Medical studies are crucial players in the journey to develop new and more efficacious treatment options for patients with rare diseases. On June 10, 2021, Vertex Pharmaceuticals Incorporated (“Vertex”) shared positive data from a Phase 2 proof-of-concept study evaluating VX-864 for patients with alpha-1 antitrypsin deficiency (A1AD). Ultimately, the trial reached its primary endpoint: statistically significant plasma functional alpha-1 antitrypsin (fAAT) improvement as compared to a placebo. However, despite this promising data, Vertex has also chosen not to continue VX-864 development moving forward. Though the treatment did prompt a response, Vertex does not believe that the results show the possibility of enhanced clinical benefit. But due to the promising results, Vertex does hope to continue advancing other A1AD treatment options in the future.

VX-864

So what was VX-864? This small molecule alpha-1 antitrypsin modulator was designed to both increase plasma AAT levels and stop AAT from misfiling.

Within the Phase 2 study, researchers evaluated the safety, efficacy, and tolerability of VX-864 for patients with A1AD who also had the PiZZ genotype. Patients received either a placebo or 1 of 3 VX-864 doses for a 28-day period, followed by a 28-day follow-up. Findings from the study included:

• VX-864 was relatively safe and well-tolerated. Most adverse reactions were mild or moderate, and no patients discontinued due to adverse reactions. Common side effects included diarrhea and nausea.
• Upon treatment, VX-864 increased fAAT levels by an average of 2.3 micromolar and antigenic AAT by up to 3.5 micro molar.

Alpha-1 Antitrypsin Deficiency (A1AD)

SERPINA 1 gene mutations cause alpha-1 antitrypsin deficiency (A1AD), an inherited condition that increases the risk of liver disease, chronic obstructive pulmonary disease (COPD) and other pulmonary issues, skin problems, and vasculitis. Normally, SERPINA 1 encodes for the production of alpha-1 antitrypsin, which protects against neutrophil elastase. The body typically releases neutrophil elastase in response to infection. However, in patients with A1AD, the lack of alpha-1 antitrypsin allows neutrophil elastase to attack body tissues. Abnormal or misfolded alpha-1 antitrypsin also becomes trapped in the liver, causing damage. An estimated 10% of infants and 15% of adults with A1AD develop liver disease. Additionally, lung disease symptoms often manifest between the ages of 20-50. A1AD symptoms, across all areas affected, include:

• Exercise intolerance
• Fatigue
• Increased heart rate upon standing
• Jaundice (yellowing of the skin and eyes)
• Elevated liver enzymes
• Wheezing
• Dark urine
• Shortness of breath and/or difficulty breathing
• Abdominal distention
• Frequent or recurrent respiratory infections
• Bleeding from the nose or umbilical stump (in infants)
• Swollen hands and feet
• Painful skin lesions or lumps under the skin
• Pruritus (extreme itching)
• Unintended weight loss
• Liver enlargement and/or inflammation
• Barrel-shaped chest (if emphysema develops)
• Harsh, hacking cough (if emphysema develops)