Playing Genes: RNA-Based Therapeutics

In 2023, the global RNA therapeutics market was valued at approximately USD 19.2 billion, with expectations to reach USD 31.1 billion by 2032, growing at a CAGR of 5.7% during the forecast period (Global Market Insights Inc.) (Grand View Research).

The market share of RNA-based therapeutics within the clinical research market is growing, driven by advancements in technology and increasing investments.

RNA-based therapeutics, including mRNA, RNA interference (RNAi), and antisense oligonucleotides (ASOs), are gaining traction, especially after the success of mRNA vaccines for COVID-19. The RNA-based vaccine segment held a significant market share, contributing to the overall growth of RNA therapeutics (Grand View Research). Despite this, RNA therapeutics still represent a smaller portion of the overall clinical research market compared to more established modalities like monoclonal antibodies (mAbs) and other biologics.

While RNA-based therapeutics are an exciting and rapidly growing segment within the clinical research market, they still comprise a smaller market share compared to more established therapies like monoclonal antibodies. For comparison, the market for monoclonal antibodies (mAbs) is substantially larger. In 2022, the global mAbs market was valued at over USD 150 billion, and it continues to grow at a robust pace due to their widespread application in treating cancer, autoimmune diseases, and infectious diseases (Market Research Future). The innovative potential and recent successes in RNA technologies suggest that their market share will continue to increase as more products gain regulatory approval and reach commercialization.

Leading Companies, Clinical Applications and Therapeutic Areas

mRNA Vaccines

The COVID-19 pandemic highlighted the potential of mRNA vaccines, with Pfizer-BioNTech and Moderna's vaccines achieving rapid development and widespread use. These vaccines have demonstrated the ability of mRNA technology to respond quickly to emerging infectious diseases.

As of now, there are no mRNA therapies (distinct from vaccines) that have been fully approved for market authorization and are available via pharmacy prescription for the general population. The majority of mRNA-based treatments in development are still undergoing clinical trials or are in early stages of research.

However, the landscape of mRNA therapeutics is rapidly evolving. Several promising mRNA therapies are being researched for various conditions, including cancer, genetic disorders, and infectious diseases. These therapies aim to harness the body's cellular machinery to produce therapeutic proteins directly within the patient's cells, offering a potentially powerful and precise approach to treatment.

While mRNA vaccines for COVID-19, such as those developed by Pfizer-BioNTech and Moderna, have demonstrated the viability and potential of mRNA technology, the translation of this success to other types of mRNA-based therapies is still in progress.

Here are ten leading companies with mRNA investigational products in their pipelines, along with the therapeutic areas and specific indications they are targeting:

1. Moderna, Inc.

• Therapeutic Areas: Oncology, Rare Diseases, Cardiovascular, Infectious Diseases

• Indications: Cancer vaccines (e.g., personalized cancer vaccines), methylmalonic acidemia (MMA), propionic acidemia (PA), cytomegalovirus (CMV), Zika virus, Chikungunya virus, and heart failure.

2. BioNTech SE

• Therapeutic Areas: Oncology, Infectious Diseases, Rare Diseases

• Indications: Cancer immunotherapies (e.g., melanoma, non-small cell lung cancer), HIV, tuberculosis, influenza, and personalized cancer vaccines.

3. CureVac N.V.

• Therapeutic Areas: Oncology, Infectious Diseases, Rare Diseases

• Indications: Prostate cancer, non-small cell lung cancer (NSCLC), rabies, yellow fever, COVID-19, and infectious diseases vaccines.

4. Translate Bio (a Sanofi company)

• Therapeutic Areas: Pulmonary Diseases, Infectious Diseases

• Indications: Cystic fibrosis, primary ciliary dyskinesia (PCD), and influenza vaccines.

5. Arcturus Therapeutics

• Therapeutic Areas: Infectious Diseases, Liver Diseases

• Indications: COVID-19, hepatitis B, and ornithine transcarbamylase (OTC) deficiency.

6. eTheRNA Immunotherapies

• Therapeutic Areas: Oncology, Infectious Diseases

• Indications: Melanoma, human papillomavirus (HPV), and COVID-19.

7. Gritstone Oncology

• Therapeutic Areas: Oncology, Infectious Diseases

• Indications: Personalized cancer vaccines, neoantigen-based immunotherapies, and COVID-19.

8. Ethris GmbH

• Therapeutic Areas: Respiratory Diseases, Genetic Disorders

• Indications: Cystic fibrosis, primary ciliary dyskinesia (PCD), and other pulmonary conditions.

9. Chimeron Bio

• Therapeutic Areas: Oncology, Infectious Diseases

• Indications: Cancer immunotherapies, COVID-19, and other viral infections.

10. Tiba Biotech

• Therapeutic Areas: Infectious Diseases, Oncology

• Indications: COVID-19, influenza, and cancer vaccines.

These companies are at the forefront of developing mRNA-based therapies, and their investigational products are in various stages of clinical trials. The success of these trials could potentially lead to new mRNA therapies available for the general population in the future.

RNAi-Based Therapies

RNAi therapies have shown promise in treating genetic disorders. These treatments work by silencing specific genes to prevent the production of harmful proteins. RNA interference (RNAi) is a natural cellular process that inhibits gene expression by neutralizing targeted mRNA molecules. This mechanism has been harnessed to develop therapies for various diseases, particularly genetic disorders and cancers. RNAi therapies work by introducing small interfering RNAs (siRNAs) that specifically bind to the mRNA of the disease-causing gene, leading to its degradation and preventing the production of harmful proteins. Here are ten leading companies developing RNA interference (RNAi) therapeutics:

1. Alnylam Pharmaceuticals

• Therapeutic Areas: Genetic disorders, cardiometabolic diseases, hepatic infectious diseases, CNS diseases.

• Key Products/Indications: Patisiran (hereditary transthyretin-mediated amyloidosis), Givosiran (acute hepatic porphyria), Lumasiran (primary hyperoxaluria type 1), Inclisiran (hypercholesterolemia).

2. Ionis Pharmaceuticals

• Therapeutic Areas: Cardiovascular, metabolic, neurological, and rare diseases.

• Key Products/Indications: TTR amyloidosis, Huntington's disease, hyperlipidemia, spinal muscular atrophy (through collaborations).

3. Dicerna Pharmaceuticals (acquired by Novo Nordisk)

• Therapeutic Areas: Rare diseases, chronic liver diseases, cardiovascular diseases.

• Key Products/Indications: Primary hyperoxaluria, chronic hepatitis B, complement-mediated diseases.

4. Arrowhead Pharmaceuticals

• Therapeutic Areas: Hepatic diseases, cardiovascular, oncology, respiratory diseases.

• Key Products/Indications: Hepatitis B, alpha-1 antitrypsin deficiency, hypertriglyceridemia, cystic fibrosis.

5. Silence Therapeutics

• Therapeutic Areas: Hematology, cardiovascular, metabolic diseases.

• Key Products/Indications: Iron overload disorders, cardiovascular diseases.

6. Vir Biotechnology

• Therapeutic Areas: Infectious diseases.

• Key Products/Indications: Hepatitis B, influenza.

7. Regulus Therapeutics

• Therapeutic Areas: Genetic and metabolic diseases.

• Key Products/Indications: Alport syndrome, autosomal dominant polycystic kidney disease.

8. Arbutus Biopharma

• Therapeutic Areas: Hepatitis B, liver diseases.

• Key Products/Indications: Chronic hepatitis B.

9. Quark Pharmaceuticals

• Therapeutic Areas: Ophthalmology, renal diseases.

• Key Products/Indications: Acute kidney injury, diabetic macular edema.

10. Benitec Biopharma

• Therapeutic Areas: Genetic diseases, oncology, infectious diseases.

• Key Products/Indications: Oculopharyngeal muscular dystrophy, hepatitis B, head and neck squamous cell carcinoma.

These companies are at the forefront of RNAi therapeutic development, working on a range of indications that leverage the gene-silencing capabilities of RNA interference to treat various diseases.

CRISPR-based genome editing

CRISPR-based genome editing is a rapidly advancing field with significant potential for treating a wide range of genetic disorders. Here are ten leading companies developing CRISPR-based therapeutics:

1. Editas Medicine

• Therapeutic Areas: Genetic eye diseases, hematologic diseases.

• Key Products/Indications: EDIT-101 for Leber congenital amaurosis 10 (LCA10), EDIT-301 for sickle cell disease and beta-thalassemia.

2. CRISPR Therapeutics

• Therapeutic Areas: Hematologic diseases, cancer, diabetes.

• Key Products/Indications: CTX001 for sickle cell disease and beta-thalassemia (in collaboration with Vertex Pharmaceuticals), allogeneic CAR-T cell therapies for cancer.

3. Intellia Therapeutics

• Therapeutic Areas: Genetic diseases, immuno-oncology, infectious diseases.

• Key Products/Indications: NTLA-2001 for transthyretin amyloidosis (ATTR), NTLA-2002 for hereditary angioedema (HAE).

4. Beam Therapeutics

• Therapeutic Areas: Genetic diseases, cancer.

• Key Products/Indications: BEAM-101 for sickle cell disease, BEAM-102 for beta-thalassemia, BEAM-201 for T-cell acute lymphoblastic leukemia (T-ALL).

5. Sangamo Therapeutics

• Therapeutic Areas: Genetic diseases, oncology, immunology.

• Key Products/Indications: ST-400 for beta-thalassemia, CAR-Treg therapies for solid organ transplantation.

6. Caribou Biosciences

• Therapeutic Areas: Oncology, genetic diseases.

• Key Products/Indications: CB-010, an allogeneic anti-CD19 CAR-T cell therapy for non-Hodgkin lymphoma.

7. Precision BioSciences

• Therapeutic Areas: Oncology, genetic diseases.

• Key Products/Indications: PBCAR0191, an allogeneic CAR-T cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma.

8. Mammoth Biosciences

• Therapeutic Areas: Genetic diseases, diagnostics.

• Key Products/Indications: Developing CRISPR-based diagnostic tools and potential therapeutics for various genetic disorders.

9. Graphite Bio

• Therapeutic Areas: Genetic diseases.

• Key Products/Indications: GPH101 for sickle cell disease.

10. Verve Therapeutics

• Therapeutic Areas: Cardiovascular diseases.

• Key Products/Indications: VERVE-101 for heterozygous familial hypercholesterolemia.

Market Authorization

As of now, no CRISPR-based therapeutics have received full market authorization. However, some are in advanced stages of clinical development:

• CTX001 by CRISPR Therapeutics and Vertex Pharmaceuticals for sickle cell disease and beta-thalassemia is in late-stage clinical trials and showing promising results.

The field of CRISPR-based therapeutics is dynamic, and many of these companies are progressing towards clinical applications that could lead to market authorization in the near future.

Aptamer-based therapeutics

Aptamer-based therapeutics are an exciting area of biopharmaceutical development, utilizing short, single-stranded nucleic acids that can bind to specific targets with high affinity and specificity. Here are ten leading companies in the development of aptamer-based therapeutics:

1. Aptamer Group

• Therapeutic Areas: Oncology, ophthalmology, infectious diseases.

• Key Products/Indications: Development of aptamers for diagnostic and therapeutic applications across various diseases.

2. NOXXON Pharma

• Therapeutic Areas: Oncology, inflammatory diseases.

• Key Products/Indications: NOX-A12 for glioblastoma and metastatic pancreatic cancer, NOX-E36 for diabetic nephropathy.

3. Ophthotech Corporation (now IVERIC bio)

• Therapeutic Areas: Ophthalmology.

• Key Products/Indications: Zimura (avacincaptad pegol) for geographic atrophy and wet age-related macular degeneration.

4. SomaLogic

• Therapeutic Areas: Diagnostics, cardiovascular diseases.

• Key Products/Indications: SomaScan platform for diagnostic applications, research collaborations to develop therapeutic aptamers.

5. AptaBio

• Therapeutic Areas: Oncology, inflammatory diseases.

• Key Products/Indications: Apta-16 for cancer immunotherapy, various aptamers for inflammatory diseases.

6. NeoVentures Biotechnology

• Therapeutic Areas: Diagnostics, agriculture, therapeutics.

• Key Products/Indications: Development of aptamer-based diagnostic tools and therapeutic agents.

7. Base Pair Biotechnologies

• Therapeutic Areas: Oncology, infectious diseases, diagnostics.

• Key Products/Indications: Custom aptamer development for therapeutic and diagnostic applications.

8. Aptus Biotech

• Therapeutic Areas: Oncology, infectious diseases.

• Key Products/Indications: Aptamer-based therapies and diagnostics for various conditions.

9. Amgen

• Therapeutic Areas: Oncology, cardiovascular diseases.

• Key Products/Indications: Collaboration with SomaLogic to develop aptamer-based therapeutics.

10. Therapeutic Aptamer Consortium

• Therapeutic Areas: Various diseases.

• Key Products/Indications: Collaborative effort to advance aptamer-based therapies for multiple indications.

Market Authorization

As of now, only one aptamer-based therapeutic has received market authorization:

• Macugen (pegaptanib sodium) by Eyetech Pharmaceuticals and Pfizer for the treatment of neovascular (wet) age-related macular degeneration. Macugen was the first aptamer-based drug approved by the FDA in 2004.

While Macugen remains the only fully approved aptamer-based therapeutic, several other candidates are in various stages of clinical development, and the field continues to advance with ongoing research and new clinical trials.

Aptamers in diagnostic applications

Aptamers have shown great promise in diagnostic applications due to their high specificity and affinity for target molecules. Here are some notable examples of aptamer-based diagnostics:

1. SomaScan by SomaLogic

• Application: A high-throughput proteomics platform that uses aptamers to measure thousands of proteins simultaneously in biological samples.

• Use Cases: Biomarker discovery, disease diagnosis, and monitoring, personalized medicine.

2. Aptasensor for Mycotoxin Detection

• Application: Rapid detection of mycotoxins (e.g., aflatoxin, ochratoxin) in food and agricultural products using aptamer-based sensors.

• Use Cases: Food safety and quality control.

3. Aptamer-based Lateral Flow Assays

• Application: Point-of-care diagnostic tests that use aptamers in lateral flow assay formats, similar to home pregnancy tests.

• Use Cases: Rapid detection of various pathogens and biomarkers, such as in infectious disease diagnostics (e.g., detecting HIV, Zika virus).

4. Aptamer-based Electrochemical Biosensors

• Application: Biosensors that use aptamers immobilized on electrodes to detect specific targets through changes in electrical signals.

• Use Cases: Detection of biomarkers for diseases like cancer, cardiovascular diseases, and infectious diseases.

5. Aptamer-based Fluorescence Assays

• Application: Aptamers conjugated with fluorescent labels to detect the presence of specific molecules through fluorescence changes.

• Use Cases: Laboratory diagnostics for detecting proteins, small molecules, and pathogens in clinical samples.

6. Aptamer-based Flow Cytometry

• Application: Using aptamers as probes in flow cytometry to identify and quantify specific cell populations or biomarkers.

• Use Cases: Cancer diagnostics, immunophenotyping, and stem cell research.

7. SELEX (Systematic Evolution of Ligands by EXponential Enrichment) Technology

• Application: A method for selecting high-affinity aptamers for various targets, used in developing diagnostic tools.

• Use Cases: Creating customized aptamers for specific diagnostic applications in clinical and research settings.

8. Aptamer-based Enzyme-linked Aptamer Assay (ELAA)

• Application: Similar to ELISA, but uses aptamers instead of antibodies to detect specific proteins or other molecules.

• Use Cases: Quantitative measurement of biomarkers in research and clinical diagnostics.

9. Aptamer-based Imaging Agents

• Application: Aptamers conjugated with imaging agents (e.g., fluorophores, radionuclides) for targeted imaging in medical diagnostics.

• Use Cases: Imaging tumors, atherosclerotic plaques, and other disease sites in vivo.

10. Aptamer-based Paper-based Diagnostic Devices

• Application: Portable, paper-based diagnostic devices that use aptamers for rapid, on-site detection of various analytes.

• Use Cases: Low-cost, point-of-care diagnostics in resource-limited settings for diseases like malaria, tuberculosis, and environmental monitoring.

These examples illustrate the versatility and potential of aptamer-based diagnostics in various fields, including healthcare, food safety, environmental monitoring, and research. The specificity and binding affinity of aptamers make them powerful tools for developing sensitive and reliable diagnostic assays.

Therapeutic oligonucleotides (ASOs)

Antisense oligonucleotides (ASOs) are short, synthetic strands of nucleic acids designed to bind to specific mRNA sequences, thereby modulating gene expression. This technology has made significant strides, and several ASOs have received regulatory approval for clinical use, with many more in development. Here’s an overview of the current status and clinical applications of ASOs:

Current Status of ASO Technology

1. Mechanism of Action: ASOs can:

• Block translation: By binding to mRNA, preventing the production of harmful proteins.

• Modulate splicing: By altering splicing patterns to produce functional proteins.

• Induce degradation: By recruiting RNase H to degrade the target mRNA.

2. Delivery: ASOs are typically administered via injection (intravenous, subcutaneous, or intrathecal) due to poor oral bioavailability. Advances in delivery systems are ongoing to improve tissue targeting and reduce off-target effects.

3. Design and Modification: Chemical modifications (e.g., 2'-O-methyl, 2'-O-methoxyethyl, phosphorothioate backbones) enhance stability, binding affinity, and resistance to nucleases.

Approved ASO Therapies

Several ASO therapies have been approved by regulatory agencies such as the FDA and EMA:

1. Nusinersen (Spinraza)

• Developer: Biogen

• Indication: Spinal Muscular Atrophy (SMA)

• Mechanism: Modifies splicing of SMN2 to increase production of functional SMN protein.

2. Eteplirsen (Exondys 51)

• Developer

Nusinersen (Spinraza)

• Developer: Biogen

• Indication: Spinal Muscular Atrophy (SMA)

• Mechanism: Modifies splicing of SMN2 to increase production of functional SMN protein.

3. Eteplirsen (Exondys 51)

• Developer: Sarepta Therapeutics

• Indication: Duchenne Muscular Dystrophy (DMD) amenable to exon 51 skipping

• Mechanism: Induces exon skipping to restore the reading frame of the dystrophin gene, producing a truncated but functional dystrophin protein.

4. Inotersen (Tegsedi)

• Developer: Ionis Pharmaceuticals/Akcea Therapeutics

• Indication: Hereditary Transthyretin-Mediated Amyloidosis (hATTR)

• Mechanism: Reduces production of transthyretin (TTR) protein to decrease amyloid deposits.

5. Golodirsen (Vyondys 53)

• Developer: Sarepta Therapeutics

• Indication: Duchenne Muscular Dystrophy (DMD) amenable to exon 53 skipping

• Mechanism: Induces exon skipping to restore the reading frame of the dystrophin gene, producing a truncated but functional dystrophin protein.

6. Viltolarsen (Viltepso)

• Developer: NS Pharma

• Indication: Duchenne Muscular Dystrophy (DMD) amenable to exon 53 skipping

• Mechanism: Induces exon skipping to produce a truncated but functional dystrophin protein.

7. Milasen

• Developer: Custom-made for a single patient by Boston Children’s Hospital

• Indication: CLN7 Batten Disease

• Mechanism: Personalized ASO designed to correct a specific mutation in the CLN7 gene.

Clinical Applications

Neurological Disorders:

• ASOs have shown promise in treating genetic neurological disorders, such as SMA and DMD, by modifying splicing or reducing toxic protein levels.

• Ongoing research includes Huntington’s disease (e.g., tominersen) and amyotrophic lateral sclerosis (ALS) with SOD1 mutations (e.g., tofersen).

Genetic Disorders:

• ASOs can target specific genetic mutations, making them suitable for rare diseases like hATTR and various forms of muscular dystrophy.

Oncology:

• ASOs are being explored to silence oncogenes or genes involved in cancer progression. Examples include targeting BCL-2 in chronic lymphocytic leukemia (CLL) and MYC in various cancers.

Metabolic Diseases:

• ASOs are being developed to treat conditions like hyperlipidemia. Volanesorsen, for example, targets apolipoprotein C-III (APOC3) to reduce triglyceride levels in familial chylomicronemia syndrome (FCS).

Ocular Diseases:

• ASOs are under investigation for retinal diseases, including inherited retinal dystrophies, where localized delivery to the eye can effectively reduce or modify harmful protein expression.

Challenges and Future Directions

1. Delivery: Enhancing tissue-specific delivery and reducing off-target effects are ongoing challenges.

2. Safety: Addressing immunogenicity and other adverse effects associated with long-term ASO therapy.

3. Cost: High development and production costs pose economic challenges for widespread adoption.

The field of ASO therapeutics is expanding rapidly, with ongoing research and clinical trials exploring their potential for a broad range of diseases. Continued advancements in delivery methods, chemical modifications, and a deeper understanding of disease mechanisms will likely enhance the efficacy and safety of ASO-based treatments.

Cold-Chain Storage and Logistics for RNA-Based Therapeutics

RNA-based therapeutics, including mRNA vaccines and treatments using RNA interference (RNAi) and antisense oligonucleotides (ASOs), often require stringent cold-chain storage and logistics. This requirement significantly impacts the cost and complexity of conducting international multicenter clinical trials compared to traditional pharmaceutical forms like tablets or capsules, which typically require only ambient storage.

1. Storage Requirements:

• mRNA Therapies: mRNA molecules are inherently unstable and prone to degradation. For instance, mRNA vaccines like Pfizer-BioNTech's Comirnaty require ultra-cold storage at -70°C (-94°F) during transportation and storage before being thawed for use (Market Research Future).

• RNAi and ASOs: These molecules also require cold storage, though not typically as extreme as mRNA. They generally need refrigeration at 2-8°C (35.6-46.4°F) to maintain stability .

2. Logistics:

• Cold Chain Infrastructure: Ensuring the integrity of RNA-based therapeutics necessitates a continuous cold chain from manufacturing to administration. This includes specialized containers, real-time temperature monitoring, and reliable cold storage facilities at clinical sites .

• Cost Implications: Cold chain logistics are considerably more expensive than ambient storage. Costs include specialized packaging, cold storage units, and temperature-controlled transportation, which can significantly increase the overall budget for clinical trials .

Cost Comparison with Traditional Pharmaceutical Forms

1. Traditional Pharmaceutical Forms:

• Storage: Tablets and capsules are generally stable at room temperature (15-25°C or 59-77°F), which simplifies storage and distribution logistics.

• Logistics: Transportation and storage for ambient pharmaceuticals are less costly and less complex, reducing the overall cost for clinical trials .

2. International Multicenter Clinical Trials:

• RNA-Based Therapeutics: The need for stringent temperature control increases logistical costs, including specialized transport containers and monitoring systems. It also necessitates infrastructure at clinical sites capable of maintaining required temperatures, potentially limiting the choice of sites and increasing costs further .

• Tablets/Capsules: Ambient storage pharmaceuticals can be shipped and stored with standard logistics, significantly lowering costs and simplifying the logistics of international trials.

Summary

The cold-chain requirements for RNA-based therapeutics add a layer of complexity and expense to their clinical development compared to traditional pharmaceuticals like tablets or capsules. The need for continuous temperature control, specialized packaging, and infrastructure increases costs for sponsors running international multicenter clinical studies. These additional costs can be substantial, impacting the overall budget and logistics planning for such trials .

Tags: RNA-based therapeutics, mRNA vaccines, RNA interference, antisense oligonucleotides, clinical trials, biotech investment, genetic disorders, drug delivery systems, long-term safety, personalized medicine