Oral Pill May Make Tough-to-Deliver RNAi Drugs Go Down Easy, RXi Says
Everywhere he goes in biotechnology circles, RXi Pharmaceuticals’ CEO Tod Woolf hears the same criticism of RNA interference drugs. What can be done to overcome the challenge with drug delivery?
The answer is, nobody knows until it’s been proven with an effective drug. But Worcester, MA-based RXi (NASDAQ: RXII) says it has obtained the exclusive right to technology from the University of Massacusetts Medical School which could hold the key for the first way to deliver these drugs through the mouth.
The problem of how to deliver RNA interference drugs has been around since the technique was co-discovered a decade ago by one of RXi’s founders, UMass researcher Craig Mello. These drugs are thought to have the advantage of being able to specifically hit targets on cells that other drugs can’t, and to get at the genetic root cause of disease. The problem is that small interfering RNA drugs can get chewed up by enzymes in the body, or flushed through the kidneys into the urine long before they ever get to the diseased cells, Woolf says.
Other companies, like Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY) are packaging the RNAi molecules along with other materials, like polymers, fat droplets called liposomes, or nanoparticles that will make them stable long enough in the blood to do their business, Woolf says. Researchers have also tried localized delivery to tissues like the lungs, a joint, or the eyes.
“A lot of people talk about delivery, delivery, delivery,” Woolf says. “We’ll all be working on this for the next 20 years.”
There doesn’t appear to be one silver-bullet answer for drug delivery. Woolf says RXi now believes the best delivery method will vary from tissue to tissue, disease to disease.
In RXi’s case, it is testing out an oral pill in animals that could work for inflammatory diseases like rheumatoid arthritis, asthma, Crohn’s disease, psoriasis, atherosclerosis, and Type 2 diabetes. This approach is unusual, because most companies have long believed oral delivery of RNA interference drugs was impossible, Woolf says.
One of RXi’s founders, Michael Czech, and a collaborator at the UMass Medical School, Gary Ostroff, believe they have found a “special trick” to make oral delivery work. The researchers have packaged an RNA interference molecule with a beta-glucan particle that disguises it to look like yeast to the body. Once the package goes through the digestive tract, surviving powerful stomach acids, it comes into contact with transporter proteins in the lining of the gut that carry it across the tissue membrane, where it comes into contact with macrophage cells. These cells, which play a role in inflammation, gobble up the cloaked form of the drug, which can then send signals internally to decrease activation of the macrophages.
It’s possible that this technique could be used to decrease the production of a particular inflammatory protein called TNF alpha. That holds big business potential, because some of the world’s best-selling drugs, like Amgen’s etanercept, Johnson & Johnson’s infliximab, and Abbott Laboratories’ adalimumab (Humira) are injectable biotech drugs that block this protein. No one has been able to develop an approved version in an oral pill.
This work still has a lot to prove before outsiders will get too excited. Much work needs to be done before one of these oral RNAi drugs can even make it to clinical trials. Woolf is undeterred. “We have an advantage with delivery of orally available RNAi therapeutics,” he says. “It’s one of the most exciting programs in the field of RNAi.”