China was the first country in the world that has approved commercial gene therapy products. The first product was called Gendicine. In the western world the first approved gene therapy product was Glybera in 2012. Below is a summary of gene therapy products that are world wide on the market. Please note that the list is not exhaustive.
In Europe, gene therapy products have to be approved by the European Medicines Agency (EMA) which is the European agency for the evaluation of medicinal products, including gene therapy medicinal products. Gene therapy products are regarded as dvanced therapy medicinal products (ATMPs). In the end, the gene therapy products needs to be approved by the European Commission.
- In the US by the FDA
- In Europe by the EMA en EC
China's medicines authority (China State Food & Drug Administration, CDFA) approved the cancer therapy after it achieved promising results in a clinical trial on October 16, 2003. The treatment, called Gendicine, has been launched commercially by SiBiono GeneTech Co. of Shenzhen, Guangdong province. Gendicine was approved for the treatment of head and neck squamous cell carcinoma. The gene therapy product is an adenovirus vector carrying the p53 tumour-suppressor gene. Gendicine is similar to Advexin developed by the Texas-based Introgen Therapeutics. Advexin is still waiting for FDA approval.
The results of the Gendicine clinical trial are published in Human Gene Therapy, says Zhaohui Peng, the SiBiono company's founder and head. Gendicine's approval was announced earlier but has gone largely unnoticed outside China (see also China approves first gene therapy. There were concerns about the approval among researchers elsewhere in the world as to quality of the trials performed and thereby the safety and efficacy of the treatment (Controversial Chinese gene-therapy drug entering unfamiliar territory). The available clinical data and conclusions drawn were obtained from a relatively small number of patients in clinical trials. There have been more patients treated, but the clinical data of these patients are hard to access, partly due to the fact that they were published only in Chinese journals. Furthermore, it seemed that approval had been made on the basis of tumour shrinkage rather than extension of patient lifetime (An update on gene therapy in China). Despite these concerns, patients have flown to China to undergo therapy (see Medical Tourism)
Gendicine enters the tumour cells by way of receptor-mediated endocytosis and begins to over-express genes coding for the p53 protein needed to fight the tumour. Ad-p53 seems to act by stimulating the apoptotic pathway in tumour cells, which increases the expression of tumour suppressor genes and immune response factors (such as the ability of natural killer (NK) cells to exert "bystander" effects). It also decreases the expression of multi-drug resistance, vascular endothelial growth factor and matrix metalloproteinase-2 genes and blocking transcriptional survival signals.
p53 mutation status of the tumour cells and response to Ad-p53 treatment are not closely correlated. Ad-p53 appears to act synergistically with conventional treatments such as chemo- and radiotherapy. This synergy still exists in patients with chemotherapy and radiotherapy-resistant tumors. Gendicine produces fewer side effects than conventional therapy.
See the following reviews regarding the developments of gene therapy in China:
- - Current status of gene therapy in Asia
- - Gene medicine for cancer treatment: commercially available medicine and accumulated clinical data in China
- - Gene Therapy in China - From a Dutch perspective (2010). This study was initiated by The Netherlands Commission on Genetic Modification (COGEM) to retrieve information from Chinese sources, esp. Chinese literature databases, Chinese scientists, scientific meetings in China, on gene therapy developments and risk assessment.
In July 2012, the European Medicines Agency (EMA) recommended it for approval (the first recommendation for a gene therapy treatment in either Europe or the United States), and the recommendation was endorsed by the European Commission in November 2012. Glybera was developed over a period of decades by researchers at the University of British Columbia and later Amsterdam Molecular Therapeutics (AMT), which acquired rights to with the aim of releasing the drug in Europe. After spending millions of euros on Glybera's approval, AMT went bankrupt and its assets were acquired by uniQure. Glybera gained infamy as the "million-dollar drug," causing its manufacturer, uniQure, to remove the drug after two years on the European market. As of 2018, only 31 people worldwide have ever been administered Glybera, and uniQure has no plans to sell the drug in the US or Canada.
Imlygic is an oncolytic viral therapy with attenuated life herpes simplex virus type 1 (HSV-1). In HSV-1, two genes are removed and one gene is added. The genes who are removed originally code for the proteins infected cell protein 34.5 (ICP34.5) and infected cell protein 47 (ICP47). ICP34.5 blocks the response of healthy cells to stop replicating and die after viral infection. However, cancer cells lack this system. By removing ICP34.5, HSV-1 cannot replicate and kill normal cells, but in cancer cells they can. ICP47 suppresses an immune response to viral infection. Removing ICP47 should trigger an immune response, in theory. A gene coding for granulocyte colony-stimulating factor (GM-CSF) is inserted to promote an immune response to cancer cells infected by Imlygic. Despite these efforts, clinical evidence for an immune response to cancer cells due to Imlygic is not available.
Zalmoxis is a type of advanced therapy medicine called a ‘somatic cell therapy product’. This is a type of medicine containing cells or tissues that have been manipulated so that they can be used to cure, diagnose or prevent a disease. Zalmoxis contains T cells (a type of white blood cell) that have been genetically modified1. To make Zalmoxis, T cells from the HSCT donor are separated from the rest of the cells in the transplant. These T cells are then genetically modified to include a ‘suicide gene’.
Because the number of patients undergoing haploidentical HSCT is low, Zalmoxis was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 20 October 2003 by the EMA. Zalmoxis is developed by MolMed S.p.A and the product has been given ‘conditional approval’ by the European Medicines Agency (EMA) in September 2016. This means that there is more evidence to come about the medicine, which the company is required to provide.
The treatment is personalized for each patient; hematopoietic stem cell (HSCs) are extracted from the patient and purified so that only CD34-expressing cells remain. Those cells are cultured with cytokines and growth factors and then transduced with a gammaretrovirus containing the human adenosine deaminase gene and then reinfused into the patient. These cells take root in the person's bone marrow, replicating and creating cells that mature and create normally functioning adenosine deaminase protein, resolving the problem.
The treatment was developed at San Raffaele Telethon Institute for Gene Therapy and developed by GlaxoSmithKline (GSK) through a collaboration with Fondazione Telethon and Ospedale San Raffaele. GSK, working with the biotechnology company MolMed S.p.A, developed a manufacturing process. In April 2016, a committee at the European Medicines Agency (EMA) recommended marketing approval for its use in children with adenosine deaminase deficiency, for whom no matched hematopoietic stem cell donor is available, on the basis of a clinical trial that produced a 100% survival rate; the median follow-up time was 7 years after the treatment was administered. Around 75% of people who received the treatment needed no further enzyme replacement therapy. Strimvelis was approved by the European Commission on 27 May 2016. As of 2016, the only site approved to manufacture the treatment was MolMed in Italy. In 2017, GSK announced it was looking to sell off Strimvelis, and in March 2018 GSK sold Strimvelis to Orchard Therapeutics Ltd.
Luxturna is used for patients with an inherited form of retinal dystrophy. Retinal dystrophy is an umbrella term for a wide range of progressive eye diseases. ‘Retinal’ means that the condition is related to the retina, which is the back layer of the eye which converts light into an understandable message to the brain. ‘Dystrophy’ is a degenerative condition. Retinal dystrophy causes progressive reduction or deterioration of vision which eventually can result in complete blindness. Luxturna can be used for patients who have mutations in the RPE65 gene in both chromosomes.
Luxturna is an adeno-associated virus type 2 (AAV2)-based treatment where the correct copy of the RPE65 gene is delivered without disturbing the genome. Luxturna is injected directly into the retina so it can infect the retinal cells. When RPE65 is expressed in those cells, it can perform its function and in principle, halt the progression of the disease.
It was invented and initially developed at the University of Pennsylvania; Novartis completed development, obtained FDA approval, and markets the treatment. In August 2017, it became the first FDA-approved treatment that included a gene therapy step in the United States. In May 2018, the FDA further approved Kymriah to treat adults with relapsed or refractory diffuse large B-cell lymphoma. In June 2018, The European Medicines Agency (EMA) has recommended marketing authorization of Kymriah. On August 27, 2018, the European Commission has approved Kymriah for the treatment of pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse; and for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.
Yescarta was developed by biotech company Kite Pharma, which was acquired by Gilead Sciences in an $11.9 billion deal in August 2017. Based on the ZUMA-1 trial, Kite submitted to the FDA a biologics license application for Yescarta in March 2017 for the treatment of Non-Hodgkin lymphoma. The FDA granted approval on October 18, 2017 for the second-line treatment of diffuse large B-cell lymphoma. In June 2018, The European Medicines Agency (EMA) has recommended marketing approval of Yescarta. On August 27, 2018, the European Commission granted marketing authorization for Yescarta as a treatment for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL), after two or more lines of systemic therapy.