Bridging the Gap With Clinical Pharmacology in Innovative Rare Disease Treatment Modalities: Targeting DNA to RNA to Protein

Abstract

Rare diseases are frequently caused by inherited ‘monogenic’ defects. Treatment interventions that target a specific genetic location or that replaces a specific protein provide rational therapeutic approaches. The current review discusses innovative targeted therapies that act or modulate at the level of DNA, RNA, or protein. They include DNA gene editing, small interference RNA (siRNA), antisense oligonucleotide (ASO), small molecule RNA splicing modifier, and bispecific antibody. With limited numbers of patients, testing multiple dose levels and regimens prior to making an informed dose decision remains one of the major challenges in rare disease drug development. Clinical pharmacology strategically bridges the gap to support drug development and regulatory approvals. Pharmacokinetic drug exposures are driven by absorption, distribution, metabolism, elimination, and in some cases immunogenicity. Drug responses are measured by pharmacodynamic biomarkers that are linked to either short‐ or long‐term clinical outcomes. Understanding the drug exposure–response relationship lies at the heart of bridging the gap that enables a dose decision by balancing effectiveness and safety. Furthermore, and importantly, understanding the influence of intrinsic and extrinsic factors on drug pharmacokinetics enables dose adjustment decisions based on drug exposures. Case examples include the identification of doses and regimens without a formal dose‐finding study, the support of new doses and regimens without conducting additional studies, and the extrapolation of adult drug–drug interaction (DDI) studies to pediatrics without performing a pediatric DDI study. With increasing discoveries of innovative treatment modalities, the responsibility of clinical pharmacologists is expected to grow and enhance the development of novel treatments for rare diseases.

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 .…”

“…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 highlighted from several articles within this issue, the role of clinical pharmacology is expanding and is especially important for rare diseases. 1,[3][4][5][6][7][8] To that end, there are a few key factors for success that are worth highlighting.…”

“…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.…”