Aptamer Therapeutics: Current Status

RNA therapeutics with their unique mechanisms of action, have provided more precise treatment options for various genetic and rare diseases. RNA therapeutics can mainly be divided into antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), messenger RNA (mRNA), RNA aptamers, etc.

Among them, there are few aptamer products, with only two approved drugs, both designated for treating age-related macular degeneration (AMD), leading to relatively low industry attention. However, the approval of the second drug in 2023 has reignited industry interest. Consequently, a thorough summary analysis of aptamer drugs is merited here.

Aptamers

Aptamers, also known as chemical antibodies, are single-stranded nucleic acid oligonucleotides with unique three-dimensional configurations that bind with a high affinity and specificity to a wide range of targets, such as proteins, peptides, small molecules, metal ions, bacteria, viruses, and whole live cells. Compared to antibodies, aptamers offer numerous advantages, including broader target specificity, better thermal stability, smaller molecular weight, synthetic feasibility, minimal batch-to-batch variation, and ease of modification. Given these features, aptamers have attracted a great deal of attention in cancer imaging, gene therapy and drug delivery.

Aptamers

Figure 1. Aptamers [2]

Pegaptanib (Macugen)- First Aptamer Approved by FDA

Pegaptanib (Macugen) was the first FDA-approved aptamer. It acts as a selective antagonist of vascular endothelial growth factor (VEGF) and is indicated for treating neovascular (wet) age-related macular degeneration (AMD). However, it was discontinued due to low sales.

Pegaptanib, a 28-base ribonucleic acid aptamer covalently linked to two branched 20kD polyethylene glycol (PEG) moieties, binds to extracellular VEGF, specifically the 165-amino-acid isoform (VEGF-165), and antagonizes its biological effects.

Pegaptanib

Figure 2. Structure of Pegaptanib [1]

Avacincaptad pegol (Izervay) - Second Aptamer Approved by FDA

Avacincaptad pegol, an RNA aptamer covalently linked to branched PEG molecules, binds to complement protein C5 and inhibits its activity. This inhibition prevents the cleavage of C5 into C5a and C5b, thereby decreasing the formation of the membrane attack complex (MAC).

Avacincaptag pegol was approved by the FDA on August 4, 2023, under the brand name IZERVAY for the treatment of geographic atrophy (GA) secondary to AMD. This approval is based on the positive results obtained from 2 phase 3 clinical trials GATHER1 and GATHER2.

These two clinical trials evaluated the safety and efficacy of monthly intravitreal administration of 2 mg Izervay in patients with GA secondary to AMD. The study assessed the growth rate of GA in patients at baseline, 6 months, and 12 months. The primary analysis results showed that compared to sham treatment, patients receiving Izervay therapy had a statistically significant reduction in the growth rate of GA, with a slowing of disease progression observed as early as 6 months, with a decrease in GA growth rate of up to 35% in the first year of treatment.

Figure 3. Structure of Avacincaptad pegol [1]

Aptamers for Other Indications

Indeed, aptamer drugs in clinical stages have extended beyond AMD into oncology, cardiovascular diseases, metabolism, immunology, antivirals, and neurodegenerative diseases. Targets include VEGF, PDGF, vWF, TFP1, C5, Factor IX, TLR-4, etc. Below, examples will be provided for illustration.

Aptamers for Cancer

AS1411 is a 26-base guanine-rich oligodeoxyribonucleotide aptamer that forms a G-quadruplex structure with many beneficial characteristics, notably its ability to bind to nucleolin. AS1411 targets cells with higher concentrations of nucleolin on the cell membrane and in the cytoplasm–a characteristic of many cancer cells and pathogen-infected cells. AS1411 is the first anticancer “G-4 forming GRO” with good biological activity, reaching phase II clinical trials for acute myeloid leukemia and renal cell carcinoma.

NOX-A12 is an RNA-aptamer that targets CXCL12 (C-X-C Chemokine Ligand 12), a key chemokine protein involved in tumor cell proliferation, the formation of new blood vessels and metastasis. NOX-A12 is currently in mid-stage clinical development as a combination therapy in brain cancer, and glioblastoma, and is one of the few agents that we believe offers the potential to address the major unmet need in this and other solid tumors such as pancreatic cancer.

Aptamers for Atherosclerosis

DTRI-031, a novel anti- von Willebrand factor (vWF) aptamer, selectively binds and inhibits vWF-mediated platelet adhesion and arterial thrombosis while enabling rapid reversal of this antiplatelet activity by an antidote oligonucleotide (AO). Aptamer DTRI-031 exerts dose-dependent inhibition of platelet aggregation and thrombosis in whole blood and mice, respectively. Moreover, DTRI-031 can achieve potent vascular recanalization of platelet-rich thrombotic occlusions in murine and canine carotid arteries. A randomized, double-blind, single-center, placebo-controlled Phase I study in healthy volunteers is currently underway to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single intravenous injection of DTRI-031 (NCT05005520).

Aptamers for Autoimmune Myocardioptis

Aptamer BC 007, a 15‐mer single‐strand DNA oligonucleotide (5'‐GGTTGGTGTGGTTGG‐3'), was developed to neutralize functional autoantibodies that bind to the extracellular domains of G protein‐coupled receptors (GPCR‐AAB), leading to the modulation of receptor‐mediated signaling cascades that induce pathophysiological states. BC-007 is under clinical development by Berlin Cures and is currently in Phase II for Dilated Cardiomyopathy. According to GlobalData, Phase II drugs for Dilated Cardiomyopathy have a 50% phase transition success rate (PTSR) indication benchmark for progressing into Phase III.

Aptamers as Anticoagulant

Currently, various coagulation aptamers are at different stages of clinical trials. REG1, an aptamer-based factor IXa inhibitor, is under development for percutaneous coronary intervention in acute coronary syndrome. It comprises the RNA aptamer pegnivacogin (RB006) with a 40 kDa PEG carrier attached to the tail, along with the antidote anivamersen (RB007). While Phase I clinical trial results for REG1 anticoagulation showed low toxicity during percutaneous coronary intervention, severe allergic reactions in the Phase II trial prompted early termination. The optimization process is currently underway.

ARC1779 is the first DNA aptamer targeting the A1 domain of von Willebrand factor (vWF). Its indications mainly include thrombotic thrombocytopenic purpura, von Willebrand disease, cerebral vascular thrombosis, and thrombotic microangiopathy. Through multi-level optimization, a PEGylated variant called BT-200 has been developed. Preliminary evidence suggests that low-dose BT-200 can correct vWF and/or FVIII deficiency in patients with hereditary bleeding disorders.

Inflammation and Diabetes

NOX-E36, a 40-nucleotide L-RNA linked to a 40 kDa PEG, boasts a slightly longer pharmacokinetic half-life of 50 hours. Its indications target type II diabetes, nephropathy, and lupus nephritis. Another aptamer, NOX-H94 (Lexaptepid Pegol), directly inhibits hepcidin, enhancing iron circulation, stimulating red blood cell production, and ameliorating anemia and inflammation. Phase I clinical trials have demonstrated dose-dependent increases in serum iron concentration and transferrin levels in healthy subjects receiving NOX-H94 treatment. Intravenous infusion of 1.2 mg/kg NOX-H94 leads to approximately a 67% rise in iron content after 8 hours.

As a global partner, Biochempeg can supply commercial quantities of high-quality functionalized PEGs, which are essential for your PEGylated therapeutic aptarmers.

References:
[1] https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
[2] Guizhi Zhu, Xiaoyuan Chen, Aptamer-based targeted therapy, Advanced Drug Delivery Reviews, Volume 134,2018, Pages 65-78, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2018.08.005.
[3] Vittoria Di Mauro, Francesca Cecilia Lauta, Jessica Modica, Silvia Lucia Appleton, Vittorio De Franciscis, Daniele Catalucci, Diagnostic and Therapeutic Aptamers: A Promising Pathway to Improved Cardiovascular Disease Management, JACC: Basic to Translational Science, Volume 9, Issue 2, 2024, Pages 260-277, ISSN 2452-302X, https://doi.org/10.1016/j.jacbts.2023.06.013.