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RNAi Therapeutics, from Possibility to Patients

September 12, 2024

Drug discovery and development is extraordinarily difficult. In fact, more than 90% of drug candidates fail to make it to market and patients in need.¹ It’s even more difficult to create a medicine based on new technology for the first time. The biotechnology field is littered with unsuccessful attempts to create new treatment methods, so the rare breakthroughs that lead to a new class of medicines represent a huge leap forward.

The discovery and promise of RNA interference (RNAi)

Scientists first reported a natural process of gene silencing called RNA interference (RNAi) in worms in 1998, and, just three years later, researchers demonstrated that it also plays a role in human cells. This suggested that it could be harnessed to create a new class of medicines. Alnylam was founded in 2002 to deliver on this breakthrough in biology for patients. Success was never guaranteed, and, in fact, the odds of success were exceedingly low.

The initial excitement about RNAi had worn off by 2010, and large pharmaceutical companies—and early investors in the field—exited the space. Inside Alnylam, however, researchers continued to see more and more evidence that their technology was starting to work, and they were determined to persevere.

“Alnylam always kept the science center stage, even if that meant it was going to take longer,” says David Corey, the Rusty Kelley Professor of Medical Science at the University of Texas Southwestern Medical Center and a longtime expert in the field of RNAi. “They solved one tough problem at a time.”

In 2018, the world’s first RNAi therapeutic—and Alnylam’s first commercial medicine—was approved after 16 years of effort. Since then, Alnylam has brought forward multiple medicines, with a robust and rapidly expanding pipeline of investigational RNAi therapeutics across major disease areas. RNAi therapeutics are now at an inflection point—poised to silence additional diseases and provide new treatment options for millions of patients with rare and common conditions.

Silencing genes to treat disease

RNAi therapeutics are a type of “gene silencing” medicine.

Genes contain the instructions for making proteins, which are responsible for almost all cellular and body functions. Sometimes, though, a mutation in a gene results in a faulty protein that causes disease, or a normal gene produces a protein that contributes to disease.

Conventional medicines target these unwanted proteins after they are already made, but RNAi therapeutics act at an earlier step and slow or stop their production. RNAi therapeutics target specific molecules called messenger RNA (mRNA) that tell the body how to make proteins. Through RNAi, the target mRNA molecules are degraded before they can pass their message to the cellular protein production machinery.

“RNAi therapeutics silence disease by attacking the problem one step above standard treatments, which is the reason why this mechanism is so potent. But we don’t make changes to the DNA, which is a key safety feature,” says Kevin Fitzgerald, PhD, Chief Scientific Officer and Executive Vice President of Research and Early Development at Alnylam. And RNAi therapeutics can reduce the levels of unwanted proteins for months, so they can be administered infrequently—every three or six months, for example.

“In theory, Alnylam could design an RNAi therapeutic to silence virtually any gene in the genome,” says Fitzgerald.

Overcoming the greatest challenge

For researchers at Alnylam, the promise of RNAi therapeutics was clear. The challenge was to deliver these powerful medicines to the right cells in the body. Unlike conventional medicines, RNAi therapeutics are composed of large molecules that struggle to get inside of cells. They can also be a target for the body’s immune system, which sees the molecules as foreign invaders to destroy.

To overcome these hurdles, Alnylam scientists started by using lipid nanoparticles, small blobs of fat-like material engineered to carry RNAi therapeutics to liver cells. “When we put our first-generation lipid nanoparticles in humans in 2011, the data were very noisy,” says Martin Maier, PhD, Senior Vice President of Research at Alnylam. “It was hard to see whether the technology was working.” 

Alnylam scientists dug deeper into the results. Amazingly, in one clinical trial participant, there was the tell-tale signature of RNAi activity. “This was a pivotal moment,” Maier says. “We had something real.”

Reinvigorated, Alnylam researchers doubled down. Over the next few years, they significantly improved the lipid nanoparticle delivery system. “We went back to the same patient population and now there was absolutely no question,” says Vasant Jadhav, PhD, Chief Technology Officer at Alnylam. “This was working like a charm.” The system was used in the first approved RNAi therapeutic and, more recently, to deliver the active ingredient (mRNA) of the COVID-19 vaccines.

A versatile delivery solution

But the lipid nanoparticle delivery system has limitations, including that it’s administered via an intravenous infusion—versus a simple vaccine-like injection—and restricted to the liver. Alnylam researchers began work on a more versatile approach. The scientists would need to crack the code of delivering conjugates—small molecules linked to RNAi therapeutics to shuttle them to specific cells or tissues.

Alnylam researchers knew they had to chemically modify the active ingredient of the therapeutic—called siRNA—to ensure it would reach its target without being destroyed. The obstacle was figuring out how, Maier says. “To give you a sense of the magnitude of the challenge, there are about 40 different positions or building blocks in an siRNA that you could modify, and we had many hundred different potential chemical modifications,” he says. “One modification in the wrong place could kill the activity. We had to figure this out iteratively, like solving a huge three-dimensional puzzle.”

They also had to find the right delivery system to shuttle the siRNAs to the right location and get them into the right cells. It took years of effort, but eventually Alnylam’s scientists found a solution and developed proprietary technology for what is now known as the GalNAc conjugate delivery approach. Based on this blueprint for delivery to the liver, Alnylam’s researchers are in the process of systematically unlocking additional tissues to bring RNAi therapeutics to bear in a rapidly growing number of diseases.

Rare to common diseases

Alnylam’s initial aim for RNAi therapeutics was to target rare diseases, which are often caused by mutations in a single gene. Beginning with rare diseases increased the odds of success: effectively targeting a single disease-causing gene means it’s more likely a patient will see a benefit. Plus, because of their rarity, rare diseases often have a high unmet medical need—there are usually few, if any, available treatments—and a well-defined patient population.

This set out a clear path for clinical development, Jadhav says. “You want to help patients who would really benefit from new treatment options,” he says. Alnylam’s first three RNAi therapeutics were approved for the treatment of rare diseases. 

“We like to think these therapies are amplifying the lives of these individuals, who in many cases have been suffering with these rare diseases for years,“ says Fitzgerald.

As the technology was proving effective in rare diseases, Alnylam researchers began to apply it to common conditions, which are generally more complicated. An Alnylam-discovered RNAi therapeutic that lowers cholesterol is now approved for a common type of cardiovascular disease, and Alnylam continues to scale up its technology to apply across rare and common diseases.

“RNAi is leading a silent revolution,” Jadhav says. “Not many people are aware that this is already happening. We have approved treatments, with encouraging safety profiles and limited side effects, for rare and common diseases. This is not some distant dream. The future is here, and RNAi is poised to help many additional patients.”