L.In one month, the U.S. Food and Drug Administration approved Lumasiran (Oxlumo), a drug used to treat a rare genetic disorder known as primary type 1 hyperoxaluria. PH1 causes the liver to overproduce a substance known as oxalate, which can build up in the kidney and urinary tract and cause a variety of effects, including kidney stones, widespread organ damage, and end-stage kidney disease.
The only cure for PH1 is a liver transplant. Lumasiran, developed by Alnylam Pharmaceuticals of Cambridge, Massachusetts, is the first drug to lower oxalate levels in patients, reducing the risk of complications in later life. “This is truly the first treatment that can medically treat the underlying effects of this disease,” says Jeffrey Saland, a pediatric nephrologist at Mount Sinai Hospital in New York and a researcher on ILLUMINATE-A, one of Alnylam’s Phase 3 studies with Lumasiran. It is also only the third drug of its kind to receive regulatory approval.
Lumasiran uses a naturally occurring process known as RNA interference (RNAi) that hijacks the production of specific proteins by silencing mRNA, the genetic blueprints for proteins. The drug reduces oxalate production in the liver by blocking mRNA that codes for glycolate oxidase, an enzyme involved in oxalate synthesis, with a fragment of double-stranded RNA known as small-interfering RNA (siRNA).
The regulatory approval of another drug, which the FDA is expected to announce this month, would mark another milestone: RNAi’s first success in treating a common disease.
There were two Phase 3 clinical studies for Lumasiran – ILLUMINATE-A, a multinational, randomized, placebo-controlled study involving 39 patients aged six years and older, and ILLUMINATE-B, an open-label study involving 16 patients aged six and under. Patients in both studies had functioning kidneys. In the first study, they received three monthly injections, followed by a maintenance dose every three months, while in the second study, the dosage regimens were adjusted according to the patient’s weight.
After six months of treatment, Lumasiran significantly lowered oxalate levels in both studies: In the first study, patients receiving the drug had an average of 65 percent reduction in urine oxalate compared to a 12 percent reduction in the control group. The patients in the second study showed an average decrease of 71 percent. No significant changes in renal function or other clinical results were observed during this period (apart from early signs of improvement in nephrocalcinosis, the level of calcium deposits in the kidneys). The company plans to continue monitoring patient outcomes in an expanded, open study. The most common side effects were reactions at the injection site, which included symptoms such as redness, pain and swelling.
There are two other FDA-cleared RNAi therapies, both of which are owned by Alnylam. Patisiran (Onpattro), an RNAi treatment for a rare genetic disorder that causes the nervous system to build up the protein transthyretin known as hereditary transthyretin amyloidosis, was approved in 2018. The second drug, givosiran (Givlaari), for acute liver porphyria, a rare genetic disease that leads to the formation of toxic polypyrin molecules, was approved in 2019. All three drugs are expensive – lumasiran, for example, costs $ 493,000 per patient per year, and patients will likely need to take the drug for life to keep oxalate levels low.
From the initial discovery of RNAi, it took two decades for the first treatment with this technology to overcome government scrutiny, and the field faced numerous obstacles and setbacks along the way. The approval of a third RNAi therapeutic “is a major milestone for the RNAi field,” said Derek Dykxhoorn, molecular geneticist at the University of Miami. “We’ve always seen the potential of this technology – the ability to use the cells’ endogenous silencing mechanisms to treat disease – but it has been a long way from these studies to actually FDA-approved therapies.
More than 20 years ago, the biologists Andrew Fire and Craig Mello discovered the RNAi process in roundworms Caenorhabditis elegans– a groundbreaking discovery that earned the couple the 2006 Nobel Prize in Physiology or Medicine. The result also aroused great interest among researchers in the early 2000s who wanted to use RNAi as a technique for basic research and the development of therapeutics.
Since RNAi could theoretically target the production of a disease-causing protein – as long as the sequence of the gene that codes for it is known – scientists began studying it as a weapon against a variety of diseases, including rare genetic disorders and cancer and infectious diseases.
Despite a flurry of research, early clinical trial results have been disappointing; Because of the low effectiveness and harmful side effects, treatments could not progress very far. One of the first treatments to make it into a phase 3 clinical trial – an RNAi therapeutic for macular degeneration from Florida-based company OPKO Health – was discontinued in 2009 after disappointing early results. As of 2010, pharmaceuticals turned away from this technique, and large companies like Roche, Pfizer, and Merck closed their RNAi research programs. The independent biotech consultant Dirk Haussecker described this period opposite The scientist 2014 as the “Era of Doubt and Despair”.
RNAi therapies with targets outside the liver have not gotten very far in clinical trials.
The main roadblock to the field was figuring out how to deliver siRNAs to the right cells in the body in high enough concentrations to be therapeutically relevant, says Dykxhoorn. A key problem is that siRNAs are easily broken down by enzymes in the bloodstream. To address this problem, scientists focused on identifying ways to package siRNAs. One of the first effective techniques was to coat them with fat droplets called lipid nanoparticles (LNPs). But those LNPs had their limits, says Phillip Zamore, director of the RNA Institute at the University of Massachusetts Medical School and co-founder of Alnylam. One drawback, he explains, was that while the LNPs would accumulate in the liver because a lot of blood – carrying the RNAi payload – flows through them, they did not explicitly target that organ. What the researchers wanted, however, was a highly selective method of delivering the drug to tissue.
Alnylam developed another technique called GalNac, in which a sugar, N-acetylgalactosamine, is attached to the siRNA. Receptors on the surface of liver cells recognize N-acetylgalactosamine and allow the conjugated molecules to reach these cells with a high degree of specificity while limiting the off-target effects. Many of Alnylam’s therapeutics, including Lumasiran, use this technology. Because of this, treatments for liver disease were the first to advance clinically. “It is now clear that everyone has a strategy in which a ligand is conjugated to an siRNA to bring it to the tissue of interest,” says Zamore. “It works incredibly well for the liver.”
With new, effective delivery methods, the RNAi field finally began to see some success, namely the three approved drugs from Alnylam. Another Alnylam therapeutic is nearing the end of the pipeline: Inclisiran, an RNAi treatment for high cholesterol that inhibits the production of PCSK9, an enzyme involved in cholesterol metabolism, in the liver. (Alnylam developed Inclisiran, but drug company Novartis licensed it.) The drug’s regulatory approval, which the FDA is expected to announce this month, would mark another milestone: RNAi’s first success in treating a common disease.
“I think anyone who follows this area is sure it will be approved,” said Judy Lieberman, a professor of pediatrics at Harvard Medical School who studies the use of RNAi in cancer and infectious diseases. “The third phase data is incredibly strong.” (Lieberman is a former member of Alnylam’s Scientific Advisory Board.)
Alnylam’s successes show that RNAi has become a platform technology, says Zamore. “We now know that it is possible to develop a global strategy that can be applied to any disease where decreasing the concentration of something in the liver has clinical benefit.” Other biotech companies like Dicerna Pharmaceuticals and Arrowhead Pharmaceuticals also have several RNAi drugs in their pipelines.
Expansion beyond the liver is the next big test. According to Lieberman, RNAi therapies with targets outside the liver have not made progress in clinical trials. The GalNac technique is specific for liver cells. To get to other organs, researchers need to find methods that can similarly target other tissues. Many groups, including Liebermans, are developing and testing various methods of delivering siRNA to other tissues, such as attaching antibodies and aptamers, which, like GalNac, are recognized by cell surface receptors unique to certain tissues, or by using lipid conjugates at home certain tissues.
In addition to several other drugs in the pipeline for liver diseases, including other genetic and infectious diseases such as hepatitis B, Alnylam also has therapies in development with targets outside the liver. The company is also currently focused on developing RNAi treatments that work in the central nervous system and eye, says Pritesh Gandhi, vice president and general manager of Alnylam’s Lumasiran program.
“There is much more to come,” says Gandhi. “This is just the beginning.”