New technologies tend to go through cycles of interest and attention. Initial excitement about the potential of a technological advance too often builds to over-blown hype, followed by a quick reversal of interest in the aftermath of a big disappointment. But if continued research later produces truly encouraging results, interest can build again as time goes on — this time generated by advancements well supported by clinical data and ultimately, product approvals and successes in the commercial marketplace.
Gene therapy is a field that exemplifies this rollercoaster ride experienced by many new technology advances. Since the idea of adding genetic material to a cell to therapeutically correct, turn on, or silence a missing or defective gene was first conceptualized in the 1970’s, the field has experienced dramatics ups and downs in scientific and commercial interest. In the 1990’s, the first treatment success — although with limited benefit — was achieved for a patient with adenosine deaminase severe combined immunodeficiency (ADA-SCID). Interest in gene therapy then grew until the risks of such efforts entered the spotlight when a patient died in a U.S. gene therapy experiment aimed at curing a form of liver disease, and patients in France developed leukemia following gene therapy aimed at resolving an immune-deficiency. These events threw a serious damper on public interest and investing in the field for many years.
Yet, research continued behind the scenes, gene therapy vectors improved, and in 2012, the European Union issued its first approval for a gene therapy treatment that we’ll talk more about in a moment. Today there are more than 425 gene therapy or gene editing clinical trials underway (Alliance for Regenerative Medicine, 2016), at least 31 of which are in Phase 3. Glaxo SmithKline has received a preliminary approval for its SCID gene therapy in the European Union, and Spark Therapeutics could win U.S. approval this year for its gene therapy approach to reverse one genetic form of blindness. Moreover, gene therapy is earning significant interest from investors; approximately $2 billion was raised by 10 publicly traded gene therapy companies in 2016.
Most recently, interest in the field was stirred again by news from Bluebird Bio about early clinical results with an improved version of its Lentigen gene therapeutic, which is being studied in a Phase 3 trial as a potential therapy for beta thalassemia, a rare genetic form of anemia. One patient in the trial was able to stop regular blood infusions within a month after receiving the gene therapy, and they achieved a normal level of hemoglobin within six months of treatment. A second patient in the trial, however, showed a lower than expected response in a biomarker for healthy hemoglobin to date, and no results have been released yet for a third patient in the study. Ultimately the company plans to enroll and treat a total of 15 beta thalassemia patients. The primary endpoint for the trial is the proportion of patients who become transfusion independent; that is, total hemoglobin levels of at least 9 gm/deciliter without any transfusion of red blood cells for at least 12 months. Thus, any chance of seeking U.S. approval for the treatment remains in the considerable future, while the European Union is allowing BlueBird Bio to seek approval using data from older studies still underway.
Uncertainty also exists with respect to the potential for long-term adverse events — such as future cancers — that may arise related to a one-time gene therapy treatment. What does this risk mean for the level of evidence that will be required to justify approvals?
But even if regulatory approval is achieved for a gene therapy, commercial success may still prove challenging. Uniquire gained European approval for Glybera (alipogene tiparvovec) as a treatment for the ultra-rare disease lipoprotein lipase deficiency, which prevents affected patients from processing fat correctly. But with a launch price for the treatment of over $1 million, the therapeutic has only been used once, and the company has dropped plans to seek approval in the United States. Ultimately there were too few patients and the drug proved too costly to gain support.
So once again, questions around gene therapy come down to pricing. Perhaps, developers will need to position their products around the severity of a disease or disease segment, or for specific types of patients where a high price might be supportable due to the promise of long-term efficacy offered by gene therapy (i.e., patients with the potential to benefit from many additional quality years of life).