Forty Years in the Making: How Three Competing Technologies Are Finally Challenging Alpha-1 Antitrypsin Deficiency

There is a particular kind of medical neglect that does not announce itself loudly. Alpha-1 antitrypsin deficiency, a rare genetic disorder that quietly destroys the lungs and liver of the people who carry it, has existed in the medical literature since the 1960s. For roughly four decades, the only meaningful treatment option was intravenous augmentation therapy, a weekly infusion of donor-derived protein that slows the disease without addressing its genetic root. On May 18, 2026, at the annual meeting of the American Thoracic Society in Orlando, two companies presented data that suggest the long wait for something better may finally be ending. A third is not far behind.

The disease itself is worth understanding before the treatments. Alpha-1 antitrypsin is a protein produced in the liver that travels through the bloodstream to the lungs, where it neutralizes neutrophil elastase, an enzyme that would otherwise degrade lung tissue during inflammatory responses. In patients with AATD, a mutation in the SERPINA1 gene, most commonly the Z variant, causes the protein to misfold and accumulate in liver cells rather than circulating to the lungs. The result is a double injury: the lungs are left unprotected against inflammatory damage, and the liver accumulates toxic protein aggregates that can cause fibrosis, cirrhosis, and hepatocellular carcinoma. An estimated 90 percent of patients with the condition remain undiagnosed, often misclassified as having ordinary COPD or asthma for years before the genetic cause is identified.

Three Approaches, One Disease

Sanofi's efdoralprin alfa, acquired through its $1.7 billion buyout of Inhibrx, represents the most advanced of the new approaches. The drug is a recombinant, bivalent Fc fusion protein engineered to last longer in the body than donor-derived augmentation therapy. At the ATS meeting, Sanofi presented detailed data from its Phase 2 ElevAATe trial, showing that a three-weekly infusion of efdoralprin alfa raised average AAT blood levels to 24.1 micromolar, well above the 11 micromolar threshold generally considered the minimum for lung protection, and far above the 7.6 micromolar achieved by the current standard-of-care weekly infusion of CSL's Zemaira. The trial also showed numerically lower rates of disease exacerbations in patients receiving efdoralprin alfa compared to Zemaira. Sanofi is now in discussions with the FDA about next steps, and the company's global medical head of rare diseases described the results as establishing functional AAT levels within the normal range across the board.

Wave Life Sciences is pursuing a fundamentally different strategy. Its candidate, WVE-006, is an RNA editor designed to correct the single-base mutation in SERPINA1 Z messenger RNA, converting it back to the healthy M variant so that the liver produces functional protein on its own. At the ATS meeting, Wave reported that a 400-milligram monthly dose of WVE-006 produced 13.6 micromolar of total AAT in the Phase 1/2a RestorAATion-2 trial, with 7.98 micromolar of healthy protein. More significantly, the drug reduced the toxic Z variant of AAT by more than 70 percent. That last number matters because protein replacement therapies like Zemaira and efdoralprin alfa do nothing to reduce Z protein accumulation in the liver. Wave's approach addresses both the lung and liver manifestations of the disease simultaneously, a capability that augmentation therapy cannot replicate. GSK recently declined to continue co-developing WVE-006, returning rights to Wave, which is now pursuing accelerated approval discussions with the FDA independently.

Beam Therapeutics is taking the most ambitious path of the three. Its candidate, BEAM-302, uses lipid nanoparticle-delivered base editing to make a permanent correction to the Z variant in the SERPINA1 gene itself, converting the pathological mutation back to the healthy sequence in liver cells. Phase 1/2 data presented last year showed durable, dose-dependent increases in functional AAT following a single intravenous dose, with the program described by analysts as setting the bar for efficacy in the space. A one-time intervention that permanently corrects the underlying genetic defect represents the theoretical ceiling of what treatment for this disease could achieve.

Why the Comparison Is Harder Than It Looks

The temptation to rank these three approaches against each other is understandable but premature. Each is targeting a different subset of the patient population, operating at a different stage of clinical development, and optimizing for a different set of outcomes. Sanofi's recombinant protein is furthest along and addresses the broadest population. Wave's RNA editor is specifically focused on patients with two copies of the Z variant, the most severely affected group, and offers the dual benefit of lung protection and liver disease modification. Beam's gene editor is the most transformative in concept but carries the inherent uncertainties of a one-time, permanent intervention in a patient population that is generally younger and otherwise healthy enough to live for decades after treatment.

What the convergence of these three programs at the same medical meeting in the same week does establish is that the field has moved decisively beyond the augmentation paradigm. The question is no longer whether better treatments for AATD are possible. The question is which approach, or combination of approaches, will prove most durable, most accessible, and most appropriate for which patients.

The Underdiagnosis Problem That No Drug Can Solve Alone

There is a structural challenge that sits beneath all of this clinical progress. Both Sanofi and Wave acknowledged at the ATS meeting that diagnosis remains the field's most persistent obstacle. An estimated 90 percent of AATD patients are undiagnosed, often because the disease presents with symptoms indistinguishable from ordinary COPD or asthma, and because testing is inconsistently applied even in populations where guidelines recommend it. A drug that works brilliantly in a clinical trial cannot help a patient who has never been told they carry the Z variant.

That diagnostic gap is not a new problem, but it takes on new urgency as genuinely transformative treatments approach the market. The value of early intervention in AATD, before significant lung or liver damage has accumulated, is well established. A patient diagnosed at 35 who receives an RNA editor or gene therapy that corrects the underlying defect has a fundamentally different prognosis than one diagnosed at 55 after decades of unrecognized disease progression. The clinical advances being presented this week in Orlando are meaningful. Whether they reach the patients who need them most will depend as much on diagnostic infrastructure and physician awareness as on the science itself.