Cell and Gene Therapies: A Giant Step Toward Curative Medicine?

By Jim Kesslick
MEDICAL WRITER

While it’s essential that your teams understand their product’s place in today’s marketplace, they must also be aware of cutting-edge therapy occurring on the forefront of medicine that could impact their business down the road. 

The emergence of cell and gene therapies (CGTs) provides a case in point. Today, CGTs appear primed to exert a major impact on medicine—and the biopharmaceutical industry.¹ Recent advances in our understanding of the human genome have converged with technological improvements in cellular manipulation, such as gene editing, to open the door for CGTs as a compelling remedy for certain previously incurable and life-threatening chronic disorders. As seen below (Table 1), there are fundamental differences between conventional therapies and CGTs in terms of mechanism of action, dosing, treatment goals, and the ability to tailor therapy to the needs of individual patients.

Table 1: Conventional Drugs vs Cell and Gene Therapies²

Traditional Drugs	Cell and Gene Therapies
Mechanism
Disrupts disease processes over short period	Changes DNA or RNA to counter a disease at the cellular level
Dosing
Several doses usually over long periods	Single administration often yields long-lasting or permanent therapeutic effect
Treatment goals
Treats symptoms of a disease	Corrects basic cellular cause of the disease
Personalized treatment
No: Same treatment approach for all	Yes: Specifically designed to treat each patient

Cell therapy and gene therapy are not identical, however. Although many aspects overlap, there are important distinctions:

• In gene therapy, faulty, disease-causing genes are replaced or silenced by modifying them inside or outside the patient’s body.³ 
• In cell therapy, potentially disease-fighting cells are removed from the patient or a donor, genetically altered to boost their therapeutic impact, and returned or transferred to the patient’s body to fight a disease more effectively.⁴

CGTs on the Rise

In recent years, the pace of CGT approvals by the FDA has quickened―9 have been approved thus far for a variety of diseases (Table 2) and almost 400 are in some stage of clinical development.^5-8 Thanks to this robust development pipeline, the FDA estimates that the number of yearly CGT approvals will increase to 20 within 4 years.⁹  

Table 2: FDA-approved CGTs 

Name Brand (generic)	FDA Approval Date	Indication	Manufacturer	Mechanism
Provenge (sipuleucel-T)	2010	Prostate cancer	Dendreon Pharmaceuticals	Patient’s immune cells are collected, altered to recognize prostate tumor cells, and returned to patient.
Laviv (azficel-T)	2011	Nasolabial fold wrinkles in adults	Fibrocell Technologies	Collagen-producing cells are harvested from the skin behind the ear, cultured, expanded, and injected to treat targeted skin areas.
Exondys 51 (eteplirsen)	2016	Duchenne muscular dystrophy	Sarepta Therapeutics	Blocks the portion of a gene that inhibits dystrophin production, allowing resumption of the protein missing in this disease.
Spinraza (nusinersen)	2016	Spinal muscular atrophy (SMA)	Biogen	Causes a genetic change that permits production of normal survival motor neuron protein missing in patients with SMA.
Luxturna (voretigene neparvovec-rzyl)	2017	Retinal dystrophy	Spark Therapeutics	Delivers a normal copy of the gene encoding for a human retinal pigment missing in patients with retinal dystrophy.
Yescarta (axicabtagene ciloleucel)	2017	B-cell lymphoma	Kite Pharma, a Gilead company	CAR-T immunotherapy: Patient’s T cells are harvested and reprogrammed to target proteins on lymphoma cells.
Kymriah (tisagenlecleucel)	2018	Leukemia	Novartis Pharmaceuticals	CAR-T immunotherapy: Patient’s T cells are harvested and reprogrammed to target proteins on lymphoma cells.
Zolgensma (onasemnogene abeparvovec-xioi)	2019	Spinal muscular atrophy	AveXis, a Novartis company	Gene therapy designed to deliver a copy of the gene encoding the human SMN protein, missing in patients with spinal muscular atrophy.
Tecartus (brexucabtagene autoleucel)	2020	Mantle cell lymphoma	Kite Pharma, a Gilead company	CAR-T immunotherapy: Patient’s T cells are harvested and reprogrammed to target proteins on lymphoma cells.

The Promise of Personalized Medicine

CGTs should be considered a possible game-changer for the treatment of some potentially fatal chronic diseases, including cancer. Historically, cancer therapy comprised the standard triad of surgery, chemotherapy, and radiation. Recently, however, a cellular immunotherapy dubbed CAR-T—for chimeric antigen receptor T cell—has garnered considerable attention as “cancer’s newest miracle cure” because of its remarkable efficacy in treating certain blood cancers.¹⁰ Due to its potentially transformative impact, CAR-T therapy was named the 2018 Advance of the Year in cancer treatment by the American Society of Clinical Oncology.¹¹ 

CAR-T development involves a series of complex steps in which the patient’s own T cells—one of the most important and effective white blood cell types in the immune system—are extracted, genetically redesigned to attack specific proteins on the surface of certain blood cancer cells, expanded, and then returned in a reinvigorated state to the patient.¹² CAR-T therapies can yield long-term—even lifelong—benefits after a single administration.¹³ Three CAR-T therapies have been approved by the FDA thus far—Yescarta, Kymriah, and, most recently, Tecartus (Table 2). 

Challenges of CGTs

There are some factors that could interfere with large-scale adoption, despite CGTs’ impressive therapeutic—even curative—potential.¹

• Distribution

For CGTs, manufacturers not only need to focus on efficacy and safety, just as they do for traditional drugs, but also on ensuring their customized and fragile products do not degrade during distribution. CGTs are a form of personalized “living medicine” that require precise and careful manufacturing, tracking, and delivery.¹ As a result, CGT manufacturers must be engaged in the entire complex and expensive distribution process from manufacturing to patient delivery to ensure consistent quality and efficacy.  

• Cost

CGTs come with a high price tag—even by today’s standards. The upfront cost of CAR-T therapy, for instance, is approximately $400,000 for each treatment. This cost does not include the management and treatment of serious side effects that may lead to hospitalization. With those factored in, actual treatment costs can exceed $1 million per patient.¹¹ Moreover, for the gene therapy Zolgensma, which targets spinal muscular atrophy in young children, Novartis pegged the price at $2.1 million—making it the most expensive drug on the market at over 30 times the national per capita income.¹⁴

Payers are not rushing to cover CGT costs either. Though CAR-T therapy is covered by most commercial insurers on an individual basis, Medicaid and Medicare coverage may be more problematic. Some Medicaid programs deny coverage for CAR-T therapy categorically, and Medicare coverage for inpatient administration is still evolving. Currently, Medicare covers 65% of the cost of CAR-T therapies, leaving hospitals and patients responsible for a substantial 35% of the cost.¹

• Side effects

Similar to traditional drug therapies, CGTs are not free of side effects. CAR-T therapy, for example, can trigger serious side effects such as cytokine release syndrome, or CRS.¹² In CRS, the massive infusion of CAR-T cells, which is part of a normal therapeutic regimen, results in a sudden, prolonged elevation in inflammatory cells called cytokines resulting in fever, malaise, fatigue, muscle aches, seizures, and potentially fatal cardiac disturbances and organ failure.¹⁵ Moreover, the available CAR-T therapies don’t focus exclusively on malignant cells—their intended target. Instead, they have off-target effects that can deplete normal immune system cells, increasing a patient’s risk for infections.¹²

Takeaways

CGTs have produced stunning and sometimes lifesaving results in select patient groups. They deserve recognition as a breakthrough paradigm for some cancers and diseases caused by identifiable and discrete genetic abnormalities. But key questions remain unanswered:

• Who are the most appropriate patients for this therapy? 
• What side effects might limit use?
• How might cost impact patient and insurance provider acceptance?

Moving forward, CGT manufacturers’ current enthusiasm may be tempered by the challenges related to manufacturing and distribution, reimbursement, and the potential for serious side effects. Even so, it’s clear that sales and marketing teams should stay abreast of this potentially transformational paradigm shift in medicine and how emerging CGTs may impact their markets.

References

1. Mooraj H, Gupta L, Kawalekar O, Shah S. Cell and gene therapies. Delivering scientific innovation requires operating model innovation. Deloitte Insights. April 17, 2020. Accessed December 11, 2020. https://www2.deloitte.com/us/en/insights/industry/life-sciences/operating-models-for-gene-cell-therapy-manufacturing-process.html
2. Novartis. A new era of medicine. Accessed December 11, 2020. https://www.novartis.com/our-focus/cell-and-gene-therapy/new-era-medicine
3. US Food and Drug Administration. What is gene therapy? How does it work? Updated December 22, 2017. Accessed December 11, 2020. https://www.fda.gov/consumers/consumer-updates/what-gene-therapy-how-does-it-work
4. American Society of Gene + Cell Therapy. Gene and cell therapy FAQ’s. Accessed December 11, 2020.  https://www.asgct.org/education/more-resources/gene-and-cell-therapy-faqs
5. US Food and Drug Administration. Approved cellular and gene therapy products. Updated July 24, 2020. Accessed December 11, 2020. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
6. US Food and Drug Administration. Exondys 51 (eteplirsen). Package insert. Sarepta Therapeutics, Inc.; 2016. Accessed January 2, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf
7. US Food and Drug Administration. Spinraza (nusinersen). Package insert. Biogen; 2016. Accessed January 5, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209531lbl.pdf
8. Powaleny A. Nearly 400 cell and gene therapies in development to target a broad range of diseases. Pharma. The Catalyst. March 10, 2020. Accessed December 11, 2020. https://catalyst.phrma.org/nearly-400-cell-and-gene-therapies-in-development-to-target-a-broad-range-of-diseases
9. Srivastava S. How cell and gene therapy is transforming healthcare. Cell & Gene. February 4, 2020. Accessed December 11, 2020. https://www.cellandgene.com/doc/how-cell-and-gene-therapy-is-transforming-healthcare-0001
10. Park A. Cancer’s newest medical cure. Time. August 10, 2017. Accessed December 11, 2020. http://time.com/4895010/cancers-newest-miracle-cure/
11. Andrews M. Staggering prices slow insurers’ coverage of CAR-T cancer therapy. The Philadelphia Inquirer. July 17, 2018. Accessed on December 11, 2020. http://www.philly.com/philly/health/staggering-prices-slow-insurers-coverage-of-car-t-cancer-therapy-20180717.html
12. National Cancer Institute. CAR T cells: engineering patients’ immune cells to treat their cancers. Updated July 30, 2019. Accessed January 4, 2021. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
13. Cancer Treatment Centers of America. Five things you should know about CAR T-cell therapy. March 20, 2018. Accessed December 11, 2020. https://www.cancercenter.com/community/blog/2018/03/five-things-you-should-know-about-car-t-cell-therapy
14. Love J. Why didn’t nonprofits and the NIH require ‘reasonable’ pricing for Zolgensma? That may happen in France. STAT. September 18, 2019. Accessed November 11, 2020. https://www.statnews.com/2019/09/18/zolgensma-reasonable-pricing-france/
15. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011. doi:10.1038/mto.2016.11 

Jim Kesslick has a master’s degree in experimental psychology with an emphasis on neurophysiology. His medical writing career includes 10 years at Johnson & Johnson and 16 years as a freelancer. Jim’s experience spans numerous therapeutic specialties and projects, including journal articles, monographs, abstracts, scripts, dossiers, sales trainings, and patient education materials. As a medical writer for Encompass, Jim has developed numerous high-quality sales training modules and video scripts.