Evidence for AATD Augmentation: FEV1 Limits, CT Density, Unmet Needs

The panel confronts the evidence gap head-on in "Evidence for AATD Augmentation: FEV1 Limits, CT Density, Unmet Needs."

Dr. Haumschild notes that no randomized trial has shown a statistically significant reduction in FEV1 decline and that long-term outcome data are sparse. He asks Dr. Kuhn how he makes the case for augmentation to patients and payers.

Dr. Kuhn says FEV1 is a poor fit for AATD. Decline is not linear. Patients lose 60 to 80 mL per year in the moderate range of FEV1 50 to 80 percent, but only about 8 mL per year in severe disease. Patient trajectories also vary widely. He describes an 86-year-old with better lung function than his own. He also describes 20- and 30-year-olds, found through family screening, who already have emphysema on CT. FEV1 also varies from day to day. A trial would need many patients, a narrowly selected population, and many years.

For those reasons RAPID used CT densitometry, which he calls a good surrogate for emphysema destruction. He also cites real-world comparisons in Canada and European countries where augmentation is not routinely available. Those natural experiments show slower lung decline with augmentation, and NHLBI data show a trend toward improved mortality. He argues the field is asking the wrong question.

Dr. Sandhaus adds that FEV1 measures airway dysfunction, while emphysema is destruction of the alveoli. Many patients have severe emphysema with normal FEV1. Dr. Kuhn compares it to the man who searches for his keys under the streetlight because that is where the light is.

Dr. Haumschild then asks Dr. Goldklang about unmet needs. She names education, familial testing to find patients before symptoms, and care coordination with liver colleagues, since ZZ patients need liver follow-up. Her largest concern is finding patients through the right testing. She hopes AATD testing will follow the growth of biologics targeting IgE and eosinophils.

In "Recombinant AAT-Fc Fusion Protein for AATD: Mechanism and Half-Life," Dr. Sandhaus explains how a fusion protein is engineered to last longer in the circulation than plasma-derived alpha-1 antitrypsin.