The expanding world of RNA therapies

The key ingredient in the coronavirus vaccines developed by Moderna and BioNTech doesn’t last very long. Once in the body, this messenger RNA, or mRNA, degrades within days. Still, that’s enough time for the vaccines to train the body to recognize and attack the virus in the event of infection.

Drugmakers have long understood the potential of RNA. These strands of genetic information play an essential role in creating proteins and regulating genes, giving drugs that harness their power the potential to treat diseases once thought to be unreachable.

Over the last decade, drugs based on multiple RNA technologies, known as RNA interference and antisense oligonucleotides, have made it to market. Yet, it took a historic pandemic to thrust RNA into the global spotlight. Equipped with new tools, scientists are now exploring how other types can be used to make therapies that last longer and treat, as well as prevent, more diseases.

At least 9 biotechnology startups are developing next-generation RNA drugs. Though years of research lie ahead, these companies have already raised hundreds of millions of dollars from venture capitalists, large pharmaceutical firms and other investment groups.

If their work pans out, it could provide new treatments for cancer, rare diseases, and chronic illnesses that affect organs, the nervous system and the immune system.

What are next-generation RNA technologies, and how do they work?

The companies working toward this new wave of RNA-based drugs use different approaches.

One of the most popular revolves around transfer RNA, which transports and delivers the molecular building blocks that cells need to make proteins. Alltrna, a startup that launched publicly in late 2021, claims to be able to engineer tRNA to correct for errors in the genetic code that would otherwise impair protein production. The company is one of many formed and financed by Flagship Pioneering, the biotech incubator and investor that founded Moderna. It’s also one of at least four pursuing tRNA in one way or another.

Another Flagship-backed company, Laronde, and a well-funded startup called Orna Therapeutics, are focused on what’s known as circular RNA. This type occurs naturally in cells and is considered much more stable than its mRNA counterpart. However, circular RNAs usually don’t make proteins.

Laronde and Orna are trying to change that through engineered versions of these molecules. Their technologies attempt to program synthetic circular RNAs with certain genetic codes, as well as outfit them with a site that many RNA viruses use to dock onto the cell’s protein-producing machinery.

Replicate Biosciences, a startup focused on self-replicating RNA, takes a page from viruses, too.

The company aims to strip viral RNA of its more worrisome attributes, like spreading uncontrollably across cells, but to leave intact the genetic instructions that allow it to continuously duplicate. This self-replicating RNA would then be designed to manufacture helpful proteins.

What advantages would this technology have over its predecessors?

Generally, these technologies are meant to overcome some of mRNA’s limitations.

Replicate’s method, for example, may lead to medicines that could be administered less frequently or at smaller doses.

“The difference with self-replicating RNA is we’re delivering a copy machine into the cell along with that instruction manual, so you can make a lot more copies and they last for a much longer period. And that creates a lot more protein,” Nathaniel Wang, one of the company’s co-founders, told BioPharma Dive in an interview in 2021.

Another goal is to make more durable medicines, given that most RNA is quickly broken down and flushed from the cell. For companies working with circular RNA, one of the draws has been the molecule’s non-linear shape, which lacks the loose ends that digestive enzymes latch onto. Laronde executives have said that their approach could, in theory, help protein expression last weeks or months.

Scientists are also trying to prevent newer RNA-based drugs from triggering unwanted reactions from the immune system. The U.K.-based biotech VaxEquity, which is focused on self-amplifying RNA, has a technology it says can suppress responses from the “innate” immune system, the body’s first line of defense.

What companies are working on these technologies?

Formed in 2018, Alltrna recently came out of stealth mode with an initial commitment of $50 million from Flagship. But it’s far from alone. Shape Therapeutics, Tevard Biosciences and HC Bioscience are all researching tRNA, too.

ReCode Therapeutics, a biotech backed by EcoR1 Capital and several pharmaceutical companies, initially was, too. But into 2022 the company decided to pivot, deprioritizing a tRNA program in favor of an mRNA one, a spokesperson for the company confirmed to BioPharma Dive after publication.

In circular RNA, Laronde and Orna have both raised significant amounts of cash. In August 2022, Orna, which was created in 2019 by MPM Capital and BioImpact Capital, brought in another $221 million through a Series B round. Merck & Co. participated in the round and has also entered a collaboration with Orna to discover, develop and sell vaccines and other therapies for cancer and infectious diseases. The deal carries a $150 million upfront payment, though Orna could take home an additional $3.5 billion should its programs hit various milestones.

A stealthy startup named Circ Bio is also reportedly working on circular RNA, though the company hasn’t yet publicly disclosed any funding.

What is the status of the technology?

Companies working with next-generation RNA technologies remain in the earlier stages of drug development, though some are advancing quickly.

In tRNA, Lovisa Afzelius, an origination partner at Flagship and the founding CEO of Alltrna, told BioPharma Dive in November 2021 that the startup could, in the “not too distant future,” reach the stage where it asks regulators for permission to begin human studies.

The leadership team at Laronde, meanwhile, has said the company is on track to request multiple circular RNA drugs be cleared for human trials in 2023.

And Orna isn’t far behind, estimating that its first program — an experimental treatment for cancer — will be ready for human testing in 2024.

Infused or injectable medicines that interfere with RNA, the messenger molecules that turn genetic instructions into proteins, have taken the spotlight in recent years, winning approvals for several rare diseases. A group of biotechnology startups are trying to find similar success by targeting RNA with pills instead.

History shows they face a daunting task. It’s long been considered futile to use chemical-based compounds to go after RNA because of its shifty nature. When scientists have succeeded, it’s typically been by accident. Last decade, for instance, Merck & Co. discovered an experimental antibiotic it was developing blocked a type of bacterial RNA. Pfizer inadvertently found one of its drug prospects affected translation of a protein that regulates cholesterol.

Now, drugmakers are doing it intentionally. Helped by better sequencing technologies, screening methods and a broader understanding of RNA, researchers can more easily capture how the information molecules look and design drugs that attach to them.

If successful, they could help unlock disease targets that small molecules can’t currently reach, bringing forward new ways to treat neurodegenerative disorders, cancer and other diseases.

At least eight startups are developing small molecules that target RNA. Large pharmaceutical companies including Sanofi, AstraZeneca, Amgen and Roche have shown interest in their research, promising hundreds of millions of dollars in a string of deals. Here’s where things stand.

What are RNA-targeting small molecules, and how do they work?

Small molecules are chemical-based drugs that usually target proteins and block or change the way they work.

Due to their size, they can reach most tissues in the human body, slip into cells and bind to the craggy parts of their targets. They are the bedrock of the pharmaceutical industry, making up a large majority of drugs on the market.

But small molecules have limited reach. About 3,000 of the roughly 20,000 known genes are considered “druggable,” meaning they can be targeted by a medicine. Of the proteins they produce, only a few hundred are targeted by available drugs. Many of the others don’t have the well-defined pockets that small molecules can nestle into, making them more challenging to reach.

Targeting the RNA molecules that help make disease-associated proteins could give drugmakers an alternate route. In theory, such a drug could stop production of a potentially harmful protein, or make more of a helpful one.

For example, Arrakis Therapeutics is working on a medicine that would block the body from making a well-known, but long thought “undruggable,” cancer protein called Myc. An experimental Expansion Therapeutics drug destroys RNA implicated in a type of muscular dystrophy. Accent Therapeutics and Storm Therapeutics, meanwhile, aim to target the special proteins involved in transcribing and modifying RNA.

They and others in the field face significant challenges, such as finding the right RNA sequences and, within them, the correct locations to target. They also need to ensure their small molecules only stick to their intended targets and not other RNA, which could lead to side effects or other health risks.

What advantages would RNA-targeting small molecules have over existing technologies?

Drugs that interfere with RNA have proven to be powerfully effective tools to treat a range of diseases.

One method, pioneered by Alnylam Pharmaceuticals and known as RNA interference, involves using small, synthetic RNA molecules to “silence” genes and prevent them from creating harmful proteins. Another, similar method, used by Ionis Pharmaceuticals and others, uses strips of nucleic acid called antisense oligonucleotides to adjust or shut off protein production.

Both have advanced RNA drug research, leading to medicines for rare genetic diseases such as spinal muscular atrophy and transthyretin amyloidosis, as well as more common conditions like high cholesterol. The effects of the medicines can last up to months at a time.

While significant progress has been made in delivering these kinds of RNA therapies into the body, they’re still largely restricted to disease targets in the liver, meaning there are many diseases they can’t yet treat.

Research has also noted their propensity to trigger immune responses and, in some cases, difficulty in crossing the blood-brain barrier or entering cells.

Small molecules could help solve these problems. They’re a better known quantity to drugmakers, easier to deliver than nucleic acid-based therapies and, because they’re taken orally, are more convenient for patients.

Small molecules might also be better at permeating cell walls and are more easily absorbed and taken up by the body. They’re cheaper to manufacture, too.

Which companies are working on small molecules that target RNA?

At least eight startups have formed to develop oral RNA-targeting drugs. Half have already caught the eye of bigger pharmaceutical companies looking to invest in the field.

The most richly funded, Skyhawk Therapeutics, has raised at least $181 million in private funding and equity, and more than $400 million in upfront cash from partnerships, according to the company. In July 2022, Sanofi partnered with Skyhawk to develop drugs for cancer and research programs for oncology and immune diseases. Skyhawk also has deals in place with Merck, Biogen and Vertex Pharmaceuticals.

Arrakis, launched in 2015 by a team of Biogen veterans, has raised $113 million to date. Its research has drawn the attention of first Roche and then Amgen, which handed the company a combined $265 million through deals to develop medicines aimed at a variety of disease targets.

Accent has also been successful in luring big pharma, having signed partnerships with AstraZeneca and Ipsen. The company, which is focusing on cancer research, has also raised more than $100 million in venture funding.

Remix Therapeutics joined the field more recently, launching late in 2020 with $81 million in funding. The company added another $70 million in May 2022, a few months after it teamed up with Johnson & Johnson.

Expansion, formed by pioneering RNA researchers at the Scripps Research Institute, has secured $135 million in funding and is backed by a wide range of investors including the venture arms of Sanofi and Novartis.

Storm, Gotham Therapeutics (which was folded in 2021 into another private biotech called 858 Therapeutics) and Twentyeight-Seven Therapeutics are also researching RNA-targeting small molecules. Storm formed a cancer drug collaboration with Exelixis in 2021.

What is the status of the technology?

While several drugs built on other RNA technologies have made it to market in recent years, small molecules capable of targeting RNA are just beginning to show their potential.

The first to do so was Evrysdi, a drug from Roche and PTC Therapeutics that was approved in 2020 and helps produce a protein that people with spinal muscular atrophy lack. An experimental Huntington’s disease drug from Novartis, known as branaplam, is also in human testing, though recent safety concerns could derail its progress.

So far, none of the startups developing RNA-targeting small molecules have brought a drug prospect into clinical testing. The pipelines for some are beginning to take shape, however.

Skyhawk Therapeutics appears on the cusp of entering clinical trials, previously indicating plans to begin to advance its first drug into human testing sometime by the end of the 2022. The company has previously said it expected to test its two lead therapies, both neurodegenerative disease treatments, in humans by the end of 2021.

Storm plans to launch a clinical trial for a cancer drug by the end of this year and Accent is working to push forward a cancer medicine with Ipsen. Both candidates target METTL3, an enzyme that affects RNA function.

Arrakis lists early research programs for cancer, dyslipidemia and a COVID-19 antiviral as its most advanced targets. Expansion, meanwhile, is pursuing drugs for muscular dystrophy and ALS.

Wave Life Sciences hopes to soon begin clinical testing of what it claims will be the first RNA editing treatment in humans and expects to deliver “proof-of-mechanism” data by 2024.

The Cambridge, Massachusetts-based company applied for regulatory permission to test its therapy, dubbed WVE-006, in healthy volunteers as well as patients with alpha-1 antitrypsin deficiency, or AATD. The inherited disorder is caused by a genetic mutation and can cause damage to the lungs and liver.

The first dosing in humans should occur in the fourth quarter, Wave said Sept. 5. The company expects to discuss the clinical program as well as other RNA editing research at a virtual “R&D Day” for investors and analysts on Sept. 28.

Success in the clinic would boost the RNA editing field as well as Wave. Broadly speaking, the technology is designed to edit specific sites in an RNA transcript without making permanent changes to a person’s genome.

It’s an approach that’s drawn interest from major players including Eli Lilly and Roche, as well as startups such as Ascidian Therapeutics. For its part, Wave signed a four-year development deal with GSK late last year that included $225 million in potential development and launch milestone payments for WVE-006.

There are about 200,000 AATD patients in the U.S. and Europe who have mutations that make them candidates for Wave’s therapy. At the moment, there are no approved medicines for AATD liver disease, and the only option for patients with AATD lung disease is weekly infusions to deliver the AAT protein.

A number of companies are also trying to fill the gap for AATD patients with new treatments. Arrowhead Pharmaceuticals is testing an RNA-based medicine, while Vertex Pharmaceuticals is studying two different treatments.

Biotechnology venture firms have become more selective about where to invest in recent months, wary of the headwinds currently blowing against the industry.

But that newfound caution hasn’t hurt Orbital Therapeutics, which said April 26 it raised $270 million in biotech’s largest Series A round in 2023.

The funds will help Orbital, which emerged from stealth in 2022 partnered with gene editing pioneer Beam Therapeutics, to build its team and select a lead program. It claims its technology could be applied in many different directions, from use in next-generation RNA vaccines to protein replacement therapies or drugs for autoimmune diseases and cancer.

Based in Cambridge, Massachusetts, Orbital has not yet named specific disease areas it’s prioritizing. However, the financing positions the company to submit its first regulatory filing, like an application to begin human testing, in the next two to four years, CEO Giuseppe Ciaramella said.

“The large raise is to give us some resilience over a few years,” Ciaramella said. “Even though we have a deep toolbox, we don't want to rest on our laurels.”

RNA-based therapies have drawn investors’ attention in recent years, boosted in profile by the success of COVID-19 vaccines built around messenger RNA. Other drugs employing RNA, which help cells make proteins and regulate genes, are approved to treat a number of rare diseases and high cholesterol. But existing technologies are largely limited to disease targets located in the liver, hampering drugmakers’ ability to target conditions that primarily affect other tissues.

A number of startups are now experimenting to make RNA-based drugs that can reach further into the body and last longer. To do so, they’ve relied on guidance from leaders in the field, such as former Alnylam Pharmaceuticals CEO and Orbital co-founder John Maraganore, as well as other industry veterans.

Joining Orbital are two seasoned pharmaceutical executives: Chief Operating Officer Niru Subramanian, who previously worked at Rheos Pharmaceuticals, Agios Pharmaceuticals and Novartis, and CFO Jonathan Piazza, who was previously at Silverback Therapeutics, Goldman Sachs and Barclays.

Orbital employs 39 people across two sites in Cambridge and South San Francisco, offices that Ciaramella said were strategically placed to tap into Boston- and Silicon Valley-area universities.

Arch Venture Partners led Orbital’s Series A round, alongside more than a dozen other investors including a16z, Newpath Partners, Abu Dhabi Growth Fund and Alexandria Venture Investments.

The company’s alliance with Beam allows the companies to use each other's technologies. For example, Orbital can use Beam's non-viral delivery technology to work on vaccines and target certain proteins, while Beam can access Orbital's gene editing research.

In September 2022, Orbital acquired a company named CircBio that owned intellectual property on so-called "circular RNA," a form of the molecule designed to be more stable. It has also licensed delivery technology from Stanford University to target tissues other drugs can't yet reach, Ciaramella said.

Swiss drugmaker Novartis in July acquired biotechnology company DTx Pharma and its pipeline of neurological disease drugs.

Per deal terms, Novartis will pay $500 million upfront and could owe up to $500 million more if certain milestones are met. The acquisition gives the pharmaceutical company access to DTx’s RNA drugmaking technology and three preclinical-stage drug candidates, including one for Charcot-Marie-Tooth disease.

The purchase of DTx is Novartis’ second biotech buyout in as many months, following a June deal for Chinook Therapeutics and its rare kidney disease drugs.

Novartis said it was drawn to DTx for multiple reasons, interested in both the biotech’s lead treatment for Charcot-Marie-Tooth as well as its capabilities with small, interfering RNA — a technology with which the pharma is already familiar.

Small, interfering RNA, or siRNA, drugs work by disrupting the way cells translate DNA into proteins. SiRNA drugs can obstruct this process, preventing or limiting the production of specific proteins involved in disease.

Novartis has bet big on this approach in the past, acquiring The Medicines Company for a cholesterol treatment called Leqvio that won Food and Drug Administration approval in 2021. It has also twice partnered with Alnylam Pharmaceuticals, including a recent research deal looking at liver failure. 

However, getting these drugs to the right location in the body is challenging, particularly for diseases outside of the liver. DTx’s technology is meant to overcome these problems by conjugating siRNAs to certain types of fatty acids that could help deliver the drug to the right cells.

The company aims to use the startup’s technology to “explore its potential to deliver drugs to extrahepatic tissues,” Fiona Marshall, head of the Novartis Institutes for BioMedical Research, said in a statement.

Novartis was also specifically interested in DTx’s treatment for a common type of Charcot-Marie-Tooth, an inherited disease that affects the nervous system. No medicines are approved to treat this type of the disease, which is caused by overexpression of a protein known as PMP22.

DTx CEO Artie Suckow said in an email that, while his company had been in touch with multiple pharmaceutical companies, the bar for doing a deal was quite high.

“Novartis stood out in that they had Dr. Robert Baloh — he clearly shared the same passion for curing [Charcot-Marie Tooth type] 1A as myself and the rest of the DTx Pharma team,” Suckow wrote. Baloh is NIBR’s global head of neuroscience.

“I’m very confident that Bob and his team have the expertise, passion and drive to bring DTx-1252 through a robust clinical development program and, if the data support, through to regulatory approval,” he added, using the drug’s code name.

The deal came about just as DTx was finalizing term sheets for raising a Series C financing round from private investors, Suckow said. The company previously raised over $110 million in venture funding.

In addition to the Charcot-Marie-Tooth treatment, Novartis also gains two early-stage programs for other neuroscience indications.

The deal closed Friday, July 14.

Drugs built from RNA have come of age in the last decade, leading to a wave of rare disease medicines as well as vaccines that helped curb a pandemic.

Yet despite the progress made by scientific researchers and biotechnology companies, the reach of medicines based on cells’ messenger molecules is still limited. They’re largely limited to targeting diseases of the liver, meaning there are many conditions they can’t readily treat.

A new, well-funded biotech incubated by venture firm MPM Capital says it could help solve that problem.

Called ReNAgade Therapeutics, the Cambridge, Massachusetts-based startup is debuting with $300 million in funding and a suite of technologies meant to more easily deliver RNA medicines.

“Delivery has been a little bit of a bugaboo, and an afterthought, for a lot of companies,” said Amit Munshi, ReNAgade’s CEO. “If you can't get to the right cell or tissue types, or right organs, then you’re going to be extremely limited in what you can do over time.”

ReNAgade claims it can deliver with what Munshi describes as an “all-in-one” system suitable for many different approaches. The company is developing lipid nanoparticles — the fatty spheres used in some COVID-19 vaccines and RNA medicines — that can get into different tissues and organs. It also has tools for editing RNA, and a delivery-focused collaboration with Orna Therapeutics, a buzzy biotech startup making drugs from synthetic, “circular” RNA.

“You will see a lot of companies focusing on circular RNA, or editing or finding new insertion technologies,” Munshi said. “But you rarely find all of that under one umbrella.”

ReNAgade is connected with Orna as well as pharmaceutical giant Merck & Co. While still in stealth mode, the startup formed a joint venture with Orna to work on delivery technology. Orna then drew a partnership and a $100 million equity investment from Merck, meaning the work the joint venture produces will flow to the big drugmaker, according ReNAgade’s chief operating officer, Ciaran Lawlor.

ReNAgade’s work is still early. It hasn’t disclosed which diseases it aims to treat, or how far it is from clinical testing. Munshi didn’t say which tissues the company is initially focusing on, either, though he noted that “over time” ReNAgade aims to target immune, kidney or muscle cells with its medicines.

The company has large ambitions, though. Munshi said the company has filed more than 100 patents since starting up in 2021 and has hired about 100 employees, many of whom previously worked at RNA-focused drugmakers Alnylam Therapeutics and Moderna.

It’s also well funded. The company’s $300 million Series A round, led by F2 Ventures and MPM’s startup incubating-affiliate, BioImpact, surpasses most other biotech financings this year and eclipses the $270 million funding another RNA company, Orbital Therapeutics, announced in April 2023.

Munshi said the financing will provide the startup with “several years” of financial breathing room, which could be crucial at a time when many young drugmakers are struggling to raise money.

“This capital base now not only allows us to go faster and build at critical scale, but also weather the current storm,” he said.

Alnylam Pharmaceuticals and Regeneron Pharmaceuticals’ bid to alter the course of Alzheimer’s disease and other central nervous system conditions got a boost April 26 from early data suggesting their experimental gene-targeting drug works as designed with manageable side effects.

The medicine, dubbed ALN-APP, uses RNA interference to quiet a gene involved in production of amyloid precursor protein, or APP. The protein is cut up by cells into smaller fragments, some of which can eventually build up as toxic plaques that are thought to play a role in the hallmark neurological degeneration seen in Alzheimer’s patients.

In a Phase 1 study of 20 patients with early-onset Alzheimer’s, researchers found the therapy could reduce levels of APP by more than 70% for a sustained period on the highest dose tested, the companies said April 26. Side effects were mild or moderate.

“When we entered into this collaboration, the idea that you could profoundly silence disease-causing genes in the brain was simply a bold dream,” Regeneron Chief Scientific Officer George Yancopoulos said in the companies’ statement. “The current data suggest that this dream is closer to becoming a reality, offering hope for the many patients suffering from incurable neurological diseases.”

Still, the positive news came with the disclosure of a new issue: a partial clinical hold on the next part of the trial issued by the Food and Drug Administration because of concerns stemming from preclinical studies. Alnylam and Regeneron said they will share the new results from human studies with the agency to lift the hold. Canadian regulators have already given the all-clear for Part B to begin.

The FDA issue should be resolvable in part because the concern stems from “exaggerated” dose levels in the preclinical tests, Stifel analyst Paul Matteis said in an April 26 note to clients. The safety findings in humans from Part A of the trial “look fine” and should help allay the FDA’s concerns, he said.

While Alnylam and Regeneron still have a long road ahead to prove the value of their therapy, the results from Part A are about as good as they can get, Matteis said. The 70% reduction in APP “is impressive and seemingly unprecedented,” he said.

The early data have been eagerly anticipated by investors and the scientific community. The companies, which are also working together on a drug for liver disease, are trying to parlay an approach that’s worked well for diseases affecting that organ to the much more difficult target of the brain.

The Phase 1 results are “the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic,” the companies said. With the proof of concept in hand, the companies are speeding efforts to find new candidates for neurological diseases, Alnylam CEO Yvonne Greenstreet said.

Though the Phase 1 trial announced this week focused on Alzheimer’s, ALN-AAP is also being developed for patients with cerebral amyloid angiopathy.

Alnylam also sees opportunities to study RNAi drugs for a form of genetic ALS and for Huntington’s disease.

The development of therapeutic vaccines for cancer has met repeated disappointment over the years, as treatments aimed at cancers of the brain, lung and kidney have failed in clinical testing.

But now, developers like Moderna, BioNTech and Gritstone Bio are pushing forward with personalized, messenger RNA vaccines that have revitalized hopes these treatments could boost human immunity to keep cancer at bay.

The American Society for Clinical Oncology’s annual 2023 meeting, held in early June in Chicago, was the latest forum for Moderna and partner Merck & Co. to disclose data for a cancer shot they’re developing, called mRNA-4157. The companies had announced the trial met its goal in late 2022, and presented more detailed results two months ago.

In the background, Roche and partner BioNTech published early clinical trial data for a pancreatic cancer vaccine last month, and the companies are working toward concluding an early-stage melanoma study sometime in 2023. Gritstone, meanwhile, expects to have early data in colorectal cancer in early 2024.

The development of messenger RNA-based COVID-19 vaccines has helped accelerate some of these advances, showing how developers can quickly tailor and produce treatments using the genetic material.

“We saw something really amazing since the winter of 2020,” Gavin Dunn, director of the Center for Brain Tumor Immunology and Immunotherapy at Massachusetts General Hospital.

“We’ve seen the high immunogenicity of nucleic acid-based vaccines,” he said. Using mRNA’s speed and applying it to cancer vaccine research, “a lot of the time frames may start to be compressed.”

There are a number of reasons why past cancer vaccines have disappointed. Some haven’t targeted enough of the mutated proteins present in tumor cells to spur an immune response, or they’ve stimulated the wrong kind of immune cells or haven’t been able to overcome cancer’s natural immunosuppression. (One approved treatment, an individualized immunotherapy derived from patients’ blood called Provenge, is considered by some to be a cancer vaccine.)

Cancer vaccines now in development target multiple mutated cancer proteins, called neoantigens, and are tailored to the specific ones present in each individual patient.

“The question is whether we didn’t have good enough vaccine technology or whether we didn’t target the correct antigen,” Olivier Michielin, a medical professor at the University of Geneva, said of past cancer vaccine disappointments in a discussion of Moderna’s data at ASCO.

Moderna is testing its shot, mRNA-4157, together with Merck’s immunotherapy Keytruda in people with melanoma who have had their primary tumors removed. The goal of such “adjuvant” treatment is to prevent cancer from returning.

In December 2022, the company reported the two drugs reduced the relative risk of death or recurrence by 44% over Keytruda alone. The new data came from an analysis of the risk of cancer spreading to distant organs or tissues, or “distant metastasis free survival.”

One-third of patients who receive Keytruda in this setting experience such spread, driving researchers’ work to come up with better options. “We know that patients with distant metastases experience more morbidity and mortality,” said Adnan Khattak, a clinical professor at Edith Cowan University in Australia, who presented the Moderna data at ASCO.

In the combination trial, mRNA-4157 and Keytruda reduced the risk of distant spread or death by 65% compared to Keytruda alone.

BioNTech’s candidate autogene cevumeran, which had the promising data in pancreatic cancer in May 2023, soon could have results from a Phase 2 trial in melanoma in combination with Keytruda, too. The company said the trial has completed enrollment and needs a sufficient number of events in order to measure the shot’s effectiveness.

However, the trial is in previously untreated patients, which could raise the threshold for determining success, SVB analyst Daina Graybosch wrote in a note to clients in December 2022. Quoting BioNTech executives, Graybosch wrote, “the bar for success is lower in adjuvant settings, as there are fewer tumor cells” for immune cells to attack.

Gritstone, meanwhile, reported in May 2023 that it had enrolled 71 of an initially planned 80 participants in a Phase 2 trial of its personalized neoantigen mRNA vaccine program in colorectal cancer. It is now expanding its planned enrollment to 100. The trial, which involves patients who typically don’t respond to Keytruda, is expected to generate preliminary results in early 2024, executives said.

Aiding the development of these personalized vaccines has been artificial intelligence-aided genetic profiling that helps identify the antigens present in patients and how to better target them. That, in turn, has helped speed clinical testing and, if the vaccines are ever approved, could help meet patient demand, said Christina Corridon, a principal at the consulting firm ZS.

“There’s a limited capacity of human pathologists to be doing all of this work,” she said. “One of the limitations to scaling [personalized vaccines] is human pathologists versus computational pathology.”

Gritstone also has an “off-the-shelf” cancer vaccine technology that targets shared neoantigens, an area where the private Swiss company Nouscom has been working.

The recent progress appears to be shifting the views of researchers and physicians, as they try to build on the cancer immunotherapy advances of the past decade.

“We have clearly a new groundbreaking technology that will open a new era in cancer vaccines,” Michielin said in comments on the Moderna data.