A recent large cardiovascular outcome trial of a drug built to lower lipoprotein(a), or Lp(a), reported that it did not reduce heart attacks, strokes or cardiovascular deaths, even though it lowered the inherited risk factor it was designed to hit. The drug, an antisense oligonucleotide, was tested in patients with established heart disease and elevated Lp(a).
That result, a lowered biomarker with no drop in events, moves attention to a newer class of siRNA medicines dosed every few months or less. Their outcome trials are larger and longer, and they will read out over the next few years.
The size of the population at stake explains why developers are willing to wait, with about one in five people worldwide having high Lp(a), according to the American Heart Association. If a long-acting drug prevents events in even part of that population, oligonucleotide output has to move from the kilogram batches that rare-disease programs run on to metric tons a year.
Months Between Doses
Durability has become a design goal in oligonucleotide drug development, and it’s engineered in two steps. Backbone and sugar modifications slow degradation by nucleases, the enzymes that break down RNA, while GalNAc conjugates then carry what survives to the liver, which is why the effect outlasts the injection. Approved siRNAs already run on that design, and their labeled dosing intervals show how far it stretches, from once every three months to once every six.
The outcome trial separated biomarker control from clinical benefit. The drug lowered Lp(a) as designed, while cardiovascular event rates matched the control arm. Long dosing intervals also make the drugs harder to study since they stay active in tissue long after they clear the blood, so a blood test alone can’t tell a developer how much drug is still working or when the next dose is due.
The Math of Making Tons
Most oligonucleotides are still built by solid-phase synthesis, one protected nucleotide at a time, with a wash between steps. A 2021 study in the Journal of Organic Chemistry analyzed eight such processes, and it found they consumed 3,035 to 7,023 kilograms of raw materials for every kilogram of drug, most of it solvent and water.
Those ratios are manageable at rare-disease volumes and punishing at cardiovascular ones. A 2025 review in Pharmaceutical Engineering estimated that one product made at a ton a year would need about 1,000 tons of ultra-dry acetonitrile annually. Even at 99% efficiency per coupling step, the maximum possible yield after 20 cycles is 82%.
Authors of a 2024 review in Science called for new approaches to deliver the “multiton quantities” of oligonucleotides now required. Developers are putting money into enzymatic ligation, which joins shorter fragments, and continuous chromatography to cut solvent use.
Where Yield and Purity Slip
Every incomplete coupling leaves a shorter strand behind, and those truncated sequences are chemically almost identical to the finished product, which makes them hard to remove. Longer, more heavily modified or conjugated molecules widen the impurity profile, adding unconjugated strands, partially conjugated products and linker-related species that all have to be separated out.
The same modifications create new ways for the molecule to degrade in storage, including oxidation at phosphorothioate linkages and depurination, both of which speed up or slow down with pH, buffer and excipients. WuXi AppTec laid out those pressure points in a September analysis of long-acting oligonucleotide development. The company is a contract research, development, and manufacturing organization (CRDMO) that works as an enabling partner to biotech and pharmaceutical innovators across more than 30 countries. Its analysis traced how early choices about sequence, chemical modification and delivery carry into purification, analytical methods, formulation and manufacturing.
“The next chapter of oligonucleotide therapeutics will not be defined by one chemistry, one delivery technology or one mechanism of action. It will be shaped by how effectively the industry connects sequence design with delivery, pharmacology, analytics, safety and manufacturing,” said Yu Lu, senior vice president, WuXi TIDES, part of WuXi AppTec. “As these medicines become more durable, more tissue-selective and more functionally diverse, development infrastructure is no longer simply supporting innovation—is is helping determine which innovations can become viable medicines.”
A Market Built on Capacity
The European Medicines Agency closed consultation in January 2025 on its first dedicated guideline for developing and manufacturing oligonucleotides. The draft covers characterization, specifications and analytical control a commercial process has to satisfy, and it hasn’t been finalized.
Demand is building ahead of those rules, with research firm MarketsandMarkets projecting that the oligonucleotide contract development and manufacturing market will grow from $3.88 billion in 2026 to $11.14 billion by 2031. Process and analytical questions that once waited for late development now arrive with the first candidate chemistry because the modification pattern that stretches a dosing interval also decides which impurities a commercial process has to control.
The outcome trials still running will decide whether twice-yearly or single-dose oligonucleotides earn a place in routine heart care. If they do, the next test takes place in the plant: making a molecule that lasts for months by the ton, batch after batch, at the purity regulators expect.
People also ask
What causes low yield in oligonucleotide synthesis?
Each coupling step in solid-phase synthesis falls slightly short of complete, so losses compound with sequence length and leave shorter sequences behind. Even at 99% efficiency per step, the theoretical maximum after 20 cycles is 82%, before any purification losses.
How are long-acting oligonucleotides designed to last for months?
Developers pair backbone and sugar modifications that resist degradation with targeting ligands such as GalNAc, which concentrate the drug in the tissue where it acts. Activity can persist in tissue after blood levels fall, so dosing intervals are set from tissue and pharmacodynamic data rather than plasma levels alone.
What causes stability problems in oligonucleotide formulations?
Common pathways include backbone cleavage, oxidation at phosphorothioate linkages and depurination. Formulation pH, buffer, excipients and temperature affect how quickly each one proceeds, and forced-degradation studies identify them early.
