May 19, 2024

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Will Moderna focus on only rare diseases after COVID pandamic?

Will Moderna focus on only rare diseases after COVID pandamic?


Will Moderna focus on only rare diseases after COVID pandamic?

The COVID-19 epidemic was fierce back then, but now it is receding quickly. Moderna, which is at the right time and place in the epidemic, is now facing the retreat of the epidemic, and it has also faded the aura of emerging vaccine companies.

If it is said that many years ago, Moderna’s researchers still had doubts about the druggability, “Can mRNA really be turned into a drug to treat patients?” Now, after the success of its $36 billion COVID-19 pneumonia vaccine, The first question the company had to face became: “What’s next for mRNA therapy?”


Will Moderna focus on only rare diseases after COVID pandamic?


Let us first look at the answers given by other companies.

BioNTech , which is known for its mRNA technology , mainly applies the advantages of mRNA therapy to the treatment of oncology and infectious diseases. Its mRNA-based individualized neoantigen-specific cancer vaccine has shown positive results in a phase 1 trial for the treatment of pancreatic cancer , and clinical trials of its mRNA vaccine targeting shingles and tuberculosis have also been launched.

Domestically, ABO2011 Injection, an mRNA tumor drug of Abbott Biotech , has obtained implicit approval for clinical trials, and its indications are advanced solid tumors that have progressed or metastasized after systematic standard treatment . The project was declared for clinical application on March 24 this year.

Recently, the clinical trial application for the non-replicating mRNA injection encoding the cytokine IL-12 independently developed by Sri Microbiology obtained the implied clinical trial approval, and the indication is for the treatment of recurrent/metastatic advanced malignant solid tumors . This is the first non-replicating mRNA injection of IL-12 approved by NMPA to enter the clinical stage in China.

Similar to the answers given by these companies, Moderna ‘s answer in the past year has been “casting a wide net.” These include expanding the infectious disease vaccine pipeline and partnering with Merck to develop a personalized cancer vaccine. Among them, for example, the research and development of flu vaccines has been full of ups and downs, with mixed results; and although the results of personalized cancer vaccines have been exposed, the market response has been mediocre.

Today, the early clinical success of using mRNA molecules to produce therapeutic proteins in the liver makes Moderna full of imagination for another application prospect of mRNA, that is, the field of rare diseases. And its imagination is huge. Stéphane Bancel, then CEO, made it clear in an interview :

” Moderna , will increase investment in the field of rare diseases and become a rare disease company.”



Moderna’s rare disease journey

The majority of rare diseases are genetic disorders that are fatal or cause major disability, and the majority of patients are children. There are currently more than 7,000 known rare diseases, but more than 90% of them lack effective treatments.

One of the reasons is the difficulty in the development of rare disease drugs. Due to the small number of patients with each rare disease, it is difficult to recruit patients during clinical trials, and it is not easy to automate and scale up drug production, which in turn increases development costs. Therefore, patients with rare diseases face huge unmet medical needs.


However, unlike many common chronic diseases, rare diseases usually have a definite and clear pathogenic mechanism.

These diseases are often caused by specific genetic variations. Therefore, by analyzing and testing the patient’s genome, the cause can be determined and developed. , Apply corresponding therapy.


In May, the company revealed an encouraging discovery from an early study of its treatment, which helped children with PA (propionic acidemia) make a key enzyme their bodies were missing.


The pathogenesis of PA is due to the accumulation of propionic acid and its metabolites due to the deficiency of the mitochondrial polymerase propionyl-CoA carboxylase (PCC), which is characterized by recurrent metabolic ketoacidosis, protein intolerance, hyperammonemia and Increased plasma glycine is the main clinical feature.


Moderna chose to use LNP to deliver the correct mRNA into the patient, helping to synthesize the enzyme encoding the corresponding deletion. Infusions of mRNA encoding the enzyme every other week reduced the fatal metabolic crisis by about 66%.



Will Moderna focus on only rare diseases after COVID pandamic?

And the success of this therapy is the signal that Moderna is longing for.


The programmability of mRNA therapy is suitable for the treatment of such genetic diseases, as long as the safety and efficacy of mRNA therapy targeting a specific part of the body (such as the liver) are verified, only the nucleic acid needs to be replaced according to the genetic variation causing the disease sequence, the same formulation can be used to rapidly develop corresponding therapies.


“We’re doubling, doubling, doubling our spending on rare diseases,” Bancel said.


Moderna’s move comes as many companies, from small biotech companies to pharmaceutical giants such as Pfizer, have cut pipelines for rare diseases. Bancel is one of mRNA’s most ardent evangelists, and investors have learned to take his statements with a grain of salt.

However, with about $16.4 billion in cash and long-term and short-term investments as of March 31, Moderna has the financial muscle to write the next chapter of this kind of planning.


Moderna has indeed sharpened its knives.


Earlier this year, when major pharmaceutical companies were laying off workers extensively, Moderna announced plans to increase its research and development budget to $4.5 billion and hire about 2,000 employees, increasing the number of employees by about 50%.

The company already has three clinical, three preclinical and several more undisclosed liver-targeted mRNA therapeutics for rare diseases.


“Our ambitions are huge,” said Kyle Holen, Moderna’s senior vice president and head of therapeutics and oncology development. “In our preclinical development program, we have a full panel of mRNAs that will hopefully be in the clinic within the next year or two.”

To this end, Moderna has also established a rare disease business team, led by Patricia Gauthier . She led Moderna’s operations across Canada during the pandemic.

The tsunami of rare disease drugs


One of the biggest selling points of mRNA technology is its programmability . Bancel has often told investors that if the company shows safety and efficacy in one mRNA drug, more drugs based on the same formulation and targeting the same part of the body should be easy. All they need to do is change the genetic sequence.


Bancel said that the company’s strategy is to “take the point to face”, starting with one disease to solve more similar diseases.


Since its founding 13 years ago, Moderna has argued that its mRNA technology could provide people with genetic diseases with the genetic code for disrupted or missing proteins.


In 2021, Moderna finally gave its first patients the drug in trials for two rare diseases : propionic acidemia and methylmalonic acidemia. In both cases, the absence of the enzyme leads to a buildup of toxic molecules in the body that can damage organs, including the brain. “If we get positive data in these two rare disease programs, then you’re going to see a lot of rare disease drugs coming out of the lab and into the clinic,” Bancel told The Boston Globe last year.


In May, the company presented its first interim data from a small study in 16 children in the treatment of propionic acidemia, showing that its mRNA therapy is working.


Despite side effects from frequent infusions of the therapy, Moderna believes the drug is sufficiently safe.


“This gives us more confidence in our ability to succeed across the entire rare disease portfolio,” Holen said.


Morningstar analyst Karen Andersen, who covers Moderna, was also encouraged by the clinical data. “There were a lot of skeptics before these data were available,” she said. “It opens the door to all kinds of proteins or antibodies that they might produce.



The Clinical True Test – Safety : ‘All children are continuing treatment’


Although Moderna is excited about the clinical results, the safety and tolerability of long-term mRNA therapy still needs to be questioned.


Unlike when used as a prophylactic vaccine, when mRNA therapy is used to treat genetic rare diseases, patients need to receive higher doses of mRNA-coated lipid nanoparticles (LNP) injections and may need to receive more frequent medication throughout their lives Treatment (1-2 injections per month), so this also makes people more concerned about the safety and tolerability of this therapy.


LNP has been linked to adverse reactions in many patients after receiving Moderna’s COVID-19 injection. With mRNA as a therapeutic approach, the key issue is immunogenicity.


All 16 patients participating in the mRNA-3927 clinical trial experienced adverse reactions including fever, diarrhea and vomiting, and half of the patients experienced serious adverse reactions.

However, all 11 patients who completed the 20-40 week trial opted to continue treatment in the open-label extension trial.

The safety and efficacy results of the therapy in follow-up trials will be the key to determining whether mRNA can be unlocked for the treatment of a large number of rare diseases.


Kathryn Whitehead, a gene delivery scientist at Carnegie Mellon University, believes that while the response was “not ideal,” she says the study was too small to make any conclusions about clinical feasibility based on the data.


Six patients also experienced infusion-related reactions, which usually occur only once or twice, but one participant had 11. These reactions are to be expected, Holen said, but can be managed with drugs that lower inflammation or by spaced dosing.


The dose of mRNA therapy is also much higher than that of vaccines. Moderna’s COVID-19 injection dose is 50 micrograms, but the company tested doses of 300 to 900 micrograms per kilogram of body weight in the treatment of propionic acidemia, which means that the dose of mRNA-filled lipid nanoparticles used by patients is about the same as that of COVID-19. Use 60 to 1600 times the dose.


Families of all 11 patients who completed the 20- to 40-week study opted to keep their children on the infusion, Moderna said. That is to say, after weighing the pros and cons of safety and effectiveness, all the family members of the patients chose to continue the medication.


“The real test, in my opinion, is that all the kids choose to stay on the drug,” Bancel said.


The long road ahead


In 2022, Moderna started a clinical trial for a third metabolic disease, glycogen storage disease type 1a. Three of the company’s preclinical programs address ornithine transcarbamylase deficiency, phenylketonuria, and Crigler-Najjar syndrome type 1, also caused by a loss of liver enzymes.

They are just a fraction of the roughly 1,500 genetic diseases caused by mutations that disrupt the body’s ability to make or break down molecules.


That is to say, the theoretical application potential of drugs will reach 1,500.


Some of Moderna’s interest in rare diseases has been revealed by scientific papers published by academic researchers working with Moderna, including UPMC’s Vockley.

Vockley thinks that mRNA therapies can be designed relatively quickly and easily stopped if safety concerns arise, which could give them an advantage over a gene therapy that’s already done.


The big problem with mRNA right now is that it’s limited to liver delivery. But it is estimated that at least 50 to 100 inherited metabolic diseases can be treated in this organ.


Also, some diseases may be too rare for Moderna to conduct research commercially, but Bancel emphasized that his company is committed to finding another way to bring these therapies to the clinic.

In 2021, for example, Moderna donated its preclinical therapy for Crigler-Najjar type 1 to the Institute for Life-Changing Medicines, a nonprofit dedicated to treating ultra-rare diseases.


Bancel said that Moderna may establish more partnerships similar to the University of Pennsylvania in the future. He also considers how to produce drugs for diseases that affect 10 or fewer people—sometimes just one.


The company has machines dedicated to making custom mRNA therapeutics for its cancer vaccines, which are used to train a patient’s immune system to target their tumor’s unique molecular blueprint. The machines could have applications in rare diseases, especially those with few patients, Bancel said.


Timothy Yu, a researcher at Boston Children’s Hospital who has pioneered the development of custom therapies for children with unique genetic mutations, finds Moderna’s vision exciting. Timothy Yu has largely used antisense oligonucleotides, which can trick cells into skipping certain genotype errors or turning off disease-causing genes. But this approach requires a deep understanding of the cause of a person’s disease, and it doesn’t work for every mutation.


“If we can really figure out how to treat many different diseases at scale, it has the potential to be a panacea for this rare disease,” said Timothy Yu.

“The road may be long, but there is always a way.”








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[3]Moderna official website

Will Moderna focus on only rare diseases after COVID pandamic?

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