Andy Szczotka, PharmD- Chief Pharmacy Officer, AscellaHealth
For the estimated 25-30 million Americans1 and 400 million people worldwide2 living with a rare disease, news of potential new gene therapies is a powerful message that resonates personally among individuals and families. Approximately 80% of rare diseases are caused by a single-gene defect in a person’s genes,3 and unfortunately, rare diseases often are difficult to diagnose, with few or no treatment options available. In fact, it is estimated that 95% of rare diseases do not yet have a single FDA-approved treatment.3 and rare diseases impact more people than cancer and AIDS combined.3
According to the U.S. Food & Drug Administration (FDA), gene therapy is a technique4 that modifies a person’s genes to treat or cure disease. Gene therapy (GT) is the process of replacing defective genes with healthy ones, adding new genes to help the body fight or treat disease, or turn off genes that are causing problems.
Gene therapies use a target gene that expresses protein products at a sufficient level to cure, or at least ameliorate, a disease caused by a genetic defect. This involves the transfer of genetic material, usually in a carrier or vector, and the uptake of the gene into the appropriate cells of the body. Cell therapy also has the potential to treat the inherent cause of both genetic and acquired diseases but involves the transfer of cells with the relevant function into the patient.
Both approaches have the potential to alleviate the underlying causes5 by replacing the missing protein(s) or cells causing the disease symptoms, suppressing expression of proteins which are toxic to cells, or eliminating cancerous cells. Many different types of cells6 may be used as part of a therapy or treatment for a variety of diseases and conditions, including hematopoietic (blood-forming) stem cells (HSC), skeletal muscle stem cells, mesenchymal stem cells, lymphocytes, dendritic cells, and pancreatic islet cells.
As of this writing, below is a list of licensed products from the Office of Tissues and Advanced Therapies (OTAT), alphabetical by brand name and uses:7
ABECMA (idecabtagene vicleucel)
Multiple Myeloma
ALLOCORD (HPC, Cord Blood)
SSM Cardinal Glennon Children’s Medical Center
BREYANZI
B-cell lymphoma
CARVYKTI (ciltacabtagene autoleucel)
Janssen Biotech, Inc.
CLEVECORD (HPC Cord Blood)
Disorders affecting the hematopoietic system
Ducord, HPC Cord Blood
Disorders affecting the hematopoietic system
GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen)
Treatment of mucogingival condition
HEMACORD (HPC, cord blood)
Disorders affecting the hematopoietic system
HPC, Cord Blood
Disorders affecting the hematopoietic system
HPC, Cord Blood - MD Anderson Cord Blood Bank
Disorders affecting the hematopoietic system
HPC, Cord Blood - LifeSouth
Disorders affecting the hematopoietic system
HPC, Cord Blood - Bloodworks
Disorders affecting the hematopoietic system
IMLYGIC (talimogene laherparepvec)
Melanoma
KYMRIAH (tisagenlecleucel)
Acute Lymphoblastic Leukemia & B cell lymphoma
LAVIV (Azficel-T)
Nasolabial fold wrinkles
LUXTURNA
Retinal dystrophy
MACI (Autologous Cultured Chondrocytes on a Porcine Collagen Membrane)
Autologous Cultured Chondrocytes on a Porcine Collagen Membrane PROVENGE (sipuleucel-T)
Prostate Cancer
RETHYMIC
Congenital athymia
SKYSONA (elivaldogene autotemcel)
Active cerebral adrenoleukodystrophy (CALD).
STRATAGRAFT
Allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen
TECARTUS (brexucabtagene autoleucel)
Acute Lymphoblastic Leukemia & Mantle Cell Lymphoma
YESCARTA (axicabtagene ciloleucel)
Follicular Lymphoma & B cell lymphoma
ZYNTEGLO (betibeglogene autotemcel)
ß-thalassemia
ZOLGENSMA (onasemnogene abeparvovec-xioi)
Spinal Muscular Atrophy
A Lexicon for Main Types of Gene Therapy Products
Viral Vectors is the term that the FDA uses when referring to viruses that are modified to remove their ability to cause infectious disease. Viruses have a natural ability to deliver genetic material into cells, and therefore some gene therapy products are derived from viruses.8 These modified viruses can be used as vectors (vehicles) to carry therapeutic genes into human cells (Figure 1).
Patient-derived cellular gene therapies refer to products where cells are removed from the patient, genetically modified (often using a viral vector) and then returned to the patient.6
Plasmid DNA describes circular DNA molecules that can be genetically engineered to carry the good therapeutic genes into human cells.
Bacteria can be modified to prevent them from causing infectious disease and then used as vectors (vehicles) to carry therapeutic genes into human tissues.
Human gene editing technology maintains a goal to disrupt harmful genes or to repair mutated genes.6
Two Categories of Gene Therapies
There are two main ways to deliver gene therapy: ex vivo and in vivo methods. The in vivo gene therapy approach as illustrated above (Figure 2) means that therapy is administered directly to the patient and the targeted cells remain in the body of the patient.4 This methodology involves use of a gene inserted into a viral envelope, often an adeno-associated virus (AAV). The gene-carrying virus is prepared in a laboratory and delivered to the target organ either by an injection or a simple infusion, where it is taken up by cells in target organs. While it is not integrated into the chromosome, it does appear to have a sturdy and long-lasting response, especially in slowly replicating cells like retinal cells, or neurons. Luxturna and Zolgensma are examples of in vivo gene therapies.
With the ex vivo approach, the targeted cells are removed from the patient and gene therapy is administered to the cells in vitro before they are returned to the patient’s body. Target cells containing the faulty or missing genes are extracted from the patient in a clinical setting, such as the hospital, and the cells are re-engineered in the laboratory to integrate a new or functional gene into the chromosome.
The reprogrammed cells are then infused into the patient and the new gene is distributed through the patient’s system as these cells multiply.
Examples of the ex vivo approach are chimeric antigen receptor T-cell (CAR-T) therapies such as Abecma (idecabtagene vicleucel), Breyanzi (lisocabtagene maraleucel), Kymriah (tisagenlecleucel), Tecartus (brexucabtagene autoleucel) and Yescarta (axicabtagene ciloleucel).
Gene Therapy Issues, Challenges and Concerns
Gene and cell therapies are prime examples of hyper-innovation that is needed and will benefit people with rare diseases who have been sidelined for too long with little to no treatment options. In fact, many rare disease patients use drugs off -label based on limited data because they have no better options available (Figure 3). While these therapies offer hope and represent a revolutionary step forward in the potential treatment of many previously incurable diseases, they present huge affordability challenges and carry very exorbitant up-front costs with no cost-minimization, elimination guarantees or impact on quality of life. Multi-million dollar price tags are becoming more common, as the FDA recently approved Skysona9 for a rare neurological disorder called cerebral adrenoleukodystrophy at a list price of $3 million.
Another concern is the longevity of response to the product, since it may be too early to tell how long the effects of the treatments will last: restored vision, disease remission or other may endure for a lifetime versus a specific time period. This is particularly problematic since there is currently minimal patient follow-up data to know whether these products will be cures or if the disease may return.
Adverse reactions are also a major issue, as serious adverse events10 (AEs) associated with these therapies are garnering more attention and the mitigation of these AEs represent an unmet need in this emerging field.11 This points to the need for recommendations regarding the design of long term follow-up studies12 for the collection of data on delayed adverse events following administration of a GT product.
Furthermore, many clinical trials have been put on hold to evaluate adverse reactions amid troublesome reports13 regarding the disadvantages to using the Adenovirus, the most commonly used vector in gene therapy clinical trials. Risks include non-integration, immunogenicity, replication competence, no targeting, and small insert size.
Other key areas of concern that include:
- Hepatotoxicity: liver damage
- Neurotoxicity: toxic substances alter normal activity of the nervous system.
- Various types of cancer including acute myeloid leukemia, often based upon animal models with tumor development.
- Autoimmune response: body attacks and damages its own tissues.
- Use in immunocompromised patients and viral load concerns: can mean the person is more infectious, such as breakthrough infections of COVID-19.
Specialty Pharmacy Optimizes Management of Gene therapies
The evolving, critical role of Specialty Pharmacy (SP) in the management of gene therapies cannot be understated. Ideally, they maintain direct relationships with product manufacturers and offer end-to-end solutions to facilitate payment reimbursement, support processes and implement ‘white glove’ services with a high-touch patient-centered model that is focused on patient outcomes. SPs that offer a full range of programs and services across the product lifecycle, from pre-commercialization and market access, distribution, fulfilment, and Hub services to compliance and monitoring for enhanced patient outcomes, are best positioned to fulfill manufacturer expectations for optimized product adoption, increased patient engagement and better outcomes as well as streamlined communications between prescriber, patient and pharmacy that decrease time to fill.
By employing a consultative approach to seamless new product launches that provide early insights into market conditions, as well as experienced teams to negotiate with payers, SPs ensure streamlined access to therapies and advantageous pricing. Progressive SPs are pioneering innovative technology-based suites of unique financial solutions, including loan-based programs for cell/gene therapies to help off set the high cost of curative medications and copay advisory services to monitor and track manufacturer copay funds, ensuring that allotted funds are utilized to help off set costs of expensive therapies for patients. This also includes alternative funding programs which means of access to philanthropic organizations, grants or other foundational programs that support access to high-cost therapies and shift the cost away from the patient and payer.
Utilization Management Approaches to Lower the Cost of Care
SPs apply programs such as step care therapy, quantity limits, partial fill programs and other initiatives to control costs. The development of criteria for prior authorization, for example, ensures appropriate use and enhances opportunity for positive outcomes. Typically, criteria is based upon clinical study inclusion and exclusion criteria, interpretation of clinical study endpoints, national guidelines and CMS/Medicare policies. Additional use of benefit maximum and deductible programs and application of rebate management programs impact the cost of care. Finally, by identifying alternative Site of Care programs, SPs can direct patients to lower cost sites of quality care that can provide cost savings to the patient and payer while making it more convenient for patients, caregivers and support team members to access care.
Cell and gene therapies are at the forefront of innovation and transforming how we treat certain diseases. Over the next few years, more than 50 new in vivo and ex vivo gene-therapy launches are already planned.14 As the urgent need for research continues, with pharmaceutical companies continuing to map the genes responsible for rare diseases and develop gene and cell therapies, these manufacturers will want to identify and collaborate with the SP community for optimal product market access.
Manufacturers and other companies developing these therapies will play an instrumental role in working closely with the complex network of industry stakeholders to advance these therapies and ensure they are reaching those in need, which is the most progressive approach for clinical development and patient care. It is anticipated that these therapies will effectively address the struggles of millions of people and their families in the journey towards better health.
References
- National Organization for Rare Diseases; Rare Disease Day: Frequently Asked Questions, 2022; Available at https://rarediseases.org/wp-content/uploads/2019/01/RDD-FAQ-2019. pdf; Accessed September 27, 2022.
- International Federation of Pharmaceutical Manufacturers and Associations; Tackling Global Health Challenges: Rare Diseases; Available at https://www.ifpma.org/subtopics/ rare-diseases/#:~:text=It%20is%20estimated%20that%20one,to%20400%20 million%20people%20worldwide; Accessed September 27, 2022.
- The Global Genes Project. RARE Diseases: Facts and Statistics. Available at Accessed September 28, 2022. https://globalgenes.org/rare-disease-facts/
- U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Long Term Follow-Up After Administration of Human Gene Therapy Products, Guidance for Industry. Available at https://www.fda.gov/ media/113768/downloadJanuary 2020. Accessed September 27, 2022.
- American Society for Gene and Cell Therapy. Gene and Cell Therapy FAQs. Available at https:// asgct.org/education/more-resources/gene-and-cell-therapy-faqs#:~:text=In%20 vivo%20gene%20therapy%20means,returned%20to%20the%20patient’s%20body. Accessed September 27, 2022.
- Association for the Advancement of Blood and Biotherapies. Facts About Cellular Therapies. Available at https://www.aabb.org/news-resources/resources/cellular-therapies/facts[1]about-cellular-therapies. Accessed September 27, 2022.
- Food & Drug Administration; Approved Cellular and Gene Therapy Products. Available at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved[1]cellular-and-gene-therapy-products. Accessed September 27, 2022.
- Food & Drug Administration; What is Gene Therapy? Available at https://www.fda.gov/ vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy. Accessed September 27, 2022.
- Fierce Pharma. A $3million dollar gene therapy. Available at https://www.fiercepharma. com/pharma/3m-gene-therapy-bluebird-breaks-own-record-fda-approval-skysona. Accessed September 27, 2022.
- CGT Live. Gene Therapy for Diabetic Macular Edema Halted Following Serious Adverse Reaction. Available at https://www.cgtlive.com/view/gene-therapy-diabetic-macular[1]edema-halted-following-serious-adverse-reaction Accessed September 27, 2022.
- CGT Live. Addressing Adverse Events in Gene Therapy. Available at https://www.cgtlive. com/view/addressing-adverse-events-in-gene-therapy. Accessed September 27, 2022.
- Food & Drug Administration. Long Term Follow-Up After Administration of Human Gene Therapy Products. Available at https://www.fda.gov/media/113768/download. Accessed September 27, 2022.
- Carrier, A. L. Risk-Benefit Analysis of the use of Viral Vectors in Gene Therapy. Available at https://www.emich.edu/chhs/health-sciences/programs/clinical-research-administration/ documents/theses/viral-vectors-in-gene-therapy.pdf. Accessed September 27, 2022.
- McKinsey & Company. How Could Gene Therapy Change Healthcare in the Next 10 years? Available at https://www.mckinsey.com/industries/life-sciences/our-insights/how[1]could-gene-therapy-change-healthcare-in-the-next-ten-years
About the Author
Andy Szczotka is the Chief Pharmacy Officer for AscellaHealth. In this capacity, he is responsible for the development, oversight and operation of clinical specialty and medical drug services for clients, including self-insured employer groups, TPAs, PBMs, Medicare and consumer-oriented markets. He provides development for programs and services to support drug formulary services, utilization management programs, national P&T Committees and cost management programs while enhancing patient outcomes. Andy supports new business development and new client acquisitions and implementation, including expansion into new service offerings.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special
offers from American Pharmaceutical Review delivered to your inbox!
Sign up now!