- Alnylam said Thursday it halted continuation of proposed liver disease drug ALN-AA based on safety concerns in a Phase 1/2 study, and will shift gears to another compound that is currently preclinical.
- While the drug showed some promise in the treatment of AAT deficiency-associated liver disease, known as alpha-1 antitrypsin, elevated liver enzyme levels were detected. AAT is a rare genetic disorder that causes disease of the lungs and liver, with liver transplant now a standard treatment option.
- The company said it remained committed to developing RNAi therapies, for alpha-1 liver disease, and an analyst said the setback is likely to have limited impact.
The clinical results from the company’s ALN-AAT program showed that the drug was "potent, dose dependent and durable" during trials, Alnylam reported. But after the drug was given to 15 patients, three had higher liver enzymes on blood tests, which could indicate inflammation or damage to cells in the liver. The company therefore halted the trial.
Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation.
The company will pursue a new compound, ALN-AAT02, and a clinical trial application will be filed in 2017, said Akshay Vaishnaw, executive vice president of R&D and chief medical officer at Alnylam in a statement.
"We plan to advance a follow-on molecule in efforts to optimize the tolerability profile for this program," said Vaishnaw in a statement. "We remain committed to developing RNAi therapeutics for alpha-1 liver disease."
The company said it is finalizing selection of the new development candidate, ALN-AAT02, and plans to "rapidly advance this compound towards the clinic."
"While disappointing, we see limited impact on the RNAi platform" since the toxicity is likely specific to the sequence that was tested, said Jefferies’ analyst Gena Wang in a note to investors. Although other factors can’t be ruled out, "it seems more likely that the reported observations are due to the specific siRNA sequence for AAT."
The data was presented at the Oligonucleotide Therapeutics Society meeting in Montreal.