Has the CRISPR revolution already arrived?

Q: What is the current state of CRISPR?

There have been many developments. We’re on the verge of getting the first CRISPR-based drugs approved, and there’s a whole pipeline of new therapies on the way. A Noble Prize was awarded and patent battles between Berkeley and MIT were settled. Additionally, there has been a major controversy in terms of human experimentation and ethical transgressions that led to a scientist being jailed for experimenting on human embryos. So it was quite dramatic and it continues to be.

Q: We last talked about CRISPR in 2018 . Has the amount of change over the past five years lived up to your expectations? Was it the way you expected?

It’s about to go from lab experiments to being about to get a drug approved – it’s a really good time. The pipeline is clustered around hematological disorders, so I might have expected there to be more progress in other diseases, but it’s about on pace.

Q: How far are we from having CRISPR-based drugs in the pharmacy or in a doctor’s toolbox?

It’s very exciting. Were very close.

The drugs closest to approval are co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics, and they collaborated on a product called Exa-cel, which is for sickle cell anemia and beta-thalassemia, two blood disorders . They presented the results late last year at major hematology conferences, and they plan to submit the BLA, which is the license application to the FDA this year. It takes about nine months or a year to go through the process, so we could see the first treatment approved at the end of this calendar year.

Q: What kind of impact do you expect for someone with sickle cell disease? Is it a gradual change? Is this a big change?

It would be a huge, radical and revolutionary change, with the potential to give a single dose of a drug and change the way these patients produce their own blood cells so that they are potentially cured of the disease.

This would have the effect of doing a bone marrow transplant, which is done in cancer centers, and is high risk and very difficult for patients. CRISPR would be much easier and better tolerated. With CRISPR, doctors take blood cells, use CRISPR technology to modify faulty genes, and reinfuse the new and improved cells, which then produce healthy red blood cells in the patient. In sickle cell disease, patients have an attack of pain because the cells have a problem with their morphology. Beta-thalassemia is a type of anemia, and similarly, red blood cells have a genetic problem with their ability to transport hemoglobin. Preliminary data from 31 patients suggests that treatment can cure the disease. So it’s a very dramatic improvement.

Q: What do you foresee as accessibility of these kinds of therapies? Are the prices extremely high? Will insurance cover them? Will there be economic or racial disparities in access?

Science has progressed. However, what is lagging behind are regulatory standards and all conclusions on pricing as well as improving access to new therapies. There is simply no set direction yet. So we’ll have to wait to see that.

The question of prices could be dramatic. Previously approved gene therapies are incredibly expensive, over $1 million, sometimes close to $3 million. Indeed, the argument of the pharmaceutical manufacturer is that, generally, the drugs must be administered repeatedly, so they expect long-term sales. But with the ability to give a single dose and cure a patient, companies say they will never recoup their investment in R&D, especially in rare diseases.

So their argument is basically, “Look, the system would pay more on the life of the patient. We just bring the payment in advance. Since these drugs have yet to be approved, we don’t know what pricing assumptions the companies will make, but I’m sure they are wrestling with these questions right now.

Regulatory-wise, this is another unknown because each time a new class of biology is presented to the FDA, they must determine how best to study safety and efficacy. A single-dose drug that affects a person’s lifetime raises questions about the appropriate timeline to monitor for safety events. It also raises important questions about the potential effects not just for that person, but possibly for their children. So how long do you monitor before you say, “OK, the security part of the trial is over and we’re comfortable with that”? These decisions have yet to be codified as standards.

Q: You mentioned that the focus has been on the hematology area. Are there other diseases that could theoretically be treated in the same way but are further down the pipeline?

There is another rare disease called A-1AT, which is alpha-1 antitrypsin deficiency. It is at an early stage of development. It’s a combination of lung and liver disease. There’s another in development for a rare condition called hereditary angioedema, as well as others that are earlier in the pipeline.

The critical issue is getting enough of the CRISPR drug into the cells that need to be changed so that you can have the beneficial effect for the patient. For some of them, like A-1AT, you’d want to target the liver, and it’s a little easier to give an infusion since the drugs go straight to the liver and get delivered appropriately. But when other organs are involved, it would be much harder to get a wide distribution of a CRISPR drug, or gene therapy, or even regular drugs. For example, getting into the brain and getting a wide distribution of a complicated drug like this would be difficult.

Q: Five years ago we talked about the possibility of making a genetic change to completely avoid a disease when someone is still an embryo. Is this still a possibility?

There have been genetic animals produced using CRISPR through this method. There have been CRISPR-modified pigs and even cows. By far the most common use of CRISPR today is to produce genetically modified mice for laboratory experiments. In the past, this was a time-consuming task where researchers had to create a “knockout mouse” – they tried to insert a gene into the mouse’s genome – and it was very hit or miss. Now, it has become almost commonplace to produce these genetically modified CRISPR mice for research purposes.

So we know that it’s theoretically possible to do all of this in mammals. There is a famous, highly controversial and unethical work that was done by a researcher in China, who modified the embryos of human babies in order to prevent them from contracting HIV from a parent. When this researcher announced his results, there was a global reaction, including from China, the scientist’s home country. He was sentenced to three years in prison. I think they reacted appropriately by condemning this use of human embryos. There is still a moratorium on human experimentation.

Q: What about using gene editing on animals to prevent the spread of animal-borne diseases?

It continues to be possible, but there is still a great deal of caution in doing so, which is appropriate. The big concern is that editing an animal’s genes can alter its reproductive cells, leading to new genetic lines with mutations that can be introduced into the population with unknown consequences. This is perhaps the biggest long-term concern.

Q: You mentioned a few risks and ethical concerns. Could you talk about the risks in general and where is the balance in terms of risks and benefits at this stage?

The greatest risk is that CRISPR edits cause germline mutation, which is the mutation of reproductive cells, and these altered genes are transferred to offspring and an entire population with unknown consequences. There is an absolute moratorium on doing this in human beings. So it’s currently a theoretical risk, and I trust the researchers and the pharmaceutical companies to stick to those limits.

However, there is a theoretical possibility that infusing CRISPR-modified cells as stem cells could have other unknown consequences, maybe germline, maybe other things. There is only a small possibility of this happening, but it should be monitored. It is also possible that the genetic benefits do not last the expected duration or the lifespan of the patients. Patients will therefore need to be monitored to be sure that lifelong benefits are achieved and to avoid risks.

Q: What other open questions are discussed in and around CRISPR?

I think the bigger question is about the business model and whether the company will accept extremely expensive single-dose drugs for rare diseases, and whether payers or governments will pay. Ultimately, if there is a contraction in the willingness to pay for these kinds of new and very expensive therapies, it will be difficult for biotech companies to get funded. But it’s a business risk that the biggest pharma companies are likely to be cautious about entering until they see economic validation and scientific proof-of-concept.