Technological Solution Sets to Create Medicines

At Moderna, we combine elements of our mRNA platform into distinct approaches to address diseases. We call these approaches modalities. A modality is a technological solution set that can be deployed to create a family of medicines for different diseases within one therapeutic area, and often across therapeutic areas.

Development Modalities

Once we or our partners have committed to advancing a research program to the clinic, that program is deemed a development candidate, or DC, and moves into Good Laboratory Practice (GLP) Toxicology studies to enable regulatory filings for human studies. Our current pipeline consists of 12 DCs that span the four modalities below. Five DCs are in clinical study, and seven DCs continue to advance to the clinic.

Prophylactic Vaccines

Vaccines work by mimicking an infection from a known pathogen, such as a virus, without causing disease. They teach the immune system to recognize antigens, which are parts of pathogens. Current vaccines introduce antigens to the body as weakened or inactivated pathogens or as selected protein antigens produced recombinantly in cells in bioreactors.

With our prophylactic approach, we deliver mRNA encoding for one or more viral antigenic proteins to the body’s cells. The mRNA directs the cells to produce and express the antigenic proteins, either secreted or on the cell surface, much like a native infection would do but without the ability to cause disease or spread. As a result, the body’s immune system responds as if the actual virus is present. The immune system produces antibodies that have the potential to neutralize the virus and prevent infection in the event the vaccinated person is exposed to the virus in the future.

Moderna has eight prophylactics vaccine development candidates. Five of these programs are currently in clinical study, and three programs are advancing toward the clinic.

Therapeutic Vaccines

Personalized Cancer Vaccines

We also developing mRNA-based personalized cancer vaccines to prime the immune system to recognize cancer cells and mount a strong, tailored response to each individual patient’s cancer. Utilizing our mRNA vaccine technology, we encode a patient’s specific neoantigens, or unique mutations present in that specific patient’s tumor. When injected into a patient, the vaccine is designed to elicit a specific immune response that can recognize and destroy cancer cells.

We are advancing mRNA-4157, our personalized cancer vaccine, through a collaboration with Merck. We believe that our personalized cancer vaccines’ ability to specifically activate an individual patient’s immune system has the potential to be synergistic with checkpoint inhibitor therapies, including Merck’s anti-PD-1 therapy, KEYTRUDA® (pembrolizumab).

Intratumoral Immuno-Oncology

Moderna’s immuno-oncology program focuses on mRNA medicines that, when injected directly into a tumor, direct the localized expression of one or more proteins, which in turn may trigger a stronger T-cell attack against the tumor. T cells are part of the immune system; they identify and mount an attack on infections from viruses or bacteria, as well as cancer. Checkpoint inhibitors enable T cells to better recognize cancer cells as foreign invaders that may otherwise go undetected and, therefore, evade attack. Unfortunately, not all patients respond to treatment with checkpoint inhibitors.

Some of the proteins Moderna’s intratumoral immuno-oncology are focused on eliciting are potent and/or may have toxic or off-target effects if expressed throughout the body. However, when directly injected into a tumor, the desired benefit of the protein can be concentrated in that specific tissue.

Additionally, our intratumoral immuno-oncology mRNA therapeutics may have the potential to elicit an abscopal effect in metastatic cancer, in which localized injection into one tumor would lead not only to shrinking of that tumor but also shrinking of tumors elsewhere in the body.

Intratumoral injection leading to localized expression of therapeutic proteins may open the opportunity to go after new targets to treat cancer, including those where the associated therapeutic potential historically has been limited either by the inability to access these targets or by systemic toxicities. Our intratumoral immuno-oncology therapeutics may generate a potent immune response to cancers alone, or likely in combination with checkpoint inhibitors, as well as the opportunity to create unique co-formulated combinations of mRNAs – delivered to patients as a single medicine, which may present important alternative immunotherapy treatment options for cancer patients.

We currently have two intratumoral immuno-oncology mRNA therapeutics advancing toward the clinic.

Localized Therapeutics

We utilize this modality when we want to direct the localized expression of one or more proteins in targeted tissue but do not want to generate systemic expression of a protein.

The initial application of this modality involves local tissue injection of vascular endothelial growth factor- A (VEGF-A) mRNA, which may potentially lead to the creation of more blood vessels and improved blood supply. Using mRNA to initiate a strong, local and transient surge of VEGF-A expression could help overcome challenges associated with previous approaches to regulate VEGF-A in tissues. One day, this approach could provide a unique regenerative treatment option for patients with heart failure or after a heart attack, as well as for diabetic wound healing and other ischemic vascular diseases.

Our partner AstraZeneca’s VEGF-A mRNA therapeutics development candidate mRNA-1861 is currently in Phase 1 study in Europe.

Research Modalities

We continue to advance many mRNA vaccines and therapeutics through the research stage. Some of these programs utilize one of our Development Modalities.  Additionally, we are advancing a number of research programs that utilize new modalities for which we have not yet advanced a program to the development stage.

Secreted

Certain proteins can have systemic effects after being secreted from cells where they are produced.  One example is antibodies, which are a key component of the immune system.  Antibodies bind to and inhibit specific targets and, when used as drugs, that activity can be harnessed for therapeutic effect.

Moderna is using its modality of systemic intravenous (IV) delivery of mRNA to stimulate the body’s cells to produce specific antibodies that can bind to cellular targets or targets on infectious pathogens.

Our first application of the IV systemic  modality is advancing the discovery of a combination of mRNA-based antibody therapeutics to help prevent human immunodeficiency virus (HIV) infection through a partnership with the Bill & Melinda Gates Foundation. By triggering the production of several neutralizing antibodies, it may be possible to prevent HIV infection.

Liver Intracellular

Many diseases are caused by defects or deficits in proteins that function inside or on the surface membranes of cells. Existing methods of protein-based therapy do not generally allow for proteins to reach the intracellular space or to be inserted onto the surface of cells.  Therefore, they are unable to replace the defective or missing disease-causing proteins within cells.

A large number of diseases, including many rare genetic diseases, are caused by defects or deficits in proteins expressed by liver cells. By delivering mRNA drugs intravenously (IV) to the liver, we can potentially stimulate production of therapeutic proteins in ways that cannot be achieved with other technologies.

Moderna is in the discovery phase with the IV liver therapeutics modality.

Lung

Through our collaboration with Vertex, we are pursuing the potential of delivering mRNA to the lungs (via inhaled delivery) to trigger the cells to produce a functional cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is known to be defective in people with cystic fibrosis (CF). With this modality, mRNA would be used as a drug to direct cells in the lung to produce functional CFTR proteins.  There are more than 1,900 known mutations in the CFTR gene.  An mRNA-based approach could be applicable to any person with CF regardless of a person’s specific CFTR mutations.

CFTR represents our first exploration of this modality, where we are in the discovery phase. It could potentially lead to treatments for other pulmonary diseases in which mRNA could be delivered to the lung to direct cells to produce therapeutic proteins.