EC Pulmonology and Respiratory Medicine

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition with heterogeneous, genotype-dependent lung and liver manifestations. In the lungs, insufficient levels of the alpha-1 antitrypsin (AAT) protein result in elastase-driven elastin destruction (‘toxic loss of function’), driving chronic inflammation and causing chronic obstructive pulmonary disease (COPD), emphysema and bronchiectasis [1]. In the liver, pathologic AAT polymerisation causes hepatocellular accumulation (‘toxic gain of function’), leading to neonatal hepatitis, cirrhosis and hepatocellular carcinoma [2].

The patient journey to diagnosis and treatment is usually challenging and brings a significant burden to patients and their families. Current treatment alternatives are also suboptimal and fail to completely halt disease progression, resulting in an unmet medical need. The development of new treatment options that reduce patient burden, stop disease progression and improve quality of life is, therefore, vital. Successful clinical trials require an end-to-end clinical development plan that anticipates regulatory expectations across regions, builds a robust safety database early and incorporates efficacy endpoints that can withstand scrutiny from regulatory agencies and brings it inside the study protocol design. Equally, successful execution depends on early and sustained patient involvement, realistic country-site strategies grounded in population availability and care pathways, and a focus on enrolment, retention and endpoint protection without imposing excessive burdens on participants and sites.

Drawing primarily on first-hand experiences of developing operational plans for AATD studies, this article outlines critical considerations for sponsors navigating the AATD clinical development pathway, including protocol design choices for early-phase and pivotal studies. The article also offers practical guidance on trial execution in this rare disease setting, including how to identify the country-site mix; the value of patient advisory boards (PABs), key opinion leaders (KOLs) and referral networks in enrolment; and how decentralised components can mitigate patient burdens to improve retention.

Keywords: Alpha-1 Antitrypsin Deficiency; Alpha-1 Antitrypsin; Rare Diseases; Genetic Disorders; Pulmonology; Hepatology; Augmentation Therapy; Clinical Trials; Clinical Development; Decentralised Trials; Patient Advisory Boards; Key Opinion Leaders; Investigative Sites

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