Phase 1 Trial Produces Positive Results for Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

Discerna Pharmaceuticals has just announced the results from a Phase 1 trial investigating their GalXC RNAi therapy (Belcesiran) for alpha-1 antitrypsin (AAT) deficiency-associated liver disease (AATLD). The results demonstrated both safety and efficacy. A Phase 2 trial called ESTRELLA is now enrolling patients, and additional trial sites are being developed.

AAT Deficiency

AAT deficiency is a rare disease which is a result of a SERPINA1 gene mutation. The condition affects the lungs and the liver because AAT is responsible for protecting them. It does so by neutralizing neutrophil elastase which causes damage to the body when not regulated by the AAT.

The condition can cause liver injury, liver fibrosis, liver cirrhosis, hepatocellular carcinoma, liver disease, emphysema, and lung disease.


In AATLD, the misfiled AAT builds up in the liver and leads to liver damage. This buildup can cause extreme liver fibrosis, liver cirrhosis, and even hepatocellular carcinoma.

Unfortunately, a liver transplant is currently the only treatment option when liver failure is reached. There is a drastic need for an improved therapeutic which can diminish the toxic AAT and minimize liver injury. Thankfully, that is exactly what belcesiran does. It reduces the body’s production of any abnormal AAT.

Phase 1 Trial

This trial was a placebo-controlled, double-blind, and randomized investigation. Its aim was to evaluate the safety, pharmacokinetics, pharmacodynamics, and tolerability of one dose of the Belcesiran therapy. Doses ranging from .1 mg/kg to 12 mg/kg were evaluated in comparison to placebo in 30 different healthy volunteers. AAT levels were measured using nephelometry assay. Spirometry and diffusion capacity of DLCO were also measured. Every patient completed their full 57 day treatment.

The researchers found that serum AAT was reduced when patients were treated with belcesiran. The results have also reaffirmed the regimen of dosing which has already been established for the Phase 2 ESTRELLA investigation.

Here are some of the most notable findings.


  1. Dose-dependent reductions in the serum AAT (up to 6 mg/kg) were found after one singular dose of the treatment.
  2. Doses of 6 mg/kg and 12 mg/kg achieved a very similar result.
  3. Maximum reduction of the serum AAT occurred 8 weeks after the treatment was given.
  4. Two participants experienced a reduction of 90%. These individuals both received the 6 mg/kg dose.
  5. No serious AEs were found.
  6. There wasn’t an increase in AEs with increased doses.
  7. Lung function was normal in all patients, regardless of dose.
  8. There were no significant differences in liver function tests or safety tests, regardless of dose.

Results from this trial were recently presented at the AASLD by Dr. Gane. You can view the full poster here.


The ESTRELLA trial is a Phase 2, randomized, placebo-controlled, and double-blind investigation. It aims to evaluate the tolerability, safety, pharmacodynamics, and pharmacokinetics of the belcesiran treatment for AATLD patients.

Patients with PiZZ-type AAT Deficiency will be divided into two cohorts, one which is 24 weeks and one which is 48 weeks.

This trial will have expanded inclusion criteria so that it can include individuals on an augmentation therapy.

You can read more about this treatment and what it could mean for patients here.

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