By Raffaele Pereno – PhD, MBA
VIENNA, Austria – A discussion with AATech CEO Rüdiger Jankowsky at BioEurope highlighted a decisive shift in how alpha‑1 antitrypsin (AAT) may be deployed in respiratory
medicine.
While most companies in the field continue to focus on treating the rare genetic disorder
alpha‑1 antitrypsin deficiency (AATD), AATech is deliberately choosing a broader and
more urgent target: non‑CF bronchiectasis (NCFB). This chronic, inflammatory airway
disease affects an estimated 500,000 to 800,000 patients across the US and Europe yet
still has no approved disease‑modifying therapy.
“We intentionally chose NCFB,” Jankowsky stated. “Not because it is simpler, but
because the biology fits, the need is enormous, and recombinant technology finally
allows us to think beyond the constraints of rare disease.” As he explained, the choice
reflects both a scientific opportunity and a shift toward scalable therapeutics.
Understanding Non‑CF Bronchiectasis
NCFB is a progressive airway disease characterised by chronic inflammation, mucus
obstruction and recurrent bacterial infections. Patients often face persistent cough,
shortness of breath and frequent exacerbations. Historically labelled “idiopathic,” NCFB
is now recognised as a disease driven by chronic neutrophil activation and excessive
release of damaging enzymes, particularly neutrophil elastase.
The biology that links AAT to NCFB
In healthy lungs, neutrophils migrate into the airways only when needed. Following
chemical signals such as IL‑8 or bacterial peptides, they pass through the endothelium
and extracellular matrix to reach the airspaces, releasing small amounts of scissor-like
proteins called proteases that degrade proteins to navigate tissue. Under normal
conditions, AAT neutralises these proteases to prevent unintended tissue damage.
In NCFB, the balance between ATT and proteases collapses. As a result, neutrophils become chronically activated and release a protease called elastase far beyond what AAT can neutralise. When overstimulated, they can also undergo NET formation, releasing web‑like strands of DNA coated with elastase and antimicrobial proteins. These NETs can trap pathogens but also thicken mucus, damage epithelial cells and perpetuate the cycle of inflammation and infection.
This mechanism is well documented. For example, a study by Chalmers et
al. demonstrated that neutrophil elastase activity is closely linked to exacerbation
frequency and disease severity in bronchiectasis (Am J Respir Crit Care Med. 2017).
Such findings underscore why restoring the protease‑antiprotease balance is central to
modifying the course of NCFB.
Why AATech’s Strategy Differs from Plasma‑Derived Competitors
Traditional AAT therapies rely on plasma‑derived protein, which is limited in supply,
expensive to manufacture and approved only for AATD. These products require weekly
intravenous infusions and cannot be scaled for broad‑population diseases like NCFB.
As a result, plasma‑based companies have remained confined to the rare‑disease orbit.
AATech’s fully recombinant AAT platform removes these constraints. Recombinant
production ensures consistent quality, unlimited scalability and the freedom to address
large indications. It also enables new formulations tailored specifically for airway
delivery.
Inhaled AAT: Precision Treatment for an Airway Disease
AATech is advancing an inhaled AAT therapy, formulated to deliver the protein directly
to the site where elastase‑driven damage occurs. Unlike systemic infusion, inhalation
permits high local concentrations in the lung, rapid onset of action and improved patient
convenience. This approach aligns with the needs of NCFB, where repeated airway
infections and inflammation are central to disease progression.
A Different Regulatory Pathway: Broad Population vs. Orphan Disease
While companies like Inhibrx and its acquirer Sanofi are pursuing AATD via the
orphan‑disease route, with benefits such as tax credits, smaller trials and premium
pricing, AATech has chosen the broader regulatory path by targeting NCFB. Although
this requires larger studies with traditional endpoints, it opens the door to a substantially
larger patient population and the possibility of establishing the first disease‑modifying
treatment for NCFB.
Comparing AAT Deficiency and NCFB
AATD arises from mutations in the SERPINA1 gene, resulting in misfolded or absent
AAT protein. Severe genotypes such as ZZ or null‑null lead to profoundly low circulating
AAT. The consequences include unchecked elastase activity, early‑onset emphysema
and, in many cases, bronchiectasis.
NCFB, while not genetic, shares the same downstream biology: chronic neutrophil
activation, excessive elastase release and collapse of protease control. The key
distinction is that NCFB reflects an acquired deficiency of functional AAT caused by
overwhelming inflammation rather than a genetic mutation. This convergence explains
why AAT therapy, long confined to rare genetic disease, has strong mechanistic
relevance in NCFB.
The Future: A Broad Platform for Neutrophil‑Driven Diseases
AATech’s recombinant technology positions the company to address diseases beyond
NCFB that share neutrophil‑driven inflammatory features. Potential future indications
include asthma, COPD, respiratory viral infections, ARDS and bronchiolitis obliterans syndrome. Each is characterised by excessive protease activity and epithelial injury,
biological pathways in which AAT plays a natural counter‑regulatory role.
As understanding of neutrophilic diseases evolves and plasma‑derived limitations
become increasingly evident, AATech stands out as a company ready to shape the next
generation of AAT‑based therapies, one defined not by rarity or scarcity, but by
scientific relevance and scalability.
For more information, visit: https://aatec-medical.com/