Novo Nordisk’s First Oligonucleotide Therapy Approved by FDA; SanegeneBio’s Lead RNAi Drug Enters Clinic — Multiple Milestones Propel the Oligonucleotide Therapeutics Sector

Oct 09, 2023 17:21 CST Updated 17:21

AcuraStem

Developer of New Drugs for the Treatment of Nervous System Diseases

| Research Team of the Drug Hunter Club

Around the double festival, smallSignificant progress has been made in the development of nucleic acid drugs:

Clinical/Marketing applications for multiple drugs approved in and outside China, such asNovo NordiskThe First RNAi Drug Approved by FDA for Marketing, and in China, there are also Viya Zhen andSinoBio's RNAi therapy approved for clinical use;
Several highly anticipated drugs have recently released clinical data, such asIonisFirst Independent LaunchAntisense Oligonucleotide Therapy OlezArsen Reached Primary Efficacy Endpoint in Phase 3 Clinical Trial for Treating Familial Chylomicronemia Syndrome (FCS)AvidityThe World's First Antibody-siRNA Drug to Enter Clinical Trials Releases Latest Clinical Data;
MNCs in this field are also seeing a constant stream of cooperation deals, such asTakedaIn6Billion Dollar Handshake AcuraStemDevelopmentASOTherapy,RocheIn6000Million USD Prepayment andIonisCollaborative Development2PaymentASOMedicine.

1.Nearly $600 Million Collaboration: Takeda Partners with AcuraStem to Develop Antisense Oligonucleotide Therapy

September 25,AcuraStemAnnouncementA licensing agreement has been reached with Takeda to develop and commercialize AcuraStem's PIKFYVE-targeted therapies, including the innovative antisense oligonucleotide (ASO) for the treatment of amyotrophic lateral sclerosis (ALS) — AS-202.

Under the terms of the agreement, Takeda will receive an exclusive global license for AcuraStem's PIKFYVE program. If all future clinical, regulatory, and commercial milestones are achieved within the agreement period, AcuraStem could receive up to approximately5.8Billion US dollarsThe upfront and milestone payments, as well as the potential to receive tiered royalties on net sales of any commercial products arising from the license.

AboutPIKFYVE

According to the AcuraStem company website, PIKFYVE is a novel therapeutic target for ALS. The company’s research shows that using ASO therapy to inhibit the gene encoding the kinase helps neurons eliminate toxic proteins and pathological aggregates, thereby protecting healthy neural function and preventing neurodegeneration.

AcuraStem identified the clinical candidate therapy AS-202 through screening on its patient-based iNeuroRx technology platform.AS-202 is aASO therapy administered via intrathecal injection can potently inhibit PIKFYVE in the central nervous system.

AboutAcuraStem

AcuraStem, founded in 2016 by Alworth, Ichida, Dr. Paul August, and Dr. Qing Liu, is committed to continuously enhancing its patient-based iNeuroRx® technology platform, aiming to discover more effective treatments in the field of neurodegenerative indications, and rapidly advancing its therapeutic programs, including the existing SYF2 and UNC13A projects for ALS and FTD.

iNeuroRx Technology PlatformPatient sample establishment using cell reprogrammingPatient-Specific Model, accurately reflecting the key aspects of disease generation in patients' DNA, and then utilizing advanced bioinformatics technology and machine learning to quantify disease characteristics in the model, while observing the effects of new drug targets across different patient types. This approach is fundamentally different from animal models that implant pathology into mice, not only aiding in the development of target engagement biomarkers and guiding clinical medication but also providing a standard reference for more targeted trials with a higher likelihood of success.

2. ViaGen Announces VSA006 Granted CDE Clinical Trial Implied Permission

On September 26, according to the announcement on the CDE official website, the VSA006 injection developed by ViyaGen Biotechnology (Shanghai) Co., Ltd. obtained clinical trial implied permission, intended for development to treat adult patients with non-alcoholic steatohepatitis (NASH).

AboutVSA006

VSA006 is a small nucleic acid drug that specifically binds to HSD17β13 mRNA in hepatocytes, downregulates the expression of the HSD17β13 protein, and thereby inhibits the progression of non-alcohol-related liver disease.The completed Phase I/II clinical trial evaluated the effects of VSA006 on normal healthy volunteers and patients diagnosed with or clinically suspected of having NASH. The results showed that VSA006 treatment was well-tolerated, with no treatment-related serious adverse events or discontinuations.VSA006 significantly reduced liver HSD17β13 mRNA and protein levels, while effectively decreasing patient alanine aminotransferase (ALT) levels.

AboutAcuraStem

ViaGen is a small nucleic acid drug therapy company based in China with a global outlook, aiming to build a biopharmaceutical enterprise with comprehensive capabilities in research, production, and commercialization. The company was founded in 2022 and has established a long-term strategic partnership with Arrowhead Pharmaceuticals, an internationally leading small nucleic acid drug company. Currently, the company's product pipeline includes three small nucleic acid (siRNA) drugs in clinical development stages targeting cardiovascular and metabolic diseases.

3.Roche Collaborates with Ionis to Develop Two Novel RNA Drugs

On September 27, Ionis Pharmaceuticals announced that the company had reached a collaboration agreement with Roche on two undisclosed RNA-targeting early-stage investigational drugs for the treatment of Alzheimer's disease (AD) and Huntington's disease (HD).。According to the agreement contentRoche has obtained the global exclusive rights for the development, production, and commercialization of Ionis' investigational drug; Ionis will be responsible for the preclinical development of the collaborative drug and will receive a $60 million upfront payment from Roche, as well as development, regulatory, and commercial milestone payments and tiered royalties.

As a leader in antisense oligonucleotide therapy, Ionis targets RNA and focuses on the research and development of neurological and cardiometabolic diseases. Ionis and Roche have been strong partners for the past decade, a collaboration that dates back to 2013 when the two companies jointly developed an antisense oligonucleotide (ASO) for the treatment of HD—Tominersen—which failed in Phase 3 due to patients experiencing disease worsening after drug administration. Currently, the two parties are designing a new Phase 2 clinical trial based on lessons learned from the failed clinical experience, aiming to explore the efficacy of different doses of Tominersen in younger adult patient populations with less disease burden.Recommended Reading：Roche: The "Top Contributor" of Small Nucleic Acids! | MNC's Small Nucleic Acid Drug Landscape Series (III)）

4. Reduce Disease Marker by 100%! IONIS Antisense Oligonucleotide Therapy Reaches Phase 3 Clinical Endpoint, Set to Submit for Market Approval

On September 27, Ionis Pharmaceuticals announced today that the antisense oligonucleotide therapy olezarsen met the primary efficacy endpoint in a Phase 3 clinical trial for patients with familial chylomicronemia syndrome (FCS). Compared to placebo, the olezarsen (80 mg once monthly) group showed a statistically significant reduction (p=0.0009) in triglyceride (TG) levels at 6 months; this reduction continued to improve at 12 months. Additionally, compared to placebo, the olezarsen (80 mg) group saw a 100% reduction in acute pancreatitis events (0 events in the olezarsen group vs. 11 events in the placebo group), achieving a key secondary endpoint. Based on these positive results, the company plans to submit a New Drug Application (NDA) to the U.S. FDA in early 2024.

AboutOlezarsen

Olezarsen is an investigational antisense oligonucleotide therapy designed to inhibit the body's production ofapoC-III，apoC-IIIIs a protein produced in the liver that regulates TG metabolism in the blood. In the first quarter of 2023, the U.S. FDA granted olezarsen Fast Track designation for the treatment of FCS. In addition to FCS, Ionis is evaluating olezarsen in a Phase 3 clinical trial for the treatment of severe hypertriglyceridemia (SHTG).

5.Novo Nordisk's $3.3 Billion RNAi Therapy Approved by FDA for Market Launch

On October 2, Novo Nordisk announced that the U.S. FDA approved the marketing application for its RNAi therapy Rivfloza (nedosiran) injection (80 mg, 128 mg, or 160 mg) to reduce urine oxalate levels in pediatric and adult patients aged 9 years and older with Type 1 primary hyperoxaluria (PH1) who have relatively preserved kidney function.

About Rivfloza

RivflozaIs a once-a-month, subcutaneous injection RNAi therapy.It can bind to the mRNA expressing hepatic lactate dehydrogenase (LDH) and inhibit the protein expression, which is a key metabolic enzyme leading to excessive oxalate production. Rivfloza was initially developed by Dicerna Pharmaceuticals and acquired by Novo Nordisk in 2021 for...33Hundred MillionDollarAcquire the company and obtain the rights to the therapy.

This approval is based on the results of the pivotal Phase 2 clinical trial, PHYOXTM2, and interim data from the ongoing Phase 3 PHYOXTM3 extension study. The analysis showed that PHYOXTM2 met its primary endpoint, demonstrating that patients treated with Rivfloza,The 24-hour urinary oxalate (Uox) excretion from Day 90 to Day 180 significantly decreased compared to baseline.。

This is the second treatment option for this disease approved by the FDA. Previously, in November 2020, the FDA approved Alnylam's RNAi therapy Oxlumo (lumasiran) for the treatment of Primary Hyperoxaluria Type 1 (PH1). In terms of administration, the two differ: Oxlumo is administered subcutaneously once every three months, while Rivfloza is administered once a month.

6. The First in China! RiboBio Discloses Its TargetingCNSPatent for Conjugates

On October 5, Ribo Biotech disclosed its conjugate patent targeting the CNS (WO2023185946A1), which might be the first publicly disclosed patent related to non-liver targeting in China. The disclosed technical solution could potentially be their claimed RIBO-OncoSTAR platform.

This case uses peptides that can bind to the transferrin receptor (TR). In specific embodiments, P7, RP7, P12, and RP12 shown below are used to deliver siRNA into the CNS.

This implementation adopts siRNA targeting SOD1 mRNA conjugated with more than one P7 or P12 (two or three: two are conjugated to both ends of the sense strand, or double triazole conjugation at one end; three use a tri-branched triazole conjugation at one end). Intracerebroventricular injection in rats or mice effectively suppresses SOD1 expression across various regions of the CNS. It also demonstrates that further conjugation of siRNA with long fatty chains achieves better suppression effects.

7. SaintGene Bio's First RNAi Drug Approved for Clinical Trials in China

On October 7, the CDE official website showed that SGB-3403 Injection, a Class 1 new drug independently developed by Shengyin Bio, obtained tacit approval for clinical trial application (acceptance number: CXHL2300741) for the treatment of hypercholesterolemia.

AboutSGB-3403

SGB-3403It is an RNAi drug targeting PCSK9. This drug isAdopted AcuraStem's proprietary new generation GalNAc conjugate delivery technologyThe First Innovative RNAi Drug, which has previously been approved for Phase I clinical trials in Australia. The excellent activity and prolonged efficacy demonstrated by SGB-3403 in preclinical studies indicate its "best-in-class" potential.The first dosing in healthy subjects was completed in Australia at the end of May this year, and the single-dose escalation trial is also proceeding steadily.

AboutSinoBio

SaintGene Biopharma, established in early 2021, is a biopharmaceutical company dedicated to developing novel small nucleic acid drugs based on RNA interference (RNAi) technology, with research and development centers in both China and the United States. The founding team consists of senior experts in the field of nucleic acid drugs, possessing years of experience in nucleic acid drug development and cutting-edge technical capabilities within the industry. Since its establishment, the company has successfully built a globally leading platform for nucleic acid drug chemical modification and intrahepatic and extrahepatic delivery technologies with independent intellectual property rights, accelerating the development of RNAi drugs with differentiated advantages. Its first core product has entered clinical trials, while multiple other pipelines are being advanced in parallel, covering disease areas such as cardiovascular and cerebrovascular diseases, metabolic disorders, immune-mediated diseases, and neurological conditions.

8. Locanabio Presents Enhanced Vectorized snRNA Platform for Exon Skipping as a Potential Treatment for DMD

On October 6, Locanabio announced data from its encapsulation and proprietary delivery small nuclear RNA (snRNA) platform using adeno-associated virus (AAV).ItsThe poster describes the specific applications of this vectorization platform.Demonstrated robust dose-dependent exon skipping at multiple exons, capable of restoring nearly full-length dystrophin in a single-dose treatment to potentially treat DMD.

AboutLocanabio's snRNA Platform

Locanabio utilizes modified small nuclear RNA (snRNA) delivered through a one-time AAV gene therapy to target pathogenic RNA without triggering an immune response. It can function through multiple mechanisms, including exon skipping to restore the gene reading frame or modulate mRNA and protein expression, targeting toxic pathogenic RNA repeat sequences, and recruiting endogenous RNA adenosine deaminases (ADARs) for therapeutic RNA editing. Their small size allows multiple snRNAs to be delivered in a single AAV vector, which can be used to enhance potency or target multiple RNAs.

AboutLocanabio

Locanabio, founded in 2016 and headquartered in San Diego, is an RNA-targeting gene therapy service provider. Since 2019, it has received $155 million in financing, for the advancement of RNA-targeted gene therapies.Locana's CORRECTX™ platform can develop a variety of RNA-binding proteins to modify RNA through different mechanisms, including cleavage, splicing, gene replacement, translation enhancement, and editing, which is expected to overcome the limitations of other RNA-targeting therapies.

9. Avidity Biosciences Announces AOC 1001LatestPositive Clinical Data

On October 7, Avidity Biosciences, a leading company in antibody-oligonucleotide conjugates (AOC), disclosed the latest clinical data for its key pipeline product, AOC 1001. The new data shows improvements in multiple functional endpoints in patients with myotonic dystrophy type 1 (DM1), demonstrating good long-term safety and tolerability, with most adverse events (AEs) being mild to moderate.

About AOC 1001

AOC 1001 is Avidity'sThe primary candidate drug, leveraging its AOC platform, aims to address the root cause of DM1 by reducing the levels of a disease-associated mRNA known as DMPK.AOC 1001 consists of a proprietary monoclonal antibody conjugated to siRNA targeting DMPK mRNA, which is associated with transferrin receptor 1 (TfR1).In preclinical studies, AOC 1001 successfully delivered siRNA to muscle cells, resulting in a persistent, dose-dependent reduction of DMPK RNA in various muscle types, including skeletal muscle, cardiac muscle, and smooth muscle.

FDA and the European Medicines Agency (EMA) have granted AOC1001 orphan drug designation, and the FDA has also granted AOC1001 fast track designation.

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