla, D. Quality of life of patients with fibrodysplasia ossificans progressiva. J. Child Orthop. 9, 489–493 (2015).

doi: 10.1007/s11832-015-0704-6 pubmed: 26564023 pmcid: 4661157

Cohen, R. B. et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J. Bone Jt. Surg. Am. 75, 215–219 (1993).

doi: 10.2106/00004623-199302000-00008

Kaplan, F. S. et al. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J. Bone Jt. Surg. Am. 92, 686–691 (2010).

doi: 10.2106/JBJS.I.00705

Kaplan, F. S., Al Mukaddam, M. & Pignolo, R. J. A cumulative analogue joint involvement scale (CAJIS) for fibrodysplasia ossificans progressiva (FOP). Bone 101, 123–128 (2017).

doi: 10.1016/j.bone.2017.04.015 pubmed: 28465250

Pignolo, R. J. & Kaplan, F. S. Clinical staging of fibrodysplasia ossificans progressiva (FOP). Bone 109, 111–114 (2018).

doi: 10.1016/j.bone.2017.09.014 pubmed: 28943457

Shore, E. M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet 38, 525–527 (2006).

doi: 10.1038/ng1783 pubmed: 16642017

Hatsell, S. J. et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci. Transl. Med 7, 303ra137 (2015).

doi: 10.1126/scitranslmed.aac4358 pubmed: 26333933 pmcid: 6164166

Upadhyay, J. et al. The expansion of heterotopic bone in fibrodysplasia ossificans progressiva is activin A-dependent. J. Bone Min. Res 32, 2489–2499 (2017).

doi: 10.1002/jbmr.3235

Alessi Wolken, D. M., Idone, V., Hatsell, S. J., Yu, P. B. & Economides, A. N. The obligatory role of activin A in the formation of heterotopic bone in fibrodysplasia ossificans progressiva. Bone 109, 210–217 (2018).

doi: 10.1016/j.bone.2017.06.011 pubmed: 28629737

Hino, K. et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc. Natl Acad. Sci. USA 112, 15438–15443 (2015).

doi: 10.1073/pnas.1510540112 pubmed: 26621707 pmcid: 4687587

Macdonald, L. E. et al. Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes. Proc. Natl Acad. Sci. USA 111, 5147–5152 (2014).

doi: 10.1073/pnas.1323896111 pubmed: 24706858 pmcid: 3986150

Murphy, A. J. et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc. Natl Acad. Sci. USA 111, 5153–5158 (2014).

doi: 10.1073/pnas.1324022111 pubmed: 24706856 pmcid: 3986188

Robert, F., Desroches-Castan, A., Bailly, S., Dupuis-Girod, S. & Feige, J. J. Future treatments for hereditary hemorrhagic telangiectasia. Orphanet J. Rare Dis. 15, 4 (2020).

doi: 10.1186/s13023-019-1281-4 pubmed: 31910860 pmcid: 6945546

Wooderchak-Donahue, W. L. et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am. J. Hum. Genet 93, 530–537 (2013).

doi: 10.1016/j.ajhg.2013.07.004 pubmed: 23972370 pmcid: 3769931

Botman, E. et al. Evolution of heterotopic bone in fibrodysplasia ossificans progressiva: an [(18)F]NaF PET/CT study. Bone 124, 1–6 (2019).

doi: 10.1016/j.bone.2019.03.009 pubmed: 30858149

Bauer, D. et al. National Bone Health Alliance Bone Turnover Marker Project: current practices and the need for US harmonization, standardization, and common reference ranges. Osteoporos. Int. 23, 2425–2433 (2012).

doi: 10.1007/s00198-012-2049-z pubmed: 22797491 pmcid: 4011662

Vasikaran, S. et al. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine position on bone marker standards in osteoporosis. Clin. Chem. Lab. Med. 49, 1271–1274 (2011).

doi: 10.1515/CCLM.2011.602 pubmed: 21605012

Vanhoutte, F. et al. Pharmacokinetics and Pharmacodynamics of garetosmab (anti-activin a): results from a first-in-human phase 1 study. J. Clin. Pharm. 60, 1424–1431 (2020).

doi: 10.1002/jcph.1638

Heymsfield, S. B. et al. Effect of bimagrumab vs placebo on body fat mass among adults with type 2 diabetes and obesity: a phase 2 randomized clinical trial. JAMA Netw. Open 4, e2033457 (2021).

doi: 10.1001/jamanetworkopen.2020.33457 pubmed: 33439265 pmcid: 7807292

Rooks, D. et al. Safety and pharmacokinetics of bimagrumab in healthy older and obese adults with body composition changes in the older cohort. J. Cachexia Sarcopenia Muscle 11, 1525–1534 (2020).

doi: 10.1002/jcsm.12639 pubmed: 33264516 pmcid: 7749589

Kenny, L. M. et al. Reproducibility of [11C]choline-positron emission tomography and effect of trastuzumab. Clin. Cancer Res. 16, 4236–4245 (2010).

doi: 10.1158/1078-0432.CCR-10-0468 pubmed: 20682702

Hawkins, R. A. et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J. Nucl. Med. 33, 633–642 (1992).

pubmed: 1569473

Grant, F. D. et al. Skeletal PET with 18F-fluoride: applying new technology to an old tracer. J. Nucl. Med. 49, 68–78 (2008).

doi: 10.2967/jnumed.106.037200 pubmed: 18077529

Hsiao, E. C. et al. Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP). Br. J. Clin. Pharm. 85, 1199–1207 (2019).

doi: 10.1111/bcp.13777

Keam, B. et al. Total lesion glycolysis in positron emission tomography can predict gefitinib outcomes in non-small-cell lung cancer with activating EGFR mutation. J. Thorac. Oncol. 10, 1189–1194 (2015).

doi: 10.1097/JTO.0000000000000569 pubmed: 26200273

Lees-Shepard, J. B. et al. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat. Commun. 9, 471 (2018).

doi: 10.1038/s41467-018-02872-2 pubmed: 29396429 pmcid: 5797136