MPM Capital Managing Director Mitchell H. Finer, Ph.D. – a 30-year gene and cell therapy veteran – describes the relatively new science of gene editing, or genome engineering, as “very exciting.” But he also is quick to add that genome engineering as a marketed therapeutic product has a long way to go, and significant challenges to overcome, before it can be integrated into the drug formularies of patients.

Finer also gives gene editing companies and their partners a deadline for demonstrating some initial progress in successfully treating human patients or risk a crash-and-burn future.

“There has to be clinical benefit in an early stage clinical trial in five years,” he said, “otherwise the value is going to evaporate.”

During his career, Finer has focused on drug development utilizing not only cell and gene therapy, but also cancer immunotherapy and regenerative medicine. He has developed products from conception through Phase III in the U.S. and Europe. He joined MPM in 2015 after serving as chief scientific officer at BlueBird Bio and since then has founded Oncorus and Switch Bio, and joined the boards of Semma Therapeutics and TCR2 Therapeutics. Finer received his Ph.D. in biochemistry and molecular biology from Harvard University, and a B.S. in biochemistry and microbiology from the University of California at Berkeley.

In an interview with WuXi AppTec Communications, Finer described his approach to investing in genome engineering companies and the significant challenges they face in manufacturing and supplying patients with their products. WuXi’s interview with Finer is part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.

WuXi: What is your approach to investing in gene editing technology?

Mitchell Finer: I joined MPM a few years ago. I had been looking at the gene editing space when I was the chief scientific officer of Bluebird Bio. We, very early, looked into the genome engineering space. Bluebird ended up acquiring Pregenen, a homing endonuclease company in 2014.

At the time, the CRISPR (clustered regularly interspaced short palindromic repeats) technologies had come to the attention of a couple of venture groups, but the technology was fairly early in 2014. While we looked at CRISPR, we thought it had a significantly farther way to go. Homing endonucleases are much more complicated to engineer and there’s not nearly the ability to target as many sequences in the genome as CRISPR. But homing endonucleases have a very large number of protein DNA interactions that provide a great deal of specificity, and the molecules also were smaller and compact enabling easier gene-based delivery.

That said, the CRISPR field has really advanced. At MPM, we’re looking at companies with novel technologies. I came to MPM as the person with the most gene therapy product development expertise, and I continually look at CRISPR-based and other genome engineering technologies. I think the questions we have are efficiency in vivo and off-target activity. I don’t think these technologies are show stoppers yet.  I think CRISPR still has a way to go with off-target editing, and depending on where people are doing the engineering, one has to look at the efficiency of guide RNAs to make sure that across the population, we want a simple product.

If you’re talking about ex vivo genome engineering, which is easiest because the delivery issues are the easiest to conquer, the question in my mind still remains: Are you going to have to identify a guide RNA patient-by-patient or can you come up with one size fits all in terms of guide RNA?

Also, if you’re going to do genome engineering in the immunotherapy space ex vivo, where delivery is in your favor, are you going to have to engineer multiple genes and how easy is that? So these are the things I constantly ask when companies come to present various improvements of genome engineering technologies. What is the delivery technique in human primary cells? What is the efficiency inside the human primary cells? How many genes is one going to have to engineer with, let’s say, ex vivo gene editing, to create something biologically meaningful? With T-cells, for instance, people want to ex vivo engineer T-cell immunotherapies, and it’s not just going to be one gene. That’s what all the ex vivo genome engineering companies are wrestling with.

In vivo genome editing involves a delivery challenge. So when you ask: What is my approach to investing in these technologies? I want to see meaningful advances in specificity and delivery efficiency in vivo, or multiplex gene knockout, or gene addition in vivo with a process that is compatible with pharmaceutical development.

When people come to us at MPM, I tell them, “I’m assuming you can do the science. Now tell me how you’re going to manufacture and develop the product.” I usually give people credit for being creative scientists and then I ask: Can we, with a meaningful cash investment, get to the next milestone? What will it take us to get to testing in humans? I like to work backwards. That’s the way I look at all of these technologies. So for a minute, I’ll suspend reality and say your science is totally spot on. I’m sure it’s going to work. But how do we develop this product? How much is it going to cost? What are the technical hurdles assuming everything you’re showing me is scientifically sound?

WuXi: What diseases are best treated with gene editing and do you see any limitations?

Mitchell Finer: Some of these companies started out with these lofty ideas of in vivo gene delivery and they miss the mark. Ex vivo gene editing clearly is the easiest way to get genes into cells and there are a lot of interesting targets.

When cells are dividing they have repair machinery and what you’re doing with genome engineering is making double-strand breaks, and cells get really nervous, that’s a value judgment. Cells get very unhappy with double-strand breaks because they are highly mutagenic, they cause chromosomal rearrangements and there are DNA damage checkpoints that cells, when they accumulate too many double-strand breaks they proceed down the apoptotic (death) pathway.

When you use a viral vector, such as lentivirus or HIV, it also creates double-strand breaks. But usually, you’re getting so few protein molecules of the lentiviral integrase that the number of double-strand breaks you’re creating are small; and cells that are not replicating are more sensitive to double-strand breaks than cells that have replication and repair machinery.

So T cells offer the greatest targets, and while hematopoietic stem cells are interesting targets, it remains to be seen. Companies going after ex vivo gene editing of T cells make the most sense. They are easiest, and those cells nominally aren’t going to last forever. So from a safety point of view, off-target editing is probably not going to be such an issue because those cells might not last forever. With hematopoietic stem cells, there is a challenge in biology of getting an expression of a nuclease just right, not to trigger a DNA damage response and apoptosis.

With in vivo gene editing, monogenic diseases are great targets, but there remain in vivo delivery challenges. People have to think about delivery. It’s location, location, location for buying a house. With gene therapy, it’s the same thing – location, location, location. You’ve got to be able to get the payload into the proper cells and express the payload at a level that’s not damaging. So for in vivo it’s the delivery.

All the CRISPR companies have limited experience developing gene-based therapeutic products. Where they have to be really smart, in terms of bringing in experienced people, is getting people who consider this not just a genome editing problem, which is very complex, but a delivery problem. If it’s genome editing and an in vivo correction of a disease of the brain or of the eyes, these are still problems for non-genome engineering therapeutics in gene delivery.

WuXi: How do you see this technology evolving over the next five to ten years?

Mitchell Finer: There has to be clinical benefit in an early stage clinical trial in five years otherwise the value is going to evaporate. All the cancer vaccine companies in the 1990s had high valuations and then we saw them fail. The CRISPR companies have to generate meaningful clinical benefits. They have a novel payload for which the information is incomplete and they have a delivery challenge. Careful selection of clinical indication is also important. So I think for all of these companies, delivery is the challenge. It still hasn’t been solved for gene therapy, but it’s being solved, and the CRISPR companies have to pay close attention.

In ex vivo T cell gene editing, the challenge is – outside of targeting hematologic malignancies – you need an antigen receptor and in addition, you have to modify a tumor micro-environment; that takes modification of multiple genes. So if you’re going to do this by genome engineering there has to be a multiplex knockout of genes or knock-in of genes, and it becomes fairly complex.

The prospect of genome engineering is very exciting. I got excited by it. That’s why when I was at Bluebird, I led the acquisition of a genome engineering company. But this was pretty far down our pipeline because we had to figure out the delivery, and we had to figure how best to justify it. Bluebird had a robust pipeline and we weren’t betting the farm on genome engineering to succeed in the short term. CEO Nick Leschly was really smart when he bought into that strategy.

WuXi: Is there still room for innovative companies or is the field saturated?

Mitchell Finer: We continue to look at several variations and new approaches to genome engineering. However, before I take a meeting, I want somebody to tell me they are not dependent on previously existing intellectual property in CRISPR Cas9.

The homing endonuclease space is still pretty wide open. Sangamo Therapeutics and Cellectis pretty much dominate the TALEN (transcription activator-like effector nucleases) space between them. In the homing endonuclease space, Precision Biosciences has its family of homing endonucleases, Cellectis has its family, and Bluebird has its family. Sangamo has the zinc finger nuclease (ZFN) technology, but ZFNs are time consuming to design. That’s why Sangamo has moved into the TALEN space as well.

The most interesting things will be Cas9 or related. In the future if somebody comes to me with a Cas9-based company I just need some assurance that it’s a novel platform. I work backwards and say, okay, assuming it works, how are you going to deliver this and what is the biological activity. I like to work backwards so I can really dig into the science.

Certainly at MPM we look at innovative technology. We take a very active role in our portfolio companies and we have partners with different roles. Some are investment partners, and others are operations partners who take operating roles in companies. There are some of us who like to pull together technologies and start a company from scratch. When we invest in a company, we have one of our partners join as CEO, chief medical officer, chief scientific officer. We also take other active roles. If a company comes to us with interesting technology, we can complement holes in the start-up team by having one of our operating partners work with the company.

I do keep a very active search for genome engineering investments.

WuXi: Do you see challenges for public acceptance of gene editing?

Mitchell Finer: In the late 1990s, when I told people I could use HIV as a therapeutic, they looked at me like I was from Mars. I know Bluebird is very far along in getting two products to the market using HIV lentiviruses, so if the public can wrap their heads around a virus, which laid waste to large percentages of populations and changed the face of the globe, being used as a human therapeutic, I think they will have a relatively easy time wrapping their heads around genome engineering.

I think the public has to be protected. There’s a risk-benefit assessment and as long as the risk is clinically meaningful; that’s the regulator’s job, to make that risk-benefit assessment before they approve a drug. Cancer chemotherapy is devastating, but if you get through it, your risk of disease recurrence is significantly less, so that’s why you take the risk.

WuXi: Where does gene editing rank in the history of biotechnology advances?

Mitchell Finer: It depends on how it’s used. People can think of all sorts of things for genome engineering. But the challenge is knowing what it takes to develop a therapeutic. Academic research, while exciting, isn’t drug development. There’s a reason why drug development is so expensive and why it takes seven to 10 years to go from concept to market. It’s because of the rigor of reproducibility and scalability to develop a drug that can be manufactured, reproduced, and scaled up to treat a patient population. That’s a huge demand.

So if one is going to say gene editing is akin to splitting the atom, I would probably disagree. It’s going to be one tool among many. For example, viral vectors are going to be required for in vivo gene therapy and people are starting to develop nanoparticles, that’s called synthetic vectors.

Genome engineering is an important addition to the arsenal, but the real advance, which is underappreciated, is the development of delivery for any kind of payload whether it’s something you want to integrate by virtue of a virus or whether it’s non-integrated, sitting inside a cell, or whether it’s a genome engineering attempt. It’s an exciting tool, but I’m looking at it as a pharmaceutical developer.

I’ve been doing cell and gene therapy and embryonic stem cell derived therapies my whole career, for 30 years. I have an appreciation of the complexities. Genome engineering is a tool in the arsenal. It’s an exciting tool, but one of many in the arsenal.