Using mRNA to Encode Biologics: Charting a Potential New Course for Medicine

February 5, 2019
 

Stephen Hoge, M.D.
President


Today, Moderna announced that we dosed the first monoclonal antibody encoded by mRNA in a human. mRNA-1944 is an antibody against Chikungunya virus and the first development candidate from Moderna’s systemic therapeutics modalities to start clinical testing. This marks an important moment for our team and their efforts to develop a new class of medicines based on mRNA.

Monoclonal antibodies and other biologics are mainstays of modern medicine. They have incredibly diverse uses, from attacking cancer to preventing severe asthma attacks to improving bone density in people with osteoporosis. Currently, the industry relies on complex manufacturing processes that use engineered cultured cell lines to produce and purify biologics at scale.

With mRNA-1944 we hope to show that we can use mRNA to give the instructions for making biologics, in this case an antibody, directly to a person’s cells to produce the protein using the body’s natural protein-making machinery. This investigational medicine is composed of two mRNAs that encode the key components of an antibody (a heavy chain and a light chain) against the Chikungunya virus, both encapsulated within our proprietary lipid nanoparticle (LNP) technology. The sequence of the mRNA was isolated by academic collaborators at Vanderbilt University from the immune system of a person who developed potent immunity against the virus. Once administered by infusion, we expect the LNP to deliver the mRNA to target cells in the body to make the protein, principally in the liver.

Our Phase 1 study [NCT03829384] will examine the safety and tolerability of mRNA-1944 in healthy adults. Additionally, it will evaluate the ability of our mRNA-encoded antibodies to neutralize the virus.

Why a Chikungunya Antibody?

We chose to advance this program for two main reasons.

First, there are currently no effective therapies or approved vaccines to treat or prevent Chikungunya infection, which is characterized by by an acute onset of fever, rash, muscle pain and sometimes debilitating pain in multiple joints. This is of special concern to groups like government or non-govermental organizations who may need to respond to a crisis in a Chikunguyna endemic area and lack an intervention to create rapid protection against the virus or what we call “passive immunity”. The research and development of mRNA-1944 was financially supported by the Defense Advanced Research Projects Agency or DARPA, an agency of the U.S. Department of Defense.

The second reason relates to our platform. An antibody represents an ideal vehicle for proving our mRNA platform technology. We can collect blood from clinical trial participants and confirm the expression level and biological activity of the antibody (via neutralization of the Chikungunya virus). Given that monoclonal antibodies have well understood pharmacokinetics and pharmacodynamics, we can also learn about the dose-dependent performance of our platform, which may help us advance this program as well others that rely on similar technologies.

The Path Forward

We group our investigational medicines into distinct categories called modalities, which are based on similarities in mRNA, delivery technologies and manufacturing processes. Two of these modalities are designed to have systemic therapeutic effects, meaning effects throughout the body. Today’s announcement about mRNA-1944 marks the fifth modality – called “systemic secreted therapeutics” – that has advanced an investigational medicine into clinical testing. As implied by the name, the focus of our “secreted” modality is to have the body create proteins, such as antibodies or enzyme replacement therapies, that act outside the cell to treat or prevent a disease.

We also believe this study will help us as we advance our first program from our sixth modality, “systemic intracellular therapeutics.” The focus of our “intracellular” modality is to produce proteins inside the cell, including inside organelles like mitochondria that are out of the reach of biologics. This could help us treat rare genetic diseases that have no disease-modifying treatment, including methylmalonic acidemia or MMA.

Among some companies in the biopharmaceutical industry with large portfolios, the beginning of a Phase 1 study could be considered an ordinary event. However, as we launch our 12th Phase 1 study in three years, we remain as enthusiastic and as deeply excited about this milestone as if this were our first Phase 1 study. Our mission is to create a fundamentally new class of medicines with mRNA therapeutics that can help patients with a wide range of conditions. The only way to achieve this goal is to make steadfast, iterative progress, where each advance builds upon the next. Today’s announcement is an important part of that path forward.