Good afternoon and welcome everyone to our webinar on gene therapy updates. First of all, I would like to introduce my co-moderator, Dr. Jaya Ganesh. She is an associate professor at Mount Sinai, New York, and my name is Kuntal Sen, and the co-director of Neurogenetics Clinic at Children's National Hospital. It's a pleasure to moderate this session on the behalf of our wonderful ACMG Therapeutics Committee. We are committed to bringing you the most cutting-edge developments in therapeutics for rare diseases through webinars, conferences, and published guidelines. As some of you might recall, we presented a webinar in 2022, and today's session is an update on that. This activity is intended for educational purposes only, and this is the standard disclaimer from ACMG. The relevant financial disclosures from our moderators and speakers. For those interested in CME credits from this webinar, here is the information you would need. One will be asked to complete a survey after the webinar on the Genetics Academy. Please allow three hours after the webinar to print your CME certificate. A recording of this webinar will be available on Genetics Academy in two weeks. For any questions, please use the Q&A feature, and for any technical issues, please use the chat box. The objectives of this seminar are to provide an overview of CRISPR and gene replacement therapy. We will review specific gene therapies in pediatric neuromuscular and neurometabolic disorders. We'll discuss gene therapy in sickle cell disease, and lastly, we'll analyze the financial and ethical aspects of gene therapy. It gives me great joy to introduce our speakers for the day. Our first speaker will be Dr. Dwight Coburn, who is a professor of pediatrics at the Duke University School of Medicine. Our second speaker will be Dr. Steve Krasinowski, a newly minted pediatric neuromuscular specialist at the University of Massachusetts. Our third speaker will be Dr. Harry Lashmana, an assistant professor of molecular medicine at the Cleveland Clinic, and our last speaker will be Dr. Hadley Smith, an assistant professor at the Harvard Medical School. Without further ado, I'll hand it over to Dr. Dwight Coburn, our first speaker. Thank you, Kintal. So my role is to give an overview, an update, and so I'll quickly go through some background. First, a very short course in gene therapy. Typically, this involves a modified virus termed a vector, and it contains a transgene, which is a therapeutic gene, as well as some viral sequences called packaging sequences that allow it to be packaged into a viral particle. And it's well known that there can be toxicities related either to the transgene expression or to the actual vector particles. There are two overall strategies for gene therapy. In vivo is an infusion of the therapeutic agent intravenously, and then it will home to certain tissues based upon its tropism. And second is ex vivo, where stem cells are modified and then infused to the patient. With regard to AAV vector gene therapy, which is used frequently nowadays, and many in the audience are familiar with it, the AAV particle will bind cells in a process called transduction as opposed to infection, and then it's trafficked to the nucleus. The AAV vector DNA or genome is uncoded. It persists in the nucleus in an epizomal form where it's transcribed, and then the messenger RNA is translated into protein. And frequently this is transduction of liver, but also heart, skeletal muscle, and even the nervous system. There's a problem with regard to liver and with regard to treating early in life. So even if we give the same overall vector dose to an infant that we would give to an adult, by the time that infant grows to adult size, they will lost a majority of the vector. It can be actively eliminated. It can be lost during cell division. And so this is a problem for treating early in life. And genome editing is one approach to dealing with that issue. As I mentioned, AAV gene therapy is gradually lost, but genome editing will correct the disease gene in a patient's cells. And we know that modifying genomic DNA will permanently correct that cell and its progeny. So as long as the corrected cells survive, the benefits will persist. And it's rather like giving that full dose to an infant and having it persist to adulthood. Mainly genome editing now is being done with CRISPR-Cas9, which is a nucleus shown here. It has several components, a guide RNA that hybridizes with a certain specific gene target, as well as the Cas9 protein. Importantly, the PAM sequence here is part of the guide RNA that helps to localize it to a specific sequence. There are two possibilities then from CRISPR-Cas9 making a double-stranded break in standard genome editing, either non-homologous end joining, which introduces small deletions and insertions, or indels, and typically will inactivate a gene at a specific location. This can be therapeutic, for example, inactivating transthyrotine in amyloidosis, or homology directed repair, which is less efficient, but it includes a donor DNA that can be inserted through homology directed repair for gene correction. And just going a little more detail here, for this standard CRISPR-Cas9 editing, we have our guide, we have our Cas9, and we can use one or more guides. With two guides, there can be a very large gene or even a chromosomal region that's deleted. With a single guide, as I mentioned, the usual fate is repair of the double-stranded break through NHEJ. But adding the donor DNA, there can be a template that will correct a gene variant very specifically, one variant at a time, or a larger donor DNA can insert a gene into a locus and stably correct that cell, introducing a normally function gene, regardless of variant. Here's an example from my lab. So we did genome editing with CRISPR-Cas9 in the liver of dogs with GSD1, and the little hand with a pen shows the edited cells that were stable over time, over 16 months. On the other hand, the cells that only contained epizomal AAV, the little rings here, those were gradually lost, as expected. And with a high enough frequency of this genome editing, that should be very stable to correct the genetic disease over time in the target tissue. And other approaches to editing include base editing. And see here in the Cas9, there's a deaminase domain that's added. There's still the guide to localize the CRISPR-Cas9. This is a NIC case. It only cuts once in one strand of the DNA. So there's deamination of cytidine to uridine or adenosine to inosine. It's shown here, adenosine to inosine. A NIC in the opposite strand. And then the inosine is viewed during base pairing as a guanine. So the end effect here is a A to G substitution through the space editing. Prime editing, this uses now a reverse transcriptase domain as part of the Cas9, as well as a prime editing guide RNA or PEG RNA. And the PEG RNA includes several motifs, including this reverse transcriptase template. So what happens is there is a NIC here. There's priming of the reverse transcriptase template here to create a DNA flap that has the introduced sequence, the little orange box. And then there—so there are two flaps at that location, at the NIC. And one is the sequence that's being introduced. This is resolved and generally in favor of the introduced sequence, which currently state-of-the-art is introducing small sequences, but there's potential to expand those even to an entire gene. Now epigenome editing, and this has a so-called dead Cas9 that doesn't cut an activating or inhibitory domain. And so just depending on the design of the Cas9, the ability to activate or inhibit a specific gene. Note that this doesn't modify DNA, so it would tend to be transient. So now we can summarize. We talked about traditional NETJ for gene activation, traditional HDR for DNA insertion, and those are all standard, well-established strategies. The risks are moderate. I haven't talked about risks, but the risks for deleting DNA, for even introducing chromosomal rearrangements, or even chromatrips—fragmentation of the entire chromosome has been reported when there's a double-stranded break. So there's some risk there. And then we have high to lower efficiency, lower for HDR. And quickly moving ahead, base editing, there's only a NIC, so the risk is just small indels. It can be high efficiency. Prime editing, currently mostly in vitro in cells, but promising for going from a low to a higher efficiency with good safety. And epigenome editing should be safe. There's a consideration, though, of—I'm sorry, epigenome editing should be generally safe without DNA breaks. So I'm back to—and now to applications, just to think a little bit about the field and what you're going to hear more. And now in vivo with AAV is very well-established, and there are approved therapies, several for hemophilia. Here's just an example for POMP-A that I participated in, where an AAV vector would go to the liver, make the therapeutic protein that can be secreted into blood and go to muscle to correct POMP disease. And liver-specific expression actually helps to prevent immune responses against the protein in advantage. So this is under development. Now, ex vivo gene therapy modifying stem cells would seem more complicated, but it's really leaping ahead, as you'll hear about, especially for sickle cell disease. So just try showing some of the examples that I've discussed here. Base editing is going ahead to correct the sickle cell disease variant, as well as lentiviral gene therapies being done to stably express beta-globin. And then the NHEGA standard editing to inactivate a suppressor of gamma-globin genes to express fetal hemoglobin. And actually, the first and the last approaches are FDA-approved, showing how the field is moving ahead. So with that, I'll stop. Here are my acknowledgments and hand-off. All right. Thanks for the great introduction, Dwight. I'll get going regarding neuromuscular and neurometabolic disorders. First, we'll talk about Duchenne muscular dystrophy, or DMD. DMD is an X-linked recessive disorder caused by out-of-frame mutations to the DND gene. It's the largest gene in the body at 2.4 megabases, and the sheer size of it is it has important treatment development implications for which we'll discuss. Frame-shift mutations lead to non-functional and absent unstable dystrophin, a variant of dystrophinopathy. Becker muscular dystrophy is caused by in-frame mutations, allowing for the production of partially functional truncated dystrophin. And this has been important, again, as we talk about the development and mechanism of treatments for Duchenne. It's known that there are several hotspots where mutations tend to cluster, and about 47% of patients with Duchenne have deletion duplications between exons 45 and 55. First ASOs, or antisense oligonucleotides, for which people are probably quite familiar with, they're synthesized complementary single-stranded DNA anchored to a stabilizing proprietary backbone designed to hybridize either pre-mRNA or mRNA target sequences. Hybridization is engineered as to alter the translation of mRNA either by activating alternative splice sites or by blocking a splice site, with the intention overall of restoring the reading frame, shifting an out-of-frame Duchenne phenotype to a Becker phenotype, allowing for the continued translation of partially functional truncated dystrophin. We can see here what has been FDA approved all the way back to 2016, the respective exons that are skipped, and the percentage of the Duchenne population for which would be targeted by each treatment. The Cholefsky trials remain ongoing, though are encouraging with measurable truncated dystrophin production and improved overall functional outcome measures, as you can see here from the first Eteplersen trial. However, there are a number of limitations. Using the current FDA approved exon skipping drugs, we can only treat about 30% of the Duchenne population. There is a number, at least 10 other exon skipping drugs at the time of this talk, in development that would treat up to 60 to 80% of Duchenne patients. And that's great, but obviously inadequate for treating our entire population entirely. Current constructs also do not have the greatest penetration, and they require relatively high doses and frequent on the order of weekly infusions. It should be noted that ASOs are simply disease modifying, they're not curative. And so moving forward to gene replacement, delay in distributing moxiparvovac, otherwise known as Alevitas, was initially approved by the FDA in June 2023 under accelerated approval for patients with Duchenne age 4 and 5. In June 2024, expanded approval was granted for individuals with Duchenne greater than 4 years of age, both of ambulatory and non-ambulatory function. What it is, is an engineered microdystrophin transgene product delivered with a muscle specific MHCK7 promoter via AAV, adeno-associated virus, RH-74 vector that was chosen specifically with the intention of having low pre-existing immunity in mind, high muscle affinity, and an overall favorable safety profile. Given the sheer size of D&D, obviously no vector is large enough to deliver the whole gene. This product, with the other ones in clinical trial development, was creatively engineered based on a 61-year-old Becker patient, engineered to preserve the most essential domains, the 5'-actin binding domain, select spectrum-like repeats, and the cysteine-rich 3' end. In theory, successful delivery of this would be a one-time infusion providing a template for both skeletal and cardiac muscle as to make microdystrophin, shifting Duchenne to Becker muscular dystrophy. Initial studies, admittedly, have been controversial, I'll say. It demonstrated limited efficacy functionally using the Northstar ambulatory assessment test, improved in the 4- to 5-year-olds, but that was only on retrospective analysis. It should be noted, in the older population, 6- to 7-year-olds, they were simply not age-matched perfectly, and so this may have confounded some of the results. Secondary outcome measures, notably microdystrophin expression, was increased in the treated populations. So the advantage is, potentially, this can treat a much broader range of individuals with different mutations, with a high potential for disease attenuation, as compared to the ASO therapies, but again, this is not a cure, and it simply shifts DMD to BMD. There are a number of limitations, which I very intentionally want to highlight. The first being, certain individuals with DMD mutations are ineligible to receive this because of a hyperimmune response that they receive. Also, we're faced with the predicament that certain families who may have potentially multiple eligible boys to receive the therapy could have one boy who receives a treatment, and then exposes his sibling to the vector, seroconverting the sibling to become seropositive, and then subsequently ineligible to treatment. That's a consideration that we have. And it's not innocuous. We've seen myocarditis, myositis, thrombotic microangiopathy, hepatotoxicity in patients, and it's almost universal that kids experience post-infusion malaise, probably just because of the viral load that they're given. So I share this. This is very promising, but much work remains. It's certainly, to me, the first iteration of gene replacement for Duchenne, and I see there's going to be, I anticipate better therapies in the future to come. One thing, building on what Dwight had brought up previously is could this be given to younger boys? Potentially in younger boys, there may be fewer comorbidities in the youngest boys with Duchenne. So this is a risk to consider in younger versus the older and also heavier boys with Duchenne. We'll next move forward to X-linked adrenal. This is caused by pathogenic variance to the adenosine triphosphate binding cassette, subfamily D, member one, or the ABCD1 gene. The ABCD transporter shuttles very long-chain fatty acids into the peroxisomes. Thus, when not functional, leads to very long-chain fatty acid accumulation outside, leading to particular damage to neurons and glial cells. There's a variety of clinical manifestations not worth getting into today. The most pertinent though being childhood cerebral ALD. Virtually all patients develop a slowly progressive myeloneuropathy and adrenal insufficiency. Classic radiologic findings that we see are these extensive bilateral posterior symmetric T2 hyper intense signal in the periventricular and subcortical area, white matter. I remember the back of the brain, X is at the back of the alphabet. That's how I remember that for boards. Historically, treatment had been limited to allergenic stem cell transplantation. Though this is inadequate because previous with stem cell transplantation survived major functional disability free survival was only 50% at five years post-transplant, better than the natural history of 20%, but inadequate. So in September, 2022, L-avalidogene on the Tema cell, a lentiviral vector used to transfect functional ABCD1 cDNA into autologous stem cells was granted accelerated approval for treatment of boys four to 17 with early active cerebral ALD. Overall L-avalidogene has demonstrated comparable efficacy for treatment of early cerebral ALD as compared to conventional allergenic stem cell transplant and better than natural history. Data collection of individuals who have received L-avalidogene versus natural history and or allergenic stem cell transplant remain ongoing, but slower disease progression is seen as measured by percentage without major functional disability. As you can see here at two years, about 72% in those treated versus 43% in the untreated group. Again, intentionally bring up the negatives or concerns that we have, not unexpectedly treatment does have a number of short and long-term complications and side effects, including a black box warning for hematologic malignancies, including myelodysplastic syndrome, AML, breath versus host disease, and this just simply requires close monitoring. Blood counts at least every three months to start and assessment for clonal expansion twice the first year and annually there forward. Metachromatic leukodystrophy, MLD, is most commonly caused by biallelic pathogenic variants to the lysosomal enzyme arylsulfatase A, ARSA. ARSA is responsible for the desulfonation of cerebroside sulfate, a major glycolipid in myelin. So decreased activity leads to accumulation of this, destroying ligodendroglial and Schwann cells, leading to a diffuse central and peripheral dysmyelination syndrome. Clinically, it's divided into subtypes by the age of onset, the late infantile, six months to four years being the blue line here, the juvenile, four years to 16, divided here further into early juvenile in orange and late juvenile in green, and adults greater than 16 years in red. In the late infantile form, developmental delay, regression of skills, gait difficulty, seizures, ataxia are commonly seen with a mitigated version of that in the older forms. Radiologically, we see the periatral and frontal horn leukodystrophy in a tigroid appearance. In March, 2024, added arsogene autotemacel was approved for treatment of pre-symptomatic late infantile and early juvenile or early symptomatic early juvenile, MLD. And in brief, kind of analogous to the previous treatment, a lentiviral vector is used to transfect functional arsa into autologous stem cells. Therefore, it transfuse back into patients. Data remains limited, but is encouraging thus far. This is a non-randomized study of 29 patients treated with added arsogene, 26 survived, and they demonstrated both functional improvement in A, on the left, as you can see, those without severe impairment death was improved in the treated group, and brain white matter involvement was reduced in the treated group as well. So in summary, we covered these three diseases. These therapies hold great promise. I hope that we've never had before, but I encourage everyone as the skeptical scientists as we are to continue to have caution and have the scientific scrutiny moving forward. I'd like to thank all the people who have made this possible, but more than the colleagues and coworkers, the patients and the families that we take care of. I show these pictures from a muscular dystrophy associated camp 20 years ago, and then more recently, really just speaking to the blossoming pipeline of therapies that we now have available. Thank you for everyone's time. Thank you, Steve. I am going to switch gear and talk about sickle cell disease. Next slide. So I believe the audience probably are quite familiar with sickle cell disease. It is an autosomal recessive conditions due to viral leak mutations in HBB genes that causes single amino acid changes that created all the consequences clinically that we see in these patients. It is estimated about 300,000 infants born annually worldwide and they are predominantly living in the low and middle income countries. If you talk about in the United States itself, approximately 100,000 people living with sickle cell disease and with multiple public health efforts, we have seen a lot of improvement in their survival. The childhood survival now has increased to 94 to 98% compared to three decades ago when it was less than 50%. And this is due to newborn screening, early interventions, vaccinations that has led to decreased mortality for children. However, there are still a lot of adult patients that die early from sickle cell disease. If you compare with the life expectancy in the United States which is in the mid seventies, the mean age of death for adults with sickle cell disease is in early place. Next. And talking about sickle cell disease, you kind of need to talk about the pathophysiology. The single amino acid substitutions created an abnormality in the shape of the red cells when they are deoxygenated and it created this unique sickling forms that triggered whenever the patient is under low oxygenation content. And it creates a lot of issues with hemolysis, recurrent hemolysis that creates a lot of abnormality in the endothelial cells, creating chronic inflammations and chronic micro circulations occlusions that led into multiple organ system involvement. And that's the major higher risk for morbidity is related to this and organ damages. Next. So what are the current standard of treatment for sickle cell disease? The standard of care includes hydroxyurea which has been used since the early nineties that increases the number of proportion of hemoglobin F that minimize the risk for sickling, the infection prophylaxis with penicillin and pneumococcal vaccinations. Suddenly a standard of cares that we need to provide for all patients and children with sickle cell disease. Chronic transfusion is also another treatment that we provide for those who already had history of stroke. This is to prevent stroke subsequently. And then during their hospitalization because of this recurrent vaso-occlusive crisis we will provide supportive and palliative care as well. There are more recently approved FDA approved medication but those are non-curative. These are disease modifying agents which I'm not going to talk very extensively here because of the time, but these three agents are two of them are oral. The L-glutamine and voxelotor are given orally while chrysanthelizumab is given IV. Those are disease modifying agents with the overall overarching goal is to minimize the risk for having vaso-occlusive crisis through multiple different modality. Next. The current only curative treatment for sickle cell disease is allogenic hematopoietic stem cells and unfortunately we do not have many options to do the best options to do transplantation which is using match sibling donors or match related donors. The data showing that the overall survival five-year overall survival is approximately about 92 to 94% pretty high but it's limited in sickle cell disease because the donor pools is limited especially because of their ethnic background only 15 to 20% actually has a match unrelated donors. And patient with sickle cell disease is also known to have a higher transplant related morbidities and mortalities due to GPHD, graft failure and secondary malignancy just like with other allogenic hematopoietic stem cell transplantations. And the cost is also not cheap especially considering that majority of those individuals living with sickle cell disease live in the middle and low income countries. So switching gear to gene therapy. Next slide. So it's a forms of autologous stem cell transplant and we do still require myeloblative conditioning regimen. As Dwight has mentioned earlier there are several strategies that can be used to minimize the symptoms of sickle cell disease through gene manipulations. There are two major strategies here that we are talking about in sickle cell disease gene therapy. The first methods will be a gene additions. This is typically delivered using a viral vectors that adding the functional copies of the beta or gamma globin, gamma light globin that has anti-sickling activities. We'll talk a bit more about that. And the second strategy will be gene editing using the newer nucleuses such as CRISPR-Cas9 that specifically targets specific genes or transcription factors that modify the expression of fetal hemoglobin with the overarching goal of increasing the production of hemoglobin F because we believe that will minimize the risk for sickling. So based on these several studies that has been ongoing the one that I would like to highlight is the one that led to the approval of by FDA for two different products. Next. The first product is the LoboT gene autotempsel or Lobo cells. So this is the lentiviral based test gene therapy that using lentivirus that will deliver a modified beta globin gene. So instead of having a healthy normal hemoglobin the lentivirus will add a modified beta globin gene that has anti-sickling properties. So this transition from T to Q in amino acid number 87 has a benefit for preventing the hemoglobin S to sickles. And the efficacy and safety of Lobo cell has been investigated in phase one, phase two and up now up to phase three but those are non-randomized open label single arm studies. And the data that presented here was based on the interim analysis with a cutoff age of February 2023 which total of 47 people enrolled in this study. If you look at the table on the left side those enrolled in the study has an annualized rate of basal occlusive crisis, this is severe either acute chest syndrome or severe chest basal occlusive crisis up to three to four times in a year. And then following the infusion, the patients followed up to 24 months post infusions. The figure on the right side showing the changes of the total hemoglobin from baseline which is around eight gram per deciliters up to close to 12 gram per deciliters which is a normal range of total hemoglobin content. If you look at the blue bar those are the percentage of the modified hemoglobin with anti-sickling properties that reaches up to 47% in majority of those patients. So it seems to have a very sustained level of productions of this anti-sickling beta globin. And then one of the primary efficacy end point that they are looking at here is the reduction in the number of basal occlusive crisis within six to 18 months period of time. Slide. And based on, slide please. Yeah, out of 34 patients that were available for this study, 30% achieved complete resolution of all the basal occlusive crisis. So 88% response rate in this study. Next slide. The second product that was approved by FDA using a different technology called CRISPR-Cas9. So this is a non-viral gene therapy that targets specific transcription factors in this case is BCL11A which is transcription factors that reduce the production of hemoglobin. And this has been studied extensively as well up to phase three of clinical trials and has very promising result on the studies that was recently published in this year. In the interim analysis up to June, 2023, there were 44 patients enrolled in this study and completed infusions. Out of those 44 patients, can you slide, expand the slide please. There are approximately 30 patients that were evaluable. The primary end points evaluated in this study is the number of patients that had complete freedom from severe basal occlusive crisis within the first 12 months after the infusion. So out of 30 patients evaluable, 29 of those or 97% has complete freedom from severe basal occlusive crisis. The figure on the left side is also kind of similar to the other trials showing improvement in overall total hemoglobin levels from baseline which is around eight up to 12 gram per deciliters with majority of those patients have higher hemoglobin F up to 40%, which is typically sufficient to ameliorate many of the symptoms of sickle cell disease. Next slide. So there are several special considerations. The data from these two studies shows that the short-term adverse events quite compatible to any other autologous hematopoietic stem cell transplantations. I think Steve mentioned about risk for secondary hematologic malignancy. There are few cases of AML reported in the earlier phase of the studies using antivirus, including one case of MDS in the long-term home court. And there has been some data that both support and against the fact that some of these patients with sickle cell disease, they have accelerated clonal hematopoiesis that might put them at higher risk to get secondary malignancy. Although the study is showing that there's no evidence of insertional oncogenesis from the products itself. High cost of gene therapy. I think we all know about that. And then the ethical and social concerns. A lot of concerns about indications, access, eligibility. And this is something that will be discussed by next speakers, but I just wanted to point out that this is unique to sickle cell disease populations. They always questions, what is the meaning of cure? Is this really a curative treatment for them? So in conclusions, next slide. Gene therapy is, we consider it as a transformative treatment options. I think we should consider it as a landmark therapies with a corrective intent instead of cure because we do not know what is the long-term efficacy and durability of gene therapy. But significantly, we have seen a lot of stride in our effort in improving quality of life of our patients with sickle cell disease, starting from hydroxyurea in 1998 and up to 2023. Now we have two products for gene therapy. I would like to, this is my last slide, which is the acknowledgement slide. And thank you. And that's my email address. Great, thank you for teeing up the considerations around costs and ethical and social concerns, Dr. Lasmana. I will be talking about how we value a cure, ethics and economics of gene therapy. So price tags of gene therapies have always made headlines. This story about the first gene therapy in 2017 to treat leukemia noted the remarkable price tag of $475,000. Gene therapies have continued to break their own records for high prices. Seven years later, that headline-worthy price tag is now $4.25 million. Along with continued conversations about prices, there has also been increasing attention paid to issues of access and equity, asking questions about who will actually benefit from the availability of gene therapies. In response, we have also seen development of innovative payment models, such as those that aim to tie payment to realized health outcomes. I'll expand on each of these points, price and value, access and payment, over the course of this presentation. So when we think about value, we can think about value from multiple perspectives, including the health care system, society, and patients and families. But there are a few ingredients that are important to consideration of value for money and budget impact or affordability of high cost therapies, such as gene therapy. So as we've heard from the previous speakers, gene therapies have the potential to impact thousands of patients' lives. The New Drug Development Paradigm, or New DIGS, group based at Tufts Medical Center has done a lot of work to estimate the product pipeline and spending on gene and cell therapy products over the next several years in the United States. And the New DIGS group estimates that by 2032, there will be 66 product indication approvals with more than 105,000 eligible Americans per year. There is a high upfront cost of these therapies with an estimated spending of $35 to $40 billion over the next decade in the US. There is also considerable uncertainty about the durability of a clinical benefit, essentially whether these products are actually one time cures. And that has sparked incentive for payment models that aim to share risk of paying for a treatment that is not effective between payers and manufacturers of these products. So what do we mean when we talk about value? I'd like to start with a few definitions to make sure that we're using language in the same way. So when we think about value, we're typically referring to cost effectiveness, which is how much of a health outcome do we buy for a given amount of spending. And that health outcome can be measured in various ways, but most commonly, it is measured in terms of quality adjusted life years, which index length of life and quality of life. The Institute for Clinical and Economic Review is a nonprofit organization in the US that assesses the clinical and cost effectiveness of pharmaceutical products. And the Institute for Clinical and Economic Review has found these high price tags of gene therapies to be justified in many cases. Value is always relative. And so when we consider the value of a gene therapy product, we have to consider a standard of care as well. And so this one time high cost upfront may offset the cost of continuous care for a chronic condition. It may also increase the length of patients' lives. We also have to consider affordability or the budget impact because these high upfront costs challenge state Medicaid budgets as well as commercial payers and employers. So for example, sickle cell disease gene therapy is estimated to have an average one year budget impact of nearly $30 million in the 10 states with the highest prevalence of sickle cell disease. We care about these cost offsets though, which are the impact of gene therapy on downstream health care costs. Although as I've noted, there are many uncertainties that remain. There's also some data to suggest that model-based analyses may underestimate the time to break even. So Brett McQueen and his team in the School of Pharmacy at the University of Colorado have looked at cost offsets using real world data from Colorado Medicaid. And when substituting standard of care with gene therapy for patients with hemophilia A and hemophilia B, the cost offsets were achieved at an eight year and six year average for break even times compared with five years in published economic evaluations. This suggests that using real world data can help state Medicaid decision makers in their negotiations with manufacturers on contracts for these products. There are also relevant ethical considerations that can be considered alongside estimates of value in health technology assessments. And that may make products appear more valuable. So treatment for severe conditions, a lack of available alternative treatments, and impacts on pediatric populations are all factors that have been considered as providing more value for money of therapy. So when payers are thinking about coverage decisions for a novel high price therapeutic or cure, they are balancing many considerations, including the budget impact, the durability of the treatment benefit, equity and the distribution of the benefit within and among their plan beneficiaries, stewardship responsibilities for health care spending at a societal level, as well as the prevalence of the condition and the characteristics of the risk pool in their particular plan. They consider clinical uncertainty. They also consider plan reputation and customer satisfaction, as payers do not want to be making headlines as a case for denying pediatric patient access to a lifesaving therapy, for example. So health plan decision makers are facing these real questions about coverage and gene therapy, and they have two potential routes to go. And evidence suggests that there is a little of both happening. So one route is to restrict coverage. Reviews of policies for state Medicaid programs, as well as commercial insurers, suggest that for many products in the cell and gene therapy space, coverage is often more restrictive than FDA labels. This obviously impacts patient access to cell and gene therapies. The second route that payers can go is to innovate and develop outcomes-based contracts, where payment is tied to outcomes that are important to patients and families. Harvard Pilgrim Health Care has long been a leader in the development of outcomes-based agreements for gene therapies and genomic sequencing. Michael Sherman, the former CMO of Harvard Pilgrim Health Care, now part of Point32 Health, has summed it up nicely in this quote. Prices are based on the idea of it being a permanent cure. We don't have permanent data. So the best way to bridge these differences is to come up with warranties, value-based agreements, and other innovative approaches that de-risk coverage decisions for the payer. I don't think there's anything wrong or unethical with expecting pharmaceutical companies to stand behind very clear endpoints that they've used to get it approved by the FDA in the first place. And I think it's even more important when they're using surrogate biomarkers versus the endpoints that we payers and patients care about. So innovations in coverage policy can be tailored to address two primary problems, first being high budget impact, and second being clinical uncertainty. So we see plans using approaches such as installment payments, where they pay a little bit over time, or subscription models, also where they pay a given amount for a certain volume of a drug to address the high budget impact of selling gene therapy products. To address clinical uncertainty, we see outcomes-based payments or rebates, as well as warranty structures and coverage with evidence development, where the price can be adjusted based on realized cost effectiveness in a population. In response to the Biden administration's initiatives to lower drug costs, the Center for Medicare and Medicaid Services has announced the Cell and Gene Therapy Access Model. So this is an example of where innovative payment approaches are being used in the public payer space. The Cell and Gene Therapy Access Model is a voluntary model that allows states and manufacturers to opt in to a CMS-led approach, where CMS essentially negotiates and administers outcomes-based agreements for cell and gene therapy products. And the stated goals of this program are to increase access to innovative treatment, improve health outcomes, and reduce health care costs and burdens to state Medicaid programs. Gene therapy for sickle cell disease will be the first product that is tested in this pilot program. The requests for applications for states and manufacturers have been released earlier this year with an anticipated start date of early 2025. And the model is expected to be in operation for approximately 11 years. So when we widen the lens on value, we can think about other novel factors that may be important either for society or health care to patients and families. Typically, we focus in economics on these green petals of qualities gained and net costs. However, there are other novel aspects of value that are very relevant for innovation in the rare disease space and in gene therapies in particular. So we conducted semi-structured interviews where we included 30 participants from different sectors, including academia, industry, payers, and patients. And we asked them to rank these value elements in order of importance for inclusion in the value assessment of gene therapies for rare diseases. Now, our value rankings are presented in this table where the most important are at the top all the way down to least important organized by stakeholder group. And we can see that quality-adjusted life years are commonly considered very important across all stakeholder groups. Equity, family productivity, scientific spillover, and net costs were also considered to be important in demonstrating value. So when we understand the value of cell and gene therapies, this is a complex task. Value is often in the eye of the beholder. We can see value through many different lenses as many different stakeholders. There are normative questions around who are we maximizing value for and who should determine how a value is defined and measured. What is most meaningful is often most difficult to be measured. And this is something that outcomes-based agreements will have to grapple with, as they must measure the outcomes that are tied to payment for these therapies. I'd like to acknowledge Megan Halley and working group members of the Value Ethics Working Group. My contact information is listed here. Thank you to all the speakers. That was an awesome presentation, and I'm now going to open the session to questions. Interestingly, we have three questions already in the chat, and I'll encourage the audience to keep them coming. The first question is from Maria Camel. Thank you so much for the lecture. Should the patient be put on gene therapy for life? Does it treat the condition so the patient can be off therapy at a certain point of time or just improve the mortality? And Dr. Cobol, do you want to take that? Yeah, I was just typing that for the gene therapies mentioned here with AAV or lentiviral vectors, there's no stopping the treatment. They're a single administration that's long-lasting, and hopefully the benefits are long-lasting and fairly stable as well. So that's by design that it's a treatment that is going to provide long-term benefits if it's effective. And I'll add to that that if you're using a viral vector, you develop antibodies to the viral vector. So introducing another dose of the virus is going to be difficult. It will be rejected. But I think there are studies in progress to see if they can top up some of these therapies in case it becomes dormant over the course of time. I'll echo on those comments, particularly for the Duchenne world with Levitas. There's some controversy regarding its recent approval because there have been limited functional improvements that the approval is based on. And so one of the ethical qualms that we face is, should we use this imperfect therapy at the present time or wait for something potentially better to come down the road that we cannot promise or guarantee, knowing that if we treat the patients here and now today, that they would develop such an immune response to a subsequent, potentially better treatment in the future? And that's something that we, unfortunately, just don't know at the present time. Thank you, Steven. So the next question is from Pamela Giral. I've read about infertility treatments for sickle cell disease. Is this relevant for the therapies you have mentioned? So this is to Dr. Leshman. Yeah, that's a great question. So I think, let me back up a little bit, that those patients with sickle cell disease are inherently at higher risk to get infertility to begin with, especially for those with untreated iron overload because they can get secondary hypogonadism just from that. Related to the treatment, I think the risk for infertility is true for any allogeneic or orthologous stem cell transplant with gene therapy included into it with the use of conditioning regimen that is toxic. Those with myeloblative conditioning regimen, those are toxic not only to your bone marrow, but also many other organs. So there is always risk for infertility. And that's something that, at least in our institution, that we offer fertility preservations for those patients who are candidates or in the process of getting any kind of transplantation, knowing that they have risk for infertility. So I don't think it's just necessarily related to gene therapy with any hematopoietic stem cell transplantation with condition, with toxic conditioning. Thank you. The next question is, are these treatments having same efficacy for de novo as hereditary genetic diseases? I think if I understand the question, I would say that the response is going to depend more on the specific variant than whether it's de novo or inherited. And I'm trying to think of a disease where there'd be many de novo variants. And I think of, say, hemophilia. And historically, that's been a lethal disease. There are many new variants. And those can be treated the same Those can be treated the same as an inherited form of hemophilia. Thank you. The next question was, with respect to Betty Begler gene, are there any concerns about ongoing ion deposition despite therapy? It appears that GI absorption of ion may continue even after this gene therapy. This is for you, Hari. Is that for me? Yes. Specifically, is this for beta thalassemia that the person is referring to? So if I understand, because the product that was mentioned, that's not something that we discuss in the sickle cell disease. So that's probably more for other products for beta thalassemia. So I think the question was related to increased risk for iron toxicity. Because patients with hemoglobinopathy, sickle cell disease, beta thalassemia, their gut are just inherently have higher affinity to absorb iron because of the ineffective erythropoiesis from the disease process itself. So again, we do not know the long-term efficacy of the study, whether that is something that will be monitored in the long term. Many of the endpoints that were used in the studies specifically look at the efficacy from the perspective of reducing in the sickle cell disease, for instance, by a special occlusive crisis. In beta thalassemia, reducing the risk for transfusional iron overload with gene therapy, whether there will be a benefit from preventing iron overload from the GI, increased GI absorption, I think that's something that needs to be proven in the long-term studies. Thank you. And we think we have one last question. What recent advancements in gene therapy have shown the most promise in terms of safety and efficacy for treatment of rare disorders? Sure. What recent advancements? Yes. Have shown the most promise in terms of safety and efficacy for the treatment of rare diseases. Yeah. Well, I'm really enthused about the treatments for sickle cell disease. Even though we see it more commonly, it's still considered a rare disease. That's a great one. I would say that the approvals of gene therapy for hemophilia have been effective in terms of reducing bleeding and reduced need for treatment. Even though those have been approved in the last couple of years, I would say there are recent advances that really show promise for those patients. I think also some of the really promising things are still in clinical trial and we should expect to see more coming out in the next few years. Thank you. Also for sickle cell disease, if I may add that with the use of in vivo gene therapy, many of the studies that are utilized right now, they are ex vivo, you need to do outside of the bodies. You require more facilities to do that. If you can do an in vivo gene therapy, just like for on paper instance, that will be an area of interest. There's some studies using base editing and primary thing that's currently under preclinical studies. Thank you, everyone. Thank you to our speakers and our participants. We wanted to mention an upcoming ACMG virtual fall seminar, which will be from September 10th to 12th. This is titled, Advancements in Genomic Medicine, Navigating Health Inequities. Please register for this for more upcoming advancements. We wanted to thank the ACMG Therapeutics Committee, especially our chairs, Dr. Lindsay Burridge and Dr. Pena, for their support with this webinar. Thank you, everyone.

gene therapy

rare diseases

advancements

sickle cell disease

Duchenne muscular dystrophy

X-linked adrenoleukodystrophy

metachromatic leukodystrophy

AAV vectors

lentiviral vectors

CRISPR-Cas9