Long-term results of alpha-1-antitrypsin deficiency treatment – RAPID program

AATD

Alpha-1-antitrypsin deficiency (AATD) is a congenital disease caused by a mutation in the SERPINA1 gene encoding alpha-1-antitrypsin, also known as alpha-1-proteinase inhibitor (A₁-PI). A₁-PI inhibits elastase, one of the proteolytic enzymes released by inflammation-activated neutrophils. In case of its deficiency, the balance between elastase and anti-elastase activity is disrupted, leading to progressive irreversible destruction of lung tissue. The result is the development of COPD and emphysema.

AATD is an underdiagnosed condition. Patients are often diagnosed late or incorrectly.

A₁-PI

The only available treatment for AATD is the administration of A₁-PI. Proving its benefit is difficult because it is a rare disease, and large groups of patients and long follow-up periods are needed to demonstrate the efficacy of the treatment based on an increase in forced expiratory volume in one second (FEV₁) or a decrease in mortality. Another obstacle is enrolling a sufficient number of subjects in the placebo group.

RAPID program

The largest completed evaluation of the efficacy of A₁-PI augmentation therapy in patients with AATD is the RAPID clinical program, specifically RAPID Extension. It included a 2-year randomized placebo-controlled study RAPID RCT and its 2-year open-label extension RAPID-OLE, which used quantitative chest CT for efficacy evaluation. The primary endpoint was the annual rate of decline in lung density (PD15 − percentile density).

Slowing the progression of emphysema

The annual rate of decline in lung density (entire lung at full inspiration) was significantly lower in 180 evaluated patients treated with A₁-PI compared to those receiving placebo (−1.45 g/L/year vs. −2.19 g/L/year; p = 0.017), corresponding to a 34% reduction in the progression of emphysema in the A₁-PI group.

This benefit was confirmed in the RAPID-OLE extension, where all patients received A₁-PI. The slowing of emphysema progression was comparable in the extension study for both early and later treatment initiation. However, the lung tissue loss that occurred during the baseline study with placebo administration could not be reversed.

Delay in respiratory crisis

Post hoc analysis of data from the full 4-year course of the RAPID studies also examined the time to respiratory crisis (defined as death, lung transplantation, or paralyzing respiratory status), which occurred at an average lung density value of 20.5 g/l. From the slowing of emphysema progression with A₁-PI treatment, it was possible to determine the number of gained life years until respiratory crisis – reaching 5.6 years.

Conclusion

The results of the RAPID clinical program show that early initiation of A₁-PI therapy in patients with emphysema due to AATD slows disease progression, has disease-modifying effects, and can extend the time to terminal respiratory failure.

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Source: Rahaghi F. F., Miravitlles M. Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence. Respir Res 2017; 18 (1): 105, doi: 10.1186/s12931-017-0574-1.