About six months ago, pharmaceutical company Takeda pledged $300M towards developing Arrowhead Pharmaceuticals’ (“Arrowhead”) ARO-AAT, an RNA-silencing treatment for patients with alpha-1 antitrypsin deficiency (A1AD). According to Fierce Biotech, the therapy has shown promise in reducing A1AD-associated fibrosis.

ARO-AAT

According to Arrowhead:

ARO-AAT is designed to knock down the hepatic production of the mutant alpha-1 antitrypsin (Z-AAT) protein, the cause of progressive liver disease in AATD patients. Reducing production of the inflammatory Z-AAT protein is expected to halt the progression of liver disease and potentially allow it to regenerate and repair.

In a Phase 2 clinical trial, ARO-AAT showed promise for patients. Altogether, 16 patients enrolled. During the trial, the patients were separated into two distinct cohorts. In the first cohort, patients received at least 3 ARO-AAT injections. Alternately, those in the second cohort received at least 5 ARO-AAT injections. If patients so chose, they were also allowed to receive another 8 doses, spaced out with about 12 weeks (3~ months) in between. From this clinical trial, researchers determined:

• 80% of patients in Cohort 2 saw fibrosis reduction after 48 weeks (11~ months). The remaining 20% of patients had no fibrosis progression.
• ARO-AAT also significantly reduced Z-AAT proteins within the liver (in both cohorts).
• In Cohort 1, 50% of patients had cirrhosis. These same patients saw fibrosis reduction during treatment. The remaining 50% of patients had no fibrosis progression.

Alpha-1 Antitrypsin Deficiency (A1AD)

SERPINA 1 gene mutations cause alpha-1 antitrypsin deficiency (A1AD), an inherited condition which causes low alpha-1 antitrypsin (A1AT) levels. Normally, A1AT protects against neutrophil elastase, an enzyme which plays a role in immune response. When A1AT levels are low, this enzyme can mistakenly attack and damage body tissues, such as the lungs. Outside of the lungs, patients with A1AD have abnormal A1AT accumulation in their liver, causing further damage. An estimated 1 in every 1,500-3,000 people with European ancestry inherits A1AD. Symptoms vary in severity and appearance.

Patients who develop A1AD-related lung disease usually see symptom onset between 20 and 50 years old. These include:

• Shortness of breath/difficulty breathing
• Exercise intolerance
• Fatigue
• Wheezing or a harsh, hacking cough (if emphysema develops)
• Emphysema
• Unintended weight loss
• Rapid heart rate upon standing
• Frequent and recurrent respiratory infections

For those who experience skin problems associated with A1AD, symptoms include:

• Panniculitis
  • Note: This condition causes skin lesions, as well as hard and painful lumps under the skin.

Finally, patients with A1AD are at risk of developing liver disease. An estimated 10% of infants with A1AD, and 15% of adult patients, experience symptoms such as:

• Jaundice (yellowing of the skin and eyes)
• Abdominal distention
• Swollen hands and feet
• Pruritus (intense and chronic itching)
• Elevated liver enzymes
• Cirrhosis (liver scarring)
• Dark urine
• Increased risk of liver cancer