Curing disease at the genetic level

European regulators poised to approve Western world’s first-ever gene therapy treatment

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LONDON—On July 19, the European Medicines Agency's (EMA)Committee for Medicinal Products for Human Use (CHMP) recommended that theEuropean Commission (EC) authorize the marketing of Glybera, a gene-therapytreatment for an ultra-rare genetic disorder affecting the pancreas—creatingnot only a regulatory pathway for an orphan disease treatment, but perhaps morenotably, the first gene-therapy medicine in the Western world.
Glybera, a gene therapy medicinal product intended to treatadult patients diagnosed with familial lipoprotein lipase deficiency (LPLD)with severe or multiple pancreatitis attacks despite dietary fat restrictions,is the work of uniQure biopharma BV, a developer of human gene-based therapies locatedon the premises of the Academic Medical Center at the University of Amsterdam.
LPLD is caused by a mutation in the gene that codes LPL. Asa result, afflicted individuals lack the ability to produce LPL enzymesnecessary for effective breakdown of fatty acids, and thus experience recurring,severe abdominal pain and pancreatitis. Because the disease is estimated toaffect no more than one or two people per million, but has no effectivetreatment, Glybera was designated as an orphan medicinal product in March 2004.
Glybera's active substance, alipogene tiparvovec, is a lipid-modifyingagent. The therapy is constructed with an adeno-associated viral vector (AAVV)carrying the gene for LPL, which is expressed in muscle after administration.Glybera must be used in conjunction with appropriate diet. It has proved to besafe and well tolerated in patients, with the most common side effect reportedas lower-extremity pain in about one-third of patients.
"Now, for the first time, a treatment exists for thesepatients that not only reduces this risk of getting severely sick, but also hasa multiyear, beneficial effect after just a single injection," says Jörn Aldag,CEO of uniQure. "The positive recommendation from the CHMP for Glyberatherefore represents a major breakthrough for both LPLD patients and formedicine as a whole. Restoring the body's natural ability to break down fatparticles in the blood in order to prevent pancreatitis and excruciating abdominalpain suffered by patients, is what gene therapy is all about: curing disease atthe genetic level."
A pharmacovigilance plan for Glybera will be implemented aspart of the marketing authorization. In addition, uniQure has committed to offerthe treatment through dedicated centers of excellence with expertise intreating LPLD and by specially trained doctors to ensure ongoing safety.uniQure has also committed to building a patient registry for continuedunderstanding of the disease.
The EC generally follows the recommendations of the CHMP. Marketingauthorization covers all 27 European Union member states.
"We expect final approval from the EC within three monthsafter the CHMP decision," says Aldag.
A relatively new therapeutic approach that targets somaticcells, gene therapy aims to correct the genetic alterations that cause disease.Gene therapy is generally easier to carry out when the disease is caused bymutations in only a single gene. Until now, most gene therapy research hasfocused on hereditary diseases and cancers, but in recent years, scientistshave started to look into using gene therapy for other diseases, such ascardiovascular diseases, liver diseases and central nervous system disorders.
The most common form of gene therapy involves insertingnormal, healthy genes into a patient so the healthy gene can replace orsupplement the activity of a damaged gene. To ensure that the functional geneis delivered inside cells where the protein can be made, it is carried by a"vector" that can enter the cell without harming it. Vector systems that arederived from viruses for use in gene delivery are usually the most efficient. Acommon, harmless type of virus known as an AAV is often used for developinggene therapy. It is generally considered safe, as most people have already beenexposed to it in the course of their normal lives. The AAV vector is altered sothat it cannot infect or replicate.
uniQure is banking on the promise for gene therapies toprovide "long-term, potentially lifelong treatment in seriously debilitatingdiseases based on a single injection of the therapeutic product. It can beexpected that gene-based therapies—much as antibody markets in the past decade—willwitness dramatic growth and lead to multibillion dollar markets," according tothe company's website.
uniQure is also developing treatments for other rarediseases such as acute intermittent porphyria and Sanfilippo B, but the companyforesees potential in not-so-rare diseases like hemophilia and Parkinson'sdisease.
"We believe that just like antibodies, gene therapy will oneday be a mainstay in clinical practice," Aldag says.
But gene therapies are not without significant controversy.They have only seen approval in one other country—China, where regulators in2003 approved a gene therapy called Gendicine to treat head and neck cancer. Inmost other geographic areas, there have been high-profile failures and concernsabout immune response and tumor development.
Dr. D'vorah Graeser, founder and CEO of Graeser AssociatesInternational, an international healthcare intellectual property firm, pointsout that "European regulators have shown themselves to be willing to take a bitof a chance in balancing risk versus benefits—this has been shown in theirwillingness to approve many medical devices and biosimilars," but she alsonotes that the CHMP's recommendation in this case came under "exceptionalcircumstances."
Indeed, Dr. Tomas Salmonson, acting chair of the CHMP, saidin a statement, "The evaluation of this application has been a very complexprocess, but the use of Glybera in a more restricted indication than initiallyapplied for, which targets the patient population with greatest need fortreatment, and additional analyses by the Committee for Advanced Therapies (CAT)have added to the robustness of the data provided and allowed the CHMP toconclude that the benefits of Glybera are greater than its known risks."
Glybera's long path to approval leaves many lessons forother companies developing cutting-edge therapies, says Kevin E. Noonan, apartner with McDonnell Boehnen Hulbert & Berghoff LLP.
"It's going to be tough," says Noonan. "You can expect thatbecause of two things: relatively cutting-edge programs inherently have a lotof failures, and the whole biotechnology industry has overpromised andunderdelivered. Gene therapy was an idea that people were talking about in thelate 1970s or early 1980s, but 30 years later, it still hasn't happened. Ithink things have gotten better in the last 10 years because there are hundredsof biologic drugs in the pipeline. But technology is difficult, and regulatorsare reticent about letting it happen without oversight. Despite this approval,I think progress in this area is still going to move at a glacial pace."
uniQure says it is also preparing to apply for regulatoryapproval in the United States, Canada and other markets. However, Graeserdoesn't foresee American regulators following the lead of their Europeancounterparts anytime soon.
"Unfortunately, I don't think the FDA is as likely to moveforward so quickly on gene therapy," says Graeser, who is also a former memberof the Human Genome Project. "I think it will take a 'wait-and-see' attitude onthe EMA's recommendation, but I do foresee the gene therapy issue coming to ahead in the next three to four years."
What Graeser does foresee, however, "is these approvalsresulting in young companies taking chances and developing new technologies,knowing that the funding they need is available. I do hope they will be takinga closer look at gene therapies," she says.
Some U.S. companies in a position to lead the gene-therapymarket include Sangamo BioSciences Inc. of Richmond, Calif., which is in thesecond of three phases of testing required on a gene therapy to tackle HIV;Neurologix Inc. of Fort Lee, N.J., which is studying use of the treatment inParkinson's disease; and Bluebird Bio of Cambridge, Mass., which is exploringgene therapies in clinical trials for blood conditions like beta thalassemiaand sickle-cell disease.

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