Genetic Therapy Revolution: Benefits and Barriers for Medicine’s New Horizon

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Genetic Therapy Revolution: Benefits and Barriers for Medicine’s New Horizon

[00:00:00] Joe Selvaggi: This is Hubwonk. I’m Joe Selvaggi. Welcome to Hubwonk, a podcast of Pioneer Institute, a think tank in Boston. It was the mid-19th century germ theory, the idea that many diseases are caused by microorganisms such as bacteria and viruses, that laid the groundwork for much of modern medicine. Now, a new field of discovery called genetic medicine, which focuses on the fundamental coding of life in the human genome, has a similar potential to revolutionize healthcare by addressing the genetic cause of many diseases.

[00:00:34] Unlike traditional medications, gene therapies offer the promise of one-time interventions that can provide long-term benefits, potentially transforming the lives of patients for years or even lifetimes. However, the unique nature of gene therapy presents significant challenges for traditional chronic medication reimbursement models, owing to their long-lasting effects and their substantial upfront costs for development.

[00:01:01] Scientists and healthcare providers who want to advocate for the promise of genetic therapies must encourage entirely new models for development, testing, and pricing that map to an emerging technology unknown only a decade ago. How is gene therapy different from traditional medicine? And what are the first steps towards retooling our healthcare system that can encourage and cultivate these therapies?

[00:01:26] My guest today is PhD in Neurobiology, Dr. Anne Sydor, who recently co-authored a paper for Pioneer Institute, along with Drs. Bill Smith and Robert Popovian, entitled Value and Pricing Models for Gene Therapy Replacements, The Current State of Affairs. In it, Dr. Sydor outlines the potential transformative power of gene replacement therapies for many debilitating and deadly diseases.

[00:01:50] She will share her views on the need for novel pricing paradigms and the importance of addressing barriers to investment and development. We will discuss possible policy changes that could help encourage this nascent field of health care and consider how the spillover benefit of genetic medicine could eventually reduce the probability of gene-related diseases for everyone.

[00:02:11] When I return, I’ll be joined by a neurobiologist and writer, Dr. Anne Sydor. Okay, we’re back. This is Hubwonk. I’m Joe Selvaggi, and I’m now pleased to be joined by Dr. Anne Sydor. Welcome to Hubwonk, Anne.

[00:02:25] Anne Sydor: Thanks, Joe. It’s a pleasure to be here.

[00:02:27] Joe Selvaggi: Well, it’s great to have you today, Anne. Today we’re going to talk about your thought piece for Pioneer Institute, the one you authored along with Drs. Bill Smith and Robert Popovian, entitled Value and Pricing Models for Gene Therapy Replacements, the Current State of Affairs, I love the piece in that it informed me about, really how very different gene replacement therapy or gene therapy is from traditional medicine, how it’s developed, how it’s ultimately priced, and who it targets but our avid listeners of Hubwonk will know that I like to start slowly at the beginning. So, for the benefit of our listeners, what is gene therapy?

[00:03:01] Anne Sydor: Sure. At a very basic level, gene therapy is the use of genetic material, which is DNA or RNA, to address diseases in human beings. There are many types of gene therapy.

[00:03:16] We can add genetic material to produce a new function. for example, activating the immune system to fight off cancer. We can add genetic material that modifies how a person’s DNA is expressed. And this is done with gene silencing therapies, which are often with RNA. The third is the one that we talk about in our paper, and that’s gene replacement therapy.

[00:03:40] This is when we add a functional copy of a gene that is not functional in a person, and because of that lack of function is causing a disease. So gene replacement therapies are relatively new. the first one was approved about six years ago, and they’ve really changed the landscape of treatment and what might become possible.

[00:04:03] Joe Selvaggi: So we are truly on the cutting edge here. So as you say, six years ago, we, again, like the Wright brothers, their first flight, six years ago. but I’m sure things are changing rapidly to make this real for our listeners. Can you share examples of what, diseases might be caused by or are caused by, genes or might be, addressed with gene replacement therapy?

[00:04:23] Anne Sydor: Sure. So right now, we’re only able to use gene replacement therapy to address diseases that we know are caused by one single gene. The variant in that gene is what causes the disease. So single gene, that can be replaced. In the future, we might be able to do different things with gene replacement therapy, but this is where we are right now.

[00:04:46] So the therapy Luxturna returns sight to people with a rare form of genetic blindness called RPE65-associated retinal dystrophy. That’s a mouthful. Uh, Zolgensma returns the ability to not only sit and walk to kids with spinal muscular atrophy, but it also prevents their muscles from degenerating so they don’t lose the ability to breathe before age two.

[00:05:12] Those kids are actually now surviving as long as age eight without having to go on respirators. Roctavian and Hemgenix treat hemophilia A and B, respectively, and Elevidys for muscular dystrophy was shown to produce the missing gene function in Duchenne muscular dystrophy. that’s been, uh, has accelerated approval for boys aged 4 to 5, and the FDA has scheduled a hearing to talk about whether that should go to full approval or not.

[00:05:43] That hearing is scheduled for this June.

[00:05:45] Joe Selvaggi: These diseases sound horrible, very difficult to challenge, lethal or life-shortening, as you describe, but do they affect large populations? Are many people affected by the terrible conditions you describe?

[00:06:02] Anne Sydor: So the diseases that gene therapy treats are less common. They are all rare diseases at this point. That doesn’t mean it’s going to remain that way. but right now, because gene therapy is so precise and is treating one gene difference that, well, one gene that has differences to treat a very specific disease, it’s really precise. And so the number of people that each gene therapy can impact is small.

[00:06:37] In the future, we may be able to use gene therapy to address genes that make a disease more likely rather than causative. That’s not where we are today. So these are small, small things. numbers of people affected, for the diseases I mentioned, just 75 to 500 people are diagnosed each year. So really not a lot.

[00:06:59] Now, as these diseases get screened for more and more in infancy, we may see that those numbers go up because when you had no treatments, there was no point in screening. And so we didn’t really know. The number of people who were affected, but it’s still not going to be hundreds of thousands. It is on the level of thousands.

[00:07:18] Joe Selvaggi: So it’s the tip of the iceberg. We’re getting started here. As you say, it’s a new technology. You described conditions, you’re talking about children with blindness or children with, muscular dystrophy, I think you said. is it always, I guess if you have a gene that needs replacing, you’re going to see that early in life rather than late in life.

[00:07:35] I’m not going to commit you to all future diseases, but is this in general targeting young people at the start of their life?

[00:07:42] Anne Sydor: So, not necessarily. Diseases that are caused by gene dysfunction are present from birth, but that doesn’t mean that the symptoms are present from birth. So, with RPE65-associated retinal dystrophy, blindness doesn’t happen from birth.

[00:08:00] It comes on gradually over time as retinal cells are lost or degenerate. Some forms of spinal muscular atrophy, and they’re rare, but some of them have adult onset. It’s even been suggested that Stephen Hawking may have had a rare form of spinal muscular atrophy rather than a mild form of ALS, which is what he was initially diagnosed with.

[00:08:29] Now, Treatment in youth is the rule. That’s the important thing. So even though the disease might not manifest until adulthood, it is present from birth. And that means usually the earlier we treat it, the more likely we are to have positive effects. So this is almost all pediatric treatment.

[00:08:51] Joe Selvaggi: Okay. All right.

[00:08:51] And again, for the benefit of our listeners, to be clear, to me, to my ear, it sounds like you’re going in and replacing a gene and in a sense, fixing the problem. But, I’m sure that’s a primitive explanation. Is gene therapy or gene replacement therapy, as we’re describing it now, is it a, I don’t want to use the term cure, but it is, it addresses the problem.

[00:09:12] Is it, a cure like, I’ll put air quotes, or is it really just making a very bad disease a little more manageable?

[00:09:21] Anne Sydor: Well, I think from the perspective of a parent who had a child who without treatment would die before age two and who is now living to age eight, that certainly feels like my child’s been cured and at the same time, it’s really from a scientific perspective. It’s too early to say that. No one treated with gene replacement therapy has lived a full life expectancy yet, so we really don’t know. Additionally, just fixing that one gene may stop the disease from causing death, but there may still be some symptoms.

[00:10:03] There may still be other consequences of the disease that happen later in life. So we just don’t know. What we talk about instead, rather than cure versus treatment, is we tend to talk about whether or not a therapy is disease-modifying. So, a disease-modifying treatment changes the course of a disease.

[00:10:29] To use one of the diseases we’ve talked about as an example, if you put an 18-month-old child with spinal muscular atrophy on a ventilator, you are addressing their ability to breathe. but the muscles have degenerated so they can’t breathe on their own or you won’t be putting them on a ventilator. So it’s a symptomatic treatment.

[00:10:49] It’s treating the symptom of not being able to breathe. But if you give them gene replacement therapy before they are six months old, those muscles in their chest remain strong enough for them to keep breathing on their own, not only at 18 months but even at eight years. So we’ve really changed the course of the disease.

[00:11:10] And that’s a disease-modifying treatment. Not all disease-modifying treatments are gene therapy. But gene therapy does have many other differences that we should talk about.

[00:11:24] Joe Selvaggi: Sure. I’m not sure I want to dive into this element of it first, but I’ll just say, I’m going to circle back to this concept a little bit later, but you’re using gene replacement therapy in a universe of, medical system that knows diseases and, the bacterias and viruses and all kinds of disorders that we’re well aware of.

[00:11:42] This is a new world. When you’re talking about gene replacement therapy in the context, and we’re going to get into all the sub-elements, is it very hard to explain to even doctors, that you’re talking about something fundamentally different that has a different, treatment, long-term, endpoint, um, uh, value?

[00:12:01] Anne Sydor: Yeah, one of the things that is really novel about gene therapy is you’re treating the disease. Possibly, and often, before you even have symptoms, so this child has not gotten sick, they have not had any symptoms, and we’re still treating their disease. in some ways, we’re preventing symptoms from developing, or we’re slowing the rate at which symptoms would develop by having disease-modifying therapy.

[00:12:30] The other thing that’s really, and what that means is, you’re looking at how things change over a much longer time period. If I’m treating a knee injury, I can do surgery and the knee gets better. Six weeks, eight weeks, of rehabilitation, it gets better. We can see very easily that we’ve had an effect. if it’s something like chronic migraine and you take a pill, And the migraine gets better.

[00:12:59] Well, if that happens in a larger proportion of people, we know that drug is more effective, and we have people continue taking that medication every time they get a migraine. With gene therapy, what you’re doing is giving people treatment once, and then seeing that the disease doesn’t develop in the same way that it would have without treatment.

[00:13:21] And so, that creates a really big difference in terms of how do we, when do we treat people, how do we monitor them, and also how do we pay for these drugs, right? The pricing and the valuation, and that’s what we really cover in the paper, that’s a huge difference. Gene therapy is paid for once when it’s delivered in infancy or childhood.

[00:13:45] Other medications are delivered month after month, year after year, and they’re paid for over the course of a person’s lifetime.

[00:13:54] Joe Selvaggi: I want to get deeper into that, a question that popped into my mind when you described this is, you’re treating somebody before they know they’re sick. Does this imply that, at least in the near future, if you know you have some sort of history of a particular disease, you might be targeted for screening?

[00:14:09] But in the future, perhaps, as this, technology gets more robust. Each of us might submit our DNA to testing and see if we have hidden in there a variation It’s more likely to get a particular disease. Is that fair?

[00:14:23] Anne Sydor: Absolutely. And there are already some genetic diseases that are screened for routinely at birth, right?

[00:14:30] Phenylketonuria. If you find that at birth, you know that people have to change their diet. that’s a complex metabolic disease. there are other diseases that we can look for at birth. Spinal muscular atrophy. Spinal muscular atrophy. It’s a little more complicated in the inheritance, so it’s not just knowing that there’s a history of it in the family.

[00:14:51] It really does have to be screened for. And a lot of states have started mandating testing for SMA, which is the acronym for Spinal Muscular Atrophy, because if we find it early, we can treat it and prevent death. so in the future, will everyone be screened for genetic diseases at birth? Yes. And is that already happening?

[00:15:14] Yes. I think it’s just going to expand even more, but the only reason to test for something is once we have a treatment for it.

[00:15:22] Joe Selvaggi: Indeed, of course. Yeah. Of what value would a test to tell you? you’re going to have a disease if there’s not much you can do about it. As you say, it is a reinforcing effect there or a virtuous cycle.

[00:15:32] I don’t really want to dwell too much on this, but it sounds like most of the treatments are effective but of course, you’re talking about genes and this is the coding of our life. are safety concerns more profound or less? I’m thinking about, of course, some drugs are ineffective, but also some are dangerous for certain people.

[00:15:53] Certainly that must be the case for gene therapy as well. is it, you keep characterizing it as very precise, very targeted. is it that nature that makes it less risky or is it even more risky than a traditional therapy?

[00:16:04] Anne Sydor: I wouldn’t call gene therapy more risky, per se. Again, there are different types of gene therapy.

[00:16:10] There is a very new type of gene therapy where the gene is actually the person’s own gene that is edited and repaired. Those are incredibly new. The 1st of those was approved just 4 months ago to treat sickle cell disease, which is a devastating and incredibly painful condition. It has a lot of health equity issues around it.

[00:16:31] I think there’s going to be a lot more to learn about gene repair and its safety, but it does appear to be a lot more to learn. Something that can be safely done right now. Gene replacement therapy is providing a gene on a viral vector. So we put an external gene inside of someone’s cells. And this has been shown to be very safe.

[00:16:55] There can be issues with administration. the liver is involved in processing the components of these genes and so there can be some liver toxicities. There needs to be a little bit of immunosuppression or steroid treatment to protect the liver when the therapies are developed. But so far, there have not been huge safety concerns.

[00:17:19] And certainly not enough to outweigh the benefits of these therapies when you think about them returning vision, saving lives, or preventing weekly blood transfusions.

[00:17:31] Joe Selvaggi: You mentioned earlier, and again, I want this to be a theme of our conversation, but we talked about the difficulty of comparing this new age of gene replacement therapy with our historical medical treatment of lifetime chronic diseases.

[00:17:46] Medicine over a lifetime, Fill in the blank, X per year times the number of years you’re alive is a lot of money. Imagine the gene replacement therapy effectively managing from the outset and not having to have a lifetime of treatment. How does one compare apples and oranges in this case?

[00:18:02] You’re looking at a lifetime, benefit, but it may be a treatment that happens in an afternoon. how do you translate that?

[00:18:10] Anne Sydor: I think that we need new paradigms. it’s very clear. We are comparing apples to oranges when we look at conventional treatment versus gene therapy. So gene therapy is delivered once.

[00:18:22] So far, the side effects seem to occur around the administration of the gene therapy and not over the long term. Whereas with conventional treatments, it is again, You take that medicine day after day, month after month, year after year, over the course of a lifetime, and whatever side effects that medication brings, whether it’s difficulty sleeping or maybe being a little agitated or having more stomach upset, whatever those side effects are, those are going to be with you for the rest of your life.

[00:19:01] Now, I have to be really clear. We don’t know the long-term side effects of gene therapy yet. It just hasn’t been long enough to say. but what we can say is so far so good. a lot less medical intervention for a lot more gain, honestly.

[00:19:19] Joe Selvaggi: Well, we’re in that conversation, we’re talking about the value, which is what, how can you put a value on, a treatment that happens once as opposed to, over a course of a lifetime.

[00:19:28] But I also want to talk about cost. We’ve had on, on, on our podcast here, a mutual friend and coauthor of this paper, Dr. Bill Smith, talking about why are drugs so expensive. But yeah, everybody wants cheaper drugs. what you described seems very complex, as you say, you’re on the bleeding edge here of this technology.

[00:19:44] New therapies in pharmaceutical companies cost a lot of money, billions of dollars. Is the gene replacement therapy, are we talking of that kind of scale? Is it difficult to make these kinds of therapies? Or is it more akin to, cranking out new forms of aspirin?

[00:20:00] Anne Sydor: So when we get into the manufacturing, that’s a whole separate issue that I think we should come back to.

[00:20:07] I want to talk a little bit about price differencing, differences right now because I think that’s also a huge issue. Gene therapies so far have been priced at two to four million dollars and there’s an understandable sticker shock when you look at a treatment that’s two to four million dollars. but when we do the math for each of these diseases, Two to four million dollars is actually about the same cost as five years of treatment with conventional therapy for the same or similar diseases.

[00:20:38] So, getting a whole lifetime for what we would pay for just five years, actually seems like a pretty decent deal. I think it’s just the shock of paying for it all at once that is hard for people to stomach. When we look at the value of gene replacement therapy, there are measurably lower related medical costs, fewer physician visits, fewer trips to the emergency room, fewer lab tests, and fewer hospitalizations.

[00:21:05] We’re also seeing decreased disability and the potential for increased productivity. And things that are harder to measure but higher value, in my opinion, are the lower burden of care. For families and patients, the improved quality of life for patients and their care partners. The ability people will have to participate in society that they wouldn’t have without these treatments.

[00:21:30] So, It’s hard to say that all of these things are going to come to fruition exactly the way they think we think they are because we’ve only had a short period of experience with them. But this is something we go into our paper when you look at the price and the value of gene therapies is higher and the price is actually lower over the course of a lifetime.

[00:21:54] Joe Selvaggi: Sure. Again, I know we keep emphasizing you’re on the cutting edge of this technology has been around six years, so you can infer a lifetime of benefit, you know, you’re confident at this point saying, look, if we did have all the facts, if we do project this out, the 80 years of a life improvement that indeed, again, we’re talking about value.

[00:22:14] Does the value of gene replacement therapy exceed the value of the alternative? Then it’s a matter of math, right? You just say, if X is more than Y, then do X, you’re getting your money’s worth with gene replacement therapy, as you see it projected into the future, we project the likely benefits when, and you compare them to the cost and benefits of the alternative, and you Gene replacement therapy, I dare say, is a relative bargain.

[00:22:40] Anne Sydor: Yeah, and, from the perspective of a scientist, I’m a scientist, I’m an analyst. From that perspective, I say we need more time, from the perspective of a mom, six more years of life with the child that would have died when they were two. Yeah, that’s worth a couple of million for sure.

[00:22:58] Anne Sydor: And then when we look as well at the number of children who are affected, we’re talking again about, a few hundred kids per year needing this treatment. So, we’re talking about a few hundred million, when the reality is we are spending billions of dollars on this. dollars on other diseases that occur in childhood and throughout the lifespan so that the overall impact on the economy is not quite as high as some of the fearmongers would leave you to believe regarding these therapies.

[00:23:32] Joe Selvaggi: Sure, when we try to take apart the value, we often, again, with our mutual friend, Bill Smith, we talk about the fact that these millions of dollars in costs do two things. One is it funds the research, but it also incentivizes the research, right? It says if you don’t have these sorts of prizes, if you will, at the end of the rainbow for all this technology, all this research, all this hard work to develop these therapies, it’s not going to happen.

[00:23:58] But, take that all aside. Is it a very expensive, complex, you know, is this, of course, it’s new, but it, is it as specialized? We’re here, I’m in, in Boston. Here in Cambridge, we’re, we’re on the bleeding edge here in our part of the world. Is this something that only, you know, a very small, high-level company can do or is this going to be, the next entrepreneurs with a lab in their basement?

[00:24:24] Anne Sydor: Well, I hope it’s going to spread out to be something that is produced on a massive scale in the future because that’s how much I believe in the potential of these therapies. but when we talk about costs, and you brought up manufacturing, the costs for gene therapy are not just the cost of developing the molecule.

[00:24:43] That’s going to treat the disease. The costs also come from manufacturing itself. So if I’m going to make aspirin, I put some chemicals in a vat, I mix them together, and then I crystallize them, and then I purify them, and then I press them into pills. It’s about six steps in the manufacturing process, and it’s done in these giant vats where you can produce it to scale.

[00:25:11] Which quantities all at once, and the price per pill is pennies, gene therapy is not like that. And so as we develop more complex medications that can solve more complex diseases, the manufacturing complexity also goes up. With a gene product, we first have to purify a biological material. And then we also have to purify the biological material, the vector, that’s going to carry it inside the patient’s cells.

[00:25:42] We can create a few molecules of DNA in a lab. We can create a few molecules of the vector in the lab. But to scale to production, both of these have to be put into biological cells, usually bacteria, that reproduce. And allow us to purify larger quantities of these biological products. Those bacteria have to be grown in rows and rows of plastic dishes, in rows and rows of incubators, tended to and cared for by highly trained technologists.

[00:26:14] Um, and then they have to be sliced or broken apart and purified so that we pull out the biological molecules that we want. then to produce the combined product of the DNA and the vector that’s going to carry it into cells, which are combined together. That whole process has to be repeated. So now we have 18 or more steps and don’t forget that with every purification step, we lose a little bit of product.

[00:26:45] So ultimately, these gene therapies, even though you’re producing very small quantities of them, to treat a person, you And much, much more expensive per treatment. These are not pennies to produce a treatment. I wouldn’t venture to say what they are, but it’s magnitudes higher in cost to produce a gene therapy versus a conventional medicine.

[00:27:10] Joe Selvaggi: Well, again, that, yeah, I’m not surprised. Again, we’re, this is new technology and a very, as you say, very targeted, very precise technology. But the other costs are many. One of the other major costs of, when a pharmaceutical company is bringing a new technology or a new, therapy to the market is getting approved, and we’ve already established there’s a, this is a brand new paradigm.

[00:27:29] We’ve got a system that, has one expectation of what, a drug looks like and what the approval process is. You’ve got. brand new technology, we’re touching or replacing genes. How would something like the FDA or whoever would be likely to put a stamp of approval on it, how would they even measure?

[00:27:44] As you say, in some cases, you’re treating someone even for the symptoms of manifest, and also it’s a lifetime of benefit, and also you’re not clear on what the side effects are, because it hasn’t been around long enough. How in the world do you get past that gauntlet of approval?

[00:28:00] Anne Sydor: Yeah, well, not easily.

[00:28:03] That’s the short answer to that and the reality is that current FDA policies are actually making it harder to develop these drugs We all believe in getting drugs to market that are safe and effective. Nobody wants to re-experience thalidomide or medications that cause birth defects. Nobody wants snake oil to get to market and cheat patients out of their hard-earned dollars for cures for so-called treatments that don’t really work.

[00:28:37] So the role of the FDA is important and nobody’s arguing against that. But some of their regulations Just are not appropriate for gene therapy because it’s not the same as conventional medicines. We really are comparing apples to oranges here. So current guidance is that a product and its manufacturing process both have to be finalized before it can even be tested in human beings.

[00:29:08] That is actually disincentivizing improvement, continuous improvement in the manufacturing process. If you have to spend all of this money upfront just to figure out how to manufacture a gene therapy before you can even test it, you’re not going to continuously improve that process. It’s going to stay exactly the same because the FDA is requiring it to stay exactly the same. So, you know, when we think about sunk costs, those costs really are sunk. And if you’re then not able to get that gene therapy to market because it did show, did prove to not be safe or not effective, all of that money that went into the manufacturing process, the vast majority of it is lost and everything has to be restarted from scratch.

[00:29:54] So again, it’s just a real disincentive to investors.

[00:29:58] Joe Selvaggi: Yeah, indeed. As you say, sunk costs. We know from, well, we here believe in markets and the magic of markets is it’s iterative. you keep improving things until it’s exactly what you want. Not possible when you have each process needing to be approved before it’s even begun. You start from scratch every time. Nothing would work. what other, you really, I think, defined well one of the problems with the FDA’s current process. What other areas might be improved or changed to address specific needs of Gene replacement therapy that the FDA, if they were listening to this podcast, could say, look, okay, we want to be safe, but we want to be safe in the right way to encourage and help facilitate a broader rollout of gene therapy.

[00:30:43] What else would you change other than, let’s say, how the process is approved?

[00:30:49] Anne Sydor: Sure, so we also have to look at the clinical trials themselves and how we show efficacy. We’ve talked about the fact that these diseases now are being treated before you even see symptoms, and if the symptoms are going to manifest over years, imagine if we had to wait until the children in trials for spinal muscular atrophy They were not only walking but going to school before we could say there was proven clinical benefits.

[00:31:20] Or in the case of children with muscular dystrophy, we use the accelerated approval pathway because we could show that the protein that’s needed was being produced and that it would Functional protein was being produced, but these children were very young and they weren’t ready to walk yet, or they might not have been able to walk a long distance yet, and it might take them a few years to develop that ability.

[00:31:48] So, do we make the trial run for those years, or can we say, hey, This proxy measure, this protein, we know is being produced? We know that having this protein or not having this protein is the problem. So, let’s approve this on the basis that we’re producing the protein and then watch what happens and see if it really does prove clinical benefit down the line.

[00:32:14] And that’s the use of the accelerated approval pathway. and I would say that it’s not just, my co-authors, Dr. Popovian and Dr. Smith, and I who make this argument. There was a recent conference, during which Dr. Peter Marks of the FDA talked about the need to use the Accelerated Approval Pathway more, and talked about the need to use surrogate markers, biomarkers that show the disease as being modified before we necessarily see an effect on symptoms.

[00:32:47] A measurement system is really necessary with the other things that can be done to account for the small numbers of people who have these diseases are our single-arm trials comparing the effects of a treatment to the natural history of a disease, rather than having to look at a placebo arm. And then, when it comes to manufacturing, we could look at things like using international harmonization or ICH standards that evaluate manufacturing with the best quality, safety, and efficacy practices. So there are a number of options for changing these policies that would make it lower investment and lower risk to develop new gene therapies.

[00:33:34] Joe Selvaggi: So from a layman’s perspective, it sounds like we want to make sure it’s safe enough, where we’re essentially restoring or replacing it with, say, an otherwise typical gene and then Is it fair to say that this would be almost like a challenge trial, where you say, okay, it’s safe enough, let’s see what happens?

[00:33:50] Do you use that term, or is that really verboten?

[00:33:54] Anne Sydor: We use the term confirmatory trials. So you can do a single-arm trial to show these children are doing better than children who didn’t get treated in the past. You can do a surrogate measure to say something we know is involved in the disease is changing, even if the symptoms haven’t been addressed yet, and then you can do confirmatory trials after an accelerated approval, where you continue looking at the people who have been treated to see, are their symptoms really different from the people who would, who were not treated in the past.

[00:34:33] Joe Selvaggi: Sure. And again, maybe this is an uncomfortable question, but of course, companies make these therapies, they want to make people healthy, but they also want to, return profits to their shareholders. We know about patent protections that help, encourage the development of drug therapies.

[00:34:50] Are similar models in place for this brand-new gene replacement therapy or gene therapy? could one protect a gene? Again, we all have them, so it’s not a foreign substance being introduced to our body, but in a sense a modification of what we already have. Is it protectable? I ask that simply because you don’t want to, you want companies to be able to, develop it, spend the money, and then ultimately return the profits if they succeed.

[00:35:15] How does that work?

[00:35:17] Anne Sydor: So, no matter what we think of it, the way drugs are developed today is that people invest money to create a treatment, expecting that they will recoup the money that was invested in research and development, and be able to charge a price that covers those costs, and the manufacturing costs, and still provide a return on people’s investment.

[00:35:37] So, how do we do things in a way that allows a return on investment is an important question, because nobody’s going to invest in this. If they can’t expect a return on investment. for patent protection, what you would be patenting is not necessarily the gene itself. Because remember, in every person, there are gene variants that may or may not affect function.

[00:36:02] What you are patenting is this particular version of this gene, which we know produces a functional protein. This manufacturing process allows us to produce a gene that can be expressed in human beings. So there’s a lot more steps to be patented and there’s A lot more intellectual property to be protected.

[00:36:27] I would say gene therapy is less vulnerable to the loss of patent protection because of those complexities on the one hand. And on the other hand, because of the much smaller number of people, because of how precise. These medications are, it’s a much smaller number of people who you can treat. Maybe patent protection needs to exist for a longer period so that companies can be assured up front and investors can be assured upfront that they’ll be able to treat enough patients to recoup those costs and get that return on investment.

[00:37:00] Joe Selvaggi: that’s a great answer. I’m glad you acknowledged that, that challenge and it sounds like this sounds even more, capable of, withstanding, someone let’s say a knockoff technology. This is tough stuff to do now we’ve had, podcast episodes, dedicated to how drug companies or insurance companies, Even PBMs, and pharmacy benefit managers measure the benefit of a drug.

[00:37:21] We want to know, we talked about improved lives, but often they use something or they have been tempted to use something already used in Europe called, quality-adjusted life years or QALY’s, which in a sense takes the benefit and, and measures it based on, How many years it improves and how much it improves your life.

[00:37:37] That is, the longer it’s going to improve your life, the more valuable it is. And the more it dramatically improves your life, the more valuable it is. So, we’ve generally frowned on quality incentives because it incentivizes drugs. perhaps for the young and almost ignores drugs for people who have less years expect, less expected years to live.

[00:37:55] So, with regard to QALY and gene replacement therapy, it sounds like it favorably compares because you’re addressing mostly younger people, but would you embrace QALY or is this something you still would eschew despite the fact you probably score pretty well?

[00:38:08] Anne Sydor: So, Dr. Smith has spoken about this and elaborated on it much more eloquently than I ever could in podcasts and articles, and I encourage folks to look for those.

[00:38:19] The fundamental problem with QALYs remains. This standard inherently devalues the lives of disabled people. when we think about QALYs, we have to ask whether we’re really comfortable saying that the life of a person who uses a wheelchair or needs assistive technology to speak is somehow less valuable than a person without those needs.

[00:38:41] The disability advocate and senator from California, Paul Silo, has pointed out that treatment that extends the life of a disabled person may actually result in fewer qualities than treatment that returns function to an older person. A year of life for a person with spinal muscular atrophy could be said to have the same value as a year of mobility.

[00:39:06] Gained from knee surgery in a much older person. And again, it just doesn’t feel like apples to apples to me. Bollie’s standard is particularly problematic in diseases that affect small numbers of people and particularly problematic in treatments that are life-saving, but still, leave people with remaining disability.

[00:39:29] So, can we say that the number of QALYs gained by society from treating 500 kids with muscular dystrophy is the same as the number of QALYs gained by thousands of people having knee replacement surgery every year? It’s just really not comparable, and I think we have to look at things in a much more holistic way when we do a cost-benefit analysis, look at the price of the drug, look at the direct and indirect medical costs, and also look at the quality of life, productivity gained, and how it makes people’s lives better.

[00:40:05] Joe Selvaggi: Indeed, and of course, the promise, that this technology may add future qualities to future therapies. Fair enough, right?

[00:40:14] Anne Sydor: Absolutely, especially with new therapies in development, we have to look at what potential gains are we missing if we don’t incentivize the development of these therapies today.

[00:40:26] Joe Selvaggi: Um, we’re running out of time. So I’m going to, cut to an important question I want to ask because I’m sure that our listeners are very interested in the technology and the promise and everybody wants to make sure those kids who are born with an atypical gene that may challenge them in life that we want treatment.

[00:40:40] But for the average person saying, what does this mean for me? Does this technology, you mentioned very precisely diseases with long names, but all of us suffer from something. And let’s assume, disease or in general our life is a giant long 80-year-old manifestation of our genes.

[00:40:57] If this technology becomes really almost ubiquitous and we understand our genes and we understand how to, improve them, Does this, technology have the potential to spill over for us all? Meaning whatever the gene is that makes us need glasses when we’re in our forties or go have, senility in our eighties or whatever it happens.

[00:41:15] Can we, can this promise something for all of us in the future?

[00:41:19] Anne Sydor: Well, I think so. right now we’re in the infancy of this technology. We’re in the infancy of development. What we do know is that most diseases are not caused by one single gene. Most diseases are caused by multiple genes interacting with the environment.

[00:41:37] That said, there are specific genes that increase people’s risk for a disease. If we develop gene therapy today, it gives us the opportunity to develop gene therapy that could address those genes that predispose us to diseases. So imagine if we could treat during infancy a gene that makes it more likely that we’ll develop Alzheimer’s disease when we’re 60.

[00:42:03] And we could mitigate the effects of that gene with gene replacement therapy. Maybe we don’t get rid of Alzheimer’s disease, but maybe we go from 10 percent of people over 80 having the, I’m sorry, from 60 percent of people over 80 having the disease to 10 percent of people over 80 having the disease because we were able to treat a gene predisposition at infancy.

[00:42:29] That had an effect 80 years later. So that’s a bit of a pipe dream right now. I’ll be honest, but I think, if you look at where the development is going and go back to your analogy of the Wright brothers and their 1st plane, I don’t think they ever imagined supersonic jets, but we certainly have them now.

[00:42:48] Joe Selvaggi: Indeed, I agree. We talked about that a little bit offline, but I agree that for our listeners saying: “What does this mean for me?”. I can imagine a hundred years ago, how to get from Boston to Chicago and be compared to an airplane like the Wright Brothers to a train. Nobody’s right mind would take an airplane.

[00:43:04] Now 99.99% of people who wanna go to Chicago would fly there and not take a train. I think we’re really at that beginning phase of this technology. It will be ubiquitous in certainly in a hundred years, but let’s hope in all of our lifetime. I always like to finish with a king for a day kind of question.

[00:43:18] Whats one thing could our listeners, if they, or our policymakers, whether they be Washington or at a state level, what could they do to help encourage and cultivate this kind of technology and accelerate how soon we can enjoy its benefits?

[00:43:32] Anne Sydor: Well, we suggest a lot of possible solutions in the paper we’ve written.

[00:43:38] Right now, FDA policies are disincentivizing the development of gene therapy, and we’ve suggested a lot of policy changes that could address that. Those would all be good steps. I think we can go even further. I think we can look for increased partnerships between regulators and treatment developers, increased public-private partnerships and underwriting some of the upfront manufacturing costs, using standards that reward innovation and manufacturing processes, and providing some guaranteed market access.

[00:44:10] But most importantly, if I could do one thing, I would help policymakers understand the potential of gene therapy. That today, we’re treating small numbers of people with very precise therapies, but if we don’t invest in this today, Treatment. If we don’t invest in developing these treatments, we could be missing an opportunity to use gene therapy to address much larger diseases that affect much larger numbers of people and really impact not only the health of our population but the health of our economy by treating diseases that have devastating effects for huge numbers of people.

[00:44:51] Joe Selvaggi: Sure. It’s not just the dollars and cents. It’s human suffering and misery and quality of life, right? It’s so much more. It’s health. It’s what really matters. Well, I appreciate you taking the time today, Anne. You’ve been a wonderful introduction to a technology that I’m sure many of our listeners have never even heard of, but now may be more excited about.

[00:45:08] Can we have access to your paper? You’ve written it for Pioneer. Where would our listeners go to read, a released version of it?

[00:45:16] Anne Sydor: We don’t have the URL yet, but I imagine that you can flash it on the screen when we’re done.

[00:45:22] Joe Selvaggi: I appreciate that. This is, hot off the presses, so we don’t have the URL yet, but we’ll do our best.

[00:45:27] That’s, above my pay grade. I think we’ll have, some wonderful technologists at Pioneer figure out how to draw a link to your paper, and I hope everyone goes there and reads it. I’m sure they will learn a little more than they already knew about, this technology. Thank you for being my guest today, Anne.

[00:45:42] You’ve been really a wonderful guest. This has been another episode of Hubwonk. If you enjoyed today’s show, there are several ways to support Hubwonk and Pioneer Institute. It would be easier for you and better for us if you subscribe to Hubwonk on your iTunes Podcatcher. It would make it easier for others to find Hubwonk if you offer a five-star rating or a favorable review.

[00:46:01] We’re always grateful if you share Hubwonk with friends. If you have ideas, comments, or suggestions for me about future episode topics, you’re certainly welcome to email me at Hubwonk at Please join me next week for a new episode of Hubwonk.

Joe Selvaggi talks with neurobiologist and writer Dr. Anne Sydor about the potential for gene therapy to address deadly and debilitation diseases and how current health care models must adapt to encourage this nascent technology.


Dr. Anne M. Sydor, PhD, directs Research Development and Communications at GHLF. She earned her BS in molecular biology from the University of Wisconsin and her PhD in neurobiology from Harvard University. With a rich background in clinical medicine publishing and consulting, Anne specializes in project management, Lean Six Sigma, and instructional design. Her passion for person-centered medicine and health equity is fueled by her experiences as a parent, and caregiver.