How many FDA approved Oligonucleotide are there?

Introduction to Oligonucleotide Therapeutics

Definition and Basic Concepts

Oligonucleotide therapeutics are a unique class of drugs based on short synthetic nucleic acid polymers. Unlike traditional small molecules that must fit into protein binding pockets or large biologics that often target extracellular proteins, oligonucleotides work on the principle of Watson–Crick base pairing. They modulate gene expression by binding directly to complementary sequences in messenger RNA (mRNA) or pre‐mRNA; the binding can promote degradation of the target RNA, block its translation, or modify splicing events. There are several classes of oligonucleotide drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNA mimics or inhibitors, and aptamers. These agents are typically chemically modified to overcome inherent challenges such as enzymatic degradation, limited tissue uptake, and off‐target effects. For example, backbone modifications like the phosphorothioate linkage and sugar modifications like 2′-O-methoxyethyl (2′-MOE) or locked nucleic acid (LNA) are standard approaches that improve metabolic stability and binding affinity.

Overview of Oligonucleotide Therapeutics

Owing to these chemical innovations, oligonucleotide therapeutics can now reach targets that were previously “undruggable” by conventional pharmaceuticals. This breakthrough has allowed treatment of patients suffering from rare genetic disorders or otherwise intractable diseases. Over the past 30–40 years, significant advances have been made both in the design and the delivery of these compounds. For instance, delivery systems have evolved from simple formulations to ligand-conjugated drugs that direct the therapeutic safely to hepatocytes or to tissues such as the central nervous system. Although the field has matured exceptionally slowly in its early stages, recent clinical successes have ushered in a new era of translational research that is now being extended to a wider variety of indications.

FDA Approval Process

Regulatory Pathways for Oligonucleotides

The approval of an oligonucleotide therapeutic by the FDA follows paths that are sometimes similar to those used for both small molecules and biologics. However, several unique considerations pertain to oligonucleotide drugs. The regulatory agencies now have guidelines that address aspects such as chemical structure, manufacturing controls, pharmacokinetic (PK) properties, and biodistribution. Because oligonucleotides are synthesized using solid‐phase chemistries rather than biological manufacturing processes, the CMC (Chemistry, Manufacturing, and Control) section of regulatory submissions must provide detailed information on synthesis, purification, and quality assurance protocols. Newer delivery technologies such as conjugates (for example, the attachment of N-acetylgalactosamine for targeting hepatocytes) have also required specific assessment by the regulators owing to their impact on tissue uptake and safety profiles.

In addition, because these therapeutics act intracellularly, preclinical studies frequently focus on the efficiency of endosomal escape, systemic exposure, and off-target effects that might result from non-specific immune stimulation. Safety pharmacology evaluations (covering cardiovascular, central nervous and respiratory systems) are tailored to the unique dose–response characteristics of oligonucleotides, with studies undertaken frequently in nonhuman primates to verify effects observed preclinically. Such an approach allows regulatory bodies (like the FDA) to grant accelerated reviews and sometimes even orphan drug or breakthrough designations when the patient populations are small or when the drugs address unmet medical needs.

Key Considerations in Approval

FDA approval does not only mean that an oligonucleotide has demonstrated efficacy—it also means that the product’s bioanalytical group has provided robust evidence of its stability, drug–drug interaction profile, and acceptable reproducibility of its CMC process. Because many oligonucleotide therapeutics are designed for rare, genetic conditions, regulators carefully balance the potential for off-target toxicities against the tremendous clinical benefit they can provide. The inherent ease of synthesis and target selection for oligonucleotides has also meant that a large number of candidates reach clinical evaluation. In many cases, the FDA has required additional pharmacodynamic (PD) biomarkers to prove that the drug is acting on its intended RNA target, even if clinical efficacy endpoints may be challenging to measure. Thus, the key factors in the approval process for oligonucleotides include demonstrating on-target engagement, favorable PK/PD profiles, and establishing a clear link between target silencing and clinical improvements.

Current FDA Approved Oligonucleotides

List and Number of Approved Drugs

When addressing the question of “How many FDA approved Oligonucleotide are there?”, various materials from our synapse sources have provided quantitative insights. According to one structured analysis cited from synapse with source reliability noted in, researchers have reported that up to 13 oligonucleotide drugs have been approved by the US Food and Drug Administration (FDA) as of recent evaluations. These drugs include, for example, antisense oligonucleotides such as fomivirsen (the first approved in 1998), mipomersen, eteplirsen, nusinersen, inotersen, golodirsen, and casimersen. In addition, several small interfering RNAs (siRNAs) such as patisiran have also received FDA approval. Some sources have detailed further that in the recent 2023 cycle, nine TIDES (a grouping that includes both peptides and oligonucleotide therapeutics) were approved by the FDA, with four of those being oligonucleotides. Taking these different counts into account—and noting that sometimes the numbers are presented on a combined FDA/EMA basis—the reliable and structured data from our synapse sources (which represent peer-reviewed and industry-accepted publications) support the view that there are approximately 13 FDA-approved oligonucleotide therapeutics to date.

One should note that this number reflects approvals as of a recent cut-off date (for instance, by 2021 for many publications) and that the total may have been subject to change with ongoing clinical advances. Nonetheless, the consensus from trustworthy synapse reports suggests that around 13 oligonucleotide therapeutics have successfully traversed the regulatory process and have been approved by the FDA.

Therapeutic Applications and Indications

The FDA-approved oligonucleotides cover an impressively wide range of therapeutic areas. Their indications include:

• Genetic neuromuscular disorders: For example, nusinersen is approved for spinal muscular atrophy, where it modulates pre-mRNA splicing to restore the production of functional survival motor neuron protein.
• Hereditary amyloidosis: Patisiran, an siRNA therapeutic, has been approved for hereditary transthyretin-mediated amyloidosis by silencing a misfolded protein unique to this condition.
• Familial hypercholesterolemia: Mipomersen is indicated to lower low-density lipoprotein (LDL) cholesterol in patients with this rare genetic disorder.
• Muscular dystrophies: Eteplirsen, golodirsen, and casimersen are approved for subsets of Duchenne muscular dystrophy patients based on specific genomic aberrations that render them amenable to exon skipping techniques.
• Ophthalmologic indications: Although fewer in number in the oligonucleotide space, aptamers such as pegaptanib have been approved for age-related macular degeneration as they block vascular endothelial growth factor (VEGF) signaling.

Each approval has come with tailored requirements that guarantee both safety and target specificity. Notably, the therapeutic applications of each approved oligonucleotide underscore the versatility of the platform—ranging from genetic disorders affecting the neuromuscular system to interventions in metabolic and vascular disease states. The regulatory milestones achieved by these drugs have helped pave the way for further advances in both drug design and delivery methods.

Future Directions and Challenges

Ongoing Research and Development

The field of oligonucleotide therapeutics continues to experience rapid growth. Ongoing research looks to extend the clinical utility of these drugs to additional patient populations, including indications that have hitherto been considered “undruggable.” For example, current clinical programs aim to treat neurodegenerative diseases, certain cancers, and chronic metabolic disorders. Research continues to optimize both chemical modifications and delivery systems that target extra-hepatic tissues. New ligand-conjugated strategies, nanoparticle formulations, cell-penetrating peptides, and even DNA nanostructures are actively under investigation to overcome the long-recognized barrier of efficient cellular and tissue‐specific delivery.

In research domains, the number of candidate oligonucleotide therapeutics far exceeds those that have reached approval. Many compounds exhibit promising pharmacodynamic signals in early‐phase trials, and feedback from regulatory agencies is assisting in fine-tuning dosing regimens and safety evaluations. As method development in quantitative bioanalysis (using LC-MS/MS and hybridization-based immunoassays) continues to evolve, regulators and researchers alike are slowly overcoming the challenge of distinguishing full-length active molecules from their truncated metabolites. Optimized analytical methods, together with innovative clinical trial designs that include novel surrogate endpoints or biomarkers, are playing a significant role in accelerating proof-of-concept studies for these therapeutics.

Challenges in Oligonucleotide Therapeutics

While the success of 13 FDA-approved drugs represents a major milestone, several challenges remain before oligonucleotide therapeutics can fulfill their full potential. One of the central hurdles is the efficient delivery of these large, negatively charged molecules to their intracellular targets in tissues beyond the liver. For example, while GalNAc conjugation has dramatically improved delivery to hepatocytes, similar efficient targeting methods for tissues such as the central nervous system (CNS) and musculoskeletal system are still lacking, meaning that frequent dosing or invasive administration routes (e.g., intrathecal injections) are sometimes necessary.

Another challenge is related to the endosomal escape. After binding and internalization by cells, only a small fraction of the internalized oligonucleotide actually escapes from endosomal compartments to reach the cytosol and execute its function. Although several studies have aimed to elucidate the mechanisms behind this process, quantitative efficiency remains low, which in turn limits the therapeutic window. Furthermore, off-target effects, including immune stimulation, remain a concern. For instance, certain oligonucleotide chemistries such as those with phosphorothioate links have been noted to interact non-specifically with plasma proteins, which can sometimes lead to altered pharmacokinetics or immunogenic responses.

Scaling-up manufacturing and quality control also present challenges. The current solid-phase synthesis methods use large volumes of reagents and solvents and generate significant waste—factors that are contributing to ongoing efforts toward greener, more efficient production techniques. There is also a major push for meeting stringent CMC requirements for oligonucleotides, including understanding the impact of impurities and demonstrating batch-to-batch consistency. These challenges are stimulating extensive industrial and academic collaborations, as evidenced by consortia like the European Pharma Oligonucleotide Consortium (EPOC) which are actively working to harmonize manufacturing processes and regulatory expectations.

Lastly, an additional challenge lies in the assessment of surrogate endpoints and long-term efficacy. Given that many oligonucleotides target genetic pathways rather than measurable biochemical endpoints in the traditional sense, designing clinical trials that effectively capture meaningful benefits (for example, improvements in quality of life or slowed disease progression) continues to be complex. Regulatory agencies require comprehensive data coupling biomarkers of target engagement to clinical outcomes, which increases the complexity and cost of these trials.

Conclusion

In conclusion, based on structured and reliable synapse sources and the analysis of multiple scholarly and industry documents, the current cumulative number of FDA-approved oligonucleotide therapeutics is approximately 13. This figure is derived from a careful examination of the regulatory approvals achieved over the past few decades—which include key drugs such as fomivirsen, mipomersen, eteplirsen, nusinersen, inotersen, patisiran, golodirsen, and others. These drugs span a wide array of therapeutic applications including neuromuscular disorders, hereditary amyloidosis, familial hypercholesterolemia, and even ophthalmologic conditions.

Our discussion started with a concise introduction to oligonucleotide therapeutics that underscored their mechanism of action and the unique modifications that set them apart from other therapeutic modalities. In the next section, we detailed the regulatory pathway for FDA approval and the unique considerations that are applied specifically to these drugs. When looking at the current pipeline, it is clear that the approximately 13 approved drugs are supported by robust evidence of safety and efficacy and reflect an evolving landscape where chemical innovations coupled with advanced delivery technologies have transformed these molecules from experimental therapies to life-changing treatments.

Looking ahead, ongoing research and development aim to resolve remaining challenges such as intracellular delivery, improved endosomal escape, and scalable manufacturing. These efforts—spanning from new conjugation approaches to innovative clinical trial designs—are set to further expand the application of oligonucleotides into new therapeutic areas. The future is promising, yet the field must continue to address these challenges through collaborative research and close regulatory engagement.

Thus, from a general perspective, the field has matured to yield approximately 13 FDA-approved oligonucleotide therapeutics, a number supported by diverse scientific literature and regulatory analyses. From a specific viewpoint, each of these approved drugs exemplifies the cutting-edge innovation in overcoming delivery barriers, safety concerns, and manufacturing challenges. Generalizing further, this milestone not only marks a completed regulatory journey but also paves the way for additional breakthroughs in increasingly complex disease states, promising a future where oligonucleotide-based therapies become even more widespread and effective.

Overall, the advances in oligonucleotide drug development have set a strong foundation for both current successes and future innovations—affirming that while 13 approved drugs stand as a testament to past achievements, ongoing research continues to drive the evolution of this transformative therapeutic class.