There are thousands of genetic disorders and rare cancers in need of treatments, so the questions of price and affordability must be addressed. Additionally, research must continue on the current therapies to learn about their long-term efficacy. The early promise of gene therapy is being realized and hopefully these issues will be addressed for the benefit of everyone.
BY ROBERT TOMAINO
For decades, gene therapy has been heralded as a potential game changer. A modern therapeutic technique that offers the hope of a cure rather than simply a treatment. Despite the great promise, gene therapy stumbled for decades, beset by setbacks and failures. However, in recent years, medical advances have led the Food and Drug Administration (FDA) to approve the first gene therapies in the United States. and have ushered in a new era of hope and excitement. However, questions still abound, including the price point of these therapies as well as the long-term, sustained effectiveness of the treatments.
INITIAL SUCCESS
In 1990, doctors treated a young girl with a rare disorder called severe combined immunodeficiency (SCID). The girl lacked an enzyme that was required for the proper function of her immune system. Consequently, she was highly susceptible to infection. In the past, SCID was also known as "bubble boy disease" after the release of a movie depicting a true story about a child born with SCID who lived in a hospital isolation contraption which prevented him from getting germs that could have otherwise killed him. The enzyme in question is produced by the ADA gene and doctors successfully inserted a healthy version of the gene into immune cells called T-cells. There was a dramatic improvement of the young girl's immune system. This provided a "proof of concept" for gene therapy.
Following this initial success, gene therapy was hailed as a coming revolution. However, the initial hope and promise quickly dissipated following two tragedies, one in the late 90s and one in the early 2000s. The first was the death of Jesse Gelsinger in 1999.
Jesse received an experimental gene therapy treatment for his rare genetic disorder called ornithine transcarbamylase deficiency (OTC). OTC causes ammonia to build up in the bloodstream, causing severe complications and potentially brain damage. Jesse had a milder form of OTC, but eagerly participated in the trial, in part, to help children in the future avoid what he went through. Researchers at the University of Pennsylvania administered the therapy and, within four days, Jesse had passed away from complications of the treatment, which caused many of Jesse's organs to shut down. The circumstances surrounding this trial, including questionable research practices, led the FDA to halt all gene thera py studies. In the United States, research into gene therapy slowed from a deluge to a trickle.
In 2003, doctors in France halted a gene therapy trial after some of the patients who had the same rare disorder as the young girl in the United states, severe combined immunodeficiency, developed leukemia following gene therapy. The therapy was initially going very well. Researchers suspected that the infusion of the gene that carried the needed enzyme probably landed in a place that did not need the enzyme and somehow activated a cancer-causing gene in the patients.
These two tragedies dimmed the outlook for gene therapy and quelled the early optimism. Researchers and govern ment regulatory agencies urged a slower, more cautious approach to gene therapy. Although gene therapy fell out of the news cycle, researchers continued to work toward refining the process. In 2017, the FDA approved the first two gene therapies in the U.S. Both treated cancers of the blood. As of August 2019, there are now five gene therapies on the market in the U.S., and a few hundred more being studied. Gene therapy has skyrocketed back to the forefront of research circles and recaptured the early promise and optimism.
VIRAL SOLUTION: Ideally, physicians would produce healthy or reprogrammed gene copies in the lab and then inject them directly into a patient. However, directly injecting the healthy gene copies into a cell does not work, and physicians quickly learned that they must use a carrier. Eventually, they found the perfect delivery vehicle — viruses.
WHAT IS GENE THERAPY?
Gene therapy involves altering genes. Genes are units of DNA. They provide instructions for creating proteins that play critical roles in the body. Gene therapy can be separated into in vivo and ex vivo forms. When a gene is defective, the protein produced by that gene may be deficient, overproduced, faulty or ineffective. In vivo gene therapy involves either replacing defective genes with healthy copies or turning off the defective genes. Researchers create healthy copies of the defective gene in a lab and then deliver the healthy genes directly into the body. Ex vivo means that the genes that are altered are removed from the body (changed and then returned). An example is when scientists filtered out certain immune system cells and reprogrammed them to fight cancer before returning them to the body.
Ideally, physicians would produce healthy or reprogrammed gene copies in the lab and then inject them directly into a patient. However, directly injecting the healthy gene copies into a cell does not work, and physicians quickly learned that they must use a carrier. Eventually, they found the perfect delivery vehicle – viruses.
Researchers choose viruses because they have a unique ability to infect cells. Viruses attach to cells in the body and establish a parasitic relationship. A virus injects its own DNA into the cell and then infects nearby cells and then repeats the process. This is how someone becomes sick from a viral infection. In gene therapy, the viruses are modified so that they no longer cause disease or illness. Instead, the viruses function as a delivery service to deliver healthy copies of the altered gene to the body. These healthy copies then begin to produce the protein or target cancer cells.
The first two gene therapy approvals by the FDA are for ex vivo treatments. Both therapies involve altering immune system cells to destroy cancer cells. They are called CAR T-cell therapy or CART therapy, which stands for chimeric antigen receptor T-cell therapy. With this treatment, physicians filter T-cells, an immune system cell, from the patient's blood. The T-cells are reprogramed (genetically altered) to fight a specific cancer and returned to the body. Two CART therapies have been approved: Kymriah® for acute lymphoblastic leukemia and Yescarta® for non-Hodgkin lymphoma. The official designation for Kymriah is for "patients up to 25 years old who have acute lymphoblastic leukemia (ALL) that has relapsed (went into remission, then came back) or is refractory (did not go into remission with other leukemia treatments)". The official designation for Yescarta is for "adults living with certain types of non-Hodgkin lymphoma who have failed at least 2 other kinds treatment." These therapies have led to remissions in children and adults who had failed to respond to other treatments.
In 2018, the third gene therapy approved by the FDA reflects the method of inserting healthy copies of an altered gene into the body. Some people in the medical community consider this the first "true" gene therapy to be approved in the United States because it is an in vivo treatment. Luxturna® is a gene therapy that treats a rare genetic eye condition called RPE65 mutation-associated retinal dystrophy. This disorder leads to the progressive breakdown of the retina, the light-sensing membrane in the back of the eye. RPE65 is the name of the gene that is altered in this disorder; it produces a protein of the same name that is essential for the health of the retina. Many people with this altered gene are visually impaired at birth and the damage to the eye is progressive and can eventually lead to vision loss or blindness. Doctors create artificial, healthy copies of the RPE65 gene and then insert these healthy copies into a patient's retinal tissue. The healthy copies will produce the RPE65 protein that is required for healthy vision.
The great appeal of gene therapy is that it offers a "cure." Whereas other treatments simply eliminate or ameliorate specific symptoms, or compensate for the effects of symptoms, gene therapy goes to the root of the problem. In vivo gene therapy fixes the underlying genetic defect causing a disease. By correcting the underlying defect, gene therapy is considered a cure and the hope is that it will be a onetime treatment.
Luxturna has been widely beneficial for many patients, stopping the disease's progression and greatly improving the vision of many of people.
QUESTIONS AND CHALLENGES REMAIN
Despite these success stories, there are issues with gene therapy. Drug pricing is a big issue throughout the world. While patients, ethicists, and others sound the alarm, more and more costly medications keep hitting the market unabated. The price of Luxturna is $850,000 (or $425,000 per eye). The most recent gene therapy approval by the FDA is Zolgensma®. Zolgensma is even more costly. The manufacturer, Novartis, has pegged the price at $2.215 million per patient. Zolgensma treats a rare neurological disorder called spinal muscular atrophy (SMA). There are many forms of SMA, and the two most severe can be fatal by the age of one or two. Other forms lead to progressive symptoms as a person grows older. Zolgensma has the potential to be a transformative medication.
The huge price tag made national news. Novartis defended the price, noting that the one time price for Zolgensma is better than the current alternative on the market, which is a drug called Spinraza® that costs $750,000 the first year and then $350,000 every year after. Within five to six years, Zolgensma becomes more cost effective. However, it becomes more cost effective than one of the most expensive drugs in the world. Is that really cost effective overall? A major insurance company, UnitedHealthcare, initially rejected covering the medication for some patients before changing its decision after appeals from affected families and the accompanying media coverage.
Sometimes the cost becomes prohibitive. The first gene therapy approved in the Western world was called Glybera®. The European Medicines Agency (EMA) approved Glybera in 2015. The manufacturer, UniQure, priced the therapy at $1,000,000, making it the most expensive treatment in the world at the time. The high costs, low number of patients, and ques tions about the therapy's long-term effectiveness led to the drug not being approved by insurers. In the end, only a few patients were treated with the drug and the company allowed the approval to lapse. The therapy is no longer listed on UniQure's website.
The Centers for Medicare & Medicaid Services (CMS) struggled to figure out how to pay for Yescarta and Kymriah, the two CART therapies approved by the FDA in 2018. In early August 2019, it was announced that Medicare would cover the medications although not the entire costs. Yescarta costs $373,000 and Kymriah costs $475,000. However, side effects can require hospitalization and, in some patients, costs are estimated to be closer to $1,000,000.
England initially denied covering Yescarta, citing the high cost. After striking a deal with the manufacturer, Gilead, the medication, will be covered for some adult patients. In Italy, the Agenzia Italian del Farmaco (Italian Medicines Agency) approved Kymriah after negotiations with Novartis. The Agency instituted a new reimbursement model called "pagamento al risultado" or payment to results, which may require the manufacturer to repay in full the treatment costs for patients who do not respond to the therapy.
The pushback on price has already started, and there are currently several hundred gene therapy clinical trials being conducted. How many, if successful, will carry a similar high price tag? How many can the market bear? How many until insurance companies cry "uncle"? At what point will the pricing decision on gene therapy open a debate on cost (and profit) versus the value of human life?
NEW CONTROVERSY
In early August of 2019, the FDA revealed that Novartis had manipulated data early in testing on animals with Zolgensma. The FDA released a statement and explained that "it was carefully assessing this situation and remains confident that Zolgensma should remain on the market."
The FDA stressed that the "the totality of the evidence demonstrating the product's effectiveness and its safety profile continues to provide compelling evidence supporting an overall favorable benefit-risk profile." So, the FDA has said that its safety and efficacy assessment hasn't changed, but this reminds us that gene therapy is a still a new success story with questions still to be answered.
Before the approval of Luxturna, the FDA asked scientists who were voting on its approval to consider whether the drug should be given more than once. According to the FDA, "it is unclear if the effect decays over time, as longer term follow up data is not available." Some scientists wonder about repeated injections into the retinal tissue. The possibility that the positive effect of treatment can wane is true for all gene therapies because they are so new and there is no data about the long-term, sustained effectiveness. And there won't be until time marches on.
It is very easy to get wrapped up in the accolades pouring forth for gene therapy. When people, including young children, receive a fatal cancer diagnosis and then become cancer free, it inspires everyone. When declining vision is restored, or children with a devastating neurological disease can walk and dance, it heralds the potential to completely change the medical landscape. The individuals and families who have benefited from these treatments must be eternally grateful. But there are thousands of genetic disorders and rare cancers in need of treatments, so the questions of price and affordability must be addressed. Additionally, research must continue on the current therapies to learn about their long-term efficacy. The early promise of gene therapy is being realized and hopefully these issues will be addressed for the benefit of everyone.•
ABOUT THE AUTHOR:
Robert Tomaino is a writer, editor and consultant. For more than 20 years, he has provided editorial support, guidance and strategic consultation to medical nonprofits, patient advocacy organizations, and pharmaceutical and biotechnology companies. Robert has extensive experience writing about rare disorders for both patients and physicians. Robert also understands the unique needs of patients in the rare disease community and works to foster better communication and understanding between these diverse groups and the industry representatives that work with them. He is a principal at Orphan Communications ( orphancommunications.com). He is also a member of the Fairfield Scribes ( fairfieldscribes.com).
References
References Finkel, E. (June, 2019). The gene therapy revolution is here. Medical Xpress. Retrieved from medicalxpress.com/news/2019-06-gene-therapy-revolution.html Marks, P. (August, 2019). Statement on data accuracy issues with recently approved gene therapy. U.S. Food & Drug Administration. Retrieved from fda.gov/news-events/press-announce- ments/statement-data-accuracy-issues-recently-approved-gene-therapy? High, KA, Roncarolo, MG. (August, 2019). Gene therapy. New England Journal of Medicine. Retrieved from nejm.org/doi/full/10.1056/NEJMra1706910 Lash, A. (October 2017). FDA to advisors: what if one-time gene therapy needs extra doses? Xconomy. Retrieved from xconomy.com/national/2017/10/10/fda-to-advisors-what-if-one-time- gene-therapy-needs-extra-doses/ Rinde, M. (June 2019). The death of Jesse Gelsinger, 20 years later. Distillations. Retrieved from sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later Graeber, D. (July 2019). How scientists built a "living drug' to beat cancer. Wired. Retrieved from wired.com/story/how-scientists-built-living-drug-to-beat-cancer Rockoff, JD. (August 2019). Medicare moves to cover costly cell therapies. The Wall Street Journal. Retrieved from wsj.com/articles/medicare-moves-to-cover-costly-cell-therapies- 11565226535 Anguela XM, High KA. Entering the Modern Era of Gene Therapy. (January 2019). Annual Review of Medicine. Retrieved from annualreviews.org/doi/full/10.1146/annurev-med-012017-043332 (August 2019). L'Agenzia del farmaco approva la terapia CAR-T per I tumori del sangue. Retrieved from ilsole24ore.com/art/l-agenzia-farmaco-approva-terapia-car-t-i-tumori-sangue-ACPcghd