Is the 11 Micromolar Threshold Right for AATD Augmentation?

Dr. Kuhn takes the lead in "Is the 11 Micromolar Threshold Right for AATD Augmentation?," tracing the origins of the protective threshold and testing its assumptions.

Dr. Haumschild notes that current plasma-derived therapies are approved around a historical threshold of 11 micromolar, set decades ago as a protective lower limit. He asks Dr. Kuhn how robust the evidence is and whether another target should be considered.

Dr. Kuhn explains that 11 micromolar is not the normal range, which runs closer to 20 to 53. Dosing 60 mg/kg to reach the normal range would require infusions every two to three days, which is impractical. Investigators instead looked at nonsmoking patients with S and Z alleles, whose lower limit of normal lands near 11 micromolar. Most of those patients do not progress to emphysema. By contrast, almost all ZZ patients, who have far lower levels, develop some emphysema in their lifetime.

The RAPID trial showed efficacy at 60 mg/kg, especially in the intermediate FEV1 range. Later population studies suggest augmentation slows lung loss toward the general population rate. Dr. Kuhn calls it an unsettled question whether more is better. He points to two upcoming trials: Elevate, examining a longer-acting agent that could reach higher levels, and SPARTA, a randomized comparison of 60 versus 120 mg/kg.

Dr. Sandhaus gently corrects the history, noting the 11 micromolar figure was set in the 1980s at the NIH during studies leading to the first augmentation product.

Asked whether a normal range of 20 to 53 might benefit patients, Dr. Kuhn says the jury is still out. In other diseases, normalizing a value has not always helped and can carry costs. On neutrophil elastase, he says it is the primary target impaired in AATD. It is helpful against infection and destructive when unchecked. It is rarely measured in practice, although RAPID showed degradation products fall with augmentation.

Our next episode, "Weekly AATD Infusions: Peak-to-Trough Levels in Practice," features Dr. Goldklang and Dr. Sandhaus on what happens between infusions and whether trough levels should be measured at all.