Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy

Lee, Seungbok; Lee, Yun Jeong; Kong, Jai-Yul; Ryu, Ho‐Sung; Shim, Young Kyu; Han, Ji Yeon; Woo, Hyewon; Kim, Soo Yeon; Cho, Anna; Lim, Byung Chan; Chae, Jong Hee

doi:10.1016/j.braindev.2021.12.006

Cited by 13 publications

(12 citation statements)

References 27 publications

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“…This ongoing study also identified a new adverse drug reaction (chorioretinal atrophy) which has not been associated with loss of visual function. Similarly, for onasemnogene abeparvovec a post‐treatment follow‐up study for up to 17 months demonstrated that all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support 86 …”

Section: Post Approval and Real‐world Evidencementioning

confidence: 85%

“…Similarly, for onasemnogene abeparvovec a post-treatment follow-up study for up to 17 months demonstrated that all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. 86 In a first by any health agency, the German health agency, has mandated the sponsor to collect RWE for onasemnogene abeparvovec to demonstrate long term clinical benefit. 87 Taking a step further, the agency has specified that the sponsor should carry out a registry study directly comparing onasemnogene abeparvovec with Spinraza (Biogen's SMA treatment product).…”

Section: Post Approval and Real-world Evidencementioning

confidence: 99%

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Model‐Informed Approaches and Innovative Clinical Trial Design for Adeno‐Associated Viral Vector‐Based Gene Therapy Product Development: A White Paper

Mitra,

Ahmed,

Krishna

et al. 2023

Clin Pharma and Therapeutics

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The promise of viral vector‐based gene therapy (GT) as a transformative paradigm for treating severely debilitating and life‐threatening diseases is slowly coming to fruition with the recent approval of several drug products. However, they have a unique mechanism of action often necessitating a tortuous clinical development plan. Expertise in such complex therapeutic modality is still fairly limited in this emerging class of adeno‐associated virus (AAV) vector‐based gene therapies. Because of the irreversible mode of action and incomplete understanding of genotype–phenotype relationship and disease progression in rare diseases careful considerations should be given to GT product's benefit–risk profile. In particular, special attention needs to be paid to safe dose selection, reliable dose exposure response (including clinically relevant endpoints), or creative approaches in study design targeting small patient populations during clinical development. We believe that quantitative tools encompassed within model‐informed drug development (MIDD) framework fits quite well in the development of such novel therapies, as they enable us to benefit from the totality of data approach in order to support dose selection as well as optimize clinical trial designs, end point selection, and patient enrichment. In this thought leadership paper, we provide our collective experiences, identify challenges, and suggest areas of improvement in applications of modeling and innovative trial design in development of AAV‐based GT products and reflect on the challenges and opportunities for incorporating MIDD tools and more in rational development of these products.

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Section: Post Approval and Real‐world Evidencementioning

confidence: 85%

Section: Post Approval and Real-world Evidencementioning

confidence: 99%

Model‐Informed Approaches and Innovative Clinical Trial Design for Adeno‐Associated Viral Vector‐Based Gene Therapy Product Development: A White Paper

Mitra,

Ahmed,

Krishna

et al. 2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

show abstract

“…The real-world data suggest that elevated serum levels of aminotransferase and reduced platelets were more frequent in heavier infants but were always well controlled by prednisolone [14][15][16][17][18][19][20]. A new concern came from the observation of thrombotic microangiopathy (TMA) which had been reported in preclinical studies but had never been observed in the clinical trials [21].…”

Section: Onasemnogene Abeparvovec: Real-world Datamentioning

confidence: 99%

New therapies for spinal muscular atrophy: where we stand and what is next

Antonaci

Pera

2023

Eur J Pediatr

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The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration. Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug’s approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.

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“…41 The delivery vector can be viral, often AAV or LVV, viral-like particles, 42 or synthetic (e.g., lipid nanoparticles). 39 For example, onasemnogene abeparvovec-xioi 13 is a method of AAV gene replacement that uses a single intravenous dose before the patient is 2 years of age to treat SMA by delivering a functional copy of the SMN1 gene to spinal neurons. As methods of nucleic acid therapeutics advance, it is conceivable that therapies could be developed for most single-gene disorders, benefiting millions of affected individuals.…”

Section: Approaches To Gene Therapymentioning

confidence: 99%

“…Recent trials in adults and children have achieved concrete steps to realizing the therapeutic potential of gene therapy or gene editing, with 2 FDA‐approved gene therapies successfully applied for diseases such as retinal blindness (voretigene neparvovec‐rzyl) 12 and spinal muscular atrophy (onasemnogene abeparvovec), 13 and investigational therapies such as valoctocogene roxaparvovec 14 for hemophilia. Numerous other therapies are in the pipeline and more could be developed for conditions relevant to prenatal therapy.…”

mentioning

confidence: 99%

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI‐FDA Meeting)

Herzeg

Almeida‐Porada

Charo³

et al. 2022

The Journal of Clinical Pharma

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We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

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Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy

Cited by 13 publications

References 27 publications

Model‐Informed Approaches and Innovative Clinical Trial Design for Adeno‐Associated Viral Vector‐Based Gene Therapy Product Development: A White Paper

Model‐Informed Approaches and Innovative Clinical Trial Design for Adeno‐Associated Viral Vector‐Based Gene Therapy Product Development: A White Paper

New therapies for spinal muscular atrophy: where we stand and what is next

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI‐FDA Meeting)

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