Clinical Pharmacology Considerations on Recombinant Adeno‐Associated Virus–Based Gene Therapy

Abstract

Recombinant adeno‐associated virus (AAV) is currently the most widely used platform for in vivo gene therapy. Clinical pharmacology is a central field for AAV gene therapy, represented by the pillars of pharmacokinetics, pharmacodynamics/efficacy, and safety. In this review, we provide a comprehensive summary of clinical pharmacology considerations for recombinant AAV. The main topics covered are biodistribution and shedding, dose–exposure–response relationship, safety, immune and stress response, and clinical dose selection strategies. We highlight how the cumulative knowledge of AAV gene therapy could help with guiding clinical trial design and assessing and mitigating risks, as well as planning and executing pharmacokinetic/pharmacodynamic /safety data analyses. In addition, we discuss the major gaps and areas of growth in clinical pharmacology understanding of recombinant AAV. These include the mechanisms of the durability of treatment response and variability in biodistribution, transduction, and immunogenicity, as well as a potential influence on AAV's safety and efficacy profiles by drug product characteristics and patient intrinsic/extrinsic factors.

Think Rare, Think Inside and Out: Simple Question‐Based Approach to Complex Rare Disease Drug Development

“…As discussed in the articles within this issue, rare diseases possess unique traits, many of which are not essentially mutually exclusive: small sample size, heterogeneity of the affected population, limited understanding of the disease pathophysiology, and natural history 1–9 . It is steadily becoming common knowledge how the multiple traits of rare diseases can complicate drug development; currently, there are >9000 serious and life‐threatening rare diseases with not a single therapeutic option 1 …”

“…Since 80% of rare diseases are genetic in origin and most of them display a family distribution compatible with a monogenic origin, mechanistically they can be considered to be pathway specific. This has enabled the development of many targeted novel modalities such as gene therapies, antisense oligonucleotides, small interfering RNA, and gene editing as reviewed by Lee et al as well as Sun and Liao 7,8 . However, the species‐specific relevance and quantitative translation of modulating the pathophysiology on downstream pharmacology is an ongoing challenge 7 .…”

“…But what exactly is our role for these modalities from a dose consideration perspective where there are no “traditional” pharmacokinetics? As reviewed by Sun and Liao, clinical pharmacologists should approach these new modalities with precise questions, based on the basic principles of clinical pharmacology 7 . For example, what are the distribution kinetics of the vector, and what is the certainty of the translation across species?…”

“…This has enabled the development of many targeted novel modalities such as gene therapies, antisense oligonucleotides, small interfering RNA, and gene editing as reviewed by Lee et al as well as Sun and Liao. 7,8 However, the species-specific relevance and quantitative translation of modulating the pathophysiology on downstream pharmacology is an ongoing challenge. 7 Unfortunately, for many rare diseases, understanding of the disease pathophysiology is incomplete; thus, adding another layer of uncertainty.…”

“…As discussed in the articles within this issue, rare diseases possess unique traits, many of which are not essentially mutually exclusive: small sample size, heterogeneity of the affected population, limited understanding of the disease pathophysiology, and natural history. [1][2][3][4][5][6][7][8][9] It is steadily becoming common knowledge how the multiple traits of rare diseases can complicate drug development; currently, there are >9000 serious and life-threatening rare diseases with not a single therapeutic option. 1 While common disease drug development programs are derisked through a stepwise approach using phase 1, 2a, 2b, and 2 phase 3 studies, rare disease drug development programs may follow an accelerated development paradigm.…”