Gene therapies: Up and coming ... and expensive

Issue: July 2019

ByEdward A. Bell, PharmD, BCPS

The treatment of serious medical diseases affecting the pediatric population has seen significant advancements in recent years, with several gene therapies newly labeled for use in infants and children. Although these therapies offer tremendous hope to patients, their families and health care professionals, their availability brings many unanswered questions, including long-term clinical efficacy and concerns over reimbursement.

Definition and mechanistic description

The FDA classifies gene therapy not as a drug but as a “biologic product.” According to the FDA, human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. Human gene therapy products are defined as “all products that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host [human] genome.” Gene therapy products vary in chemical or mechanistic actions, including the use of in vivo viral vectors to introduce a normal gene to a patient with a specific abnormal gene defect disorder, or the use and instillation of ex vivo genetically modified human cells. Thus, gene therapy can be applied both inside and outside the human body.

The mechanisms of action of gene therapies are complex. Certainly, the talent and work of researchers and manufacturers developing them are deserving of respect and admiration. Gene therapy research is rapidly advancing, with the FDA reporting more than 700 active investigational new drug applications, most of which are intended for the treatment of rare diseases — or those that affect less than 200,000 people. Most rare diseases result from a single gene abnormality, and approximately 50% affect children. Multiple cellular and gene therapy products are now labeled for use by the FDA and are commercially available (see Table). Several of these products have efficacy and safety data in the pediatric population and are FDA labeled for use in children. Although Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics) and Zolgensma (onasemnogene abeparvovec-xioi, AveXis) are newly approved for use in children (2017 and 2019, respectively), gene therapy clinical research and evaluation is not new. The first human gene therapy trial was conducted nearly 30 years ago and included children with adenosine deaminase deficiency. Unfortunately, there were significant efficacy and safety setbacks in some trials. Yet, there has been progress as the technology has advanced over recent years, resulting in newly available therapies.

Luxturna

Luxturna is the first gene therapy product approved for the treatment of a genetic disorder (mutations in the RPE65 gene). It is labeled to treat retinal dystrophy, and as an adeno-associated virus vector-based gene therapy product, Luxturna inserts a copy of the gene encoding for the human retinal pigment epithelial 65 kDa protein (RPE65) into retinal cells. Luxturna’s package insert (PI) contains efficacy and safety data for children aged 4 years and older. The treatment is injected into the subretinal space in a surgical environment. The PI cites data showing visual improvements in study participants up to 1 year after treatment. Lay media reports of the cost of Luxturna are approximately $425,000 per eye. According to their website, Spark Therapeutics is developing contracting reimbursement models that pharmacy benefit management companies and CMS can participate in, such as an outcome-based rebate program linking payments to short-term efficacy and long-term durability measures.

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Zolgensma

Zolgensma is also an adeno-associated virus vector-based gene therapy product labeled for use in the pediatric population. It is indicated for use in children aged younger than 2 years with spinal muscular atrophy (SMA), resulting from mutations in the survival motor neuron 1 (SMN1) gene. Zolgensma is administered as a single IV infusion dose, and it inserts a copy of the gene encoding for the SMN1 protein. The efficacy of Zolgensma, described in its PI, was established on the basis of patients’ survival (defined as the time from birth to either permanent ventilation or death), the achievement of developmental motor milestones — such as sitting without support — as well as assessments of ventilator use, nutritional support and clinical scores. Lay media reports of the cost of Zolgensma are approximately $2 million.

AveXis has plans to create 5-year outcome-based agreements and a pay-over-time option as the company works with payers. The annualized cost of Zolgensma is $425,000 per year for 5 years, and according to information supplied by AveXis, this is less than 50% of the value-based pricing benchmarks for long-term SMA therapy.

Unknowns and concerns

Although the gene therapies described earlier provide advanced treatment options and hope to children with rare genetic disorders, their availability and use raises unique questions and concerns. For example, who will pay for these very expensive therapies? The manufacturers of Luxturna and Zolgensma provide patient support services for families to assist with insurance and reimbursement concerns. The cost of developing gene therapies for rare disorders is partially offset by financial incentives provided by the FDA for research and development, including reduced license fees and increased market exclusivity. Additional considerations include the willingness of payers to provide reimbursement for uncommon disorder therapies, the risk of paying for unique and new therapies without proven long-term benefits, and very high initial costs for just one treatment (as compared with more conventional long-term therapies). Thus, risk sharing between the payer and manufacturer becomes increasingly important to consider. The published literature describes different payment methods for new and expensive gene therapies, including annuity-style payments or “pay-for-performance.” Additionally, from a regulatory perspective, issues pertaining to the development, review, approval and manufacturing of new gene therapies must be addressed, and in 2018, the FDA provided a new framework for doing so. Although gene therapies offer great hope, many questions remain.

References:
Carr DR, et al. Regen Med. 2016;doi:10.2217/rme-2016-0010.
Colins FS, et al. N Engl J Med. 2019;doi:10.1056/NEJMc1815776.
FDA. Approved cellular and gene therapy products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed June 24, 2019.
FDA. Guidance for Industry Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. https://www.fda.gov/media/72225/download. Accessed June 24, 2019.
FDA. Statement from FDA Commissioner Scott Gottlieb, M.D. on agency’s efforts to advance development of gene therapies. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-efforts-advance-development-gene-therapies. Accessed June 24, 2019.
Luxturna [package insert]. Philadelphia, PA: Spark Therapeutics, Inc.; 2017.
Spark Therapeutics. Spark Therapeutics Announces First-of-their-kind Programs to Improve Patient Access to LUXTURNA(voretigene neparvovec-rzyl), a One-time Gene Therapy Treatment. https://sparktx.com/press_releases/spark-therapeutics-announces-first-of-their-kind-programs-to-improve-patient-access-to-luxturna-voretigene-neparvovec-rzyl-a-one-time-gene-therapy-treatment/. Accessed June 24, 2019.
Zolgensma [package insert]. Bannockburn, IL: AveXis, Inc.; 2019.

For more information:
Edward A. Bell, PharmD, BCPS, is a professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.

Disclosure: Bell reports no relevant financial disclosures.