Moderna announced positive data in the first analysis of safety and activity in its Phase 1 study evaluating escalating doses of mRNA-1944 administered via intravenous infusion in healthy adults. mRNA-1944 encodes for an antibody (CHKV-24) with activity against chikungunya virus. At all three dose levels, the administration of mRNA-1944 led to detectable levels of CHKV-24 antibody in all participants, ranging from 1 µg/mL to 14 µg/mL. These results mark the first systemic mRNA therapeutic to show production of a secreted protein in humans.
mRNA-1944 is being developed with financial support from the Defense Advanced Research Projects Agency (DARPA), an agency of the U.S. Department of Defense. mRNA-1944 is the first development candidate from the Company’s systemic therapeutics modality to start clinical testing and utilizes the same lipid nanoparticle (LNP) formulation as the Company’s rare disease program for methylmalonic acidemia (mRNA-3704).
A total of 22 healthy adults have been enrolled in the study to date. The initial analysis evaluated the safety and pharmacology of intravenous administration of mRNA-1944 at three dose levels of 0.1 mg/kg (n=6), 0.3 mg/kg (n=6) and 0.6 mg/kg (n=4); six participants received placebo.
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Administration of mRNA-1944 resulted in dose-related increases in CHKV-24 antibody levels, with average Cmax antibody levels of 2.0, 7.9 and 10.2 ug/mL at the low, middle and high doses, respectively. At all doses, all participants exceeded the levels of antibody expected to be protective against chikungunya infection (> 1 µg/mL) following a single dose, with the middle and high doses projected to maintain antibody levels above protective levels for at least 16 weeks. All participants also showed circulating neutralizing antibody activity against chikungunya virus replication in an NT50 assay, demonstrating that mRNA-1944 resulted in the production of fully functional protein in vivo.
All participants in the study received antihistamine premedication. No participants received corticosteroids either as premedication or treatment.
None of the participants treated with mRNA-1944 at the low (0.1 mg/kg) or middle (0.3 mg/kg) doses experienced significant adverse events (AEs). Three of the four participants at the high (0.6 mg/kg) dose had infusion-related AEs, with the highest grade by subject being Grade 1 (n=1), Grade 2 (n=1) and Grade 3 (n=1). The Grade 3 AEs were tachycardia and an elevated white blood cell count. The same participant experienced Grade 2 AEs of nausea, emesis, fever and inverted T waves on a routine EKG (without associated cardiac symptoms and which later resolved). The fourth participant at the high dose had no related adverse events. There were no meaningful changes in liver or kidney laboratory results. There have been no serious AEs in the study. All AEs were transient and resolved spontaneously without treatment.
“These Phase 1 data represent a significant scientific breakthrough: this study shows for the first time the ability to generate therapeutic levels of a complex protein in humans through systemic administration of an mRNA, essentially instructing the body to make its own medicines,” said Tal Zaks, M.D., Ph.D., chief medical officer at Moderna. “The findings not only show the potential of mRNA-1944 to protect against chikungunya infection at a well-tolerated dose, but also the ability of our platform to translate therapeutically relevant pharmacology from preclinical species to humans.”
This is an interim analysis of an ongoing study. At this time, the Company has not enrolled the last two participants at the 0.6 mg/kg dose. The Company is evaluating further exploration of the safety and pharmacology of mRNA-1944, which may include repeat dosing or dosing in combination with commonly used steroid premedications to prevent infusion-related reactions.
CHKV-24, the antibody encoded by mRNA-1944, was isolated from B cells of a patient with potent immunity against chikungunya infection by scientists at Vanderbilt University Medical Center. mRNA-1944 is composed of two mRNAs that encode respectively for the heavy and light chains of CHKV-24 that are formulated within Moderna’s proprietary LNP technology for systemic intravenous injection.
“Protection against infectious diseases like chikungunya is urgently needed around the world. While we are often able to identify protective antibodies to emerging infections, a major challenge is the ability to rapidly scale such discoveries into humans,” said James Crowe Jr., M.D., director of the Vanderbilt Vaccine Center. “These exciting data demonstrate a new way to address infectious diseases that uses mRNA to make antibodies in humans, establishing a powerful technology that could be deployable in a pandemic setting.”
The randomized, placebo-controlled Phase 1 study is designed to evaluate the safety and tolerability of up to four escalating doses (0.1, 0.3, 0.6 and 1 mg/kg) of mRNA-1944 administered via intravenous infusion to healthy adults. Secondary objectives are to determine the pharmacology of mRNA-1944 and to evaluate whether the antibodies produced neutralize chikungunya virus in vitro, thereby confirming the potential for passive immunization of individuals via the production of functional circulating antibody. Passive immunity provides transient but rapid protection against an infectious disease and is particularly important when immediate protection is needed, such as in a pandemic setting.
mRNA-1944 encodes a fully human IgG antibody originally isolated from B cells of a patient with a prior history of potent immunity against chikungunya infection. It is composed of two mRNAs that encode the heavy and light chains of this anti-chikungunya antibody within Moderna’s proprietary lipid nanoparticle (LNP) technology. Preclinical data published in Science Immunology have shown mRNA-1944 was well-tolerated, resulted in linear dose-dependent protein expression and provided 100% protection in animal models.
Chikungunya is a mosquito-borne virus that poses a significant public health problem in tropical and subtropical regions. The disease is characterized by an acute onset of fever, rash, muscle pain and sometimes debilitating pain in multiple joints. There are no vaccines approved to prevent chikungunya infection or disease, and effective mosquito control is challenging. Currently, people infected with chikungunya are treated with non-steroidal anti-inflammatory drugs to relieve some symptoms. In addition to a systemic secreted antibody that could provide passive immunity, Moderna is also exploring using mRNA to encode viral antigens as a prophylactic vaccine against the chikungunya virus (mRNA-1388).