siRNA on the Precipice as Candidates Reach Beyond the Liver

In March, Alnylam chalked up two FDA approvals, for Amvuttra in transthyretin-mediated amyloidosis and, with Sanofi, Qfitlia in hemophilia A and B. Such approvals have become par for the course for Alnylam, leading multiple other companies—including GSK, AbbVie, Boehringer Ingelheim and Eli Lilly—to follow suit in pursuing therapies based on small interfering RNA (siRNA). And it’s not just the number of companies involved that’s expanding: while all siRNA therapies approved so far target the liver, Alnylam and others are now seeing some success in targeting other organs as well.

The past two years have seen billions of dollars change hands in a bid to be part of this rapidly growing field. In January 2024, for example, Boehringer Ingelheim announced an agreement potentially worth more than $2 billion with Chinese biotech Suzhou Ribo Life Science and its Swedish unit Ribocure Pharmaceuticals to develop siRNA-based treatments for nonalcoholic or metabolic dysfunction-associated steatohepatitis (MASH), a disease expected to afflict 27 million Americans by 2030. And just last month, GSK plunked down $1.2 billion for Boston Pharmaceuticals’ investigational FGF21 analog efimosfermin alfa, also targeting MASH.

“I think the siRNA space, for rare disease predominantly, has been revolutionary in a handful of cases,” said Myles Minter, a senior biotech analyst at William Blair. “And I do think that the large promise of the field to go into broader, more prevalent indications and to get more approvals is largely ahead of us.”

The term RNA interference dates back to a 1998 paper by Craig Mello and colleagues, who found that double-stranded RNA was more effective than single strands in silencing genes with corresponding sequences in C. elegans. The mechanism turned out to also work in mammalian cells, and in 2002, multiple researchers who’d led key studies of the phenomenon, including Mello, teamed up with investors to found Alnylam. It took 16 years to gain FDA approval for the first siRNA drug, Onpattro, for polyneuropathy of hereditary transthyretin-mediated amyloidosis, a rare genetic disorder caused by mutations in the transthyretin (TTR) gene.

One challenge Alnylam faced in the intervening years was in designing siRNAs that could escape degradation within the body for long enough to be effective, explained Vasant Jadhav, the company’s chief technology officer. But the biggest hurdle—one not unique to siRNAs—was getting the nucleic acid payloads where they needed to go. Then, in 2014, Alnylam researchers and their academic colleagues reported that linking siRNAs with a ligand called GalNAc would get them into cells in the liver, but not into other organs.

Onpattro, approved in 2018, is a GalNac-linked siRNA. The drug “was pretty revolutionary at the time,” Minter said, because rather than simply treating symptoms or even slowing the toll of polyneuropathy of hereditary transthyretin-mediated amyloidosis, it elicited functional improvement.

“The way I like to think about siRNA is that it’s a way that you can titrate, so you can dose at a genetic level. And it’s really one of the only modalities that you can do that with,” Minter told BioSpace.

Other therapies followed from Alnylam for hypercholesterolemia (Leqvio, developed and commercialized by Novartis), acute hepatic porphyria (Givlaari) and primary hyperoxaluria type 1 (Oxlumo). Apart from Alnylam and its partners Sanofi and Novartis, the only other company to get an siRNA drug onto the market so far is Novo Nordisk, whose Rivfloza (nedosiran), approved by the FDA in 2023, treats the rare genetic disease primary hyperoxaluria type 1 (PH1).

So far, all of these therapies have targeted processes in the liver—including Amvuttra, which takes aim at cardiac outcomes via knocking down transthyretin (TTR) in hepatic cells. But experts who spoke with BioSpace said that could soon change. “Where we’re starting to see innovation—and it still is early stage, although it looks very promising—is trying to deliver to new tissues,” Minter said. That targeting problem is “the major question in the field that we’re working on right now.”

Andrew Adams, Eli Lilly’s group vice president, molecule discovery and director of the Lilly Institute for Genetic Medicines, echoed this. GalNAc has thus far been a “unicorn” in the field in terms of its specific and safe delivery, and “we have a lot of work to do to open up si[RNA]beyond the hepatocyte, but . . . probably once we crack it is going to be similar to when Alnylam and others initially cracked GalNAc, and you’ll just sort of walk your way down the list of indications in the new tissue that you open up,” he told BioSpace.

“I think probably the most interesting space for the field right now is in delivery to the brain and going after diseases of the brain,” he said, citing Alnylam’s candidate mivelsiran, currently in Phase II for cerebral amyloid angiopathy and Phase I for Alzheimer’s disease. Lilly, too, is pursuing neurodegenerative targets with siRNA, Adams added. Other tissues with promising early data include adipose and lung.

In a March conference presentation, for example, Arrowhead Pharmaceuticals released mouse data on two siRNA candidates devised to reduce body fat while preserving lean muscle mass. One targets hepatic cells’ expression of a gene, INHBE, that is involved in metabolic processes, while the other silences expression of ALK7, a gene needed for fat storage, in lipocytes. Early clinical studies on both candidates have begun.

And last spring, Arrowhead announced interim results of a Phase I/II study of ARO-RAGE, an siRNA that targets lung tissue and silences the receptor for advanced glycation end-products, a mediator of type 2 inflammation. In study participants with asthma, two doses of the candidate reduced serum levels of the target protein by up to 88%, the company reported.

siRNA’s limitations don’t end at targeting. It can’t be used to completely knock out expression of a gene, only knock it down, and it can’t by itself be used against multiple genetic targets, Jadhav noted.

In addition, RNAi can only dial gene expression down, so it can’t be used to directly boost levels of a deficient protein. Researchers have found workarounds for this in some cases, though. Jadhav cited the example of Givlaari, which treats acute hepatic porphyria. “In this metabolic pathway, the heme biosynthesis, one of the enzymes is mutated, and because of that, you have toxic intermediates that build up,” he said. Since siRNA can’t replace the mutated enzyme, the therapy instead targets a different enzyme, GO, that’s upstream of the toxic intermediates, lowering their levels.

siRNA’s successes could pave the way for a more permanent treatment option, Adams said. “Once you’ve generated enough evidence over a long enough period of time in enough patients that getting rid of this protein [via siRNA] has no negative consequences in an adult . . . Probably at that point you start to feel confident to permanently change something, but I think the bar should be and is high for things that people will tolerate permanent genetic changes for,” he said. He raised the example of Leqvio, which targets the enzyme PCSK9 in order to lower cholesterol levels. Verve Therapeutics now has a gene editor targeting the same enzyme in early clinical trials.

Jadhav allowed that gene editing could become a competitor to siRNA in some cases. “I think at the end of the day, any solution . . . biopharma brings for the patients would be great,” he said. “At the same time, we feel that with RNAi, we can achieve [a] durable level of activity and still be reversible. You kind of get the best of both things. So we remain very confident and very optimistic about the future of RNAi.”

Looking ahead, Minter summarized what he sees as the prospects for siRNA: “we’re at the precipice where we’re waiting, but it’s an exciting five to ten years ahead for the field, no doubt.”