Intravenous alpha-1 antitrypsin improves survival in patients with deficiency

Key takeaways:

• Augmentation therapy increased survival in patients with a severe alpha-1 antitrypsin deficiency.
• Augmentation therapy may be effective in those with a higher FEV₁ than that for which it is currently licensed.

Patients with severe alpha-1 antitrypsin deficiency had improved survival with intravenous plasma-purified alpha-1 antitrypsin therapy, according to results published in American Journal of Respiratory and Critical Care Medicine.

Researchers further found a group of patients with this deficiency who experience a more rapid decline in lung function when they are younger, namely “lung indexes” who may especially benefit from augmentation therapy.

“The findings of this study should encourage physicians to consider the diagnosis of alpha-1 antitrypsin deficiency (AATD) as early as possible as the condition has now been shown to be medically actionable and people with severe deficiency are likely to gain considerable benefit from upcoming clinical trials, once treatment is commenced early enough into their disease progression,” Daniel D. Fraughen, MB, PhD student in the department of medicine, Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, told Healio. “Most people with AATD who are recruited into clinical trials are over the age of 50, an age when the investigational product is unlikely to show a significant benefit on lung function decline.”

In an observational, real-world study, Fraughen and colleagues assessed 615 patients with severe AATD to determine the impact of intravenous plasma-purified alpha-1 antitrypsin (IV-AAT), called an augmentation therapy, on lung function and survival over an average of 58 months.

Notably, patients included in this study resided in Ireland (n = 211; mean age at diagnosis, 44.94 years; 55% men), Switzerland (n = 109; mean age at diagnosis, 44.47 years; 56% men) or Austria (n = 295; mean age at diagnosis, 45.09 years; 59.7% men) where there is unequal access to IV-AAT, with augmentation therapy being reimbursed in Switzerland and Austria but not in Ireland, according to researchers.

Findings

When evaluating the study population, researchers unexpectedly found that patients either belonged to the lung index group (diagnosed for respiratory reasons; n = 431) or the non-lung index group (diagnosed for nonrespiratory reasons; n = 178), and this classification signaled differences in lung function decline, Fraughen told Healio.

Between ages 20 to 50 years, those in the lung index group had larger decreases in FEV₁ compared with those in the non-lung index group (41 mL/year vs. 31 mL/year), but these declines plateaued with minimal decline observed after lung indexes turned 50 years old (36 mL/year vs. 47 mL/year).

“One major finding had confirmed what pulmonary physicians anecdotally suspected for a long time — that is, pulmonary function decline in those with severe AATD appears to be more pronounced when patients are younger than 50 years old, and after the age of 50, pulmonary function decline appears to plateau,” Fraughen told Healio.

For most patients, FEV₁ decline did not change with use of IV-AAT. According to researchers, the only group of patients who had less lung function decline with IV-AAT was those with a Global Initiative for Chronic Lung Disease (GOLD) stage 2 lung index (FEV₁ between 50% and 80%).

“Interestingly, a recommendation to start this therapy is not typically presented to patients with this classification, rather it is reserved for those with an FEV₁ between 30% and 65%,” Fraughen said.

“Augmentation therapy appears to be effective at higher FEV₁ values than what it is currently licensed for, which begs the question — are we providing augmentation therapy too late for those with severe AATD, at a point where there is advanced lung disease?” he asked.

When compared with patients who did not receive IV-AAT, researchers found that patients who received the therapy had a survival benefit (P < .001), and this is “decoupled from its effects on preventing lung function decline,” Fraughen told Healio.

In a Cox proportional hazard model, the risk for mortality was reduced with use of IV-AAT (HR = 0.61; 95% CI, 0.45-0.83).

Importance of early diagnosis

Considering these findings, Fraughen emphasized the importance of diagnosing AATD early.

“Early diagnosis empowers people to make informed lifestyle choices like stopping or never smoking, which greatly reduces lung risk and has been shown to decrease the likelihood of their children smoking,” Fraughen told Healio. “An earlier diagnosis also allows for the administration of augmentation therapy at the earliest possible time so as to mitigate the potential rapid lung function decline.

“Another benefit would be that it allows people to be identified for potentially beneficial current and future clinical trials for their condition in the absence of being able to receive augmentation therapy,” he added.

One practice that could help identify AATD early on in a patient’s life is newborn screening, Fraughen told Healio.

“We should reconsider the need for newborn screening in populations where severe AATD is most prevalent as it has been shown to be an actionable disease,” he said. “Populations with the highest proportions of those with severe AATD are generally of northern European descent.”

Based on the results of this study, Fraughen recommends enrolling patients aged younger than 50 years in further research to capture the impact of IV-AAT on lung function.

“Future studies will likely need to recruit patients who are much younger than those who are currently being recruited, ie, those under the age of 50 years old, where the effects of any therapies are most likely to show a slowing of lung decline while the patient is in a phase of more rapid decline,” Fraughen told Healio.

For more information:

Daniel D. Fraughen, MB, can be reached at danielfraughen@gmail.com. For more information on AATD, visit www.alpha1.ie or www.alpha1.org.

Reference:

• RCSI study shows survival benefit of augmentation therapy for people with the genetic lung condition AATD. https://www.rcsi.com/dublin/news-and-events/news/news-article/2023/11/rcsi-study-shows-benefit-of-augmentation-therapy-for-people-with-aatd. Published Nov. 1, 2023. Accessed Nov. 1, 2023.