Liver involvement in alpha-1 antitrypsin deficiency: First treatment option in sight

Pavel Strnad and members of his team: Moritz Kleinjans, Barbara Burbaum, Samira Amzou

Alpha-1 antitrypsin deficiency can affect many organ systems, most notably the liver and lungs. For lung involvement, augmentation therapy is a proven treatment option because the lungs are primarily damaged by the protein deficiency. The liver is affected by the excess of misfolded alpha-1 antitrypsin. Until now, there have been no therapies for this, apart from liver transplantation as a last resort.

Thanks to medical and biological advances in recent years, several therapeutic approaches have been developed to correct the excess of misfolded AAT in the liver. One approach focuses on promoting the elimination of the altered protein from the liver, while another aims to inhibit the production of this potentially harmful protein. While there is currently no evidence of efficacy in humans for the first approach, Promising data on the second one were recently published. This approach uses a so-called siRNA (small interfering RNA) and therefore does not alter human genetic information, also known as DNA, but acts at a level below. Protein production involves several steps. One of these is the production of an RNA molecule, which represents the working copy of the DNA and is used directly for protein synthesis. With siRNA, the reading of a specific RNA molecule can be prevented: siRNA therapeutics are therefore considered a new secret weapon in the fight against genetically inherited diseases. The first siRNA-based drug was approved in 2018, and another therapeutic followed this year. The first inhibits the production of a mutated protein called transthyretin in the liver, which otherwise leads to congenital transthyretin amyloidosis; the second suppresses enzyme production that leads to acute hepatic porphyria. In both cases, the siRNA is primarily taken up by liver cells.

Since summer 2019, Arrowhead has been conducting two comparable studies investigating the efficacy of alpha-1 antitrypsin-specific siRNA in patients with liver involvement and severe alpha-1 antitrypsin deficiency. Currently, only Pi*ZZ patients without significant lung involvement are being enrolled in the study; patients with more severe symptoms will be examined at a later date. The first data from these studies were recently published in a press release. The four patients described who have already completed the study were all treated at Aachen University Hospital. Recruitment was carried out in close collaboration with Alpha1 Germany and Alpha-1 Plus Belgium. The investigational drug was administered subcutaneously, directly under the skin, similar to a vaccination or thrombosis injection. Patients received three doses at intervals of four and twelve weeks. A liver biopsy was performed at the beginning of the study and again 24 weeks after the start of therapy, and regular blood tests were also conducted. After 24 weeks, the amount of alpha-1 antitrypsin in the subjects was reduced in both serum (by up to 931 TP3T) and liver (by up to 951 TP3T). In three out of four patients, the amount of already polymerized alpha-1 antitrypsin in the liver was also reduced, with the maximum reduction reaching 971 TP3T. All subjects showed a decrease in the established liver damage markers ALT and GGT. Liver stiffness, used for the non-invasive assessment of liver scarring, decreased in all study participants. No relevant pulmonary side effects were reported, and all patients opted for the offered extension of therapy after completion of the initial 24-week study. Although this is very early clinical data, further development and marketing of the product are already being considered.