Gene Therapy: Moving Toward Commercialization

Insight Pharma Reports’ Gene Therapy: Moving Toward Commercialization”, outlines the progress of the gene therapy field since its inception in the 1970s, with a special focus on clinical-stage gene therapy programs that are aimed at commercialization, and the companies that are carrying out these programs. A major theme of this report is whether gene therapy can attain commercial success by the early-to-mid 2020s, which types of gene therapy programs have the greatest likelihood of success, and what hurdles might stand in the way of clinical and commercial success of leading gene therapy programs.

In accord with the focus of this report, we have been asking:

• Whether gene therapy can attain commercial success by the early-to-mid 2020s,


• Which types of gene therapy programs have the greatest likelihood of success,


• What hurdles might stand in the way of clinical and commercial success of leading gene therapy programs.

In addition to chapters that focus on various areas of commercial gene therapy, this report includes:

• An expert interview with Sam Wadsworth, Ph.D., the Chief Scientific Officer of Dimension Therapeutics and former Head of Gene Therapy R&D at Genzyme.


• Survey data from 88 researchers involved in gene therapy


• Companies profiled:  uniQure, Voyager Therapeutics, Oxford BioMedica, GeneQuine Therapeutics, Celladon Corporation, and bluebird

Topics covered:

• Development of improved vectors (integrating and non-integrating vectors)


• Gene therapy for ophthalmological diseases


• Gene therapy for other rare diseases


• Clinical-stage gene therapies for selected rare diseases other than hemophilias


• Gene therapy for more common diseases


• Companies whose central technology platform involves ex vivo gene therapy


• CAR T-cell immunotherapy as an area of ex vivo gene therapy


• Gene editing technology


• Outlook for gene therapy


• Market outlook for eight gene therapy products

Executive Summary

In addition to chapters that focus on various areas of commercial gene therapy, this report includes:

An expert interview with Sam Wadsworth, Ph.D., the Chief Scientific Officer of Dimension Therapeutics and former Head of Gene Therapy R&D at Genzyme. This interview is appended to Chapter 5.

A survey on gene therapy, which was conducted by Insight Pharma Reports in conjunction with this report, and is discussed in Chapter 9.

Chapter 1 discusses the history of gene therapy, including early FDA-approved human studies of gene therapy in academic and government laboratories in the 1990s. These were based on studies in the 1970s and 1980s, in which researchers applied such technologies as recombinant DNA and development of viral vectors for transfer of genes to cells and animals to the study and development of gene therapies.

Chapter 2 focuses on development of improved vectors, which are designed to circumvent the problems seen in early clinical gene therapy studies. These vectors are of two general types—integrating and non-integrating vectors. Integrating vectors insert themselves into the DNA of the host genome. The advantage of using integrating vectors is that when host cells replicate their chromosomal DNA and divide, they replicate the vector DNA (including inserted therapeutic transgenes) as well. In contrast, non-integrating vectors used in gene therapy would be lost as the result of any cellular proliferation. Thus non-integrating vectors should be used in tissues in which cell division does not occur.

Chapter 3 focuses on one company, uniQure (Amsterdam, the Netherlands). The reason for this is that uniQure is the first company to commercialize a gene therapy. This therapy is Glybera (alipogene tiparvovec), which is a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD). As of now, it is the only gene therapy product to have received regulatory approval in a regulated market.

Chapter 4 focuses on gene therapy for ophthalmological diseases. Retinal diseases constitute an attractive target for gene therapy. Researchers can target the retina easily via intravitreal injection or subretinal injection. The retina is also an immunoprivileged site. The existence of a contralateral control—the other, untreated eye—also provides an advantage in targeting the eye. There are also non-invasive methods that may be used to monitor therapeutic effects. The small size and compartmentalization of the eye also constitute advantages for gene therapy (especially when compared to targeting much larger organs or tissues such as the skeletal musculature, the liver, or the heart). There is also the issue of medical need, since blindness severely reduces the quality of life.

Chapter 5 focuses on gene therapy for other rare diseases. The first section of this chapter discusses clinical-stage gene therapies for hemophilias. Hemophilias are important genetically determined bleeding disorders, which include hemophilia A and B. Both are X-linked recessive disorders, and thus affect mainly males. Hemophilia A involves a deficiency in factor VIII (FVIII), and hemophilia B involves a deficiency in factor IX (FIX). Both of these are clotting factors that are made in the liver.

Chapter 6 focuses on gene therapy for more common diseases. The great majority of preclinical and clinical gene therapy programs are directed toward treatment of rare diseases. A key question in the gene therapy field is whether gene therapy is applicable (both in terms of technical feasibility and in terms of commercialization strategies) to more common diseases. Chapter 6 focuses on the efforts of four companies—Voyager Therapeutics, Oxford BioMedica, GeneQuine Therapeutics, and Celladon Corporation—to develop gene therapies for common human diseases. It illustrates both the promise and the difficulties of developing gene therapies for such diseases.

Chapter 7 focuses on companies whose central technology platform involves ex vivo gene therapy. Several ex vivo gene therapies discussed in this report are based on studies with retroviral vectors from the earliest days of gene therapy research. In contrast, development of the therapies discussed in Chapter 7 has been initiated much more recently.

The first section of Chapter 7 focuses on bluebird bio (Cambridge, MA). bluebird is a publicly-traded clinical stage biotechnology company that is developing and commercializing gene therapies designed to be one-time treatments for severe genetic and rare diseases and cancer. The company’s technology platforms encompass gene therapy for rare diseases, cancer immunotherapy, and gene editing. The second section of Chapter 7 focuses on CAR T-cell immunotherapy as an area of ex vivo gene therapy.

A full discussion of CAR T-cell therapy, especially a discussion of the technical aspects of this field, belongs in a report on cancer immunotherapy. As such, it is beyond the scope of this gene therapy report. For such a full exposition of CAR T-cell therapy (and of other aspects of cancer immunotherapy), see our September 2014 Insight Pharma Report, “Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies”. 195.

Chapter 8 focuses on gene editing technology. In recent years, a growing number of researchers have been seeking to develop gene therapies that work via “gene editing”—directly changing DNA sequences of deleterious genes in a patient’s genome into functional sequences. Gene editing, which is in its early stages, is considered “next generation” gene therapy.

Outlook for gene therapy

In accord with the focus of this report—which we have entitled “Gene Therapy: Moving Toward Commercialization”—we have been asking:

• Whether gene therapy can attain commercial success by the early-to-mid 2020s,


• Which types of gene therapy programs have the greatest likelihood of success,


• What hurdles might stand in the way of clinical and commercial success of leading gene therapy programs.

In Chapter 9, we list eight gene therapy products that in the opinion of leading researchers and corporate leaders in the field have the greatest prospect for reaching the market before 2020. One product (uniQure/Chiesi’s Glybera) has been approved in Europe, another (GSK/TIGET’s GSK2696273) is in preregistration in Europe, and the others are in or nearing pivotal clinical trials. We therefore conclude the answer to the question as to whether gene therapy can attain at least some degree of near term commercial success is yes.

Of the eight therapies highlighted in Chapter 9, six are ex vivo gene therapies, which suggests that the ex vivo strategy (exemplified by bluebird bio) is a potentially successful one for moving gene therapies toward registration and marketing in the near term. Three of these ex vivo gene therapies are CAR T-cell cancer therapies that target CD19.

All of the eight therapies are for rare diseases. However, several of the diseases addressed by these therapies are for some of the more common rare diseases, especially beta-thalassemia and sickle cell disease. Thus the concern that gene therapy will only be applicable to ultra-rare diseases such as lipoprotein lipase deficiency (LPLD) is likely to be unfounded. However the prospect for gene therapies for common diseases has not yet been realized.

In terms of expected revenues for gene therapy products reaching the market in the near term, there is a great deal of uncertainty. However, at least some analysts project sales of Lenti-D of around $250 million and of LentiGlobin of around $4 billion. As for the CAR T-cell therapies, one analyst projects peak sales of around $1.7 billion for Kite’s KTE-C19. Other CAR T-cell therapies may achieve comparable results, depending on competition and payer acceptance of the therapies and their prices. These projections suggest that near-term gene therapies may attain commercial success.