A Look at Gene Therapies in Development

Gene therapy involves the administration of genetic material to modify or manipulate the expression of genes or alter the biological properties of living cells. This treatment can be used to introduce a new or modified gene to treat a disease, replace a disease-causing gene with a healthy copy, or inactivate disease-causing aberrant genes. The treatment can be done by inserting a new copy of gene into target cells or modification of part of a gene to remove repeated or defective elements. Nicole Trask, PharmD, a clinical consultant pharmacist at the University of Massachusetts Clinical Pharmacy Services, discussed the latest on this topic.

Dr. Trask first discussed the methods of gene transfer. Non-viral vectors are referred to as transfection, and are an inefficient method of gene transfer, but are generally considered safer than viral vectors, which are referred to as transduction and are the most common method used in approximately 70% of clinical trials. Viral vectors are an efficient gene transfer in vivo, but there are significant safety concerns.

The concept of gene therapy dates back to the 1960s, she said, with the first clinical study in humans published in 1990: In five patients, a retroviral vector was used to transfer neomycin resistance marker gene into tumor-infiltrating lymphocytes for the treatment of metastatic melanoma. The lymphocytes were expanded and reinfused.

The slow clinical progression is largely due to safety concerns and vector inefficiencies, she said, as well as several challenges. First, precision is required for the technique: Delivery to the wrong cells or tissues could be “catastrophic.” In addition, it disrupts normal processes and may cause “collateral damage” to nearby genes, she said. These therapies also come with a high cost since many target rare diseases. There are also safety concerns surrounding patient deaths.

Between 1989 and 2015, 2,335 clinical trials were completed, are ongoing, or have led to approval for gene therapies. The most common vectors used in clinical trials are adenovirus (22.1%), retrovirus (18.8%), naked/pDNA (18.0%).

Last year, the U.S. Food and Drug Administration approved voretigene neparvovec for the treatment of confirmed biallelic RPE63-mediated retinal dystrophy, which uses recombinant adeno-associated virus  (AAV) vector to deliver normal copy of the RPE65 gene directly to the retinal cells. The cost of this treatment can reach $850,000 (for both eyes) for most patients.

Dr. Trask then presented some gene therapies that are in late stage trials. Valoctocogene roxaparvovec is in development for the treatment of hemophilia A. This AAV5-factor VIII (FVIII) vector is administered as a single intravenous (IV) infusion. Data from a phase I/II trial found that this therapy resulted in FVIII activity ≥50 IU/dL by week 20 and a median FVIII activity of 77 IU/dL at week 52.

EB-101 is in development for the treatment of recessive dystrophic epidermolysis bullosa. This autologous ex vivo gene-corrected cell therapy involves six sheets of corrected cells grafted to each affected area. A phase I/II study demonstrated that, at three months, 100% of patients (n=7; n=42/42 wounds) had wound healing; at six months, 90% (n=7; n=38/42 wounds) had wound healing; and at 12 months, 83% of patients (n=4; n=20/24 wounds) had wound healing.

GS010 is in development for Leber hereditary optic neuropathy. This rAAV2 containing wild-type ND4 gene uses a single intravitreal injection to the more severely affected eye. In a phase I/II study, at 2.5 years post-injection, the treatment was well-tolerated with no reports of worsening vision, ocular sequelae, or serious treatment-related adverse events.

Elivaldogene tavalentivec is in development for pediatric cerebral adrenoleukodystrophy. This lentiviral vector containing ABCD1 cDNA is administered via a single IV infusion. Interim results from a phase II/III study showed that at 24 months post-infusion or treatment discontinuation, 88% of patients (n=15/17) were still alive and free from major functional disabilities (95% CI 64-99). There was no incidence of engraftment failure, graft-versus-host disease, or life-threatening infection.

RT-100 is in development for heart failure with reduced ejection fraction (EF). The adenovirus vector encoding Ad5.hAC6 is delivered as a one-time gene transfer infusion into the arteries. A phase II study found that the two highest dose groups had increased EF at four weeks (P<0.004), but not at 12 weeks. The placebo group did not achieve increased EF at either time point. Heart failure symptoms were reduced at 12 weeks post-treatment in the gene therapy group but not in the placebo cohort (P=0.0005). There were no significant differences between the RT-100 and placebo cohorts in terms of exercise duration.

Dr. Trask concluded that agents in late-stage development may provide important clinical advances for both common and rare diseases, but warned that these costly therapies will pose significant challenges to payers.

Presentation S2: A Whole New World: Navigating the Gene Therapy Pipeline. AMCP Annual Meeting 2018.