Efo/alpha-1-antitrypsin Deficiency

1. Disease Summary:

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder characterized by low levels of alpha-1-antitrypsin (AAT), a protein that protects the lungs and liver from damage caused by enzymes released by white blood cells. AATD is inherited in an autosomal co-dominant manner, meaning that individuals can inherit different alleles from each parent, leading to varying levels of AAT. The most severe form is associated with the "ZZ" genotype, which significantly increases the risk of developing chronic obstructive pulmonary disease (COPD), emphysema, and liver cirrhosis. Patients often experience progressive lung disease and liver complications, which can lead to significant morbidity and mortality.

2. Global Prevalence and Disease Burden:

AATD is estimated to affect approximately 100,000 individuals in the United States, with a global prevalence of around 235,000 cases. However, it is severely underdiagnosed, with fewer than 10,000 individuals diagnosed in the U.S. alone (PMID: 29191952). The incidence of AATD is about 1 in every 1,500 to 3,500 individuals of European descent, making it one of the most common hereditary disorders in adults (PMID: 32103933). The economic burden of AATD is substantial, as it leads to increased healthcare costs due to hospitalizations, long-term care, and the need for specialized treatments. The costs associated with managing AATD-related complications can be significant, although specific figures vary by region and healthcare system.

3. Unmet Medical Need:

Despite advancements in understanding and managing AATD, several unmet medical needs persist:

Underdiagnosis and Delayed Diagnosis: Many patients remain undiagnosed or are misdiagnosed with other conditions such as asthma or COPD. This delay in diagnosis can lead to irreversible lung damage and liver disease (PMID: 29191952). Increased awareness and improved diagnostic methods are essential to address this gap.
Access to Treatment: There are significant disparities in access to augmentation therapy, the only FDA-approved treatment for AATD-related lung disease. Patients in regions without reimbursement for this therapy face barriers to accessing necessary treatment (PMID: 32103933).
Limited Treatment Options: Current treatments primarily focus on augmentation therapy, which is not a cure and does not address the underlying genetic defect. There is a need for disease-modifying therapies that can effectively target the root cause of AATD (PMID: 29191952).
Patient Education and Support: Patients often report a lack of understanding regarding their condition and treatment options. Improved educational resources and support systems are necessary to empower patients in managing their health (PMID: 32103933).

4. Current Treatment Options:

The primary treatment for AATD is augmentation therapy, which involves intravenous infusions of purified human AAT. This therapy aims to increase AAT levels in the blood and lungs, thereby reducing the risk of lung damage. However, it has several limitations:

Efficacy: While augmentation therapy can slow the progression of lung disease, it does not reverse existing damage or prevent liver disease (PMID: 29191952).
Accessibility: The therapy is expensive and may not be covered by all insurance plans, limiting access for many patients (PMID: 32103933).
Administration: Augmentation therapy requires regular infusions, which can be burdensome for patients and may lead to adherence issues (PMID: 32103933).
Lack of Alternatives: There are currently no approved treatments specifically targeting liver disease associated with AATD, highlighting a significant gap in treatment options (PMID: 29191952).

5. Current Clinical Trials:

Several clinical trials are underway to explore new treatment options for AATD:

Fazirsiran: A Phase 3 trial is evaluating the efficacy and safety of Fazirsiran, an RNA interference therapeutic, for treating liver disease associated with AATD (source: ClinicalTrials.gov).
INBRX-101: This is a Phase 1 study assessing the safety and pharmacokinetics of a new drug designed to treat AATD (source: ClinicalTrials.gov).
Gene Therapy: Ongoing research is focused on gene therapy approaches to correct the underlying genetic defect in AATD, which could provide a more definitive treatment option in the future (PMID: 32103933).

6. Additional Context:

The European Alpha-1 Research Collaboration (EARCO) and the European Reference Network for Rare Lung Diseases (ERN-LUNG) are initiatives aimed at improving research and treatment access for AATD patients. These organizations are working to establish registries, improve diagnostic methods, and enhance patient care (PMID: 32103933). The need for international cooperation is crucial, given the rarity of the disease and the geographical dispersion of patients.