Moderna Therapeutics Trial Results
Moderna Therapeutics (MRNA) trial results mark the first systemic mRNA therapeutic to show the production of a secreted protein in humans.
Moderna’s Product 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). The antibody level reached is predicted to protect against chikungunya infection achieved within hours. It is projected to be maintained for at least 16 weeks at the middle and high doses.
mRNA-1944 encodes for CHKV-24 against chikungunya virus. At all three dose levels the administration of mRNA-1944 led to detectable levels of the CHKV-24 antibody in all participants. These results mark the first systemic mRNA therapeutic to show the production of a secreted protein in humans.
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.
The financial support for mRNA-1944 development has come from the Defense Advanced Research Projects Agency (DARPA), an agency of the U.S. Department of Defense. The product is the first development candidate from Moderna’s systemic therapeutics modality to start clinical testing utilizing the same lipid nanoparticle (LNP) formulation as the Company’s rare disease program for methylmalonic acidemia (mRNA-3704).
DARPA’s financial support of mRNA-1944 is 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 DARPA please visit, http://www.darpa.mil/about-us/about-darpa.
Intravenous Administration of mRNA-1944 Results
Intravenous administration of mRNA-1944 resulted in dose-related increases in CHKV-24 antibody levels.
At all doses, all participants exceeded the levels of antibody expected to protect them 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 only antihistamine premedication. and no corticosteroids were used as premedication or treatment.
None of the participants treated with mRNA-1944 at the low or middle doses experienced significant adverse events (AEs).
In the high dose: Three of the four participants had infusion-related AEs with the highest grade by subject being Grade 1, Grade 2 and Grade 3. The Grade 3 AEs were tachycardia and an elevated white blood cell count. These participants 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.
In low and middle doses no significant adverse events were observed. In high doses infusion-related adverse events were observed. They resolved spontaneously without need for treatment.
These positive results came from 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.
A Comment from Moderna Therapeutics
Explaining the reason that the Phase 1 data represent a significant scientific breakthrough, Tal Zaks, M.D., Ph.D., Chief Medical Officer at Moderna, stated that, the study has demonstrated 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. Dr. Zaks added, “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, Moderna has not enrolled the last two participants at the 0.6 mg/kg dose. The firm 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 pre-medication to prevent infusion-related reactions.
The Product History of mRNA-1944
The antibody CHKV-24, which is 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.
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).
As Stéphane Bancel, Moderna’s Chief Executive Officer, stated, the data from the trial add to the validation of Moderna’s mRNA platform in humans. The CEO reminded that this is the fifth modality for which Moderna has 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.
The current results further validate Moderna’s approach, the scientific platform it built and the potential that its mRNA products become a new class of medicines.
We are also looking forward to learning from the ongoing Phase 1/2 study of mRNA-3704 for methylmalonic acidemia; the first of Moderna’s rare disease programs to enter the clinic as it utilizes the same technology demonstrated in this chikungunya study.
By the way, Moderna has also announced today positive interim Phase 1 data for its mRNA-1647 cytomegalo virus or CMV vaccine. A summary of data from both the antibody against chikungunya virus and CMV vaccine programs was presented at the Company’s annual R&D Day held today in New York City beginning at 8:30 a.m. ET.
Cytomegalovirus (CMV) Vaccine
Moderna is advancing mRNA-1647 CMV vaccine to a Phase 2 study and preparations have already begun for a pivotal Phase 3 study designed to evaluate the efficacy of mRNA-1647 against primary CMV infection. The Phase 2 study is to test the intended Phase 3 formulation, which contains the same proprietary lipid nanoparticle (LNP) used in this Phase 1 study.
In the trial results mRNA- 1647 has induced high levels of durable immune responses that exceed the levels generated by natural CMV infection.
mRNA-1647 is a wholly owned program in Moderna’s prophylactic vaccine portfolio.
The importance of a vaccine for Cytomegalo virus is that CMV is the leading infection that causes birth defects. As a result the medical community believes that there is a great need for a vaccine that blocks transmission of the virus from the mother to the fetus. That’s why good results during clinical trial is exciting. The interim data divulged today demonstrate mRNA-1647 ability to induce immune responses in seronegative individuals that are greater than what is seen in those naturally infected with CMV.
We will be posting the complete results from Moderna’s product mRNA-1647 as soon as we finish studying them.
Moderna is on the right track.
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