AptamiR Therapeutics Summary

Structure: AptamiR is a US modular Biotechnology Company currently executing the pre-clinical development phase of its targeting OligoNucleotide Therapeutic (ONT) drug candidates

Mission: Develop safe, effective and convenient therapeutic agents to cure unmet medical needs:

• The miRNASH Project: Treat fat accumulation, inflammation and necrosis to cure related cardiometabolic disorders (obesity, dyslipidemia, diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD), MASH (Metabolic dysfunction-Associated SteatoHepatitis)) without altering brain functions, but improving patients’ quality of life
• The OvamiR Project: Develop targeting microRNA Oligonucleotide Therapeutics (ONTs) to treat the proliferation, migration, apoptosis, invasion, metastases, differentiation, Epithelial-Mesenchymal Transition and chemoresistance of Epithelial Ovarian Cancer

Strategy: Use the pleiotropic concept of One Drug-Multiple Targets by developing targeting microRNA ONTs which simultaneously modulate several target genes involved in complex diseases like obesity, MAFLD/MASH and ovarian cancer

Accomplishment to date: Proofs of efficacy for our first generation of microRNA-based ONTs were achieved in vitro in primary cultures of human cells and in vivo in specific animal models

Goal for the next 24 months:

• Complete the pre-IND and IND phases for our new generation 2.5 of active targeting miR-22-3p Antagomirs to treat the Metabolic Pandemics obesity, diabetes and fatty liver disease
• Achieve the pre-clinical selection of the microRNA-based active targeting ONTs drug candidates to cure Epithelial Ovarian Cancer (EOC)

Gap to achieve this goal: Secure the first tranche of financing ($10M) of Series B financing

Major milestones:

• Initiate within 2 years the clinical studies for our Generation 2.5 lead miR-22-3p antagomir drug candidate for Metabolic Pandemics
• Initiate within 2 years the clinical studies for our lead microRNA-based active targeting ONT drug candidates to cure High Grade Serous Ovarian Cancer (HGSOC)

End goal:

• Help patients live longer, productive and healthier lives while reducing healthcare costs
• Develop safe, effective, convenient and affordable treatments for:
  • Obesity, diabetes, and MAFLD/MASH
  • Epithelial ovarian cancer

News

1. M. Thibonnier. Criteria for developing active cellular targeting microRNA Oligonucleotide Therapeutics with a Peptide Nucleic Acid backbone for cardio-metabolic pandemics, INNOSC Theranostics and Pharmacological Sciences, Volume 7 Issue 3 (2024).

2. M. Thibonnier & S. Ghosh. Review of the Different Outcomes Produced by Genetic Knock Out of the Long Non-coding microRNA-host-gene MIR22HG versus Pharmacologic Antagonism of its Intragenic microRNA product miR-22-3p. MicroRNA Journal. 2024 Jun 28 doi: 10.2174/0122115366282339240604042154

Global Health & Pharma Technology Award

AptamiR Therapeutics, Inc. was selected as the 2021 Most Innovative Cardio-Metabolic Disorder Therapeutics Biotech Company:

• Oral presentation at the 2021 TIDES USA (Oligonucleotide & Peptide Therapeutics) Conference in Boston, MA:

Title: Oligonucleotide Therapeutics with a Peptide Nucleic Acid Backbone to Treat Metabolic Pandemics

AptamiR Therapeutics is developing its second generation of miRNA antagomirs with a Peptide Nucleic Acid backbone which are conjugated to a fatty acid or a short peptide for targeted and preferential cytoplasmic delivery to adipocytes through the trans-membrane transporter Fatty Acid Translocase (FAT). The effective dose of these drug candidates should be much lower with a greatly improved safety and PK/PD profile, especially their mean residence time inside the targeted cells.

Slides:

• Article recently published in BMJ Open Diab Res Care:

BMJ Open Diab Res Care 2020;8:e001478. doi:10.1136/bmjdrc-2020-001478. PMCID: PMC7534675

Title: Metabolic and Energetic Benefits of microRNA-22 Inhibition

Abstract

Introduction: We previously demonstrated in primary cultures of human subcutaneous adipocytes and in a mouse model of diet- induced obesity that specific microRNA-22- 3p antagomirs produce a significant reduction of fat mass and an improvement of several metabolic parameters. These effects are related to the activation of target genes such as KDM3A, KDM6B, PPARA, PPARGC1B and SIRT1 involved in lipid catabolism, thermogenesis, insulin sensitivity and glucose homeostasis.

Research design and methods: We now report a dedicated study exploring over the course of 3 months the metabolic and energetic effects of subcutaneous administration of our first miR-22- 3p antagomir drug candidate (APT-110) in adult C57BL/6 male mice. Body composition, various blood parameters and energy expenditure were measured at several time-points between week 12 and week 27 of age.

Results: Weekly subcutaneous injections of APT-110 for 12 weeks produced a sustained increase of energy expenditure as early as day 11 of treatment, a significant fat mass reduction, but no change of appetite nor physical activity. Insulin sensitivity as well as circulating glucose, cholesterol and leptin were improved. There was a dramatic reduction of liver steatosis after 3 months of active treatment. RNA sequencing revealed an activation of lipid metabolism pathways in a tissue- specific manner.

Conclusions: These original findings suggest that microRNA-22- 3p inhibition could lead to a potent treatment of fat accumulation, insulin resistance, and related complex metabolic disorders such as obesity, type 2 diabetes mellitus and non- alcoholic fatty liver disease.

• Article recently published in the Journal of Clinical Endocrinology and Metabolism

Title: Study of circulating microRNAs and metabolic parameters during a short-term cold
exposure in healthy adult subjects

J Cell Mol Med 2022 Jan;26(2):548-562. PMCID: PMC8743656

Abstract

Background: The rediscovery of brown adipose tissue (BAT) in adult humans, and the
ability to generate beige adipocytes from white adipocytes suggest that
pharmacological activation of BAT/beige fat hold promise to treat metabolic diseases
like obesity, diabetes mellitus, dyslipidemia and non-alcoholic fatty liver disease.
Several microRNAs (miRNAs) are involved in the regulation of multiple metabolic
pathways and ‘browning “ of adipose tissues.

Aim: This discovery study investigated in healthy adult human subjects whether a short term cold exposure may trigger the release of circulating miRNAs and metabolic factors that could indicate or facilitate the activation of BAT and non-shivering thermogenesis.

Results: In ten healthy male volunteers, wearing a cooling vest perfused at 14ºC for 2 hours reduced the local skin temperature without triggering shivering, increased norepinephrine and blood pressure while decreasing copeptin, C-peptide and hear rate. Circulating miRNAs measured by NGS before and after wearing the cooling vest twice (14ºC or room temperature) identified 196 mature miRNAs with excellent reproducibility over 72 hours. Several miRNAs modulating metabolic gene targets were differentially expressed in response to cold exposure. Common gene and pathway targets of the differentially expressed miRNAs were identified. Significant correlations of miRNA expression to copeptin, norepinephrine and C-peptide were found. A co-expression based miRNA-miRNA network, as well as miRNA pairs displaying differential correlation as a function of temperature were also detected.

Conclusions: This study demonstrates that circulating miRNAs are differentially expressed and co-regulated upon cold exposure in humans, supporting their use as predictive and dynamic biomarkers of cardio-metabolic disorders.