Gene Therapy Strengthened by Recent Successes

April has been a busy month for Gene Therapy news, the most significant being the decision of a European Regulatory Committee to recommend approval of GlaxoSmithKline’s Gene Therapy for the treatment of “bubble baby disease”. If approved, this would be the first Gene Therapy approved for children. While GSK’s therapy certainly appears to be the most likely next approved Gene Therapy, there are many others making their way through clinical trials. According to a recent article published by Regulatory Focus, “FDA Sees Spike in Gene and Cell Therapy Applications,” the number of gene and cell therapies in clinical trials is growing and FDA is utilizing their Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) to address concerns about handling the increase in applications.

Gene Therapy Background

There are currently no gene therapies approved by the FDA, but there are several currently in clinical trials. The research behind Gene Therapy demonstrates that a missing or defective gene can be replaced by a correct copy. However, since DNA cannot be directly inserted into cells, Gene Therapy requires a carrier or vector, most commonly inactivated viruses.

Gene therapy can either take place outside the patient’s body with patients’ cells collected, expanded, and treated with the vector in the lab prior to infusion back into the patient’s body or patients can also be treated directly with the vector. Most Gene Therapy cancer treatment candidates either focus on attacking cancer cells and inducing cell death or they focus on boosting immune system cells in attacking the cancer.

One Gene Therapy has been approved by the European Commission, UniQure’s Glybera was approved in November, 2012 for treatment of lipoprotein lipase deficiency (LPL). The therapy is currently the world’s most expensive medicine with costs at close to 1 million dollars per treatment.

Gene Therapy Pipeline Highlights

According to The Journal of Gene Medicine, there are over 2,200 gene therapies in clinical trials. While the majority of these trials are still in Phase I/II, there are some treatments that have been grabbing headlines recently as they make progress through clinical trials. A summary of these therapies is below.

GSK’s Strimvelis for treatment of Severe Combined Immune Deficiency (bubble baby disease)

In early April, GSK issued a press release announcing that the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) had recommended approval of Strimvelis for treatment of ADA-SCID (severe combined immunodeficiency due to adenosine deaminase deficiency). While official EMA approval may still be a month or two away, they usually follow the advice of the committee. ADA-SCID, commonly known as bubble baby or bubble boy disease is a very rare genetic disorder that affects around 15 patients in Europe annually. With ADA-SCID, patients have inherited a faulty gene from both parents and this prevents the production of the protein adenosine deaminase, which is required for production of lymphocytes and thus prevents patients from developing a healthy immune system.

ADA-SCID treatment usually involves a bone marrow transplant, but Strimvelis is designed to treat patients in which there is no suitable bone marrow donor. With Strimvelis, bone marrow is collected from the patient and a vector is used to insert a normal copy of the ADA gene into the cells, then the engineered cells are administered back into the patient. Because cells are collected from the patient there is no risk of graph vs. host disease (GvHD). The treatment is a one time procedure and clinical trial results were very impressive with 100% of patients treated surviving at 3 years post treatment. Without proper treatment children typically don’t survive a year. If approved as expected, it will be the first Gene Therapy approved for children and will be submitted to the FDA for approval, but not before the end of next year according to GSK.

Spark Therapeutics Treatment for RPE65-mediated inherited retinal dystrophies

In October 2015, Spark Therapeutics announced positive top-line results for their Phase III clinical trial of their Gene Therapy product candidate SPK-RPE65 for treatment of RPE65-mediated inherited retinal dystrophies. Inherited retinal diseases are caused by mutations in one or more genes. RPE65 mutations can cause a range of visual impairments that ultimately progress to blindness. Spark Therapeutics estimates about 3,500 individuals in the US and Major European markets have forms of this disease.

In the Phase III study, patients in the intervention group achieved statistically significant improvement over the control group in both functional vision and light sensitivity with no drug related serious adverse events reported.

Several in the industry have speculated that Spark Therapeutics’ SPK-RPE65 may be the first Gene Therapy approved by the FDA. SPK-RPE65 has already received orphan drug designation in the US and EU and breakthrough therapy designation in the US. Spark Therapeutics has announced that they will be submitting a Biologics Licensing Application (BLA) to the FDA in 2016.

Bluebird Bio Treatment for Cerebral Adrenoleukodystrophy

Yesterday, Bluebird Bio released Interim Clinical Data from Starbeam Study of Lenti-D™ at AAN 2016 Annual Meeting. Bluebird’s Lenti-D product is being evaluated in the Phase II/III Starbeam Study for treatment of cerebral adrenoleukodystrophy (CALD), which is a rare, but fatal genetic disorder that negatively affects the nervous system of boys and men. The treatment involves collecting the patient’s hematopoietic stem cells then inserting a functional copy of the ABCD1 gene and then administering the modified cells to the patient.

CALD, also known as Lorenzo’s Oil disease involves a progressive destruction of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. “The worldwide incidence rate for ALD is approximately one in 21,000 male newborns; of those, 30-40 percent are affected by CALD, the cerebral form of the disease.”

Study results are early but demonstrated that of the 17 patients that received the Lenti-D drug product all remain free of major functional disabilities and have had no progression in neurological function score. “While the interim results from the Starbeam study are early, with only three of the 17 patients having completed the study thus far, we are pleased to see evidence of neurologic and radiographic stabilization of CALD,” said David Davidson, M.D., chief medical officer, bluebird bio. “All patients are free of MFDs and most have had no progression in NFS. Brain MRI is the primary tool to quantify disease activity, and it is encouraging that most patients in the study have had stabilization of Loes score and resolution of gadolinium enhancement.”

Which gene therapies do you think have the most potential? Please add your thoughts to the comment section.

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