Crispr gene-editing breakthrough is a big deal. How big?

Sam Fazeli, a Bloomberg Opinion contributor who covers the pharmaceutical industry for Bloomberg Intelligence, answers questions after Intellia Therapeutics Inc. and Regeneron Pharmaceuticals Inc. released promising findings from the first human clinical trial using gene-editing Crispr technology in the body to treat a disease. Intellia shares surged more than 40% on the news. The conversation has been edited and condensed.

This is the first successful in-human gene editing with Crispr that we know of, and it seems to work really well. Is this a big deal?

The answer is an emphatic yes. This new data, even though from just a handful of patients, shows not only that this new technology works in humans, but that it is also very safe, at least at the two doses that were tested in this trial. It's important because it's the first time that scientists have been able to modify DNA in a patient's cells in a very specific way. This fascinating technology, very simply, is a molecular scissors (Cas9) that is led by a "guide RNA" to cut a specific part of DNA. Bacteria use this method to inactivate invading viruses. In Intellia's trial, the system is used to deactivate the gene for a misfolded protein known as transthyretin, or TTR, which can build up in patients in some rare cases, leading to neurological and heart damage that is eventually fatal.

Why might it work better than other forms of genetic therapy that are already approved?

The beauty of what Intellia has done is that it has produced a highly specific "knockdown" of one disease gene, though more data is needed to prove that is 100% specific in humans. The other way that people have been tackling this type of disease involves either using antibodies targeted against a protein or some form of RNA-silencing or anti-sense methods, to stop the production of a protein. Indeed, there is already an approved drug from Alnylam (Onpattro) for the rare disease that Intellia is targeting. But these are drugs that need continuous therapy, whereas the gene-editing methods should be one and done.

This sort of editing is permanent -- that's probably a good thing in terms of having the desired effect on disease, but that also sounds scary. Is there any reason it might be problematic?

Not really, especially if scientists prove that it is indeed as specific as the technology is designed to be and has appeared to be so far in animal studies. But more data is needed to prove that. The problem is that the human body is very complex, and there will always be some risk that it works much better in some than others. Indeed, the data showed that the effects from the same dose varied among three different people. One good thing about the Intellia technology is that it uses lipid nanoparticles to deliver its payload -- similar to those used in the mRNA vaccines from Pfizer-BioNTech and Moderna. This reduces the risks that are associated with using viruses, which most other gene therapies use.

Are there any safety concerns?

The data showed few side effects, which was amazing. But the company is going to go to a higher dose in the next set of patients -- one that's three times higher than the highest dose tested so far. This may increase the side effects. But the technology may be good enough at cutting the problem protein at the current dosage that Intellia may not need to take that risk. There could also be an immune response to the Cas9 protein the system needs to do its job correctly. If that is the case, it is unlikely to cause a problem by itself but may make delivering a second dose problematic, which means that the effect from the first needs to stick.

Speaking of which, what about durability. Is the effect going to last?

This is a key question. In animal studies, the effect has been maintained for at least 52 weeks. But in humans, the data stops at 28 days for now. So the company needs to show that the reductions in protein levels in humans are maintained. Otherwise, as noted above, the opportunity for redosing with the same drug is likely very limited. Other companies are working on different versions of the technology that may allow for redosing, but a lot more work needs to be done to see if they're needed or that's possible.

What's the path forward for Intellia and for this sort of gene editing in general? When might it be more broadly available?

Durability and long-term safety will be important because the drug may cost hundreds of thousands of dollars or more. But Intellia also needs to show clinical benefit in the patients, though I suspect, given the direct correlation between TTR levels and disease, this is not a huge risk in this setting. On the path forward, these findings prove the feasibility of "gene knockout" in humans. Intellia has other programs using this technique to treat other diseases, including a swelling disorder called hereditary angioedema. The next step is whether scientists can literally "edit" a gene to correct a mutation. Intellia and several other gene-editing companies have such programs under way. The critical questions are: Can real gene editing be done at high efficiency in patients, and can this be done in any organ and not just those that are relatively easily accessible, such as the liver? The other issue is whether the system can be used to correct multiple mutations because not all diseases are caused by just one.

Is Crispr definitely the way forward in gene editing, or could we do even better?

There are other technologies in development, such as TALENs, Sangamo's zinc-finger nucleases, and site-specific nucleases. But in the end, they all try to achieve the same thing. Intellia's data shows that, at least in some settings where the target organ is easy to access, this can be done inside a human being. This opens the door for all these technologies to be tested. It will take additional study and in-human data to show any advantages or problems.

Gene editing comes with some ethical concerns -- how do we make sure it's used in the right way?

That's a big societal issue. We have seen it play out when it came to cloning Dolly the sheep. In the end, it is the job of science to come up with new technologies and for regulators and governments to ensure that they are applied for the right reasons, in the right way and in the right context.

You touched on the likely high cost of the drug above. Other gene therapies have been extremely expensive, with companies invoking the "one and done" aspect of these treatments as a justification. Will this follow the same path?

I think this is where we will have to have more discussion and find better ways of encouraging innovation without making treatment unaffordable. I have heard of buying clubs, for example, for Novartis's gene therapy Zolgensma for spinal muscular atrophy, a rare but devastating disease for some babies. But at a cost of about $2 million, this is extremely difficult to finance. If gene editing does eventually deliver on its promise, given the number of single-gene diseases, it could create a significant cost burden on society that is still reeling from the economic effects of the pandemic.

Sam Fazeli

Sam Fazeli is a Pharmaceuticals analyst.