TY - JOUR
AU - Canfield, Scott L
AB - Abstract Purpose To provide health systems with baseline knowledge on existing and pipeline gene therapy treatments, including considerations that health-system pharmacies and specialty pharmacy programs may reference when evaluating and implementing services around gene therapies. Summary Advancements in research and biotechnology have recently led to the development and launch of the first commercially available gene therapy treatments in the United States. These treatments have the ability to significantly alter and even effectively cure diseases. Alongside these significant advances and clinical benefits, these therapies present unique challenges due to their cost and complexity. Given the large number of additional gene therapy treatments that are currently in late-stage clinical development, stakeholders across the healthcare industry must increasingly adapt and ready themselves to meet these challenges. The diagnosis and treatment of patients with diseases being targeted by gene therapies largely occurs within health systems, and judging by the gene therapy pipeline, this trend is likely to continue. To prepare for these novel treatments, health systems must understand and consider the methods in which gene therapies are developed, procured, reimbursed, administered, and monitored. Conclusion The future of health-system pharmacy practice must include comprehensive gene therapy services and stakeholder engagement strategies to ensure patients have access to these life-changing treatments. gene therapy, health system, specialty pharmacy KEY POINTS Existing and pipeline gene therapy treatments present unique challenges due to their cost and complexity. Most disease categories targeted with gene therapy are managed within health systems, which presents an opportunity for the development of fully integrated pharmaceutical care models. Health-system pharmacy departments must understand and consider the methods in which gene therapies are developed, procured, administered, and monitored in order to develop effective stakeholder engagement and product management strategies within their institutions. Without a doubt, this is the most important, most wondrous map ever produced by humankind. Bill Clinton, June 2000 The gene therapy renaissance is upon us. After the “wondrous map” that is the human genome was decoded in 2000, the implications for the future of medicine seemed endless and provided a renewed hope for the development of therapies intended to cure genetic diseases. Years later, with remarkable treatment results tied to staggering costs, it is no wonder that stakeholders across healthcare are paying special attention to gene therapy. The exploration of genetic treatments traces its roots to the early 1970s with the invention of recombinant DNA technology.1 The first human gene therapy experiments with the intent to treat disease occurred in 1980, targeting beta β-thalassemia, but did not demonstrate effective gene expression.2 After decades of limited success, a sentinel event occurred in 1999 with the tragic death of an 18-year-old patient who had received an experimental adenovirus gene therapy to treat ornithine transcarbamylase deficiency.3 This event, combined with the development of leukemia in some patients after receiving gene therapy treatments for severe combined immunodeficiency a few years later, resulted in widespread skepticism and fear towards gene therapy.4,5 Despite these events, and thanks to enhancements in research and biotechnology, there are over 370 active gene therapy clinical trials in progress today.6 Now more than ever, it is clear that gene therapies hold one of the most important keys to the future of medical and pharmacy practice. Gene therapy definitions and delivery mechanisms Gene therapies change the expression of genes within the human body and act by correcting a malfunction in gene expression, typically through replacement of a missing gene, regulation of a dysfunctional gene, or inactivation of a gene that is not functioning properly. The nomenclature used in the description of gene therapies is evolving. Gene therapies are often described in conjunction with various types of cell therapies, and although the terms are often intertwined, they refer to different mechanisms for changing the course of a disease. The term gene therapy most directly refers to a process that introduces, removes, or changes a person’s genetic code by transferring genetic material.7 In contrast, cell therapy involves the transfer of live cells that perform a desired function into a patient, with or without genetic modification.7 These live cells may either originate from patients themselves (autologous cells) or from a donor (allogeneic cells). Examples of existing cell therapies that involve genetic modification or gene therapy techniques include the chimeric antigen receptor (CAR)-T cell therapies tisagenlecluecel and axicabtagene ciloleucel. The modified CAR-T cells then serve as an immunotherapy to target and eradicate cancerous cells within the body, which differs from the genetic modification seen in other gene therapy treatments that directly transfer genetic material to a patient and result in changed expression of a missing or dysfunctional gene.8 Other relevant terms used when discussing gene therapy include in vivo and ex vivo. In the case of gene therapy, in vivo refers to a gene therapy vector that is directly administered to the patient, whereas ex vivo refers to a process in which cells are removed from the patient to receive genetic modification prior to being returned to the patient’s body. This article will focus on gene therapies that are delivered to patients through use of a viral vector, or in vivo gene therapies. Gene therapy vectors Most commonly, in vivo gene therapies deliver genetic material through the use of a viral vector, which carries the relevant gene to the target cell after an injection or infusion. Historically, nonviral vectors such as liposomes and naked DNA were also evaluated.9,10 Adenovirus vectors were one of the first viral vectors used, with early vectors eliciting strong immune responses.11 More recently developed adenovirus vectors have demonstrated substantially reduced immunogenicity due to the creation of “gutted” adenovirus vectors that do not encode for certain viral proteins that are associated with increased immune reponse.12 The role of various viral vectors used in modern gene therapy has been summarized previously.13,14 Most recently, the use of adeno-associated viruses (AAVs) has been heavily studied as a vector for in vivo gene therapy and has led to the approval of the first commercial gene therapies in the United States.15-18 AAVs are often preferred over adenoviral vectors due to their low pathogenicity, high titer, ability to infect a broad range of cells, and mild immune response.19 Retroviruses (including lentiviruses) have also been studied. They are used as the vector for a number of gene therapies within clinical development and are also used in currently available genetically modified cell therapies.20,21 There are 13 AAV serotypes (designated as AAV1 through AAV13), each with some specificity towards different tissues or cell types within the body.22 In order to deliver gene therapies intact to affected cells, AAVs must avoid a highly reactive host immune response. This means that patients receiving systemic gene therapy treatments using AAVs as a vector must be tested for and have low levels of anti-AAV antibodies specific to the AAV used to deliver the gene therapy. Additionally, although various serotypes of AAVs may target certain types of clinically relevant cells with greater affinity (eg, motor neuron cells), additional cells throughout the body may also be impacted either directly by the virus or by the host immune response, and this may lead to adverse drug events or harm, such as acute liver injury.16 Review of approved products As of the time of writing, 2 in vivo gene therapies had been approved by the Food and Drug Administration (FDA) for use in the United States. At the most basic level, both of these gene therapy treatments work by delivering a functioning copy of a missing gene to affected cells using an AAV vector, leading to proper expression of the gene and subsequent key protein translation and cell survival. Voretigene neparvovec-rzyl (Luxturna). The first gene therapy approved by FDA in the United States, voretigene neparvovec-rzyl (VN) from Spark Therapeutics, was approved in December 2017 and is indicated for the treatment of patients with inherited retinal dystrophies (IRDs).17,23 Specifically, VN is approved for treatment of confirmed biallelic RPE65 mutation-associated retinal dystrophy. RPE65-associated IRD is rare, with an estimated 1,000 to 2,500 individuals affected in the United States.24 VN is an AAV vector–based gene therapy (AAV2) that is administered by surgeons as a one-time subretinal injection and carries a wholesale acquisition cost (WAC) of $425,000 per eye, or $850,000 per treatment. VN works by delivering a functioning copy of the RPE65 gene to retinal cells. Within normal retinal function, the RPE65 gene encodes a key protein (RPE54) in the visual cycle. Biallelic mutation of the RPE65 gene thus leads to a deficiency of RPE54 protein and subsequent build-up of toxic precursors and damage to retinal cells and eventually complete blindness. Treatment with VN has been shown to significantly improve vision for patients with RPE65-associated IRD as demonstrated by improved performance during a multi-luminance mobility test (MLMT), in which patients are evaluated on their ability to navigate an obstacle course at varying light levels.17 Timing of treatment with VN has been a subject of debate. Improved efficacy in younger individuals with healthier retinal structure has been hypothesized, though the small patient population living with RPE54-associated IRD has made evaluation of this using an adequately-powered subgroup analysis challenging. Onasemnogene abeparvovec-xioi (Zolgensma). The second gene therapy approved by FDA in the United States, onasemnogene abeparvovec-xioi (OA) from AveXis, Inc. (a Novartis company) was approved in August 2019 and is indicated for the treatment of children less than 2 years of age with spinal muscular atrophy (SMA) with biallelic mutations in the survival motor neuron 1 (SMN1) gene.18,25 SMA occurs in about one in every 10,000 births.26 Similar to VN, OA is an AAV vector–based gene therapy (AAV9). OA is administered as a one-time intravenous infusion over approximately 60 minutes and has a WAC cost of $2,125,000 per treatment. VN works by delivering a functioning copy of the SMN1 gene to spinal motor neuron cells. Within normal motor neuron cell function, the SMN1 gene encodes a key protein called survival motor neuron (SMN), which is necessary for cell survival. Biallelic mutation of the SMN1 gene leads to a deficiency of SMN protein, leading to motor neuron death and subsequent muscle weakness and eventual disability or death due to respiratory failure in the most severe types of SMA.27 One of the keys to treatment with OA is for patients to receive treatment as soon as possible after diagnosis of SMA, or at least prior to showing signs of weakness due to the disease. Patients receiving OA prior to the development of symptoms of SMA have shown tremendous clinical results, with some children maintaining normal levels of physical function depending on their SMA type and when the treatment was administered.18 The clinical progression of patients with SMA is outlined by categorizing patients into one of 4 main SMA types, as described in Table 1.27,28 All patients with SMA have a mutation or deletion of SMN1, but disease severity is primarily driven by the presence or absence of a second gene (SMN2). SMN2 also codes for SMN protein, though less efficiently and less accurately than SMN1. Patients with a higher number of copies of SMN2 maintain a higher level of SMN production and subsequently experience a longer period of time before developing signs of weakness, though all patients with SMA eventually progress towards some level of disability. Table 1. Classification of Spinal Muscular Atrophy Type . Age of Disease Onset . No. SMN2 Copies . Prognosis and Development . 0 In utero 1 Respiratory insufficiency at birth; death within weeks of birth I (Werdnig-Hoffman disease) <6 months 2 Ventilation dependent early in life and death by 2 years of age II (Dubowitz syndrome) 6-18 months 3-4 Survival into adulthood; patients typically have ability to sit but never to walk III (Kugelberg-Welander disease) >18 months (early childhood to early adulthood) 3-4 Normal life span; ability to stand and walk lost over time IV >21 years (adulthood) 4-8 Normal life span; potential for loss of ability to stand and walk Type . Age of Disease Onset . No. SMN2 Copies . Prognosis and Development . 0 In utero 1 Respiratory insufficiency at birth; death within weeks of birth I (Werdnig-Hoffman disease) <6 months 2 Ventilation dependent early in life and death by 2 years of age II (Dubowitz syndrome) 6-18 months 3-4 Survival into adulthood; patients typically have ability to sit but never to walk III (Kugelberg-Welander disease) >18 months (early childhood to early adulthood) 3-4 Normal life span; ability to stand and walk lost over time IV >21 years (adulthood) 4-8 Normal life span; potential for loss of ability to stand and walk Abbreviation: SMN2, gene encoding survival of motor neuron 2 (protein). Open in new tab Table 1. Classification of Spinal Muscular Atrophy Type . Age of Disease Onset . No. SMN2 Copies . Prognosis and Development . 0 In utero 1 Respiratory insufficiency at birth; death within weeks of birth I (Werdnig-Hoffman disease) <6 months 2 Ventilation dependent early in life and death by 2 years of age II (Dubowitz syndrome) 6-18 months 3-4 Survival into adulthood; patients typically have ability to sit but never to walk III (Kugelberg-Welander disease) >18 months (early childhood to early adulthood) 3-4 Normal life span; ability to stand and walk lost over time IV >21 years (adulthood) 4-8 Normal life span; potential for loss of ability to stand and walk Type . Age of Disease Onset . No. SMN2 Copies . Prognosis and Development . 0 In utero 1 Respiratory insufficiency at birth; death within weeks of birth I (Werdnig-Hoffman disease) <6 months 2 Ventilation dependent early in life and death by 2 years of age II (Dubowitz syndrome) 6-18 months 3-4 Survival into adulthood; patients typically have ability to sit but never to walk III (Kugelberg-Welander disease) >18 months (early childhood to early adulthood) 3-4 Normal life span; ability to stand and walk lost over time IV >21 years (adulthood) 4-8 Normal life span; potential for loss of ability to stand and walk Abbreviation: SMN2, gene encoding survival of motor neuron 2 (protein). Open in new tab Cost, distribution, and payment models The unpreceded costs of these gene therapies have led to a high degree of scrutiny and attention. The Institute for Clinical and Economic Review (ICER) has performed evaluations of the effectiveness and value of both VN and OA.29,30 In the economic analysis of VN, ICER stated that VN would need to cost 75% to 82% less than the current WAC price of $850,000 per treatment to be cost-effective based on a cost-effectiveness threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY) gained.30 Additional consideration was given to societal benefits, such as lower caregiver burden and greater productivity, though the need for a cost reduction of between 50% and 57% was still demonstrated. To reach the same cost-effectiveness threshold per QALY gained, a value-based price benchmark for a single lifetime dose of OA was estimated at $1.1 million to $1.9 million.29 Based on this measure, the current WAC pricing of OA ($2,125,000) places the product cost slightly above the highest threshold, though this price differential may be offset by additional rebating and discounts paid by the manufacturer to payers. The respective manufacturers of VN and OA offer 2 distribution channels to get product to the administering provider—a traditional purchasing method (ie, buy-and-bill) or a model for acquisition through an external specialty pharmacy. The more traditional model includes purchase of the product by the administering entity and subsequent billing of the payer for costs associated with drug purchase, administration, and monitoring. Within the external specialty pharmacy distribution model, the product is billed to the payer by the specialty pharmacy and then delivered to a clinic or other healthcare setting for administration (commonly referred to as white-bagging). The administering entity then typically bills the payer for costs related to administration and/or monitoring when allowed to do so. Within either model, payer coverage for the gene therapy may fall under the medical benefit, pharmacy benefit, or both and may involve complex authorization processes. The extremely high upfront cost of these therapies present a new era in treatment coverage wherein the long-term return on investment in such treatments may never be directly realized by the insurance companies that pay for them due to the likelihood of insurance changes over the lifetime of any given patient. This new dynamic is evidenced by OA being used in patients less than 2 years of age but leading to benefit over the course of a patient’s lifetime. The sheer cost of these therapies can present financial challenges for health plans and employers attempting to pay for patients to receive them. Due to these challenges, a number of strategies have been introduced by insurance companies in an effort to address cost containment. These approaches include the mandated use of specialty pharmacies, site of care restrictions, value-based contracting strategies, and extended or unique payment terms. These models may appeal to payers due to reimbursement methodologies that are more predictable or favorable (eg, specialty pharmacy dispensing, site-of-care restrictions), opportunities for cost sharing if patients do not meet certain criteria after treatment (eg, value-based contracting), or improvement of their cash flow (extended payment terms). Challenges, opportunities, and recommendations for health systems Given the small patient populations and degree of subspecialization typically involved in the care of patients with retinal dystrophy and SMA, most specialist physicians and researchers with expertise in treating these conditions reside within academic institutions and large health systems. Research on the therapies used to treat these conditions is also generally conducted within these institutions. As of the time of writing of this article, a total of 10 treatment centers were listed to provide treatment as VN Ocular Gene Therapy Treatment Centers by Spark Therapeutics.31 All 10 site are within academic centers, integrated delivery networks, or health systems. The vast majority of SMA treatment centers documented by the Cure SMA patient advocacy group are also located within these types of settings.32 It is clear that health systems are, and will continue to be, a prominent care provider for patients receiving gene therapy. Previous health-system pharmacy–focused articles on gene therapy have focused on biosafety handling, environmental controls, and caregiver training.33,34 Along with these important considerations, additional reflection and planning around stakeholder engagement, procurement methods, risk tolerance, sites of care, financial navigation, and system nomenclature should be considered by health-system pharmacies when evaluating their role in the gene therapy marketplace. Stakeholder engagement. Given the likelihood that patients will receive care from physician experts within health systems, combined with the high cost of treatment and complexities associated with gene therapies, health-system pharmacy departments must proactively identify and engage with internal physician experts and other key stakeholders likely to be involved in gene therapy treatments. To be successful in this, health systems must also develop processes to proactively monitor the pharmaceutical pipeline and understand potential timelines for FDA action and product launch. A primary method for performing this monitoring has historically been the use of pharmacy and therapeutics committees, though the degree to which such committees proactively monitor pipeline products vs react to recent product approvals may vary between institutions. No matter the processes selected, responsibility for monitoring of the pipeline and proactive internal stakeholder engagement should be assigned. In addition to internal physician and disease group stakeholders, executive leaderships should be aware of existing products and processes, as well as pipeline products, to ensure health-system pharmacy departments can quickly react to FDA action. As part of gene therapy pipeline monitoring, direct engagement with pharmaceutical manufacturers is also vital to system preparation and readiness. Pharmaceutical manufacturers are increasingly turning to limited drug distribution networks in efforts to maintain control and gather insight into product use and the patient treatment experience. Given the cost of gene therapies, small treatment populations, and models used by companies with existing products, future gene therapies are also likely to see distribution restrictions. Such restrictions may be dependent on the pharmacy designation (eg, acute care, ambulatory, retail, specialty), and proactive manufacturer engagement will help health systems both advocate for a model that will work best for their patients and provide opportunity to prepare for successful service implementations upon product launch. Lastly, engagement with payers is key for successful gene therapy services within health systems. Pharmacy departments need to identify and engage with health system–level payer relations or managed care leaders. Payer stakeholders may be limited in their ability to share information regarding potential coverage policies or criteria prior to FDA action, but the identification of and engagement with key payer decision makers may help team members navigate payer processes more easily. This is especially important in the early stages of product launch, when specific coverage criteria, billing codes, and policies are unlikely to exist. Proactive engagement also allows pharmacy departments to share information on potential service models and capabilities and to influence policies to support appropriate use of these products. Additionally, physician experts may also have the opportunity to provide key information on how gene therapy treatments will fit into their practice. Product acquisition, risk tolerance, and site-of-care implications. For health systems, the strategies most often used by payers in an effort to control cost can present large barriers to providing care to patients. For example, mandated dispensing of product from an outside specialty pharmacy results in a lack of direct control and oversight by the integrated pharmacy team and may also conflict with policies related to the use of product obtained from pharmacies outside of the health system. Alternatively, given the cost of gene therapies, some health systems may choose to allow or prefer outside specialty pharmacy dispensing (when available) in order to avoid the risks of potential insurance denials or cash flow implications of having to purchase and bill for these products. As more gene therapies come to market, health systems’ executive leaderships must constantly consider their risk tolerance levels and the impact such choices may have on their ability to provide care for complex patients within an integrated model. Health systems should also determine their internal capabilities to handle the complexities of these therapies through their pharmacy programs, including an evaluation of specialty pharmacy capabilities across product types (eg, infusion, oral, injectable) and coverage types (eg, medical benefit or pharmacy benefit). Site-of-care restrictions, such as requiring administration by a healthcare provider in a nonhospital location, may lead to an inability to treat a patient if an appropriate site of care does not exist within the health system. Health systems must carefully consider the clinical characteristics of any gene therapy product and conduct a detailed evaluation of the expertise and environment required to safely administer the product. Financial clearance and purchasing. Whether or not a health system pursues acquisition internally or externally, special attention must be paid to processes involved in the financial clearance and purchasing of gene therapies. For health systems electing to handle gene therapy acquisition and payer billing internally, proactive and detailed preauthorization processes are necessary to minimize the risk of high-dollar rejections and ensure timely payment for services provided. The high financial burden may also be shared with patients and families that have benefit plans with deductibles or coinsurance. Therefore, resources are needed to understand and provide transparent billing and financial information to patients when treatment options are being discussed. Manufacturers with existing gene therapy products offer copayment assistance support programs, which may be used for commercially insured patients. Patients unable to access such programs may require navigational support to acquire grant or foundation assistance to avoid significant financial hardship. Since such services are often key components of specialty pharmacy practice, health systems with specialty pharmacy programs may increasingly see gene therapy cases referred to their teams in such scenarios. Since the dollar amount related to purchasing gene therapies may easily surpass institutional thresholds for capital purchases, health systems may need to create oversight systems or sign-off procedures at an executive level to obtain gene therapies or accept patient cases. Even if health systems elect to obtain gene therapies from external specialty pharmacies, consideration must be given to costs associated with product administration and risks associated with product storage, manipulation, and oversight. Given the potentially time-sensitive nature of gene therapy administration, any procedures should include clear expectations for timely stakeholder review and decision making and be developed in collaboration with the executive leadership of the health system. Product and unit nomenclature. Health-system pharmacy departments have seen many unique and challenging dosing units over the years, but the era of gene therapy presents new challenges. For example, patients receiving OA receive a dose of 1.1 x 1014 vector genomes per kilogram (vg/kg), meaning the actual dose of a 4-kg patient is 4.4 x 1014 vg. For VN, dosing is at a flat amount per eye of 1.5 x1011 vg. Challenges such as the dosing unit “vg” simply not existing in the lexicons of pharmacy systems or electronic medical records may be encountered. Additionally, limits on the number of digits available in claims or order processing systems related to either price or dose administered may be encountered. Further complicating things, pharmacies must pay special attention to weight standardization and billing units when building systems to support gene therapy administration. For example, dosing of OA has been weight standardized by the manufacturer. In the case of OA, a patient weighing between 5.1 and 5.5 kg (and those in other, similar weight ranges) receive a standardized dose and subsequent dose “kit” based on the upper limit of the weight range (in this example, 5.5 kg) instead of a dose specific to the patient’s exact weight. There are 22 standardized weight-range kits for OA, with each assigned a unique National Drug Code (NDC) and upper weight limit between 2.6 and 13.5 kg. Dose standardization and NDC assignment in this way allows for a consistent single price to be set per treatment, instead of variable pricing based on dose administered. Special care must be taken to ensure the proper number of units is accounted for, both for clinical documentation and for potential billing purposes. In summary, recommendations for health-system pharmacy services include the following: Actively monitor the gene therapy pipeline and engage with drug manufacturers in advance of potential FDA action. Proactively identify and engage key physicians and stakeholders within departments and specialties where gene therapies are likely to be utilized. Involve the pharmacy leadership in health system–level payer relations discussions relevant to gene therapy and high-cost pharmaceuticals. Discuss risk tolerance with executive leaders and review the implications of internal vs external product acquisition methods with them. Evaluate financial clearance processes and ensure that proactive authorization and integration points for patient financial assistance are established. Develop a core team to lead service exploration, implementation, and standardization, with representation from key physicians, service line administrators, the pharmacy leadership, and personnel involved in operations, formulary management, billing, payer relations, and financial clearance. Develop standardized processes for product acquisition or purchasing as well as high-risk case acceptance to expedite fulfillment of urgent gene therapy treatment needs. Review any existing policies related to product acquisition from outside pharmacies, and develop a clear message as to how this scenario is handled or escalated within your institution. Evaluate the existence and viability of non–hospital-based gene therapy administration locations, or develop strategies to combat payer restrictions based on site of care. Create standardized product nomenclature within clinical and financial documentation systems to facilitate proper ordering, documentation, and billing. Gene therapy pipeline The pipeline for gene therapies is growing rapidly, with at least 31 additional unique agents in phase 2 or later clinical trials according to data posted in the ClinicalTrials.gov database as of the time of writing. Like approved in vivo gene therapies, many of these investigational agents deliver missing genes to key cells using adenovirus or AAV vectors and target heritable diseases caused by clearly defined genetic mutations or deletions. Others employ ex vivo gene-altering techniques, primarily lentivirus alteration of autologous cell lines. A specific area of key interest may be found in the use of gene therapy treatments in hemophilia A and hemophilia B. As of the time of writing, a number of products were in late-stage development, including one product whose maker has filed a biologics license application (BLA) with FDA (Table 2).35-42 Since many hemophilia treatment centers exist within health systems, these gene therapies are likely to have significant impact on patient care and treatment decision making for many health systems. Additionally, given that the annual treatment cost for many patients with hemophilia can exceed $1 million with use of existing factor replacement therapies, these new gene therapies are likely to carry the largest drug costs seen to date. Table 2. Hemophilia Gene Therapies in Late-Stage Pipeline Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . Valoctocogene roxaparvovec Hemophilia A Intravenous In vivo AAV5 vector BioMarin BLA submitted December 23, 2019 SPK-8011 Hemophilia A Intravenous In vivo AAV vector Spark Therapeutics Phase 3 Etranacogene dezaparvovec Hemophilia B Intravenous In vivo AAV5 vector uniQure Phase 3 Fidanacogene elaparvovec Hemophilia B Intravenous In vivo AAV vector Spark Therapeutics and Pfizer Phase 3 FLT180a Hemophilia B Injectable In vivo AAVS3 vector Freeline Phase 3 Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . Valoctocogene roxaparvovec Hemophilia A Intravenous In vivo AAV5 vector BioMarin BLA submitted December 23, 2019 SPK-8011 Hemophilia A Intravenous In vivo AAV vector Spark Therapeutics Phase 3 Etranacogene dezaparvovec Hemophilia B Intravenous In vivo AAV5 vector uniQure Phase 3 Fidanacogene elaparvovec Hemophilia B Intravenous In vivo AAV vector Spark Therapeutics and Pfizer Phase 3 FLT180a Hemophilia B Injectable In vivo AAVS3 vector Freeline Phase 3 Abbreviations: AAV, adeno-associated virus; BLA, biologics license application. Open in new tab Table 2. Hemophilia Gene Therapies in Late-Stage Pipeline Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . Valoctocogene roxaparvovec Hemophilia A Intravenous In vivo AAV5 vector BioMarin BLA submitted December 23, 2019 SPK-8011 Hemophilia A Intravenous In vivo AAV vector Spark Therapeutics Phase 3 Etranacogene dezaparvovec Hemophilia B Intravenous In vivo AAV5 vector uniQure Phase 3 Fidanacogene elaparvovec Hemophilia B Intravenous In vivo AAV vector Spark Therapeutics and Pfizer Phase 3 FLT180a Hemophilia B Injectable In vivo AAVS3 vector Freeline Phase 3 Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . Valoctocogene roxaparvovec Hemophilia A Intravenous In vivo AAV5 vector BioMarin BLA submitted December 23, 2019 SPK-8011 Hemophilia A Intravenous In vivo AAV vector Spark Therapeutics Phase 3 Etranacogene dezaparvovec Hemophilia B Intravenous In vivo AAV5 vector uniQure Phase 3 Fidanacogene elaparvovec Hemophilia B Intravenous In vivo AAV vector Spark Therapeutics and Pfizer Phase 3 FLT180a Hemophilia B Injectable In vivo AAVS3 vector Freeline Phase 3 Abbreviations: AAV, adeno-associated virus; BLA, biologics license application. Open in new tab Gene therapies for variety of other rare diseases, such as β-thalassemia, cerebral adrenoleukodystrophy, and mucopolysaccharidosis type IIIA, are in late-stage development. Aside from those targeting rare diseases, gene therapies for ischemic heart disease and heart failure are also in late-stage clinical development. A summary of select gene therapy products in late-stage development is found in Table 3.43-58 Table 3. Select Additional Gene Therapy Products in Late-Stage Pipeline Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . LentiGlobin BB305 β-Thalassemia Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 Lenti-D Cerebral adrenoleukodystrophy (CALD) Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 LYS-SAF302 Mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) Intracranial In vivo AAVrh10 vector Lysogene and Sarepta Therapeutics Phase 3 Timrepigine emparvovec Choroideremia Intravitreal In vivo AAV2 vector Nightstar Therapeutics and Biogen Phase 3 OTL-101 Severe combined immunodeficiency due to deaminase deficiency (ADA-SCID) Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 OTL-103 Wiskott-Aldrich syndrome Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 EB-101 Recessive dystrophic epidermolysis bullosa Modified skin graft Ex vivo retrovirus altered Abeona Therapeutics Phase 3 Alferminogene tadenovec Ischemic heart disease Intracoronary In vivo adenovirus vector Angionetics and Huapont Phase 3 Nadofaragene firadenovec Bladder cancer Intravesical In vivo adenovirus vector FerGene and FKD Therapies Phase 3 RT-100 Congestive heart failure Intracoronary In vivo adenovirus vector Renova Therapeutics Phase 3 Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . LentiGlobin BB305 β-Thalassemia Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 Lenti-D Cerebral adrenoleukodystrophy (CALD) Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 LYS-SAF302 Mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) Intracranial In vivo AAVrh10 vector Lysogene and Sarepta Therapeutics Phase 3 Timrepigine emparvovec Choroideremia Intravitreal In vivo AAV2 vector Nightstar Therapeutics and Biogen Phase 3 OTL-101 Severe combined immunodeficiency due to deaminase deficiency (ADA-SCID) Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 OTL-103 Wiskott-Aldrich syndrome Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 EB-101 Recessive dystrophic epidermolysis bullosa Modified skin graft Ex vivo retrovirus altered Abeona Therapeutics Phase 3 Alferminogene tadenovec Ischemic heart disease Intracoronary In vivo adenovirus vector Angionetics and Huapont Phase 3 Nadofaragene firadenovec Bladder cancer Intravesical In vivo adenovirus vector FerGene and FKD Therapies Phase 3 RT-100 Congestive heart failure Intracoronary In vivo adenovirus vector Renova Therapeutics Phase 3 Open in new tab Table 3. Select Additional Gene Therapy Products in Late-Stage Pipeline Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . LentiGlobin BB305 β-Thalassemia Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 Lenti-D Cerebral adrenoleukodystrophy (CALD) Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 LYS-SAF302 Mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) Intracranial In vivo AAVrh10 vector Lysogene and Sarepta Therapeutics Phase 3 Timrepigine emparvovec Choroideremia Intravitreal In vivo AAV2 vector Nightstar Therapeutics and Biogen Phase 3 OTL-101 Severe combined immunodeficiency due to deaminase deficiency (ADA-SCID) Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 OTL-103 Wiskott-Aldrich syndrome Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 EB-101 Recessive dystrophic epidermolysis bullosa Modified skin graft Ex vivo retrovirus altered Abeona Therapeutics Phase 3 Alferminogene tadenovec Ischemic heart disease Intracoronary In vivo adenovirus vector Angionetics and Huapont Phase 3 Nadofaragene firadenovec Bladder cancer Intravesical In vivo adenovirus vector FerGene and FKD Therapies Phase 3 RT-100 Congestive heart failure Intracoronary In vivo adenovirus vector Renova Therapeutics Phase 3 Product . Disease Category . Route . Delivery Mechanism . Manufacturer . Development Stage . LentiGlobin BB305 β-Thalassemia Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 Lenti-D Cerebral adrenoleukodystrophy (CALD) Intravenous Ex vivo lentivirus altered cell therapy Bluebird Bio Phase 3 LYS-SAF302 Mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A) Intracranial In vivo AAVrh10 vector Lysogene and Sarepta Therapeutics Phase 3 Timrepigine emparvovec Choroideremia Intravitreal In vivo AAV2 vector Nightstar Therapeutics and Biogen Phase 3 OTL-101 Severe combined immunodeficiency due to deaminase deficiency (ADA-SCID) Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 OTL-103 Wiskott-Aldrich syndrome Injectable Ex vivo lentivirus altered cell therapy Orchard Therapeutics Phase 3 EB-101 Recessive dystrophic epidermolysis bullosa Modified skin graft Ex vivo retrovirus altered Abeona Therapeutics Phase 3 Alferminogene tadenovec Ischemic heart disease Intracoronary In vivo adenovirus vector Angionetics and Huapont Phase 3 Nadofaragene firadenovec Bladder cancer Intravesical In vivo adenovirus vector FerGene and FKD Therapies Phase 3 RT-100 Congestive heart failure Intracoronary In vivo adenovirus vector Renova Therapeutics Phase 3 Open in new tab Conclusion Recent advances in gene therapy have led to both remarkable clinical impact and noteworthy challenges related to treatment cost and complexity. Health-system pharmacists are ideally positioned to lead and support effective implementation, oversight, and quality improvement processes surrounding gene therapy treatments. As additional improvements in the specificity and tolerability of gene therapy vectors and delivery mechanisms are made, the applications of these novel treatment modalities will grow and their impact on health-system pharmacy practice will expand. There are opportunities for health systems to provide unique solutions to key challenges related to gene therapy treatments. The future of health-system pharmacy practice must include comprehensive gene therapy services and stakeholder engagement strategies to ensure patients have access to these life-changing treatments within environments that provide integrated and comprehensive care. Disclosures The author has declared no potential conflicts of interest. This article is part of a special AJHP theme issue on specialty pharmacy. 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TI - Decoding gene therapy: Current impact and future considerations for health-system and specialty pharmacy practice
JO - American Journal of Health-System Pharmacy
DO - 10.1093/ajhp/zxab064
DA - 2021-03-02
UR - https://www.deepdyve.com/lp/oxford-university-press/decoding-gene-therapy-current-impact-and-future-considerations-for-SS2Of5wN5d
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -