Moderna Announces Positive Phase 1 Results for the First Systemic Messenger RNA Therapeutic Encoding a Secreted Protein (mRNA-1944)
mRNA-1944 successfully encoded for functional antibody (CHKV-24) in humans at all dose levels tested (0.1, 0.3 and 0.6 mg/kg)
Antibody level predicted to protect against chikungunya infection achieved within hours; projected to be maintained for at least 16 weeks at the middle and high doses
No significant adverse events were observed at the low and middle doses; infusion-related adverse events were observed at the high dose, which resolved spontaneously without treatment
mRNA-1944 is being developed with financial support from the
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.
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
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
“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
“DARPA has been advancing nucleic-acid-based technologies for infectious disease for several years, and the results of this clinical trial validate that approach," said Dr.
DARPA’s financial support of mRNA-1944 is part the Agency’s ADEPT: PROTECT (Autonomous Diagnostics to Enable Prevention and Therapeutics: Prophylactic Options to Environmental and Contagious Threats) initiative. The goal is to develop platform technologies that can be deployed safely and rapidly to provide the U.S. population with near-immediate protection against emerging infectious diseases and engineered biological weapons, even in cases when the pathogen or infectious agent is unknown. For more information about
“These data represent another critical milestone for the validation of Moderna’s mRNA platform in humans,” said Stéphane Bancel, Moderna’s chief executive officer. “This is the fifth modality for which we have shown translation from preclinical research to humans and the first demonstration of mRNA as a systemic therapeutic capable of creating high levels of protein at a well-tolerated dose. We believe these results further validate our approach, the scientific platform we have built and the potential of mRNA to become a new class of medicines. We look forward to learning from the ongoing Phase 1/2 study of mRNA-3704 for methylmalonic acidemia, the first of our rare disease programs to enter the clinic, as it utilizes the same technology demonstrated in this chikungunya study.”
About the Study
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.
More information about the study can be found at ClinicalTrials.gov. Full Phase 1 data will be presented at a future medical meeting.
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,
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Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended including, but not limited to, statements concerning: predicted levels to protect against chikungunya infection; projected protection against chikungunya infection for at least sixteen weeks at the 0.3 and 0.6 mg/kg doses of mRNA-1944;
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