Gene Therapy: New Developments and Organizational Readiness for Pharmacists

The research and development pipeline for gene therapy products addresses a variety of indications. Voretigene neparvovec-rzyl was the first gene replacement therapy approved by FDA in December 2017 for the treatment of Leber congenital amaurosis (also known as RPE65 mutation-associated retinal dystrophy), an inherited retinal disease that causes blindness. Diseases for which gene therapy is under investigation include the following:

• Alzheimer’s disease
• Amyotrophic lateral sclerosis
• Cancers
• Cerebral adrenoleukodystrophy
• Crigler-Najjar syndrome
• Cystic fibrosis
• Glycogen storage diseases
• Hemophilias
• Huntington’s disease
• Infectious diseases
• Leber congenital amaurosis
• Mucopolysaccharidosis
• Muscular dystrophies
• Neuronal ceroid lipofuscinosis
• Parkinson’s disease
• Rett syndrome
• Severe combined immunodeficiency
• Sickle cell disease
• Spinal muscular atrophy
• X-linked myotubular myopathy

Many (but not all) gene therapies are designed to treat rare diseases with no other available treatment. Rare diseases are defined by the National Organization for Rare Disorders and in the Orphan Drug Act of 1983 as any disease that affects fewer than 200,000 people in the United States. Some diseases are so rare that clinical trials of gene therapies for these diseases enroll substantial percentages of the affected worldwide patient population. The majority of gene therapy clinical trials are conducted in the United States, although gene therapy is under investigation all over the world.

The FDA may rely on data from a single clinical trial for use as a pivotal trial to accelerate product approval. Surrogate endpoints may be used to evaluate outcomes, and studies of the natural history of the disease may be used instead of a placebo or the standard of care as a control.

Several breakthrough developments in gene therapy for hemophilia recently were announced. Hemophilia is a rare hereditary bleeding disorder caused by a recessive genetic mutation on the X chromosome that results in a deficiency or absence of clotting factor VIII (hemophilia A) or less commonly, clotting factor IX (hemophilia B). In the past, frequent administration of clotting factors was required to avoid bleeding episodes in patients with hemophilia. Restoration of clotting factor levels to normal or near-normal levels, dramatic reduction in bleeding episodes, and improved quality of life have been reported with some gene therapies. These therapies have curative potential after one-time administration, although the long-term durability of the response and safety remain to be evaluated.

The gene therapies involve the use of a viral vector to deliver the gene for clotting factor VIII or IX to the liver where clotting factor production occurs. Dozens of gene therapy products are in development for hemophilia, including valoctocogene roxaparvovec and SPK-8011 for hemophilia A and fidanacogene elaparvovec (formerly known as SPK-9001) and AMT-061 for hemophilia B.

More information

• Anon. Breakthroughs in gene therapy for hemophilia. ASH Clinical News. October 1, 2018. View Article Online (accessed 2019 May 1).
• High KA, George LA, Eyster ME et al. A phase 1/2 trial of investigational SPK-8011 in hemophilia A demonstrates durable expression and prevention of bleeds. Presented at the American Society of Hematology Annual Meeting. San Diego, CA: December 2, 2018. View Article Online (accessed 2019 May 1).

Although rare diseases are the focus of much gene therapy research, momentum is building in the development of gene therapies for more common diseases, such as Alzheimer’s disease and certain cancers. For example, the anti-CD19 chimeric antigen receptor (CAR)-T cell therapy products tisagenlecleucel and axicabtagene ciloleucel are approved by FDA for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Recent data suggest that the durability of response to these therapies is good. Lisocabtagene maraleucel is a third anti-CD19 CAR T-cell therapy under investigation for relapsed or refractory DLBCL.

B-cell maturation antigen, CD20, CB22, and CD123 are targets for other CAR T-cell products in development for treating B-cell malignancies.

More than 400 clinical trials of CAR T-cell products are under way worldwide. Evaluating the efficacy of combination therapies, identifying subsets of patients who are most likely to benefit from CAR T-cell treatment, and determining the optimal strategy for treating or preventing toxicities from these therapies are among the goals of current research.

Patient access to treatment and high costs are among the challenges in using CAR T-cell therapies, with implications for therapies developed for diseases that are not rare because of the potential impact on large numbers of patients. Nevertheless, these therapies have been in the news lately because they appear promising for patients with limited treatment options.

More information

• Abramson JS, Gordon LI, Palomba ML et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018; 36(15 suppl):abstract 7505. View Article Online (accessed 2019 May 1).
• Hitchcock S. Experts remark on CAR T-cell therapy at 1-year milestone, where it is headed. October 19, 2018. View Article Online (accessed 2019 May 1).

In 2016, FDA approved eteplirsen, the first gene-related therapy for Duchenne muscular dystrophy (DMD). This rare genetic disorder is caused by loss-of-function mutations in the gene that encodes dystrophin, a protein that functions primarily to strengthen muscle fibers. Eteplirsen is an antisense oligonucleotide gene therapy product that provided some benefit to a small percentage of DMD patients with specific genetic mutations.

A handful of adeno-associated virus gene replacement therapies for DMD are currently in human trials. Additionally, a new gene therapy using Clustered Regularly Interspaced Short Palindromic Repeats-Associated Protein 9 (known as CRISPR-Cas 9) to correct point mutations that cause DMD by inserting a gene encoding micro-dystrophin (a small form of dystrophin) into patient cells is in development. Results from preclinical use of this gene therapy in three patients with DMD appear promising. Most CRISPR-Cas9 research is still in the early phases, but many investigators see use of the technology as the potential future of gene therapy.

More information

• Offord C. Positive trial results for experimental DMD therapy. June 20, 2018. View Article Online (accessed 2019 May 1).

Onasemnogene abeparvovec-xioi (formerly known as AVXS-101) is a gene replacement therapy designed to treat the genetic root cause of spinal muscular atrophy (SMA) type 1, the leading genetic cause of infantile death. This investigational product is a one-time potentially curative gene replacement therapy. Nusinersen, an antisense oligonucleotide (i.e., regulator of gene expression), was the first treatment for SMA approved by FDA in December 2016.

A decision by FDA about approval for onasemnogene abeparvovec-xxxx is expected in late May 2019. Initial approval is sought for SMA type 1, the most common and severe form, but approval for types 2 and 3 may be pursued later based on findings from research in patients with these types.

More information

• Gingerich CP. STR1VE trial in SMA1 demonstrates positive interim results. MD Magazine. April 17, 2019. View Article Online (accessed 2019 May 1)
• Lopes JM. Zolgensma (AVXS-101) under priority FDA review as possible gene therapy for SMA type 1. SMA News Today. December 4, 2018. View Article Online (accessed 2019 May 1).

Institutional policies and procedures for handling gene therapy products vary widely in part because specific information about preventing occupational exposure to gene therapies is lacking. Guidelines for handling gene therapy in the laboratory setting originally developed by the National Institutes of Health (NIH) have been extrapolated to pharmacy practice. Guidelines on handling hazardous drugs from United States Pharmacopeia (USP) Chapter <800> and updated guidelines released by ASHP in December 2018 are relevant when planning strategies to handle gene therapy products, although it should be noted that USP Chapter <800> requires health systems to establish a list of hazardous drugs handled in the institution based on the National Institute for Occupational Safety and Health (NIOSH) list of antineoplastic and other hazardous drugs in healthcare settings, and to date no gene therapy products are on the NIOSH list. Requirements of the Environmental Protection Agency and Occupational Safety and Health Administration also should be taken into consideration.

Most gene therapies are stored and handled by the pharmacy department, although cellular gene therapies are managed by the cell lab or blood bank at some institutions. Gene therapy products are approved by FDA as biologics or drugs, and some products are subject to risk evaluation and mitigation strategy (REMS) requirements. Members of the pharmacy department are uniquely qualified to manage these products and ensure that REMS requirements are met.

Safe handling practices for gene therapy products, such as use of personal protective equipment (PPE), biological safety cabinets, other engineering controls, and certain work practices, depend on the risk for harm to personnel from exposure. The viral vectors used for cellular gene therapy are classified in one of four gene therapy risk groups based on their association with human disease, its seriousness, and whether interventions are available to prevent or treat disease caused by exposure.

Four biosafety levels with specific requirements for equipment, PPE, and work practices have been established by NIH and the Centers for Disease Control and Prevention (CDC) to protect workers, patients, and the environment from the harmful effects of gene therapy products. The biosafety levels are based on the agent used (i.e., risk posed by the product, such as the gene therapy risk group for viral vectors) and tasks performed. Biosafety level 1 is used for products with the lowest risk of harm, and level 4 is used for the highest risk products. The latter are seldom handled in health system pharmacies.

Product-specific data obtained from the manufacturer should be used for establishing policies and procedures for handling gene therapy products and managing accidental exposure. Some pharmacies err on the side of caution by using biosafety level 2 equipment and work practices for preparation of all gene therapy products, although some products with a low risk of harm can be safely handled using biosafety level 1 equipment and work practices.

If gene therapy products have not yet been used in your institution, the likelihood is high that they will be in the not too distant future because of the rapid pace of FDA product approvals. Efforts to improve organizational readiness should address the following aspects of gene therapy product handling:

• Receipt and storage
• Preparation
• Dispensing
• Disposal
• Decontamination of spills
• Accidental exposure

Health-system pharmacists should establish specific policies and procedures for the infrastructure, equipment, and work practices needed for each gene therapy product used in the institution. Standard operating procedures for product handling at each biosafety level should be drafted and maintained.

Training of pharmacists and pharmacy technicians who handle gene therapy products and documentation of this training should be provided. Personnel without this training should not handle gene therapy products. Training should be provided on an ongoing basis to incorporate new information. Education on proper gene therapy administration and handling of waste should be provided for other healthcare providers, patients, and caregivers.

Ideally, a pharmacist should be assigned the responsibility for managing gene therapy products. Many investigational gene therapies are not supply chain ready or integrated into the institutional medication-use process, especially the information technology (IT) system and electronic medical record. Collaboration among members of the pharmacy department, investigational drug service, and IT department is needed. In addition, early and frequent engagement with stakeholders is among the strategies used by health system pharmacists to manage the cost of gene therapies. An interprofessional approach can ensure the safe and appropriate use of gene therapies in the institution.

More information

• DeCederfelt HJ, Grimes GJ, Green L et al. Handling of gene-transfer products by the National Institutes of Health Clinical Center pharmacy department. Am J Health-Syst Pharm. 1997; 54:1604-10.
• Hematology/Oncology Pharmacy Association. HOPA investigational drug service best practice standards. 2014 (content last reviewed for accuracy and relevancy July 20, 2018). View Article (PDF) (accessed 2019 May 1).
• Power LA, Coyne JW. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2018; 75:1996-2031. http://www.ajhp.org/content/75/24/1996 (accessed 2019 May 1).
• The United States Pharmacopeial Convention. <800> hazardous drugs: handling in healthcare settings. In: USP compounding compendium. 2018:84-102.