FDA Authorizes First Human Study to Use In Vivo Genome Editing Application

Posted 08 December 2015 | By Zachary Brennan 

FDA Authorizes First Human Study to Use In Vivo Genome Editing Application

The US Food and Drug Administration (FDA) broke new ground last week when it authorized the world’s first human clinical trial for an in vivo genome editing application.

The investigational new drug (IND) application approval for California-based Sangamo, which is the first and only company to put a gene editing therapy into clinical trials, allows the company to begin conducting in 2016 a Phase 1/2 open-label, dose-escalation study in up to nine male adults with severe hemophilia B. The study will examine the gene therapy’s safety, tolerability and potential efficacy.

Edward Lanphier, Sangamo's president and chief executive officer, told Focus on Tuesday that the company “fully expects” the trial to be up and running, with patients receiving the single-treatment therapy SB-FIX in 2016, though he said it was too early to tell if that trial would be enough to submit the treatment for FDA approval.

“We really ought to treat a couple patients before we talk about approval,” he said.

Based on Sangamo’s first clinical application of its proprietary In Vivo Protein Replacement Platform (IVPRP), the trial will involve the insertion of a copy of the human FIX (hFIX) gene into a specific location within the albumin gene of liver cells.

According to some of the efficacy and specificity data used for the IND approval and unveiled Monday at the American Society of Hematology (ASH) meeting, the studies show how Sangamo’s technology can use zinc finger nuclease (ZFN)-mediated genome editing to insert the hFIX gene into the genome, which enables it to be expressed for the lifetime of the cells and their progeny.  

And due to the high expression rates from the promoter, only a small percentage of the liver cells need to be edited in order for the modified cells to produce stable, therapeutic levels of hFIX protein, Sangamo says.

The company also reported this week that its clinical protocol for SB-318, its first IVPRP lysosomal storage disorder (LSD) program, for the treatment of Mucopolysaccharidosis I (MPS I/Hurler Syndrome), recently received unanimous approval from the NIH's Recombinant DNA Advisory Committee (RAC). 

“We expect to file the IND application for SB-318 with the FDA by the end of 2015," Lanphier said. Tthe companyalso expects to file an IND application for MPS II (Hunter syndrome) in the first half of 2016 and three more INDs in the second half of 2016 for hemophilia A, Gaucher disease, and one other LSD target.

FDA Interactions

Because Sangamo has run ex vivo genome editing clinical trials for the past five years, the company has been at the forefront of industry discussions with FDA on gene therapies. FDA has yet to approve a gene therapy, though the European Medicines Agency approved the gene therapy Glybera back in 2012 to treat a rare condition called lipoprotein lipase deficiency.

“FDA has been a very engaged, constructive, very thoughtful and curious group in which we’ve engaged on this process for years,” Lanphier said.

He also spoke at length on Sangamo's discussions with FDA and NIH at the Piper Jaffray Healthcare Conference last week on how these studies will progress in the absence of significant adverse events, which have cropped up over the years for gene therapies.

More broadly, Lanphier said last week, the company's goal is to develop a safety profile across an adult population to allow it to move into a pediatric population where there's the "greatest amount of patient benefit" if we can establish circulating levels of these proteins -- "the value for some of these communities is enormous."

FDA Guidance

Products using gene-editing technologies, like Sangamo’s, are regulated by the FDA’s Center for Biologics Evaluation and Research (CBER), which has published a number of guidance documents addressing gene therapy (though no specific guidance on the use of genome-editing technologies) including:

FDA spokeswoman Sarah Peddicord told Focus that most of the current products involving genetic editing technologyare mostly in the research stage of development. Generally speaking, the FDA does not regulate biological products that are intended for use in laboratory research only.”

And unlike with some other emerging development programs, such as biosimilars, Sangamo is not waiting on FDA to issue any additional guidance to progress its clinical programs.

“There is additional work going on with standards and things like that that will be helpful. But no one is delayed by waiting for whatever is in the discussions,” Lanphier added.

As far as interactions with other regulators worldwide on gene therapies, Lanphier told Focus, without giving away any proprietary information, that “largely speaking, FDA is as up to speed, if not more so than other agencies around the world, in terms of the gamut of their issues – from manufacturing, to toxicology, to CMC [chemistry, manufacturing and controls], to clinical trial approaches.”

Gene Editing Summit

Lanphier also weighed in on last week’s international gene editing summit in Washington, DC, noting that there was unequivocal, “table-pounding support” for genome editing in somatic cells, which are cells that are not transmitted to the next generation. He also mentioned, as explained in the summit’s statement, that there was caution expressed around the idea of making genetic alterations to gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations.

But as far as parsing the different genome editing modalities, Lanphier noted that speakers did not get into too much detail, though they did point out how CRISPR/Cas9 editing is ubiquitously available now, though “less than perfect,” whereas the data around ZFN-editing technology, with which Sangamo owns and licenses the intellectual property for to companies like Sigma Aldrich and Biogen, are so far“unambiguous.”

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