RNA Interference Therapies Could be on the Verge of Success
In the mid-2000s there was a wave of excitement across the pharmaceutical industry: a new discovery about cells that had the potential to transform medicine.
“The world became enamored with this idea because it was very powerful. If you can inject something into a person that can silence only one gene, you can treat an awful lot of diseases that no one could before,” says Christopher Anzalone, chief executive officer of Arrowhead Pharmaceuticals. “It was hyper specific. It was truly a surgical drug.” But just a few years later, the industry that had sprung up around this discovery had “crashed”, he says.
The industry in question is RNA interference (RNAi) therapeutics. RNA, or ribonucleic acid, is the lesser-known cousin of DNA, deoxyribonucleic acid. Scientists discovered RNA’s important function in the expression of genes many years ago. Segments of DNA are copied into something called messenger RNA (mRNA), which is used as a template for the synthesis of proteins. The problem is that if the template is faulty, so is the protein, which can cause many diseases. However, it was not known that a whole other type of RNA is able to shut this process down.
It was found that double-stranded RNA (dsRNA), with a sequence complementary to one encoded by mRNA, targets the mRNA for destruction before it can be used as the template to build a protein. By introducing a small dsRNA molecule into a cell, called small interfering RNA (siRNA), a gene can be effectively silenced. When it was established in 2002 that this process was common to mammals, “it became apparent that this could work as a therapy because all the machinery was already there”, says Mark Kay, a geneticist at Stanford University, in California, who was the first to demonstrate RNAi in mammals.
Investments and disinvestments
A string of new companies and multimillion-dollar investment deals followed. “People got excited that this was going to transform medicine so there was a lot of hype,” says Anzalone.
New companies emerged: Alnylam, one of the first and biggest RNAi companies was founded in 2002; and Dicerna, founded in 2007, hoped to capitalize on the new discoveries in the field. Pharmaceutical corporations such as Novartis Pharmaceuticals, Roche, and Merck, stepped in by investing in the new biotechnology companies.
One of the reasons for all the interest in RNAi was that it has several potential advantages over existing strategies. RNAi takes up residence in the cell where it has a “sort of catalytic mechanism” enabling it to destroy one piece of mRNA after another: “A very low dose can last for a long time,” says Brendan Martin, general manager of Alnylam Pharmaceuticals for the UK and Ireland.
However, bringing RNAi to the clinic has not been quick or easy. The first clinical trial of an RNAi was in 2004, with a study on the potential for siRNAs to treat wet age-related macular degeneration, a common cause of blindness. Despite promising early results, when the candidate progressed to phase III, in 2008, the trial was terminated because of a lack of efficacy. Suspicions were later raised that the strategy could itself cause another form of blindness in certain patients. The company developing the candidate dropped it.
By 2010, two years later, the pharmaceutical industry’s initial optimism was dead. This was when the industry “crashed”, says Anzalone, and it was “because the world realized: actually, this is hard and there’s an awful lot of questions in this brand-new technology that we need to answer.”
A new focus
Bob Brown, chief scientific officer at Dicerna, says that “the biggest hurdle has always been delivery”. In 2010, the idea of using lipid nanoparticles started to gain traction to protect the RNA molecules from degradation and also facilitate their transport across the cell surface. Kay, at Stanford, says that lipid nanoparticles mostly ended up in the liver because it is the organ responsible for first-pass metabolism, and also because liver cells have unique openings that allow large molecules to get close.
This new focus on the liver led to one of the most significant developments in the field when, in 2012, Alnylam made a breakthrough: “having tried to explore a number of different diseases, we cracked the code for getting these molecules into the hepatocytes in the liver and making sure that they remain active there,” says Martin. That ‘code’ is a sugar molecule called N-acetylgalactosamine (GalNAc). GalNAc is the ligand for a receptor present only on the surface of liver cells. Attaching GalNAc to siRNA targets it to the liver and triggers internalization. Alnylam subsequently “rationalized the targets we were looking at back to the liver” and the whole field turned its focus to the liver too.
With some progress being made, by 2014 there was also a shift in the investment landscape.
Now, Alnylam, Dicerna and Arrowhead all have their own patented methods of conjugating GalNAc to siRNA, and between them they have ten drug candidates in clinical trials, but it was the long-awaited announcement of positive phase III results that has really buoyed the field.
In September 2017, Alnylam’s drug, patisiran, was found to be effective and safe for treating a rare genetic disease called hereditary transthyretin (TTR) amyloidosis with neuropathy. The disease stems from a mutation in the protein that transports vitamin A around the body, causing deposits of amyloid in the nerves, heart or eyes, depending on the specific mutation the patient has. Most of the faulty protein is produced in the liver and patisiran is an siRNA designed to silence its production.
“The therapeutic hypothesis was that if you weren’t making any more, if you were turning off the tap that was supplying more and more of this faulty protein, your body would have the chance to deal with some of the amyloid that had deposited,” says Martin.
In all, 225 patients were enrolled in the 18-month study and those who received patisiran saw symptoms of neuropathy improve compared with baseline, whereas patients who received placebo had a worsening of neuropathy. No significant safety concerns were identified. Martin says the results proved the therapeutic hypothesis beyond expectations. Biopsies indicated some clearance of amyloid in the nerves and indicators suggested recovery of function and quality of life. “It’s very unusual in peripheral nerve disease that you can actually see people recover,” he adds.
The drug is currently with the US Food and Drug Administration (FDA) awaiting approval.
RNAi and Alpha-1 Antitrypsin Deficiency (Alpha-1)
Earlier this year, Arrowhead Pharmaceuticals announced that it has dosed the first subjects in a Phase 1 clinical study of ARO-AAT, which is being developed as treatment for a rare genetic liver disease associated with Alpha-1 Antitrypsin Deficiency (Alpha-1).
ARO-AAT is the first clinical candidate to utilize Arrowhead’s proprietary Targeted RNAi Molecule (TRiMTM) technology. The second candidate, ARO-HBV, which is being developed as a potentially curative therapy for patients with chronic hepatitis B virus (HBV) infection, was also on schedule to dose the first subjects in a Phase 1/2 study at the end of March, 2018.
You can learn more about this study here.