In the intricate world of molecular biology, oligonucleotides stand out as versatile, powerful molecules. Oligonucleotides are essentially short, single strands of DNA or RNA that modulate gene expression. There are various oligonucleotide therapy (ONT) agents (such as antisense, deoxyribozymes, siRNA and CRISPR/Cas) that offer promising therapeutic tools.A variation of gene therapy, oligonucleotide gene therapies (OGTs) are manufactured using synthetic oligonucleotides. These therapies are designed to enter cells. ONTs act like tools that can fine-tune the behavior of certain genetic instructions, and are therefore often designed to treat rare and genetic diseases and cancers. Sometimes, they may be delivered into cells through lipid nanoparticles or adeno-associated viruses (AAV), halting the translation of a specific protein. Oligonucleotides have also revolutionized vaccine development through the creation of nucleic acid vaccines, such as mRNA vaccines.The first oligonucleotide
drug, known as fomivirsen, was approved by the
US Food and Drug Administration (FDA) back in 1998. It was developed by Ionis Pharmaceuticals (then known as Isis Pharmaceuticals), and was approved to treat a rare eye disease. However, ONT approvals have picked up since 2016. Currently, there are 20 oligonucleotide drugs approved by the FDA and the European Medicines
Agency (EMA) and a majority of them treat orphan and rare
diseases.In 2023, FDA approved four ONTs — AstraZeneca-Ionis’ Wainua (eplontersen), Novo Nordisk owned Dicerna Pharmaceuticals’ Rivfloza (nedosiran), Biogen-Ionis’ Qalsody (tofersen) and Iveric Bio’s Izervay (avacincaptad pegol).In 2021, the global ONT market size was estimated to be US$ 18.2 billion. It is expected to increase to US$ 51.4 billion by 2029, growing at a compounded annual rate (CAGR) of 13.85 percent. Similarly, the market for oligonucleotides synthesis (or the process of producing oligonucleotides) was estimated at US$ 7.7 billion globally in 2022
and is expected to grow 11.8 percent CAGR to reach US$ 16.4
billion by 2030. Some of the bigger players in oligonucleotides synthesis are Danaher Corporation, Thermo Fisher Scientific, Merck KGaA, Eurofins, Agilent, Bio-Synthesis, EUROAPI, Eurogentec, STA Pharma, and Bachem.View Our Interactive Dashboard on Oligonucleotide Therapies (Free Excel Available)ONTs address neuro disorders; four ONTs bring in US$ 1.24 bn for AlnylamONTs are widely applied to treat
neurodegenerative diseases, such as Duchenne muscular dystrophy (DMD). Multiple ONTs have been approved in Europe and the US for
DMD, such as Exondys 51 (eteplirsen), Vyondys 53 (golodirsen), and Amondys 45
(casimersen) from Sarepta and NS Pharma’s Viltepso (viltolarsen). Last year, Ionis bagged two approvals in the
space. FDA
approved its Biogen-partnered
therapy Qalsody (tofersen) to treat patients with amyotrophic lateral sclerosis
(ALS). The agency
also approved AstraZeneca and Ionis’ drug Wainua (eplontersen), rendering it as the
first self-administered treatment for a rare nerve damage
disease, known as hereditary transthyretin amyloidosis (ATTR-PN). Analysts
estimate global peak sales for Wainua to come in at US$ 750
million for ATTR-PN alone. The drug is also being
tested for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), a rare
heart muscle disorder.Alnylam
Pharmaceuticals has also successfully brought four ONTs to market in recent years — Onpattro (patisiran) and
Amvuttra (vutrisiran) for rare
nerve diseases, and Givlaari (givosiran) and Oxlumo (lumasiran). Givlaari has been approved to treat acute hepatic porphyria (a liver enzyme deficiency) while Oxlumo treats primary hyperoxaluria (a disorder characterized by increased urinary oxalate excretion). The four ONTs brought in US$ 1.24
billion for Alnylam in 2023.View Our Interactive Dashboard on Oligonucleotide Therapies (Free Excel Available) Novartis
buys rights to siRNA therapy, GSK bets big on ONT pipeline through dealsAfter Alnylam discovered
inclisiran (Leqvio), Novartis acquired
global rights to the therapy in a US$ 9.7
billion deal. Leqvio was the first
FDA-approved small interfering RNA (siRNA) therapy
for LDL-C (bad cholesterol) reduction. It brought in US$ 355
million for Novartis in 2023.GSK has increasingly
been investing
in its ONT pipeline. The British
pharma has promised over US$ 5 billion in upfront and milestone payments in
multiple deals. In February, GSK exercised
its option to license Elsie Biotechnologies’ discovery platform to find
and develop novel ONTs. GSK has also entered a discovery collaboration with Wave Life Sciences.Last July, Japanese drugmaker Astellas Pharma completed its
approximately US$ 5.9 billion buyout of New
Jersey-headquartered Iveric Bio. Iveric focuses on retinal diseases and the deal gives Astellas drug candidates to treat about 160 million people with eye ailments. Subsequently, in August, Iveric’s Izervay (avacincaptad pegol) was approved by the FDA as a new
treatment for geographic atrophy (GA) secondary to age-related macular
degeneration (AMD).After Novo Nordisk acquired RNAi technology company Dicerna Pharmaceuticals for US$ 3.3 billion in 2021, the latter’s once-monthly RNAi therapy Rivfloza (nedosiran) saw FDA approval last October. Rivfloza was
okayed for children nine years and older to treat a rare genetic condition that affects the kidneys,
known as primary hyperoxaluria type 1 (PH1).View Our Interactive Dashboard on Oligonucleotide Therapies (Free Excel Available) Ionis tees up NDAs for rare
disease treatments after two late-stage trial winsThe industry is looking for cures to a wide spectrum of diseases like cancer (such as melanoma, pancreatic, liver, glioblastoma, breast and ovarian cancer), cystic fibrosis, Alzheimer’s disease, Parkinson’s disease, hepatitis B, asthma, Rett syndrome, non-alcoholic steatohepatitis, and IgA nephropathy through its research on ONTs.In January, Ionis announced late-stage results wherein its
RNA-targeted hereditary angioedema (HAE) candidate, donidalorsen, significantly
reduced the rate of HAE attacks in patients
treated every four weeks and patients treated every eight weeks. The
California-based biotech is readying a new drug application (NDA) to submit to the FDA. HAE is a rare and life-threatening genetic disease that causes unpredictable and frequent severe swelling of the skin, gastrointestinal (GI) tract, upper respiratory system, face and throat. This year, Ionis’ olezarsen was granted fast track designation by
the FDA for the rare genetic disease familial chylomicronemia syndrome (FCS).
Last September, olezarsen had met its primary endpoint of reducing abnormally high
levels of triglycerides in a late-stage trial in patients with the metabolic disorder. Currently, there are no
FDA-approved treatments for this condition. If okayed, olezarsen is likely to
bring in US $849 million in sales for Ionis by 2032.In March, FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 12 to two in favor of the clinical
benefit/risk profile of imetelstat for the treatment of transfusion-dependent (TD) anemia in certain adult patients with myelodysplastic syndromes. The agency assigned a Prescription Drug User Fee Act (PDUFA) target action date of June 16, 2024, for Geron’s NDA for imetelstat. It is among the most anticipated drug launches this year.View Our Interactive Dashboard on Oligonucleotide Therapies (Free Excel Available) Our viewDeveloping ONTs is a field fraught with challenges, such as toxicity and drug delivery. There are safety concerns as well as concerns around delivering the therapy. However, technological breakthroughs and collaborations between pharma firms and contract research organizations that focus on drug delivery are continuously working towards addressing these challenges. All in all, we foresee exciting times ahead for ONTs.
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