Moderna's problems with mRNA (2017 article)

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Lavishly funded Moderna hits safety problems in bold bid to revolutionize medicine

Moderna Therapeutics, the most highly valued private company in biotech, has run into troubling safety problems with its most ambitious therapy, STAT has learned — and is now banking on a mysterious new technology to keep afloat its brash promise of reinventing modern medicine

It never proved safe enough to test in humans, according to several former Moderna employees and collaborators who worked closely on the project. Unable to press forward with that technology, Moderna has had to focus instead on developing a handful of vaccines, turning to a less lucrative field that might not justify the company’s nearly $5 billion valuation.

“It’s all vaccines right now, and vaccines are a loss-leader,” said one former Moderna manager. “Moderna right now is a multibillion-dollar vaccines company, and I don’t see how that holds up.”

The company’s premise: Using custom-built strands of messenger RNA, known as mRNA, it aims to turn the body’s cells into ad hoc drug factories, compelling them to produce the proteins needed to treat a wide variety of diseases.

But mRNA is a tricky technology. Several major pharmaceutical companies have tried and abandoned the idea, struggling to get mRNA into cells without triggering nasty side effects.

He describes mRNA as a simple way to develop treatments for scores of ailments. As he told STAT over the summer, “mRNA is like software: You can just turn the crank and get a lot of products going into development.”

It seems clear, however, that the software has run into bugs.

In Moderna’s eyes, the one-in-million disease looked like an ideal candidate for mRNA therapy. The company crafted a string of mRNA that would encode for the missing enzyme, believing it had hit upon an excellent starting point to prove technology could be used to treat rare diseases.

But things gradually came apart last year.

Every drug has what’s called a therapeutic window, the scientific sweet spot where a treatment is powerful enough to have an effect on a disease but not so strong as to put patients at too much risk. For mRNA, that has proved elusive.

In order to protect mRNA molecules from the body’s natural defenses, drug developers must wrap them in a protective casing. For Moderna, that meant putting its Crigler-Najjar therapy in nanoparticles made of lipids. And for its chemists, those nanoparticles created a daunting challenge: Dose too little, and you don’t get enough enzyme to affect the disease; dose too much, and the drug is too toxic for patients

Yet Moderna could not make its therapy work, former employees and collaborators said. The safe dose was too weak, and repeat injections of a dose strong enough to be effective had troubling effects on the liver in animal studies.

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