We are publishing this report from the "Financial Times" in the Italian version by the reporter Nikou Asgari who, from New York, covered the entire story of the Coronavirus for the newspaper, including from the scientific and pharmaceutical point of view of the search for an antidote and a treatment. The article highlights the potential of mRNA technology which appears immense also for the treatment of cancer in which science and medicine have marked time for too many years. Now new hopes seem to be opening up.
The pioneering work of Vinod Balachandran
In 2017, Vinod Balachandran published an article in the scientific journal Nature explaining an interesting phenomenon he had discovered in a small sample of pancreatic cancer survivors. The T cells in their blood had developed the ability to identify, remember and fight tumor proteins.
The surgeon of the Memorial Sloan Kettering Cancer Center in New York defined this phenomenon as "self-vaccination". Balachandran believes vaccines using messenger RNA molecules could be used to replicate the sample's immune response and allow patients to defend themselves against often fatal cancers.
His research attracted the attention of a then little-known scientist, Ugur Sahin, CEO of the German biotechnology company BioNTech. Sahin, intrigued by the results of Balachandran's work, invited him and his team to Mainz, the headquarters of BioNTech. Over a dinner at the Heiliggeist, a thousand-year-old church-turned-restaurant on the banks of the Rhine River — also attended by scientists from the Swiss pharmaceutical company Genentech — the group discussed the potential of mRNA vaccines in treating pancreatic cancer.
“It was beautiful,” Balachandran recalls of the restaurant that was once a hospital and of the conversation: “Between us, the purpose and mission were common.”
It's just the beginning
Survival rates among pancreatic cancer patients are low. Only 10 percent survive more than five years, according to the American Cancer Society. This makes it one of the deadliest forms of this disease. In comparison, 90 percent of breast cancer patients survive the same amount of time.
In the two years of research, following the December 2019 dinner, 20 patients were enrolled in the first clinical study aimed at evaluating the efficacy of mRNA vaccines in pancreatic cancer patients. Sadly, with the world succumbing to a novel coronavirus, BioNTech and the other dinner attendees would soon refocus their mRNA work toward creating a vaccine against Covid-19.
While mRNA vaccines made by BioNTech/Pfizer and Moderna have become indispensable in dramatically reducing deaths from Covid-19, Balachandran, along with a growing group of scientists, are using this medical technology to develop treatments for other diseases.
Proponents of mRNA say fighting Covid-19 is just the beginning, and the widespread adoption of mRNA technology heralds a revolution in modern medicine. Treatments for some forms of cancer are among several areas that are beginning to be seriously tested.
The awakening of Big Pharma
Pharmaceutical companies are now turning their attention to mRNA's ability to treat a range of diseases, from seasonal flu to heart disease, HIV to cancer. Also underway are the first trials of vaccines for Zika virus, yellow fever and rare diseases such as methylmalonic acidemia, where the body is unable to break down proteins.
Says Michael Choy, head of life sciences at the Boston Consulting Group:
“Five years ago there was a reluctance from big pharmaceutical companies to invest in this space. But seeing so many people receiving the mRNA product [for Covid] has made a huge difference.”
The success of the Covid-19 vaccines has transformed the scientific and commercial fate of this technology. No mRNA-based product had ever been approved by regulators until the pandemic crisis, and despite years of research, the technology was viewed by industry bigwigs as difficult to commercialize.
“It's often a combination of medical necessity and feasibility,” Sahin says, of how companies choose which diseases to focus on.
BioNTech's goal has always been to create individualized vaccines tailored to target specific tumors. It is an approach that Sahin, an oncologist, believes will revolutionize the treatment of the disease. The company has begun trials of drugs to treat colorectal, breast, skin and other cancers.
Personalized cancer vaccines
Other pharmaceutical companies, including Moderna, are studying personalized mRNA-based cancer vaccines. It is hoped that it will be able to cure diseases that are among the leading causes of death worldwide and also profit from the multibillion-dollar oncology market.
According to McKinsey, sales of cancer therapies are expected to reach $250 billion by 2024, up from $143 billion in 2019.
"The foundation of this individualized cancer vaccine is that every tumor is different," says Sahin, also specifying that "patients with the same type of cancer do not have identical diseases." Which means that personalized treatment is likely to be more effective than a one-size-fits-all approach.
Therapeutic cancer vaccines aim to stimulate an immune response against existing cancers, rather than prevent a disease such as the flu.
They are tailored to the specific mutations of a patient's tumor. Scientists remove tissue from the tumor through a biopsy and then sequence the mutations present in the diseased cells. The results, compared to the patient's DNA, are analyzed by algorithms to predict which specific proteins will produce the strongest immune response. These proteins are then encoded into an mRNA molecule that forms the essence of the cancer vaccine.
How the mRNA vaccine works
Once inoculated, instructions conveyed by the mRNA vaccine tell the body's cells to produce certain proteins that train the immune system to recognize mutated cancer cells as foreign agents and then attack and destroy them. Sahin specifies:
“We started in 2014 and the time between biopsy and vaccine was about three months, but now with automation… it takes less than six weeks”
Existing cancer vaccines primarily target the virus that causes cancer, rather than the tumor itself. In the United States, the non-mRNA HPV vaccine is given to children starting at age nine to protect them from cervical cancer, which can be caused by human papillomavirus.
Pfizer's plans
In addition to cancer, mRNA vaccine trials are underway for various infectious diseases. Influenza vaccine trials should yield faster results. An infectious disease such as Covid or flu mutates over time and therefore vaccines must be updated annually for new strains. Vectored influenza vaccinations use inactivated versions of the virus and provide between 40% and 60% protection, because by the time the vaccine is made to when it is administered, the virus is often already mutated.
It is hoped that mRNA, which can be adapted more quickly, will dramatically increase the effectiveness of seasonal flu vaccines. Continuing its partnership with BioNTech, Pfizer in September began trials of an mRNA flu vaccine for adults ages 65 to 85, one of the groups most vulnerable to the disease.
Philip Dormitzer, chief scientific officer of Pfizer, points out that the company was already working with BioNTech on the development of a flu vaccine when Covid hit:
“At that point, of course, we moved on to work on a Covid-19 vaccine using a lot of technology that we had come up with for the flu vaccine. As bandwidth now widens, we're getting back to work on the flu vaccine."
So far, Pfizer's flu vaccine is the only other mRNA collaboration with BioNTech. Dormitzer says:
"I think we're capable of going it alone for everything, but that doesn't necessarily mean that's the path we'll ultimately choose."
The company has yet to reveal what other areas it plans to target with mRNA, but Dormitzer says rare diseases, protein replacement and gene editing "are all of interest." Then he adds:
“There may be companies that say 'we have 20 vaccines in our production line'. This will not be the type of approach by Pfizer ”.
Moderna's plans
By contrast, at Moderna's annual R&D day in September 2021, the company showcased its 34 plans linked to mRNA, across six different areas of medicine. The 11-year-old biotech group, whose stock symbol is MRNA, is spending half of its energy on tackling respiratory viruses and other infectious diseases, according to Stephen Hoge, its chairman, and the other half on vaccines against cancer, rare diseases and gene therapy. Hoge specifies:
“It is tragic that we will have 4 million deaths from Covid this year, but every year there are 4 million deaths from respiratory viruses. The difference is that the latter only occurs in small groups… half a million here, a hundred thousand there. But, every year, the total is a terrifying number."
The Massachusetts company aims to create a pan-respiratory vaccine that would provide combined immunity from Covid-19, influenza and other infections such as respiratory syncytial virus — a common disease that can cause lung infections. All in one vaccine. adds Hoge.
“Nobody wants to have a pincushion anymore. We can actually put all of that into one needle."
Each respiratory vaccine developed by Moderna must be evaluated individually before being combined with others. The company began trials of its flu vaccine in July, while the vaccine for cytomegalovirus, a disease that has no vaccine and can cause birth defects in babies, is in Phase 2 and still a long way from approval. of the competent authorities.
Responding to criticisms that Moderna — whose Covid vaccine is its only drug agency-approved product to date — is aiming too high with its 34 programs, Hoge replies that if other pharmaceutical companies are "playing around" on the mRNA, now that its effectiveness is demonstrated by Covid vaccines, Moderna is focused on this technology.
Investors bet
The scientific and commercial success of the two Covid-19 mRNA vaccines has spurred a rush of investment in the sector. New mRNA treatments are expected to begin entering the market in 2025, according to research by the Boston Consulting Group.
Revenues are expected to peak at $23 billion in 2035, with prophylactic and therapeutic cancer vaccines accounting for 50 and 30 percent of sales, respectively.
Julia Angeles, investment manager at Baillie Gifford, an early investor in Moderna, believes mRNA is set to revolutionize many aspects of medicine. Baillie Gifford, who is the largest single investor in Moderna with an 11,4 percent stake and is the fourth largest shareholder in German mRNA-focused company CureVac, underscores investors' faith in the future of this technology. She tells Angeles of Moderna, a company currently valued at $124 billion:
“I sincerely think Moderna will be the first biotech company to achieve a $1tn valuation. That's likely to happen in five years…because no one has the breadth and depth of Moderna's technology yet.”
Some might dismiss this as investor hype, but other companies are already preparing to enter the arena of competition.
Sanofi and Merck
In October, French pharmaceutical group Sanofi halted its search for its own Covid mRNA, on the grounds that it was too late to enter a market dominated by BioNTech/Pfizer and Moderna. However, the company has seen the potential of the technology and has created an mRNA research center to develop vaccines in which it will invest 400 million euros a year.
Sanofi also bought partner Translate Bio in August for $3,2 billion, hoping to capitalize on mRNA-based therapies in areas such as cystic fibrosis and lung disease.
The American pharmaceutical company Merck is also on the lookout for acquisitions: it is betting on various mRNA therapeutics companies. In the UK, AstraZeneca sealed its first RNA deal in September by partnering with VaxEquity to develop up to 26 new medicines.
It will take some time
Yet despite the optimism and breakthroughs of the Covid era, it will take years for trials in some areas to start producing results. It will also take some time for the drugs to be approved. Regulators around the world have accelerated approval processes during the pandemic due to the urgent need for a vaccine, a speed that is unlikely to be achieved for other drugs.
Hoge says Moderna's respiratory syncytial virus vaccine, which is set to move into phase 2 trials, could be ready in three years if data confirms its efficacy. But he acknowledges that the Covid pandemic has been a "unique circumstance", difficult to replicate. Hodge is nonetheless optimistic:
“If people want to be… a little more conservative, or see a little more data before making a decision, it could take a few years. But I hope for a speed greater than this”.
The need for caution
The chances of failure are incredibly high. Fewer than 10 percent of drugs entering phase 1 trials make it to market, according to research by the Biotechnology Innovation Organization in Washington. Nearly 60 percent of drugs that make it to stage 3 fail anyway.
David Braun, a kidney cancer oncologist at the Dana-Farber Cancer Institute in Boston, says it's a long road from the Covid vaccine to a personalized cancer vaccine. Braun warns:
“Medicine has made this mistake many times in the past, going from hype and big ideas to overpromising. There is too much expectation that mRNA will be used beyond infectious disease. Still, it's a big leap."
mRNA vaccines don't always deliver blockbuster results. German biotech CureVac has abandoned its mRNA Covid vaccine after disappointing test results showed it was only 48% effective. The company decided to instead focus on its mRNA Covid jab with GlaxoSmithKline.
“It's one example: We still don't know everything we need to know about what makes these therapies work,” says BCG's Choy.
Knowing how to choose
Selecting which diseases to target will be a crucial decision for entrants to the mRNA market.
“It makes no sense to replace, for example, a protein-based vaccine with 95% efficacy, with an mRNA,” says BioNTech's Sahin.
The question here is: “what benefit does this change bring”?
Vaccines for chickenpox, shingles and MMR are unlikely to be replaced by mRNA-based treatments, because traditional vaccines are already effective. Researchers are focusing on diseases for which the new vaccine's patient outcomes could be improved.
However, buoyed by the success of the Covid vaccines, the best scientists in the industry have big and bold ambitions.
Sahin points to an interesting perspective of gene therapy to repair damaged tissues and organs. This is a possible frontier that mRNA may cross in the coming decades, potentially paving the way for new gene therapies such as Crispr.
Sahin concludes:
“Organ repair will be an important topic for the future. This is exciting."
. . .
From: Nikou Asgari, Covid success of mRNA vaccines opens way to a new generation of drugs, “The Financial Times”, October 13, 2021
