Drug services providers gird for an oligonucleotide surge

Late last year, GSK announced a deal putting Wave Life Sciences’ oligonucleotide discovery and development platform to work on drug targets identified by GSK. Licensing one of its key drugs in development to GSK, Wave got $170 million and could get more.

The 4-year deal is a big one for GSK, which has three oligo drug candidates in Phase 2 studies for hepatitis B. It’s even bigger for Wave. And it’s just one of several recent pacts highlighting the rapid rise of oligonucleotides for therapeutic as well as genetic research applications.

Although Wave is an exception, most drug discovery firms can't manufacture oligonucleotides in the volumes and purities needed for human pharmaceutical use. But most of the companies that can have announced significant expansions over the last year in response to an anticipated surge in demand for the short DNA and RNA molecules.

Powered by recent advances in the chemistry of oligo production, that surge is arguably well under way. The number of oligonucleotide drug approvals by the US Food and Drug Administration has shot up, from just three between 1998 and 2013 to a dozen beginning in 2016.

Oligonucleotides are nucleic acid strings synthesized by linking phosphoramidites. They are the basis of therapies with names like antisense and small interfering RNA (siRNA) that work by silencing or promoting the degradation of target RNA. Oligos can also bind to target RNA and modulate its function, a mechanism called splicing. And oligonucleotides can edit adenosines in RNA to affect the function and production of proteins.

While the first wave of oligo therapies some 20 years ago addressed orphan diseases with limited patient populations, technology advances have opened the field to indications with huge patient need, such as central nervous system (CNS) disorders and cancer.

“We’re hitting a golden time,” Wave CEO Paul Bolno says. “What you are seeing is oligonucleotides and RNA therapeutics in general are now just like small molecules and antibodies—like a formal class of commercially viable medicines.”

Several well-established oligonucleotide manufacturers are expanding to meet current and future demand from drug firms like Wave and GSK.

Agilent Technologies entered the oligo arena in 2006 with the acquisition of Synpro in Boulder, Colorado. Two years later, it acquired Dow’s oligo business and moved it to Colorado, making several expansions in Boulder before eventually opening a second site, in Frederick, Colorado, in 2019.

The company announced a $150 million doubling of capacity in Frederick in 2020 and a $725 million project that will double capacity again earlier this year. “I don’t think this is the end,” says Brian Carothers, vice president of Agilent’s nucleic acid division, of the steady increases in capacity.

He says the oligo field has evolved significantly since Agilent entered it. “A lot has had to do with technical improvements and trying to understand how to get the active ingredient in the place where it does the work.” He points to the development of techniques employing N-acetylgalactosamine (GalNAc), a complex sugar that disguises the oligo and allows it to enter a cell.

“That evolution has exploded this environment,” Carothers says, and led to oligos that enter the liver and to research on drugs for cancer and CNS diseases. The use of oligonucleotides as guide RNAs in CRISPR gene editing has fostered another stream of investments across the oligo supply sector, he adds.

Agilent supplies oligos to Alnylam Pharmaceuticals, a pioneer in oligonucleotide therapies. Four of the five commercialized oligo active ingredients that Agilent supplies are for Alnylam drugs. The fifth was developed by Alnylam and acquired by Novartis in 2020.

Bachem, a supplier of pharmaceutical peptides for decades, began work on oligos in 2018. Daniel Samson, Bachem’s head of oligonucleotides, says manufacturing synergies between the two “tides” gave the company a running start on oligonucleotides.

Last year, Bachem announced it would spend about $760 million to build a third peptide and oligonucleotide plant in Switzerland. The company is already spending about $560 million to expand an existing facility in Bubendorf, Switzerland.

According to Samson, Bachem was among the first drug services firms to invest in large-scale oligo production capacity and was the first to install continuous chromatography for purification.

Sustainability is emerging as a frontier for innovation in oligonucleotide production, Samson says. Building on industry-standard solid-phase synthesis, Bachem is using stirred-bed reactors that eliminate the need for pumping reagents through reactor columns and thus reduce solvent and energy use. “It’s at least equal or superior in terms of quality,” Samson says. “And it’s scalable, almost infinite.”

Another player, BioSpring, recently announced the purchase of 40,000 m² of land in Offenbach, Germany, where it plans a major increase in capacity. The company produces oligonucleotides at multihundred-kilogram scale for early-stage drug development and commercial supply at a plant in Frankfurt, Germany, and will be able to produce at metric-ton scale in Offenbach.

BioSpring chief scientific officer Hüseyin Aygün says the company is expanding to accommodate projects as they advance from discovery to the clinic and commercialization. There will also be an increasing number of new projects requiring larger-scale manufacturing capacity, he says.

In addition, BioSpring supplies the gene-editing sector with guide oligos, which require complex chemical processing, Aygün says. While antisense and siRNA therapeutics average between 16 and 20 nucleotides in length, guides for gene editing require up to about 100 nucleotides.

BioSpring is working with solution-phase chemistry in some postsynthetic conjugation applications—to attach GalNAc to oligonucleotides, for example. But the company sees solid-phase manufacturing as the best way forward for producing oligonucleotides, Aygün says.

Whereas firms like BioSpring and Bachem are specialists, WuXi AppTec is the rare pharmaceutical services generalist to be involved in oligos. It began producing oligonucleotides in 2017 and entered a synthesis collaboration with Regulus Therapeutics the following year.

WuXi recently formed a division, WuXi Tides, that combines peptide and oligonucleotide services. The group will coordinate services from discovery to finished drug manufacturing at four sites in China. WuXi plans to spend $1.5 billion over the next 10 years on a new site in Singapore that will include oligonucleotide synthesis, and it is building a complex in Middletown, Delaware, that will formulate finished oligo drugs. The company also plans to put a fifth oligo site in China.

“This market has a huge potential,” says Yu Lu, head of the Tides division.

Lu says WuXi’s strength in conjugation chemistry benefits its oligonucleotide customers. “At our Changzhou site we have a small-molecule team, oligonucleotides, and peptides, so we can handle all these different styles of conjugation chemistry—oligonucleotides conjugated with peptides or lipids, carbohydrates, fluorescent dyes.”

Another oligo producer, Nitto Avecia, is adding a second plant at its site in Milford, Massachusetts. It expects the $190 million expansion to come on line later this year. The company also has plants in Cincinnati and Irvine, California.

The new capacity will be geared toward later-stage, larger-volume production, according to Tammy Cooper, Nitto Avecia’s vice president of business development. As oligos move into large-population indications, they will be going up against small-molecule and biologic alternatives, Cooper notes. “The cost of goods is going to be key for the success of oligos,” she says. “So we have increased the scale so that you can get more output for the time that you’re in the plant.”

Suppliers are also developing technology to accommodate innovations from their drug industry customers.

Oligo Factory, which launched in 2006 to serve customers with projects in early-stage development, recently opened a 1,200 m² manufacturing facility in Holliston, Massachusetts. Around the same time, the company received an undisclosed amount of investment from firms including Research Corporation Technologies and BroadOak Capital Partners.

CEO Chris Boggess says Oligo Factory emphasizes cost-effective supply and tailoring oligonucleotides to novel applications. “Since the inception of the company, we have built our own instrumentation and our own software and used our own engineering expertise,” he says.

Boggess sees a lot of room for innovation. “I got three calls yesterday—a preclinical therapeutics company, a diagnostics company, and a life science tools company,” he said recently. “All three want oligonucleotides that have never been made in the history of oligo synthesis. And we can say, ‘This is what you can expect from us.’ ”

A lot more innovation is expected. “Oligonucleotides are at an early stage,” despite the rising number of drug approvals, says John Lepore, senior vice president and head of research at GSK. “I think the field will markedly open up when we crack the ability to deliver oligos to organs like the kidney, lung, and heart.”

Agilent’s Carothers acknowledges the potential for further growth. “We are trying to stay a few steps ahead,” he says. “As our new facility comes on line in the late 2026 time frame, I expect we will be in design work” on further expansion.