NucleoSpace Announces Phase II Clinical Success of Novel Long-Acting siRNA Therapy for Hypertension

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2024-35, Alnylam and Roche announced that the investigational RNAi therapy Zilebesiran for treating hypertension met the primary endpoint in the Phase II clinical trial named KARDIA-2. When added to the standard treatment regimen, Zilebesiran significantly reduced patients' average 24-hour systolic blood pressure (SBP) at the third month. Notably, the trial data supports maintaining sustained blood pressure reduction with just twice-yearly dosing.

KARDIA-2 is a randomized, double-blind, placebo-controlled Phase II clinical trial designed to evaluate the efficacy and safety of Zilebesiran in combination with standard antihypertensive drugs in adult patients with mild to moderate hypertension. This global multicenter study enrolled 672 adult patients with hypertension. They were first randomly assigned to three different cohorts to receive open-label treatment with the antihypertensive drugs olmesartan, amlodipine, or indapamide for at least four weeks. Eligible patients were then randomly assigned to receive either 600 mg of Zilebesiran or a placebo, in addition to standard antihypertensive drug therapy, for six months.

The trial results showed that at the 3rd month of treatment, compared with the placebo group, the 24-hour SBP measured by Ambulatory Blood Pressure Monitoring (ABPM) demonstrated a clinically significant reduction. The full results of the study will be presented at a scientific conference on April 7, 2024.

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2024-3-8, Arrowhead has completed the first dosing of subjects in a Phase Ⅰ/Ⅱa double-blind, placebo-controlled, dose-escalation study to evaluate the company's investigational RNA interference (RNAi) therapeutic agent ARO-DM1 in up to 48 subjects with Type 1 Myotonic Dystrophy (DM1) for single and multiple ascending doses.

Among them, ARO-DM1 is designed to reduce the expression of the dystrophia myotonica-protein kinase (DMPK) gene in muscles. The pathogenesis of DM1 is driven by the expanded CUG trinucleotide repeats in the 3' untranslated region of DMPK transcripts, which cause the misregulated splicing of certain messenger RNAs.

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2024-3-6, GenSight Biologics, dedicated to the development and commercialization of innovative gene therapies for retinal neurodegenerative and central nervous system diseases, announced that recent prospective real-world data from the Early Access Program (EAP) confirmed the benefits of LUMEVOQ for patients with Leber's Hereditary Optic Neuropathy.

Data Show That After One Year of LUMEVOQ Treatment, Eyes of Patients with Bilateral Injections Increased by an Average of 1 Best Corrected Visual Acuity (BCVA) from the Lowest Point, Equivalent to +23 ETDRS Letters, Greater Than the Average Gain of 18 Letters in Patients Injected in Only One Eye. In Both Groups, Clinical Improvement Exceeded the Traditional Definition of Clinical Significance, Where a Gain of 15 Letters Is Considered Meaningful. The Safety of Gene Therapy Remains Comparable Between Bilaterally Treated Patients and Unilaterally Treated Patients.

Among them, LUMEVOQ targets Leber's Hereditary Optic Neuropathy (LHON) by utilizing the proprietary Mitochondrial Targeting Sequence (MTS) technology platform. When associated with the target gene, this platform allows the use of AAV vectors (adeno-associated viruses) to specifically address defects within the mitochondria. The target gene is transferred into cells for expression and production of functional proteins, which then shuttle to the mitochondria via specific nucleotide sequences to restore missing or defective mitochondrial function.

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2024-3-4, Avidity Bio, dedicated to the development of AOC drugs, announced new positive long-term data from the MARINA open-label extension (MARINA-OLE) for its investigational drug AOC 1001. The data showed that, compared with END-DM1 natural history data, disease progression in patients with type 1 myotonic dystrophy (DM1) was reversed across multiple endpoints, including vHOT, muscle mass, and activities of daily living. The primary endpoint of the phase III HARBOR trial is video hand opening time (vHOT), with key secondary endpoints including muscle strength measured by grip strength and quantitative muscle testing (QMT) total score, as well as activities of daily living measured by DM1-Activ.

Currently, Avidity is accelerating the initiation of the global Phase III HARBOR trial, which is expected to commence in Q2 2024.

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2024-3-4, Neurogene Achieves Significant Progress in the Field of Rare Neurological Disease Treatment. The company announced that the scale of clinical trials for its innovative gene therapy, NGN-401, under development has significantly expanded. The Phase I/II clinical trial, originally planned to include 5 patients, has now been expanded to 16 patients. This important move aims to more comprehensively and deeply evaluate the safety, tolerability, and preliminary efficacy of NGN-401.

Among them, NGN-401 is a unique gene therapy that uses an adeno-associated virus (AAV) vector to deliver the MECP2 gene, aiming to correct rare genetic disorders caused by abnormal MECP2 gene function. The latest clinical trial results show that the first three patients treated with NGN-401 demonstrated good tolerance. These patients did not experience any serious adverse events directly related to the treatment after receiving it. Moreover, there is currently no evidence indicating that overexpression of the MECP2 gene induces toxic reactions. This positive clinical feedback provides strong support for accelerating the trial process.

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On March 5, 2024, Jingyin Pharma announced that its independently developed novel small nucleic acid FXI anticoagulant drug (SRSD107 injection) received clinical trial approval from the CDE. This is the first small nucleic acid drug targeting this site to be approved in China. Currently, SRSD107 is undergoing Phase I clinical trials in Australia.

Among them, SRSD107 injection is a double-stranded small interfering ribonucleic acid (siRNA) drug independently developed by Jingyin Pharmaceutical with proprietary intellectual property rights. By specifically targeting the liver-directed coagulation factor XI (FXI) mRNA, it inhibits the protein expression of FXI, blocking the activation of the intrinsic coagulation pathway, thereby achieving anticoagulant/antithrombotic effects. Preclinical trial data shows that a single subcutaneous injection of SRSD107 can achieve an almost 100% knockdown effect on FXI expression, lasting up to half a year, without any bleeding observed. With its potent and long-lasting efficacy as well as favorable safety profile, SRSD107 has the potential to become a first-in-class and best-in-class next-generation safer anticoagulant drug.

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On 2024-3-4, Lilly registered the Phase III clinical trial of Lpa siRNA therapy Lepodisiran on the Clinicaltrials.gov website. This Phase III clinical trial plans to enroll 12,500 patients with elevated Lpa who are at risk of atherosclerosis or cardiovascular events, and is expected to be completed by March 2029. At the end of 2023, the Phase I clinical data of Lepodisiran was published in the JAMA journal, showing that one injection of Lepodisiran can maintain efficacy for up to one year.

Among them, Lepodisiran was initially developed by Dicerna. In 2018, Lilly and Dicerna reached a strategic cooperation to develop multiple siRNA therapies, with Lepodisiran being the second pipeline jointly developed by Lilly and Dicerna. Dicerna was acquired by Novo Nordisk for $3.3 billion in 2021.

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On 2024-3-1, DeepTrust Bio registered a Phase I clinical trial in the U.S. for its bivalent RSV mRNA vaccine on Clinicaltrials.gov. This Phase I trial plans to enroll 200 healthy participants, with an expected start date of 2024-8 and preliminary completion by 2026-4.

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On March 6, 2024, Biogen announced interim 6-month biomarker data from the first 29 participants in the open-label RESPOND study. This Phase IV study evaluates the clinical outcomes and safety after 2 years of SPINRAZA treatment in infants and children with spinal muscular atrophy (SMA) whose clinical needs were not met following treatment with Zolgensma (onasemnogene abeparvovec).

New data show that plasma neurofilament light chain (NfL) levels (an objective biomarker of axonal injury and neurodegeneration) were reduced in nearly all study participants treated with SPINRAZA. These data will be presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference (March 3–6, 2024).

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2024-3-7, Solid Bio, dedicated to developing precision gene therapies for neuromuscular and cardiac diseases, announced a non-exclusive global licensing and collaboration agreement with Armatus Bio. Under the agreement, Armatus will use Solid's proprietary capsid AAV-SLB 101 to develop and commercialize its vectored RNAi candidate for the treatment of facioscapulohumeral muscular dystrophy (FSHD). The AAV-SLB 101 capsid has demonstrated enhanced biodistribution and improved expression in muscle cells in preclinical studies.

Under the terms of the agreement, Solid grants Armatus a non-exclusive global license to use AAV-SLB101 for the treatment of FSHD and will provide Armatus with AAV-SLB101 plasmid materials, preclinical data characterizing AAV-SLB101, and manufacturing and regulatory technology to facilitate development. In return, Solid will receive an upfront payment, payments upon the achievement of certain development and sales milestones, and tiered royalties on net sales of any products containing AAV-SLB101. Armatus will be responsible for the development and commercialization of the licensed products containing AAV-SLB101.

Among them, AAV-SLB101 is a proprietary, rationally designed capsid aimed at enhancing muscle tropism and reducing liver uptake. The incorporation of AAV-SLB101 into AAV delivery therapies has the potential to become a significant step in the treatment of neuromuscular and cardiac diseases. Solid Biosciences aims to widely license AAV-SLB101 to companies and academic institutions seeking treatments for rare diseases.

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2024-3-6, Precision BioSciences, a leading gene editing company, announced that its partner iECURE has received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) for its Clinical Trial Authorization (CTA) application to expand the Phase I/II OTC-HOPE study evaluating ECUR-506 into the UK. The OTC-HOPE study is investigating ECUR-506, which includes the ARCUS nuclease, for the treatment of infant ornithine transcarbamylase (OTC) deficiency. The MHRA's CTA approval follows the Australian Therapeutic Goods Administration (TGA) approval to initiate the OTC-HOPE study.

Among them, Precision's novel and proprietary ARCUS® genomic editing platform differs from other technologies in terms of cutting method, smaller size, and simpler structure. Its key functionalities and differentiating features may enable ARCUS nucleases to drive more predictable and well-defined therapeutic outcomes. In 2021, Precision licensed the ARCUS nuclease to iECURE, which inserts a functional copy of the OTC gene for the treatment of OTC deficiency.

Among them, the gene editing approach for iECURE's initial projects (including OTC deficiency) relies on the delivery of two adeno-associated virus (AAV) capsids, each carrying a different payload. ECUR-506 includes two vectors: one is an ARCUS® nuclease vector targeting gene editing at the well-characterized PCSK9 gene site, and the other is a donor vector inserting the desired functional OTC gene. iECURE has obtained the ARCUS nuclease license for ECUR-506 from Precision BioSciences. The nick at the PCSK9 site serves as the insertion site for the OTC gene, providing a potential pathway for the permanent expression of a healthy gene.

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On February 1, 2024, Basking Biosciences announced the completion of a $55 million financing. The proceeds will be used to accelerate the clinical development of its potential "first-in-class" reversible RNA aptamer thrombolytic therapy, BB-031, and to advance the reversal oligonucleotide BB-025, which can rapidly neutralize the pharmacological activity of BB-031, into Phase I clinical trials.

Basking will use the financing to accelerate the clinical development of BB-031. This is a first-in-class reversible RNA aptamer targeting von Willebrand Factor (vWF), designed for rapid onset and short duration of efficacy.

In 2023, Basking Biosciences announced positive Phase I clinical trial results for BB-031, which demonstrated good safety and tolerability with no serious adverse events reported in the study. BB-031 also showed dose-dependent inhibition of vWF. The company plans to initiate a Phase II proof-of-concept trial in acute ischemic stroke (AIS) patients in 2024, while advancing BB-025 into Phase I clinical research.

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James E. D. Thaventhiran, a researcher from the MRC Toxicology Unit at the University of Cambridge, UK, and Professor Anne E. Willis published an article titled "N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting" in Nature.

The article points out that in vitro transcribed (IVT) mRNA can be used to treat human diseases, such as serving as a vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After being transfected into target cells, the mRNA is translated into recombinant proteins, which produce the desired therapeutic effects through their biological activity or immunogenicity. To reduce the immunogenicity of IVT mRNA, modified ribonucleotides are commonly introduced; however, the impact of ribonucleotide modification on the fidelity of mRNA translation has not been thoroughly investigated.

In the article, the author demonstrates that the incorporation of N1-methylpseudouridine (1-methylΨ) into mRNA leads to +1 ribosomal frameshifting. After mice and humans were vaccinated with the mRNA vaccine BNT162b2 containing 1-methylΨ, cellular immunity against the +1 frameshift translation products was observed. The observed +1 ribosomal frameshifting events at ribosome slippage sequences are likely due to ribosome stalling caused by 1-methylΨ during IVT mRNA translation. Additionally, the author shows that synonymous targeted mutations of these slippage sequences can effectively reduce the production of frameshift translation products. In summary, these findings enhance the understanding of how ribonucleotide modifications affect the fidelity of mRNA translation. Although no studies have found that mistranslation of SARS-CoV-2 mRNA vaccines causes adverse effects in humans, the author's research highlights potential off-target effects for future mRNA therapeutics and underscores the importance of mRNA sequence optimization.

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