As a co-founder of two gene therapy companies and investor in five others, F-Prime Capital Partner Ben Auspitz says that after decades of research in academia and industry, the science is finally on the cusp of realizing its therapeutic potential.

The US Food and Drug Administration’s approval of the first gene therapy in 2017 is just the beginning, Auspitz says. “I can think of at least five programs where I would expect an approval in a three-year horizon. That’s never been the case in this field before.”

To date, gene therapies, including cell therapies such as CAR-T, are beginning to prove themselves for genetic diseases and cancer. The hope is to apply their therapeutic power for more common diseases, eventually raising gene and cell therapies to the level of a co-equal treatment modality with small molecules and monoclonal antibodies.

For that to occur, Auspitz observes, significant advances in basic research and technology are still needed. “The hope that (cell and gene therapies) can be used more broadly than very high unmet need settings such as cancer and genetic disease, is not just an aspirational future, but a plausible future,” he explains.

Auspitz has worked in pharmaceuticals and life-science for more than 20 years. Before joining F-Prime Capital, he served as Therapeutic Area Head for Immuno-Inflammatory products at CombinatoRx Inc. during its growth from an angel-backed start-up to a publicly-listed company.

At F-Prime, he focuses on therapeutics, with a particular interest in Series A and company formation. He co-founded the gene therapy companies Orchard Therapeutics, which closed a $225 million initial public offering in early November 2018, and Dimension Therapeutics, which was acquired in 2017 by Ultragenyx.

Auspitz also serves on the Board of Directors of Indalo Therapeutics, Akrevia Therapeutics, Turnstone Biologics, Checkmate Pharmaceuticals, and Compass Therapeutics and is Chairman of Modis Therapeutics. He holds a B.A. from Harvard University.

WuXi AppTec Communications’ interview with Auspitz 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 strategy for investing in cell and gene therapy companies?

Ben Auspitz: Gene therapy can be defined either narrowly or broadly. There is the narrow sense, which is using a vector to achieve gene addition, and then there is a broader sense, which can span gene addition, gene editing, gene knockdown –  and that can be in either in vivo or ex vivo where you are gene modifying the cells and the cells are the drug. We think about gene therapy in that broader sense.

Second, we think very carefully about the match of the technology to specific therapeutic applications. The appeal of these technologies is the potential to provide transformative clinical benefits. The hope is these modalities go beyond incremental improvement; and to deliver that level of effect, the technology really needs to fit the clinical application.

So the way we think about it is: What is the gene modification that is most relevant; and in what tissues does that gene modification need to occur? Whenever we see a new gene therapy company – and when we think about starting a new company in cell and gene therapy – usually that’s the way we think about it. We tend to see the platform technology through the lens of therapeutic application.

WuXi: How does your approach differ from other venture capital firms?

Ben Auspitz: I’m not confident (our strategy) is so different. I do think, in general, examining the platform through the lens of the application is a way we tend to approach these (investments). That’s not to say we don’t look at platforms, but we do have that particular way of looking at it, with the medical and clinical application driving the choice of technology and the fit of technology. But I wouldn’t say we’re the only ones who see it that way.

WuXi: When you talk about clinical applications, do you have a specific disease focus?

Ben Auspitz: No, I just mean that we now have investments across the gamut of various gene and cell platforms. That can include gene editing, base editing and all these various technologies. In general, the way we think about the field is: What are the therapeutic problems today that, for example, adeno-associated virus (AAV) looks like it’s very well suited for; What are the ones where a lentivirus in an ex vivo setting are well suited for? And so, when we approach those fields, we tend to look for the companies that have either adapted their technology for those uses where it’s the best fit; or where the programs that are the most advanced are the best fit.

WuXi: What is an example of the kinds of companies you are funding?

Ben Auspitz: The most recent company that just had an IPO (initial public offering) is called Orchard Therapeutics, which uses lentiviral gene therapy. What is really striking about the company is the profound clinical effects of the therapies; and that it’s not just one case, it’s multiple therapies that are achieving these results.

Orchard has a pipeline of multiple gene therapies, many of which now have demonstrated robust efficacy in patients. These are in areas as diverse as primary immune deficiencies to CNS (central nervous system) conditions, and the therapies are producing profound patient benefit. To me that’s the exciting potential of gene therapy; getting transformative clinical effects across diverse types of diseases. That’s what the field is hoping for.

WuXi: Although gene therapy has been around for decades, the first FDA approval just occurred in 2017. Are we going to see a wave of approvals in the near term?

Ben Auspitz: It is an incredibly exciting time in the field. You have people who have been working as academics or in industrial research for decades to get us to this point. I think we are at a point where the science is really being translated in a robust way. I can think of at least five programs where I could imagine an approval in a three-year horizon. It’s never been the case in this field before that we have had that level of potential.

WuXi: What kinds of diseases are targeted with cell and gene therapies?

Ben Auspitz: This kind of goes to the define gene therapy question. Are we talking about genome modified cells or the use of viruses to deliver a local gene or antigen construct to a tumor? Broadly I would say to date the lion’s share of focus has been on monogenic diseases; diseases where a single gene defect is the source of the problem; and in cancer, where I do consider gene modified cells gene therapy – CAR-T is an example of that. I would also include efforts to deploy various vectors to deliver transgenes or antigen constructs directly to the tumor itself. This makes the tumor a factory of either proteins or antigen constructs that will yield an effective response.

That being said, there are forays into more common diseases, and conditions which have a more diverse cause of pathology, using a therapeutic transgene. Wet macular degeneration is an area with significant efforts; Parkinson’s disease; and even areas like heart failure and angina. So that work is starting and in some cases is reasonably well along.

WuXi: Are there still scientific advances that need to be made at the basic research level to make gene therapies more effective?

Ben Auspitz: Absolutely, and the answer to this question depends on how much time you have on this topic because the advances are very specific to the modality.

The advances that are needed to make adeno-associated viruses more effective are distinct, in many cases, from those needed to make an ex vivo integrating virus approach, like lentiviral transformed cells, more effective. And all those are different from some of the advances that are needed to make gene editing more effective.

If you were to think generally, what are you trying to accomplish across these approaches? One way to think about it is how to make gene and cell therapy more drug like. How do you have a therapeutic that you can get to all the tissue types in the body in sufficient quantities; which can be manufactured readily and reliably and cheaply; where the relationship between dose and effect can be more consistent and controlled? Can there be an ability to titrate the effect or as they say, turn it off; and can it be delivered to all patients in a convenient setting?

These are all features of therapy that we take for granted when we take a pill. But in gene therapy we often don’t have these features, and many, many technical innovations will be necessary to help us get there.

WuXi: Will there ever be a time when gene therapies are the dominant medicine?

Ben Auspitz: I don’t know about gene therapies being a dominant modality. But an analogy – and maybe this is a little bit of a cliché analogy – is that if you go back to the early days of antibody therapy, I think it would have surprised many people to learn that today antibody therapies are approved and used for conditions like osteoporosis and high cholesterol. That would have seemed very exciting at the onset of antibody therapy to think that the modality would be used in treatment of these common diseases.

For gene and cell therapy that is still a visionary future – where gene and cell therapy can be relevant for common diseases. I suspect that there will always be many, many places where a small molecule is an effective drug and many, many places where an antibody is an effective drug, so I don’t know what the time scale is when gene and cell therapy become co-equal with those types of modalities.

But I do think that the hope that they can be used more broadly than the very high unmet need in cancer and genetic disease settings, is not just an aspirational future, but a plausible future.

WuXi: What are some of the limitations of cell and gene therapies?

Ben Auspitz: One important limitation today is that we don’t have compelling evidence that the current approaches can always robustly get the genetic modification where we want it to go in sufficient quantities. That’s just a fundamental question.

If you want to get gene therapy everywhere in the brain, do we know that we can do that? If we need to get it broadly to skeletal muscle, can we do that? That’s very important for a number of conditions. Second, we just don’t have the level of dose control that we’re accustomed to in the small molecule and antibody world. And fundamentally we don’t have a method for turning the therapy off. All of these are things that are very important to the evolution of the field.

WuXi: Does it seem a little surreal to talk about developing a therapeutic that requires a fail-safe mechanism to turn it off?

Ben Auspitz: All of these therapies have an aspect of science fiction about them. The idea that you are gene modifying a patient’s cell and putting it back in – and it migrates to the place that you want it to go in the body and then has these remarkable therapeutic effects – is amazing.

The idea that cells can possess a second gene construct, and if I dose with a small molecule, it turns the primary effect off; it all sounds like science fiction. Yet, it is what is being achieved now, which is why it’s such an exciting time.

WuXi: Do you see combination therapies being helpful with cell and gene therapies?

Ben Auspitz: Yes I do. I absolutely do. And in fact, if you look at the current class of cell and gene therapies, the vast majority of them have been deployed in the clinical setting in combination with other therapeutic modalities; from applications as simple as using steroids to make the inflammation related to AAV more tolerable to a role as integral as the use of conditioning agents to make ex vivo lentiviral gene therapy possible. So I do think that it already is the case and I suspect it will continue for some time.

WuXi: Aside from the scientific challenges, what are some of the other barriers in bringing gene therapies to patients?

Ben Auspitz: Manufacturing is clearly one of the barriers. We still have a long way to go before gene and cell therapy manufacturing looks like our manufacturing for other biologics.

I think there is also fundamentally a challenge in having a large enough safety data base to really understand the characteristics of some of these therapies. One of the reasons you see more utilization of these modalities in very high unmet need conditions is because the risk-benefit of gene transfer is more acceptable in those settings.

As we get a better sense of what the safety and tolerability profiles are over time, and as we have more approaches to ameliorate potential risks, I think that will be important for bringing gene and cell therapies to a broader patient set.

Then there is the question of the pricing. If, in fact, the profile of these therapies is a single administration with really profound duration of activity – so moving from a model where you’re taking an injection or pill periodically and continuously to a single intervention that provides long-term benefit and maybe, we hope, lifetime benefits – what’s the appropriate pricing model?

WuXi: How do you think cell and gene therapies should be priced?

Ben Auspitz: I think across our industry pricing needs to be linked to medical value. If you had two choices – a medicine that had 10 years of benefit that you had to take once and one that you had to take every day for 10 years to provide that benefit – it seems like there is a rational process by which you could figure out a one-time price that was as valuable to give upfront as the medicine you take every day for 10 years. I think these are surmountable questions.

The real question is, do we have therapies that provide profound medical benefit for multiple years. I think if we have that, the other problems can be solved either by one-time payments or periodic, pay over-time schemes. All of them have various complexities to them. But I think these are solvable problems.

WuXi: How will health care systems be able to afford all these new, wonderful cell and gene therapies?

Ben Auspitz: I don’t think of this as a gene therapy specific question, and that’s why I say it has to be linked to medical value. If there is an amazing medicine for cancer, it doesn’t matter if it’s a gene therapy or a small molecule, you still have this question of how do you pay for it.

We saw a little bit of a preview of some of these considerations with the launch of the new drugs for hepatitis C. Although they were small molecule therapies, they were curative therapies and carried a one-time price for a cure. Interestingly, there was a lot of sticker shock because it hit the health care system all at one time and people weren’t prepared for that.

But I think a strong argument can be made that those (drugs) were priced quite conservatively relative to the medical benefit they provided.  Any time you have a one-time charge it creates problems. But there’s a more general problem: If we have lots of great medicines how do we pay for all the benefit that’s provided? That would be a really high quality problem.

WuXi: How will gene and cell therapies evolve over the next 10 years?

Ben Auspitz: The hope is that on a 10-year horizon you’ll see broadening saturation of these approaches for genetic disease and initial success in more common diseases.

I do think you’re going to see these therapies be more important in genetic disease and be more important in cancer over time. We can already see that happening. What I think everyone is still looking for is some signs of success in more common diseases.