Work advances on drug for hepatitis B the rare disease alpha-1 antitrypsin deficiency.
The silencing technique called RNA interference (RNAi) is being used in clinical trials in Europe, Asia, and the United States against hepatitis B (HBV).
The technique was shown to be effective using technology licensed from the Wisconsin Alumni Research Foundation. Arrowhead Pharmaceuticals is in the midst of a private stock offering aimed at raising $45 million to advance the HBV drug, and another at treating the rare disease alpha-1 antitrypsin deficiency.
“Our strategy is to use RNAi to decrease the production of the viral proteins that weaken the immune system, allowing it to recover to the point that it will be able to clear the virus like it does in the other 90% of people who became infected,” said David Lewis, chief scientific officer at Arrowhead Pharmaceutical’s research facility.
RNAi was discovered in 1998, and many had high hopes that it could fight disease by shutting down the problematic genes. However, this proved difficult to achieve, and so far there are no FDA approved RNAi medications available, but there are 2 investigational drugs in the final phase of clinical trials.
During the early development of RNAi, the short strands of RNA that were injected into the body were usually excreted and produced no real benefit. The result was a “very expensive pee,” Lewis said.
However, things seemed to change in finding a strategy for RNAi when researchers invented a system to connect the strand of RNA to a molecule that could latch onto liver cells. The silencing technology seemed to hold a lot of promise, and persuaded the pharmaceutical company Hoffmann-La Roche to buy Mirus’ RNAi division in 2008.
However, within 3 years Roche decided to sell the business to Arrowhead. Lewis first learned about RNAi while working in UW-Madison geneticist Sean Carroll’s laboratory.
“Sean wanted to know how genes used in the butterfly wing could make different patterns, and so he wanted to manipulate where the genes are expressed,” Lewis said. “I expressed these genes in the wrong places, or knocked them down with RNAi to see their effects.”
Arrowhead is also in the process of developing other RNAi drugs, including medications for a cardiovascular condition. However, most of the effort is going towards phase 2 trials for HBV.
“Every country has its own regulatory requirements, and it’s truly a massive effort to file all those applications in over a dozen countries,” Lewis said.
Lewis noted that the HBV drug is undergoing testing at different dosing schedules and sometimes in combination with other antiviral drugs.
“This drug will not, by itself, clear the virus,” Lewis said. “That’s the job of the immune system. Even if they still have viral DNA hiding somewhere, now the immune system can recognize a cell that produces viral antigens and destroy it.”