Small interfering RNA bound to a messenger RNA. [Image courtesy of Adobe Stock]
Interest in mRNA therapy has exploded in recent years following the development of mRNA-based COVID-19 vaccines, but can the platform live up to the initial hype that surrounded it? More companies have announced clinical trial data from mRNA trials for conditions ranging from cardiovascular disease to cancer.
mRNA, or messenger RNA, is a type of genetic material involved in protein synthesis. The therapeutic use of mRNA has an array of applications, but a handful of factors are dampening enthusiasm in the platform, including the warning immunity of mRNA COVID-19 vaccines. Additionally, mRNA-based flu vaccine candidates have yet to prove their superiority over traditional vaccines in the clinic.
In addition, mRNA therapies are currently more expensive to manufacture than traditional small-molecule drugs. They require a complex manufacturing process and specialized equipment and materials. But the platform also offers advantages in terms of its scalability and modularity.
Interest in mRNA research, however, remains strong and a growing number of companies are reporting clinical trial data. This article touches on recent developments in mRNA therapy, ranging from cardiovascular applications to oncology applications.
Cardiovascular applications: Scant data
It appears to be too early to tell whether mRNA has significant promise for cardiovascular applications. There are some early positive data, but mRNA-based COVID-19 vaccines have also been associated with reports of myocarditis and pericarditis.
In early 2022, researchers at the University of Pennsylvania shared positive data on mRNA and CAR-T cell therapy to treat cardiac fibrosis in a mouse model.
In 2022, AstraZeneca removed the mRNA-based cardiovascular disease candidate known as AZD8601 from its pipeline, which it had developed with Moderna. AstraZeneca had earlier announced positive results from the Phase 2a study of AZD8601, which involved injecting naked mRNA into the hearts of coronary artery bypass patients.
A 2013 article in Nature Biotechnology found that an injection of mRNA encoding human vascular endothelial growth factor-A into the heart expanded endogenous heart progenitors.
CMV: Positive Phase 2 data
Human Cytomegalovirus image from NIH
Moderna’s cytomegalovirus (CMV) vaccine candidate mRNA-1647 was generally well-tolerated and demonstrated immunogenicity in a Phase 2 study. CMV infection can have severe long-term health consequences if left untreated. The mRNA-1647 vaccine features a lipid nanoparticle formulation with six mRNA sequences encoding two CMV antigens. The study tested three doses of mRNA-1647 in healthy adults aged 18 to 40. Moderna announced a Phase 3 study known as CMVictory in 2021.
Flu data are mixed in Phase 3 study
In theory, mRNA therapy developers could create flu vaccines based on the platform in a matter of days after identifying a flu virus sequence. It is unclear, however, whether mRNA-based flu vaccines have an efficacy advantage over traditional vaccines.
In February, Moderna revealed mixed interim data in adults from its Phase 3 study of mRNA-1010, an mRNA-based seasonal flu vaccine candidate. The vaccine candidate achieved superiority on seroconversion rates for A/H3N2 and A/H1N1 influenza subtypes compared to a licensed flu vaccine. It also was superior in terms of geometric mean titer ratios for A/H3N2 and non-inferior based on geometric mean titer ratios for A/H1N1. However, the vaccine did not fare as well as the comparator for either endpoint for the influenza B/Victoria- and B/Yamagata-lineage strains.
mRNA-1010 was also not as well tolerated as a conventional flu vaccine. A total of 70% of those in the mRNA group reported solicited adverse reactions, compared to only 48% in the comparator group.
Analyst firm Evaluate concluded that the interim flu data did not bode well for Moderna’s post-COVID prospects.
Pfizer and BioNTech’s mRNA-based flu vaccine candidate BNT161 is currently in a Phase 3 study, but no data from that study are publicly available.
Sanofi has not provided any update on its SP0273 mRNA flu vaccine, which showed positive results in a Phase 1/2 trial conducted with its partner, Translate Bio. CureVac and GSK are also developing an mRNA-based flu vaccine, which remains in Phase 1 testing.
Shingles: Too early to gauge mRNA’s potential
Varicella zoster virus [Image courtesy of Adobe Stock]
In February, Pfizer and BioNTech launched a Phase 1/2 trial to test their mRNA-based shingles vaccine candidates. The U.S. study will enroll about 900 healthy adults aged 50 to 69.
According to the CDC, one in three people in the U.S. will develop shingles, caused by varicella zoster virus, in their lifetime. There is presently a single FDA-approved vaccine for shingles in the U.S. — GSK’s (NYSE:GSK) recombinant, adjuvanted Shingrix.
The global shingles vaccine market could hit $6.35 billion by 2028, Grand View Research projected.
Lyme disease: Positive preclinical data
In 2021, Yale researchers announced that an investigational mRNA vaccine for Lyme disease fared well in an animal study involving guinea pigs. Science Translational Medicine published the research.
There is currently no Lyme disease vaccine in distribution in the U.S. GSK debuted a Lyme vaccine in 1998 but yanked it in 2002 owing to poor demand.
HIV: Positive data in one Phase 1 trial
HIV viruses [Image courtesy of Adobe Stock]
A Phase 1 study published in Science found that an mRNA HIV vaccine had a favorable safety profile and elicited an immune response in 97% of individuals. The IAVI G001 study is the first stage in a multi-stage HIV vaccine regimen.
Researchers at George Washington University, Scripps Research, IAVI, Fred Hutchinson Cancer Center and the National Institutes of Health (NIH) collaborated on the vaccine candidate.
A Phase 1 NIH study of three mRNA vaccine candidates is currently underway.
Moderna currently lists two prophylactic HIV vaccine candidates, mRNA-1644 and mRNA-1574, as the focus of Phase 1 trials. Moderna developed mRNA-1644 in collaboration with researchers at IAVI and Scripps Research.
Cancer: Research is ramping up
In recent decades, scientists have assumed that mRNA held potential in oncology. mRNA therapies could deliver genetic material to cells, telling them to make specific proteins that prompt an immune response against cancer. The treatment could potentially selectively target cancer cells while sparing healthy cells, in contrast to chemotherapy. In addition, mRNA therapy has advantages in manufacturability over traditional medicines used in oncology.
More mRNA-based research has headed to the clinic. Last year, Mayo researchers announced early success using mRNA technology with immunotherapy. In addition, BioNTech and Moderna both have a range of mRNA-based oncology therapies in their pipelines.
BioNTech has four oncologic mRNA therapies in Phase 2 for indications. Two target melanoma, while the others target head and neck cancer and colorectal cancer.
Moderna collaborates with Merck on a personalized cancer vaccine in a Phase 2 study. The company also has mRNA therapies in Phase 1 studies in oncology, including a KRAS vaccine and two for intratumoral immuno-oncology.
Zika virus [Image courtesy of NIH]
CureVac (Nasdaq:CVAC) also has a handful of mRNA-based therapy candidates in early-stage clinical development.
Zika: Promising Phase 1 data
Moderna is developing a Zika virus vaccine mRNA-1893 against the Zika virus, which was well tolerated at all evaluated dose levels and induced strong Zika virus-specific serum nAb responses after two doses in a Phase 1 study, regardless of baseline flavivirus serostatus. An article in Lancet summarized the results from two Phase 1 trials testing investigating mRNA-1893 and another Zika vaccine candidate known as mRNA-1325. Only the former remains in development. A Phase 2 trial is underway for Moderna’s mRNA-1893 Zika vaccine candidate.