September 25, 2023

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Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs. 

In recent years, FDA has approved multiple small nucleic acid drugs primarily for the treatment of rare diseases.

As of 2023, there are nearly 80 small nucleic acid drugs in various stages of clinical development worldwide.

These drugs span a wide range of therapeutic areas, including neurology, cardiovascular, infectious diseases, and oncology.

A total of 15 small nucleic acid drugs have successfully received market approvals.

However, there are two early-stage ASO (Antisense Oligonucleotide) drugs that deserve special attention.

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

1. Global Phase III Clinical Overview of Small Nucleic Acid Drugs

1.1  Tivanisiran

Tivanisiran (SYL1001) launched by Sylentis is an siRNA for the treatment of dry eye syndrome . 

Dry eye disease ( DED ) is characterized by tear film alterations with ocular inflammation and neurosensory abnormalities , and the main clinical symptoms of this condition are tear instability and ocular damage. Tivanisiran is used to silence transient receptor potential vanilloid TRPV1 mRNA . 

Tivanisiran is designed to reduce ocular discomfort and pain and has been shown to improve ocular congestion and tear quality in humans and animal models. 

Tivanisiran is currently in a phase III trial, evaluating the safety of the treatment for dry eye syndrome and dry eye syndrome caused by Sjogren’s syndrome. The study is expected to be completed in the second half of 2023 to the first half of 2024 ( NCT05310422 NCT04819269 ).

1.2  Bepirovirsen

Bepirovirsen launched by GSK is an ASO therapeutic drug for the treatment of hepatitis B. Phase II clinical results show that it can reduce the levels of hepatitis B surface antigen ( HBsAg ) and hepatitis B virus ( HBV DNA . The hepatitis B virus uses these RNAs to replicate itself in infected liver cells to produce viral antigens (proteins), and the generated viral antigens can help the virus escape the immune system to clear, thereby promoting the chronicity of hepatitis B disease.

ASO works by recruiting the liver’s own enzymes to degrade viral RNA into an inactive form and clear it. Decreased RNA levels reduced both viral and hepatocyte production of HBsAg . Bepirovirsen has the property of stimulating the immune response through Toll- like receptor 8 ( TLR8 ), which may help the immune system to durably clear the virus from the blood circulation. Phase III clinical trials for the efficacy and safety of Bepirovirsen are expected to end in early 2026 ( NCT05630807 NCT05630820 .


1.3  Leqvio® ( Inclisiran )

Leqvio® (Inclisiran) , launched by Novartis Pharma GmbH , is used as an adjunct to diet control for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia. Leqvio is an siRNA therapy . The use of this drug can continuously reduce the incidence of cardiovascular diseases caused by LDL-C in patients. Leqvio can bind to the mRNA encoding PCSK9 protein and prevent the liver from producing PCSK9 protein through RNA interference . The role of the PCSK9 protein is to inhibit the recycling and reuse of LDL receptors. Reducing the level of PCSK9 in the body allows more LDL receptors to come back to the surface of liver cells, bind more LDL , and clear them from the blood. The drug is currently undergoing a phase III clinical trial to evaluate the benefit of major adverse cardiovascular events ( MACE ) in participants with established cardiovascular disease ( CVD ).

Completion expected in 2027 ( NCT05004675 .

1.4  Oxlumo® (Lumasiran)

Lumasiran, developed by Alnylam, was approved by the FDA on November 23 , 2020 as the first drug for the treatment of primary hyperoxaluria type 1 PH1 ) . PH1 is a rare genetic disorder. Oxlumo received Orphan Drug Designation and Breakthrough Therapy Designation. Lumasiran , an siRNA targeting HAO1 , covalently linked to a ligand containing N- acetylgalactosamine, targets the mRNA of hydroxyacid oxidase HAO1) ​​in hepatocytes by RNAi , thereby reducing glycolate oxidase (GO) enzyme levels . Reduced levels of GO enzymes can reduce the availability of glyoxylate, a substrate for oxalate production. PH1 is caused by glutamic acid decarboxylase located inUpstream of the alanine:glyoxylate aminotransferase (AGT) deficient enzyme, Lumasiran ‘s mechanism of action is independent of the underlying AGXT gene mutation. This drug is currently undergoing multiple phase III clinical trials ( NCT04152200 NCT04152200 ) , aiming to evaluate the efficacy and safety of  Lumasiran in primary hyperoxaluria type 1 infants , children, adults and patients with advanced primary PH1 properties, pharmacokinetics and pharmacodynamics.

1.5  QR-110

QR-110 is an RNA-based oligonucleotide designed to address the underlying cause of Leber congenital amaurosis 10 (LCA10) caused by the p.Cys998X mutation in the CEP290 gene. LCA is the most common cause of blindness from genetic disorders in children and consists of a group of disorders of which LCA 10 is one of the more severe forms. The p.Cys998X mutation is a substitution of one nucleotide in the pre-mRNA, resulting in aberrant splicing of the mRNA and non-functional CEP290 mRNA. QR-110 is designed to restore normal (wild-type) CEP290 mRNA by binding to a mutated position in the pre-mRNA resulting in normal splicing of the pre-mRNA, resulting in normal CEP290 protein .

ProQR Therapeutics is conducting a double-blind, randomized, controlled, multiple-dose Phase II/III study to evaluate the efficacy, safety, tolerability and efficacy of QR-110 administered by intravitreal injection in subjects with LCA. Full body exposure .

1.6  Ultevursen

ProQR Therapeutics is conducting a Phase II III clinical trial of Ultevursen (formerly known as QR-421a ) . The purpose of this study is to evaluate the efficacy, safety and tolerability of Ultevursen administered by intravitreal injection ( IVT ) for the treatment of patients with USH13A Subjects with retinitis pigmentosa ( RP ) caused by mutations in exon 2 of the gene. The study is expected to be completed in 2024 . Ultevursen is a single-stranded RNA -based oligonucleotide that blocks vision loss in patients with retinitis pigmentosa caused by mutations in exon 13 of the USH2A gene , which encodes the usherin protein . It is administered by intravitreal injection in the eye and has received Orphan Drug Designation in the US and EU and FDAFast Track and Rare Pediatric Disease Designations. The study is expected to be completed by the end of 2024 ( NCT03913143 NCT04855045 ) .

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

2. Global Phase II Clinical Overview of Small Nucleic Acid Drugs

2.1S  YL1801 

The phase II clinical trial of SYL1801 was initiated by Sylentis SYL1801 is an siRNA targeting NRARP ( NOTCH Regulated Ankyrin Repeat Protein ) engineered using Sylentis’ proprietary Sir Finder ™ to prevent and or control the progression of wet age – related macular degeneration ( AMD ) . 

SYL1801 was administered as eye drops to transcriptionally downregulate the expression of N RARP , which plays an important role in the control of neovascularization in the retina, a different target than conventional anti-angiogenic therapies based on anti  VEGF drugs 

At present, the drug is undergoing Phase II clinical recruitment. The purpose of this clinical trial is toA comparison of the safety and effects on vision of three different doses of SYL1801 eye drops is expected to be completed by November 22 2022 ( NCT05637255 ) .


2.2  ALN-HSD

Phase II clinical research on ALN-HSD initiated by Regeneron and Alnylam, ALN – HSD is used as subcutaneous injection of RNAi  therapeutic drug targeting HSD17B13 gene for the treatment of NASH This study evaluated the efficacy and safety of ALN-HSD in adult patients with NASH and fibrosis with genetic risk factors (NASHGEN-2) in patients with nonalcoholic steatohepatitis ( NASH NCT05519475 ) . NASH, a form of nonalcoholic fatty liver disease ( NAFLD ) , occurs when fat builds up in liver cells, damaging them and making the liver inflamed and stiff with fibrosis (scar tissue ) NASHCan progress to cirrhosis (long term scarring) and liver failure Estimated completion December 09 , 2026 .


2.3  OLX10010

A randomized, double-blind, within-subject, placebo-controlled phase IIa clinical trial initiated by OliX to evaluate the efficacy of OLX10010 as an adjuvant therapy in reducing the recurrence of hypertrophic scars after scar revision surgery. OLX10010 is a cell-penetrating asymmetric siRNA cp asiRNA ) that interferes with the expression of connective tissue growth factor ( CTGF ) . The purpose of this study is to determine the efficacy of OLX10010 in reducing the recurrence of hypertrophic scars . The study will evaluate the reduction and recurrence of hypertrophic scars after scar reconstruction surgery.

Completion is expected in September 2023 ( NCT04877756 .


2.4  ALN-KHK

ALN-KHK is an investigational RNAi therapeutic targeting ketohexokinase ( KHK ) for the treatment of type 2 diabetes ( T2DM ) . ALN-KHK utilizes Alnylam ‘s Enhanced Stabilization Chemically Enhanced ( ESC+ ) GalNAc conjugate technology, which enables subcutaneous delivery with increased selectivity and broad therapeutic index Type 2 diabetes is a global disease affecting more than 6% of the world’s population , and its incidence and prevalence are increasing worldwide, with more than 45.055 billion people estimated to be affected. Alnylam initiated a randomized, double-blind, placebo-controlled, two-part Phase I /II study in March 2023 to study the effect of single-dose ALN-KHK on overweight and multiple-dose ALN-KHK in obese adult healthy volunteers in obese 2Safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics in patients with type 2 diabetes . The study is expected to be completed in the first half of 2024 NCT05761301 ).

2.5  ALN-AGT01

Also initiated by Alnylam to evaluate the efficacy and safety of RNA therapy drug ALN-AGT01 in patients with mild to moderate hypertension ( KARDIA-1 ), a randomized, double-blind, placebo-controlled, dose-ranging study A multicenter phase II study is underway and is expected to be completed in 2025 NCT04936035 ) .


2.6  SQY51

In April 2023 , SQY Therapeutics initiated a single-center, open-label Phase I IIa study to evaluate the safety, pharmacokinetics and pharmacodynamics of SQY51 in patients with Duchenne muscular dystrophy . Duchenne muscular dystrophy ( DMD ) is a genetic disorder that causes progressive degeneration of all muscles in the body. It is caused by an abnormality (mutation) in the DMD gene, located on the X chromosome , which codes for dystrophin, a protein that is essential for muscle fibers to function properly.

QY51 is an antisense oligonucleotide designed to hybridize to specific sites on the pre-mRNA transcript of the DMD gene in order to remove certain elements of the mutant gene during mRNA maturation (exon skipping) to Restoration of production of functional truncated dystrophin. SQY51 uses unnatural nucleotides of the ” tricyclic DNA” family , which have the advantage of being very stable and hybridizing to RNA targets more efficiently than their natural counterparts . Twelve patients over 6 years old will be enrolled in the trial. In Phase 1 of the study , which will last 13 weeks, they will all receive six escalating doses of SQY51 intravenously. For Phase 2a , Phase participants will be divided into cohorts and each cohort will be treated with different doses of SQY51 for 32 weeks ,This study is expected to be completed in 2025 NCT05753462 ) .


2.7 K3228836

GlaxoSmithKline ‘s ASO compound , GSK3228836 , is currently conducting a single-blind, randomized, controlled Phase II study to quantify the efficacy of sequential therapy and to determine the relative efficacy of sequential therapy compared to GSK3228836 in CHB patients receiving NA therapy added value The study started in March 2022 and is expected to end in 2026 ( NCT05276297 .


2.8 STK-001

Stoke Therapeutics launched STK-001 for the treatment of Dravet syndrome in children and adolescents. STK-001 , an antisense oligonucleotide drug, has the potential to be the first improved therapy targeting the underlying cause of Dravet syndrome. Dravet syndrome is a severe progressive genetic epilepsy characterized by frequent, persistent, and refractory seizures beginning within the first year of life. Because of the associated developmental delays and cognitive impairment, the disorder is classified as a developmental and epileptic encephalopathy. STK-001 restores physiological NaV1.1 gene expression by using a non-mutated (wild-type) copy of the SCN1A gene, which in turn upregulates NaV1.1 protein expression, thereby reducing seizures and significant non-seizure complications. Stoke ‘s current preclinical data have demonstrated the mechanism of action and concept of STK-001 . The FDA has granted STK-001 Orphan Drug Designation as a new potential treatment for Dravet syndrome.

Stoke Therapeutics is currently evaluating the safety and tolerability of single and multiple ascending doses of STK – 001 in patients with Dravet syndrome , with completion expected in 2027 and 2025 NCT04740476 NCT04442295 .


2.9  IGV-001

Imvax is currently conducting a randomized, multicenter, double-blind, placebo-controlledPhase IIb study to evaluate the efficacy of IGV-001 , an antisense oligonucleotide IMV-1 ) targeting IGF-001R Safety and Efficacy of Autologous Cellular Immunotherapy) in Patients with Newly Diagnosed Glioblastoma ( GBM .

IGV-001 is a vaccine against glioblastoma multiforme consisting of three substances the patient’s tumor cells an IGF-1R antisense oligonucleotide ( IMV-001 an infiltration chamber  bio-diffusion chamber which allows macromolecules to seep out IGV-001 begins by collecting surgically resected tumor cells from GBM patients, which are then treated with IGF-1R antisense oligonucleotides ( IMV-001 ) to push the tumor cells toward controlled cell death. These treated cells were then mixed with an excess of IMV-001 (as an adjuvant) in an infiltration chamber and implanted in the patient’s abdomen within 24 hours of surgery. After the implantation time reaches 48 hours, it is taken out to complete the whole process of vaccination. This innovative vaccine has been granted orphan drug status by the US FDA .

The trial started in March 2023 and study completion is expected in 2027NCT04485949).

2.10  BP1001

Bio-Path Holdings is currently conducting a Phase IIa open-label clinical trial evaluating BP1001 (liposomal Grb2  antisense oligonucleotide ) in combination with venetoclax plus decitabine in patients not amenable to intensive induction therapy Safety, Pharmacokinetics, Pharmacodynamics and Efficacy in Patients with Refractory / Relapsed Acute Myeloid Leukemia ( AML Growth factor receptor-binding protein -2 ( Grb2 ) is critical for oncogene signaling and tumor progression.

 BP1001 is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. A Phase I/Ib single-center study demonstrated that BP1001 was as safe as the dose and efficacy of 90 mg/m 2 BP1001 combined with low-dose cytarabine ( LDAC ) in patients with AML . 

This timeThe primary objectives of the study were to evaluate:

( 1 ) whether the combination of BP1001 plus venetoclax plus decitabine is more effective than venetoclax plus decitabine in untreated AML subjects who cannot or choose not to receive higher-intensity chemotherapy (Complete remission [CR] , complete remission with incomplete hematological recovery [CRi] , complete remission with partial hematological recovery [CRh] ) ; 

( 2 ) Is BP1001 – based therapy more effective than intensive chemotherapy ( By historical comparison) provided greater efficacy ( CR , CRi , CRh ) in subjects with refractory / relapsed AML .

The study is expected to be completed by the end of 2024 ( NCT04196257 NCT02781883 .

2.11  QR-1123

A prospective first-in-human study initiated by ProQR Therapeutics to evaluate the safety and tolerability of QR-1123 in subjects with autosomal dominant retinitis pigmentosa (adRP) caused by a mutation in the rhodopsin ( RHO gene P23H sex . QR-1123 is an antisense oligonucleotide designed to specifically target mutant P23H mRNA to selectively reduce expression of P23H protein while preserving expression of wild-type ( W RHO protein .

Presumably, the reduction of mutant P23H mRNA would reduce the deleterious effects of the dominant-negative protein and should lead to increased function of the WT rhodopsin protein in photoreceptors. Restoration of WT RHO function is expected to improve vision in patients with adRP due to P23H mutations NCT04123626 ) .

2.12  PRAX-222

PRAX-222, launched by Praxis Precision Medicines , is an antisense oligonucleotide designed to selectively reduce the expression level of the protein encoded by the SCN2A gene in patients with SCN2A acquired epilepsy . PRAX-222 reduces SCN2A gene expression and protein levels in in vitro studies . In the SCN2A mouse model, PRAX-222 significantly and dose-dependently reduced seizures, improved behavior and motor activity, and increased survival in mice, making it the first therapy to alleviate the disease. 

Currently, PRAX-222 has received Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA , and Orphan Drug Designation from the European Medicines Agency ( EMA ) for the treatment of SCN2A-DEE . The drug is currently undergoing a Phase II clinical trial to investigate the safety and efficacy of multiple doses of PRAX-222 in pediatric participants with early-onset SCN2A developmental and epileptic encephalopathy NCT05737784 ) .

2.13  BNT112

BNT112 consists of messenger ribonucleic acid ( mRNA [ or RNA] ) targeting five antigens expressed in neonatal and metastatic prostate cancer , which are complexed with liposomes to form serum-stable RNA lipoplexes ( RNA- LPX ) . BioNTech SE is conducting a phase I II clinical trial to evaluate  the BNT112 cancer vaccine monotherapy or in combination with cimiprizumab in metastatic castration-resistant prostate cancer ( mCRPC : Part 1 and Part 2 Arm 1A and 1B ) and high-risk localized prostate cancer ( LPC ) patients with safety, tolerability, immunogenicity and preliminary efficacy. The study is expected to be completed in the second half of 2023 ( NCT04382898 .

2.14  mRNA-3705 & mRNA-3927

mRNA-3705 is an investigational mRNA therapy for the treatment of methylmalonic acidemia ( MMA ) , administered by intravenous infusion, for the treatment of methylmalonyl-CoA mutase ( MUT ) deficiency Caused MMA patients. mRNA-3927 is designed to direct the body to restore missing or dysfunctional proteins that cause propionic acidemia ( PA ).

Phase II study to evaluate the long-term safety of mRNA-3705 and to evaluate the long-term safety of mRNA-3927 administered to participants with propionic acidemia ( PA ) previously enrolled in study mRNA-3927-P101 ( NCT04159103 ) The trials were initiated by ModernaTX , and both trials are expected to conclude after 2030 ( NCT05295433 NCT04899310 ) .

2.15  Sapablursen

Sapablursen , formerly known as ISIS 702843 IONIS-TMPRSS6-LRx , launched by Ionis , a company that focuses on small nucleic acid technology research and development and innovative technologies , is an investigational ligand-conjugated antisense ( LICA ) drug designed to target the TMPRSS6 gene to regulate Production of hepcidin .

 Hepcidin is a key regulator of iron homeostasis. By modulating the expression of hepcidin, Sapablursen has the potential to positively impact diseases characterized by iron deficiency, such as polycythemia vera ( PV ).

 The drug is currently in phase IIa clinical research, and the study aims to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacokinetics of Sapablursen in patients with phlebotomy-dependent polycythemia vera ( PD-PV ). Efficacy . 

The study is expected to be completed in early 2025 ( NCT05143957 .


In addition to the above 15 small nucleic acid drugs in phase II clinical trials and 6 small nucleic acid drugs in phase III clinical trials, there are nearly 40 drugs in phase I clinical trials, covering siRNA mRNA ASO , etc.

Small nucleic acid drug technology has formed two types of representative companies in terms of enterprise distribution, one is companies that focus on small nucleic acid technology research and development and innovative technologies, such as Ionis, Alnylam, etc., and the other is biopharmaceutical giants through cooperative development. In the field of small nucleic acid drugs, such as Roche, AstraZeneca, Novartis, etc.

Small nucleic acid drugs have strong target specificity, long-acting drug effects, short development cycle, rich targets and high efficiency.

Compared with traditional drugs, they have multiple technical advantages. Use more efficiently.

 At present, the small nucleic acid drug industry as a whole has the characteristics of high prosperity, good competition pattern, and large potential market size, and it is gradually developing steadily and rapidly.



1. Moreno-Montañés J, Bleau AM, Jimenez AI. Tivanisiran, a novel siRNA for the treatment of dry eye disease. Expert Opin Investig Drugs. 2018;27(4):421-426. doi:10.1080/13543784.2018.14576 47
2. Girach A, Audo I, Birch DG, et al. RNA-based therapies in inherited retinal diseases. Therapeutic Advances in Ophthalmology. 2022;14. doi:10.1177/25158414221134602
3.Ana Isabel Jimenez ,  Veronica Ruz ,  Laura Rico ,  Tamara Martinez ,  Susana Monteiro ,  Ascension Cuesta ,  Amor Guerra ,  Alba Cuenca ,  Victoria Gonzalez ; SYL1801: Preclinical Efficacy and Safety of a siRNA-based eye drops treatment for Age Related Macular Degeneration.  Invest. Ophthalmol. Vis. Sci.  2019;60(9):5389.

Overview of Global Phase II/III Clinical Trials for Small Nucleic Acid Drugs

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