MiNA Therapeutics and Nippon Shinyaku Announce Strategic Collaboration to Advance saRNA Therapies for Rare Neurodegenerative CNS Disorders

Apr 10, 2024 08:21 CST Updated 08:21

MiNA Therapeutics

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Nippon Shinyaku

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April 4, 2024, Pioneer of Small Activating RNA (RNAa) TherapyMiNA TherapeuticsCompanyAnnouncement withNippon Shinyaku Co., Ltd.（Nippon Shinyaku Co., Ltd(hereinafter referred to as "Nippon Shinyaku")Option to enter into a research collaboration and license agreement. The collaboration between the two parties will be used to discover, potentially develop, and commercialize RNAa candidate therapies targeting rare neurodegenerative diseases for which there are currently no treatment options.

According to the agreement, MiNA Therapeutics will utilize its proprietary RNAa algorithm and technology platform to identify and characterize RNAa molecules targeting rare genetic diseases of the central nervous system (CNS). Nippon Shinyaku Co., Ltd. will also have the right to exercise an exclusive license to further research, develop, and commercialize candidate drugs based on early preclinical results.

Almost all monogenic diseases are caused by insufficient or missing gene function expression, rather than overexpression or gain of function, and the same is true for most polygenic diseases. This creates the largest unmet clinical need facing drug development — the demand for gene activation/supplementation therapies, andsaRNA (small activating RNA) isAn excellentMeans to activate genes targeting the cause.

saRNA Pioneer MiNA Therapeutics Partners with "Japanese Small Nucleic Acid Leader" Nippon Shinyaku in a Powerful CollaborationCan RNA illuminate the R&D black hole of CNS?

saRNA: A Targeted Strategy for CNS Gene Activation

At present, the difficulty in CNS drug development seems to have become a consensus. There are many factors hindering CNS drug research and development, including complex disease mechanisms,Drugs are difficult toLow reliability of animal models, difficulties in clinical research, and high patient demands for safety and compliance.

Corresponding to the difficulties in new drug development is the increasing proportion of neurological diseases in the incidence of modern diseases. With the further intensification of societal aging, CNS diseases have become a major global public health issue. According to WHO assessments, globally...Over 1 billion peopleSuffering from CNS diseases.

According to Frost & Sullivan data, the global CNS drug market size in 2019 was$124.5 billion, forThe Fourth Largest Pharmaceutical Market; In the next 15 years, the CNS drug market is expected to maintain steady growth, reaching$172.1 billionLooking at the entire CNS, there is a significant gap in medical needs.

Global Projected CNS Drug Market Size from 2015-2034 (Source: Frost & Sullivan)

Nucleic acid therapeutics have been proven to be a promising option for treating central nervous system (CNS) diseases. In the treatment of CNS diseases, small nucleic acid drugs offer advantages over antibody drugs.With advantages such as rapid drug target screening and high R&D success rates, it is expected to fundamentally address CNS diseases, showing considerable therapeutic potential.。

Currently, there are 6 small nucleic acids in the CNS field on the market.Nusinersen (Spinraza) was approved in 2016 for the treatment of SMA, becoming the first small nucleic acid drug in the CNS field to receive FDA approval; thereafterinotersen（tegsedi）、Patisiran（Onpattro）、Amvuttra(Vutrisiran)、WAINUA(eplontersen)、Qalsody(Tofersen) has been successively approved, mainly targeting rare neurological diseases.In addition,14% of small nucleic acid therapies under research target the central nervous system (CNS) field.

The 6 Approved Small Nucleic Acids in the CNS Field

In addition to Nusinersen, which upregulates similar proteins through the Splice-in mechanism（Spinraza），The marketed small nucleic acids mainly exert their inhibitory effects on disease-causing proteins by degrading or modulating target genes, whileFor target proteins that need to be upregulated, the emergence of the RNA activation (RNAa) mechanism provides a more targeted development strategy for diseases requiring gene activation.

RNAa is an RNA regulatory mechanism that activates target gene expression at the transcriptional level. Small RNA molecules capable of activating gene transcription are called small activating RNAs (saRNAs). As short double-stranded oligonucleotides, saRNAs have a chemical structure similar to small interfering RNAs (siRNAs), but...aRNA isFunctions through the RNA activation (RNAa) mechanism,Recruitment of endogenous transcription complexes to target genes, leading to increased mRNA expression and upregulation of target proteins.。

Since their discovery in the mid-2000s, improvements in saRNA design, synthetic chemistry, and understanding of biology have shaped the maturation of RNA applications.Overall, although no saRNA drugs have been approved for marketing yet, their application potential is enormous:

Multiple activatable targets：The number of target sites that can be activated is extremely large. Multiple studies in mammals have demonstrated that saRNA can activate a variety of genes. If calculated according to the disease landscape,The activated target is at least one order of magnitude higher than the inhibited target.
Agonists Have Broad Application Prospects：Upregulating the expression of certain proteins holds great potential in some CNS diseases.. For example, in the DMD field, utrophin, encoded by the UTRN gene, is structurally and functionally similar to dystrophin, and its upregulation may potentially compensate for the function of dystrophin, andTreat all DMD and BMD patients，Regardless of the location of the DMD mutation。
saRNA is relatively easy to develop into a drug.: The development of agonists is relatively more difficult and risky compared to inhibitors. Currently, whether it is large-molecule or small-molecule drugs,Develop aAgonistIt is extremely difficult in itself.，saRNAThis drug form provides an excellentTargeting the EtiologyActivationGenetic methods。
Less competitive: For inhibitory targets, there will be competition among different types of drugs such as small molecules and antibodies. On the other hand, for activating targets, competition from agonists with other mechanisms is limited, but the range of applicable diseases is very broad.
Cost Controllable: RNAa upregulates target expression with a smaller number of molecules, whichReduced overall research and CMC (Chemistry, Manufacturing, and Control) costs。
Safety: Unlike the introduction of exogenous genetic material that causes abnormalities, RNAa utilizesReversible Upregulation of Endogenous Genes，Good safety and tolerability。

Currently, there are only two companies globally that are commercially developing RNA activation drugs, one of which is the UK-basedMiNA TherapeuticsCompany, another one is founded by Professor Li Longcheng in China.RactagenIn terms of IP origin, MiNA Therapeutics initially obtained the patent license for RNA activation technology from Dr. Li Longcheng's lab at the University of California, San Francisco (UCSF), thereby launching the development of RNA activation drugs. The two companies can be considered to have a "common origin" relationship.

MNCs have naturally also set their sights on the broad application prospects of saRNA in the CNS field. Servier, Eli Lilly, and others have gradually started to acquire assets, mainly targeting MiNA Therapeutics' pipeline.

In January 2021, Servier and MiNA Therapeutics entered into a collaboration agreement to leverage MiNA’s core technology for the development of saRNA (small activating RNA) therapies aimed at treating neurological disorders.
On May 11, 2021, Lilly and MiNA Therapeutics jointly announced that they had reached a drug development partnership. Lilly will utilize MiNA's proprietary small activating RNA (saRNA) technology platform to add five novel drug candidates to its core pipeline, covering areas including cancer, diabetes, immunology, neurodegenerative diseases, and pain. It is reported that Lilly will pay MiNA an upfront fee of $25 million, as well as commercial milestone payments of up to $225 million per product at later stages, totaling up to $1.25 billion.

In terms of clinical progress,saRNA PioneerMiNA TherapeuticsThe first saRNA clinical trial has been conducted for patients with advanced hepatocellular carcinoma, yielding promising results.; Ractigen Therapeutics' First DrugRAG-01 has also recently been in AustraliaCompletion of First Participant Dosing。

MiNA Therapeutics：

The First Small Activating RNA (saRNA) Drug Development Company

MiNA Therapeutics was founded in 2008.Is the first company to use small activating RNA (saRNA) as a molecular entity for drug development.Co., and is currently advancing a proprietary drug pipeline based on saRNA, primarily focusing onCancerAndGenetic DiseasesAt the same time, MiNA Therapeutics collaborates with leading pharmaceutical companies to apply its technology platform across a wide range of therapeutic areas.

MiNA Therapeutics' RNAa technology platform increases the expression of naturally processed mRNA and upregulates target proteins by recruiting endogenous transcription complexes to target genes through RNAa therapy.

1. RNAa is loaded onto the Argonaute protein (Ago) in the cytoplasm, and the active complex is transported into the nucleus.

2. In the nucleus, the Ago complex binds to the promoter elements of target genes or natural antisense transcripts that serve as docking sites.

3. Ago complexes activate gene messenger RNA (mRNA) transcription by recruiting endogenous transcription complexes, including RNA polymerase II (Pol-II).

4. New messenger RNA is naturally processed into proteins. In multiple preclinical models, MiNA has demonstrated the therapeutic potential of upregulating several proteins.

In addition, MiNA has developed a powerfulBioinformatics PlatformTo design RNAa therapies targeting gene activation, enabling RNAa sequences to recognize elements upstream of the mRNA transcription start site and downstream of the polyA site.

MiNA is building a comprehensive patent portfolio covering a large number of RNAa compounds and methods of use, which is based on the work of its founders.Pål SætromThe invention, Pål Sætrom isNorwegian University of Science and Technology(NTNU) Professor of Bioinformatics in the Department of Cancer Research and Molecular Medicine, Professor of Bioinformatics in the Department of Computer and Information Science, primarily engaged in developing and utilizing computational models to predict how changes in gene regulation control development and cause diseases. RNAa-related patents have been assigned by the Norwegian University of Science and Technology to MiNA.

MiNA TherapeuticsFounderPål Sætrom

In delivery technology, MiNA collaborates with leaders in the drug delivery field to obtainSMARTICLES® Liposome Delivery TechnologyAuthorization for the clinical candidate product MTL-CEBPA. SMARTICLES® liposome delivery technology was developed by Novosom and is now owned by Marina Biotech. Similar to SNALP, Smarticles technology can alter its surface charge to enhance stability and endosomal release. Smarticles are composed of cationic, anionic, and neutral lipids. Negatively charged Smarticles avoid the toxic effects commonly associated with positively charged lipids at physiological pH but convert to a positive charge in the acidic environment of the endosome, facilitating their release.

Based on the RNAa technology platform, the company has developedMTL-CEBPAThis is the first small activating RNA to enter clinical trials, which can upregulate C/EBPa, a key regulator of myeloid cell differentiation. Currently, four clinical trials are underway, including: monotherapy, combination with pembrolizumab, combination with sorafenib, and combination with atezolizumab and bevacizumab. The most advanced of these is in Phase II clinical trials.

As the first RNA therapy to enter clinical trials, it was reported at the 2018 ASCO meeting.MTL-CEBPAAs a single-agent therapy for HCC (hepatocellular carcinoma)The good safety profile. After discontinuation of MTL-CEBPA, 5 patients received sorafenib treatment.3Example of Complete Remission (CR), lasting for 7-18 months; among them, 2 patients had relief of lung metastases within 1 year.

At the 2020 ASCO meeting, MiNA Therapeutics once again announced new data on the prospective treatment of MTL-CEBPA in combination with sorafenib:TKIFirst-line TreatmentIn the cohort of 14 evaluable patients,2Example achieves complete remission(CR), 3 cases achieved partial response (PR), and 7 cases had stable disease (SD);TKIDrug ResistanceAmong 10 evaluable patients in the cohort,9Example reaches SD。

In addition to MTL-CEBPA, the company's other small activating RNA (RNAa) product targeting fetal hemoglobin (HbF) has recently released preclinical data.MiNA's HbF program may be the first in vivo functional cure for SCD and β-thalassemia.MiNA's treatment method is to increase the transcription of the HBG gene, enabling patients to produce higher levels of fetal hemoglobin (HbF). HbF is a surplus hemoglobin that, when produced at sufficient levels, has been shown to rescue or cure patients with SCD or β-thalassemia. Results from preclinical in vivo studies indicate,MiNAThe company's RNAa therapeutic drugs can be delivered to erythroid progenitor cells in the bone marrow, and the drug levels are clinically significant for treating β-hemoglobinopathies.

MiNA Therapeutics' HbF product via liposome delivery technologyNOV340, without the need for harmful pre-treatment or complex cellular engineering, can effectively deliver RNAa therapy in vivo. Previously, the NOV340 product has demonstrated its safety and pharmacodynamic activity in clinical trials involving more than 290 patients, including 130 patients treated with MTL-CEBPA, the first RNAa candidate drug developed by MiNA Therapeutics. The company expects to advance its HbF product into preclinical development in 2024, which will be the first product in its genetic medicine portfolio.

To date, MiNA Therapeutics has received 3 rounds of financing. On July 6, 2021, MiNA Therapeutics announcedEli Lilly and CompanyTo make an equity investment of approximately 15 million US dollars in it.

Nippon ShinyakuMedicine:Viltepso™Later, the development of nucleic acid therapy continues

Nippon Shinyaku Co., Ltd..）Originally known as Kyoto Shinyaku, established in 1911, it is a renowned Japanese pharmaceutical, food research and development, and manufacturing enterprise. Its main businesses include pharmaceuticals and functional food products, with pharmaceutical R&D primarily focusing on four key areas: urology, hematology, rare and intractable diseases (such as PAH/pulmonary arterial hypertension, muscular dystrophy, etc.), and gynecology.

The company initially focused on agrochemicals and the food industry, and by the end of the 20th century, began its global expansion, concentrating on novel drug development and health food businesses. Nucleic acid drug developmentThe layout begins withAfter 2020, it has become the mainstay of the company's pipeline:

In its early days, Nippon Shinyaku earned its first fortune through the insecticide Santonin®. In the 1960s, Nippon Shinyaku began to develop new drugs by expanding its R&D facilities (including building new research laboratories) and introduced products through alliances with overseas companies, moving towards the prescription drug sector. It also started its food business around this time.
In the 1990s, the company opened offices in Germany and the United States, and promoted internationalization through business expansion in Japan, the United States, and Europe. It launched distinctive new products in fields such as gastroenterology, cardiology, urology, and otorhinolaryngology, and concentrated its business resources on the research and development of key drugs. In the food business, the company began to provide health food ingredients.
After 2000, Nippon Shinyaku formulated a mid-term management plan, allocating resources in key areas such as urology and hematology, and invested in the Discovery Research Laboratories in Tsukuba.Nucleic Acid DrugsResearch. By actively seeking out unmet medical needs, the company continuously launches products in various fields of large companies, some of which have grown into business drivers.
Starting in 2014, the company proposed "pursuing originality" in its business strategy and has been working to establish a unique foundation by continuously launching new products. This includes the independent development of a small molecule compound and a nucleic acid drug, achieving global expansion, and establishing and developing a new business model for the company, such as buildingNS Pharma, began its marketing in the United States.

In 2020, NS Pharma, a wholly-owned subsidiary of Nippon Shinyaku, launched a treatment for Duchenne muscular dystrophy.Viltepso（viltolarsen), which is the first small nucleic acid drug approved in the United States from an Asian company.VILTEPSO is an antisense oligonucleotide (ASO) drug that works by skipping exon 53, converting out-of-frame deletions in the DMD gene to in-frame deletions for some patients, thereby alleviating symptoms (to approximate the external manifestations of BMD). The drug binds to the pre-mRNA at the position of exon 53 of the DMD gene. After the formation of mature mRNA, the exon 53 portion is excised, thus partially correcting the mRNA reading frame. The drug is administered via intravenous infusion. In August 2020, the U.S. FDA announced...Accelerated ApprovalViltolarsen Launched for the Treatment of DMD Patients Suitable for Exon 53 Skipping Therapy.

VILTEPSO's revenue has entered the "Billion Yuan Club”。The third-quarter report of Japan's new drugs for the fiscal year 2022 (2022.3.31-2023.4.1), released in March 2023, shows that VILTEPSORevenue in the first three quarters was 10.7 billion yuan, including 3.19 billion yen in Japan and 7.53 billion yen in the United States.The Company Forecasts Full-Year Revenue18.3 billion yen($130 million, based on the 2023 average exchange rate of 1 USD = 140.5 JPY)，Compared to 14.34 billion yen in the same period last year, an increase of 27.6%.

Thanks toThe Growth of Viltepso™ for the Treatment of Duchenne Muscular Dystrophy，And royalty income from overseas sales of another marketed drug — Uptravi™ (a treatment for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension).In the fiscal year 2022, Nippon Shinyaku's revenue exceeded 144.175 billion yen, increasing by 4.9% year-on-year. Among this, the pharmaceuticals business accounted for 84.6%, reaching 121.988 billion yen.

Main Financial Data of Nippon Shinyaku in the Past 5 Years

Back to NS Pharma, its research and development in the field of rare diseases such as DMD continues., relying on exon skipping technology,Pipeline RemovalIn addition to the marketed Viltepso, these include NS-089/NCNP-02, NS-050/NCNP-03, NS-051/NCNP-04, as well as NS-229 and NS-161, which are under development for inflammatory diseases.

The most advanced candidate drug isNS-089/NCNP-02（brogidirsen）, an ASO drug targeting DMD patients with exon 44 mutations., and currently there is no ASO therapy for DMD patients receiving exon 44 skipping treatment.。

The therapy was jointly researched and discovered by Nippon Shinyaku, the parent company of NS Pharma, and the National Center of Neurology and Psychiatry (NCNP). The clinical development of NS-089/NCNP-02 includes a planned Phase 2 study conducted by NS Pharma in the United States and a Phase 2 study conducted by Nippon Shinyaku in Japan. In April this year, the FDA agreed to the planned Phase 2 study, which will evaluate the expression of dystrophin and motor function. In July 2023, the drug received FDA Rare Pediatric Disease Designation (RPDD).。

Source:

1.Official Websites and Financial Reports of Various Companies

2.Cortellis

3.RNA Drug Hunter | Wenkai Xie from RiboNova: RNA Activation, China's World-Class "Underlying Technology" in Small Nucleic Acids

4. Frost & Sullivan

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