FierceBiotech 综述复盘 Moderna/默沙东 mRNA 癌症疫苗 intismeran 8 月 III 期成功，无新增事实且已被大幅定价

The announcement from Merck & Co. and Moderna last month that their mRNA cancer vaccine had successfully lengthened patient survival in a phase 3 study affirmed the two companies' years of hard work and reignited hopes for the field of personalized medicine.
There's a lot riding on exactly how well intismeran autogene—alternatively known as V940 or mRNA-4157—performs, and the companies have held back any detailed data for a future medical meeting. But intismeran seems to do its best work against resected late-stage melanoma when paired with the standard-of-care immunotherapy Keytruda.
Merck and Moderna's INTerpath-001 trial enrolled 1,137 patients who had previously had their cutaneous melanoma surgically removed. These participants either received intismeran along with Keytruda, or Keytruda alone. According to the August update, the group who received the adjuvant therapy showed statistically significant and clinically meaningful improvements in recurrence-free survival, the study's primary endpoint, and survival without a distant metastasis, a secondary endpoint.
Since that announcement, experts and industry insiders have suggested to Fierce that the news has not only renewed hopes in the intismeran program, which hit a regulatory hurdle back in 2024, but also boosted prospects for other biopharmas exploring mRNA as a vehicle for personalized cancer treatments.
What continues to make oncology treatments so difficult to perfect is that every type of cancer is different and even patients who have the same cancer have tumors that behave differently under the same treatments. Being able to customize a vaccine to each patient’s particular tumor would be a boon.
“I think it's the start of a personalized medicine revolution,” said Jeff Coller, Ph.D., a professor of RNA biology and therapeutics at Johns Hopkins University, when speaking with Fierce about the intismeran update. “This is going to catalyze so much incredible research and development and innovation.”
When the full data do become available, investors will be looking to see whether intismeran could be used against other cancers and as broadly as Keytruda, said Myles Minter, Ph.D., a William Blair analyst.
“We’ll have to see what the data look like, but if they look really good and this is a stepwise change in efficacy, this is standard-of-care shifting,” he told Fierce.
Knock-on effect
By the time the markets closed on the day of the therapy's phase 3 announcement, Moderna’s stock was up 177%—but it wasn't alone. Share prices were up as much as 20% for other biotechs that are playing in the mRNA arena, such as Arcturus Therapeutics.
The San Diego-based biopharma has been developing therapies for infectious diseases, such as COVID-19 and influenza, as well genetic conditions like cystic fibrosis and ornithine transcarbamylase deficiency, the most common urea cycle disorder. Currently, its COVID-19 vaccine Kostaive is approved in Japan, the U.K and the EU.
Arcturus’ approach to mRNA therapies is to leverage self-amplifying mRNA, which CEO Joseph Payne argued is better at expressing the antigen than personalized antigens. Arcturus’ self-amplifying mRNA includes a replicase, which allows for more and sustained protein production.
The uniqueness of this type of mRNA also means it can be administered at lower doses with higher antibodies and for a longer time, Payne told Fierce. In combination with this platform, Arcturus has developed a lipid nanoparticle delivery system, Lunar, which it's testing in a phase 2 trial as an inhalable mRNA therapy for patients with cystic fibrosis.
Arcturus entered into a research pact with London-based Achilles Therapeutics in 2024 to explore personalized mRNA cancer vaccines. The goal of the collaboration is to combine Achilles' AI platform Peleus, which identifies patient neoantigens, with Arcturus’ self-amplifying mRNA technology.
For now, Arcturus' broader strategy focuses on infectious and life-threatening genetic diseases, but Payne does think the technology can be applied to cancer. “I think the field is moving towards oncology,” he said.
German biopharma BioNTech is already in that race. Even before its pivot to become a “fully integrated immunotherapy powerhouse,” the company had been working on its FixVac mRNA cancer vaccine platform, which uses a fixed combination of mRNA-encoded non-mutated tumor antigens in an effort to enhance the stability of mRNA in the body. Vaccines from the platform are designed to target antigen-presenting dendritic cells and trigger a strong immune response.
The lead candidate, dubbed BNT113, is an mRNA cancer immunotherapy candidate that encodes a fixed set of two oncoproteins that are frequently found in human papillomavirus type 16 positive (HPV16+) solid tumors. BNT113 has reached phase 2/3 development in head and neck cancer with a readout on the first of its two primary endpoints anticipated this year.
Ugur Sahin, M.D., and Özlem Türeci, M.D., founded BioNTech in 2008 to research mRNA technology, which was overlooked in science at the time. The company made its name during the COVID-19 pandemic, with the release of Pfizer-partnered Comirnaty, the first COVID-19 vaccine to get a full approval from the FDA.
In collaboration with Genentech, BioNTech has another flagship personalized mRNA platform known as individualized neoantigen-specific immunotherapy (iNeST). The iNeST platform encodes up to 20 patient-specific neoantigens and uses a unique delivery platform called a lipoplex that enables administration of the vaccines to key “boot camps of the immune system,” like the spleen, lymph nodes and bone marrow, a BioNTech representative explained to Fierce.
With this approach, the company aims to eliminate polyclonal residual disease and is focusing on cancers for which immunotherapies have not worked well, such as pancreatic cancer.
BioNTech recently scrapped a phase 2 study of an iNeST candidate called autogene cevumera in patients with surgically removed stage 2 or 3 colorectal cancer. Genentech originally told Fierce that this move was down to “more deaths in the vaccine arm in this specific patient population,” with a representative from BioNTech later clarifying that the “decision was not safety-related” and was instead due to a “numerical imbalance in overall survival between treatment arms.”
BioNTech noted that a phase 2 trial evaluating autogene cevumera in combination with checkpoint inhibitors and chemotherapy in pancreatic ductal adenocarcinoma “will not be affected and continues as planned.”
Another contender in the programmable mRNA field is Strand Therapeutics, which is studying two self-replicating mRNA therapies that deliver IL-12, an immune signaling protein, for treatment of solid tumors. STX-001 was designed to be injected directly into tumors and is being tested in phase 1/2 trials as a monotherapy or in combination with Keytruda for triple-negative breast cancer and melanoma. Strand is concerned not just with delivery, cell-selective expression, and durability but also with controlling the RNA after delivery, according to CEO Jacob Becraft, Ph.D.
“Some of the most powerful therapeutic proteins have been difficult to use safely throughout the body,” Becraft said in an interview with Fierce. “Our goal is to make those proteins usable by programming where and how they are produced.”
Phase 1 data from the study unveiled at the American Society of Clinical Oncology conference last year included a confirmed complete response and multiple partial responses from patients with immune checkpoint inhibitor-refractory solid tumors.
Strand, which has received Big Pharma backing from the likes of Regeneron, Amgen and Eli Lilly, has another key asset in the form of STX-003. The programmable mRNA cancer immunotherapy was developed to be injected intravenously and enable IL-12 expression in tumors, allowing for a possible multi-pronged approach to targeting disease at multiple sites.
“What excites me most is the possibility of opening up an entirely new set of usable medicines,” Becraft said. “Once we can reliably deliver and control RNA in a particular cell type, we can explore multiple therapeutic payloads using that foundation. That could substantially accelerate how quickly new biological insights become treatments.”
Looking back
Moderna and Merck may have captured the headlines with intismeran, but the two companies have been working together since 2016 to develop a series of mRNA vaccines. mRNA, short for messenger ribonucleic acid, makes it possible for every cell in the body to transform DNA code into an active protein the cell uses to do a specialized job. Although scientists first discovered these naturally occurring little helpers in 1961, it would take them three more decades to wrangle mRNA as a tool for vaccination against viruses and yet another three decades before that application found mass commercial success in humans.
Along this slow rise, squaring up mRNA vaccine technology against the vagaries of cancer specifically has remained elusive. All of this time and anticipation is latched to intismeran's journey to FDA approval and the impact such an approval would have on other mRNA therapies.
“This program sits at the convergence of decades of advances in cancer research, genomic sequencing, computational biology and informatics,” said Michelle Brown, Ph.D., Moderna's oncology lead for intismeran. “mRNA is the technology that was able to galvanize and bring it all together.”
Moderna has centered itself on mRNA medicines since its founding in 2010, but as with BioNTech, it was the COVID-19 pandemic that pushed the technology mainstream. Moderna developed the Spikevax vaccine as part of Project Warp Speed during President Trump’s first term.
“Those policies that were made by the Trump administration really have led to this new revolution in neoantigen personalized cancer approaches,” Coller told Fierce.
Despite this initial support, the tone changed last year when the Department of Health and Human Services announced a plan to end mRNA vaccine work funded by the Biomedical Advanced Research and Development Authority (BARDA), a major escalation of Health Secretary Robert F. Kennedy Jr.’s campaign against both vaccines and mRNA in general.
Moderna executives explained to Fierce a few months later that this shift in sentiment had encouraged the biopharma to focus its efforts on cancer rather than infectious disease. Still, the company secured a major success in the latter category last month when the FDA made mFlusiva the first-ever mRNA flu vaccine to receive regulatory approval in the U.S.
Accelerated approval, again
Intismeran is customizable because it targets neoantigens, proteins that appear on the surface of cancer cells that are specific to each patient, almost like “tumor fingerprints,” Moderna's Brown told Fierce. Before receiving intismeran, each patient had their tumor sequenced and scientists designed the vaccine to fit its unique signature.
To make this match, the tumor's sequence was funneled into a bioinformatic algorithm that ranked the mutations based on expression, not just presence. The algorithm assessed whether antigens were “up and available for the immune system to see,” Brown said, and which neoantigens would be able to generate the best killer T-cell response while also recruiting other immune cells to the tumor.
For Merck and Moderna, 34 neoantigens was the ideal number, compared with iNest’s 20. Intismeran’s phase 2 study, which launched in 2019, cut the risk of disease recurrence by 49% at five years of follow-up. “It was the first time that we saw an inkling that a doublet could improve upon [Keytruda] standard of care,” Brown said. “It also showcased the ability to create benefit on recurrence-free survival and distant metastasis-free survival.”
The wider intismeran program encompasses a total of nine phase 2 and 3 trials in indications beyond melanoma, such as non-small cell lung cancer and renal cell carcinoma.
But it hasn't all been plain sailing for the vaccine. Back in 2024, intismeran encountered a regulatory setback when the biopharmas attempted to secure an accelerated approval pathway and the FDA rebuffed them. At the time, Moderna said it would not return to seek accelerated approval until it had a “substantially enrolled” phase 3 trial in for an adjuvant melanoma therapy.
That patience appears to have paid off with the recent announcement of the trial's primary endpoint win. Despite holding back the data, the companies said they plan to engage with regulators on filing approval submissions for a combo regimen of intismeran and Keytruda. Moderna’s Brown remains steadfast in waiting for the full phase 3 data readout, although she is excited about what is to come with intismeran and the wider field of immunotherapy.
“It increases our confidence in the biological rationale and the power of what mRNA can provide, and it definitely showcases the clinical benefit in melanoma,” Brown said. “It gives us learnings for the rest of the portfolio overall.”