The Food and Drug Administration's approval last week of Elelyso (taliglucerase alfa), a new treatment for Type 1 (non-neuropathic) Gaucher disease, is remarkable for a number of reasons. Not the least of these is the fact that it provides a competitor and alternative to Cerezyme (imiglucerase), one of the primary alternative treatments for Type 1 Gaucher, and which unfortunately has recently been one of the raft of important drugs in short supply due to a contamination problem in the production facility.
Arguably more noteworthy is the fact that, because the incidence of Gaucher is quite small even for an orphan disease (only about 6,000 patients in the US suffer from Type 1 Gaucher), FDA was willing to approve the product on the basis of two Phase III clinical trials that enrolled a total of 56 patients. That's truly remarkable, given that a single, typical Phase III trial will often examine 1,000 to 3,000 patients. And many Phase III trials enroll thousands more.
One of the trials was a "parallel-dose" study, seldom permitted in Phase III, in which 31 patients were double-blinded and randomized into one of two arms. In one arm, patients received 30 units of the drug per kilogram of body weight, and in the other they received 60 units. No placebo or active alternative control. In the other study, 25 patients already taking Cerezyme were switched to Elelyso and monitored for nine months.
The director of FDA's Office of Drug Evaluation III, Julie Beitz, says that the agency's flexibility on trial enrollment and methodology "demonstrates FDA's commitment to developing treatments for rare diseases." And though I am often quite critical of the FDA's rigidness and risk aversion, I have to applaud the agency for its decision in this case.
But, what I personally find most remarkable about Elelyso is that this is the first ever FDA-approved human drug produced in genetically engineered plants -- in this case, carrots, developed by the Israeli biotechnology company Protalix Biotherapeutics -- a phenomenon that lets me indulge my interest in medical AND agricultural applications of biotechnology at the same time.
Scientists first figured out how to genetically engineer plants in 1983, and we've been growing them commercially since 1994. Yet, even though scores of medical drugs and countless industrial chemicals have been produced in non-genetically engineered plants for over 100 years, there has been a bit of a taboo against growing medically or industrially useful proteins in genetically engineered plants.
Elelyso is not the first commercial medical product to be produced in genetically engineered plants. In 2006, the US Department of Agriculture approved a poultry vaccine against Newcastle disease produced in genetically engineered tobacco plant cell cultures grown in a laboratory environment. Since the late 1990s, Ventria Biosciences has been growing a protein called avidin, which is used in a number of approved diagnostic tests, in whole, genetically engineered corn plants. And there are a number of other not yet approved plant-grown therapeutic proteins in the development pipeline. All of which is really, really cool.
Aside from being scientifically fascinating (in fan-boy geek sort of way), producing medically useful proteins in genetically engineered plants has a number of advantages over the more conventional way of producing biotech drugs in engineered bacteria, yeasts, or mammalian tissue cultures. Those other methods are very good in many ways. But bacteria and yeasts are too genetically and biologically simple to produce some of the more complex proteins, which require post-translational modifications that single-celled organisms cannot manage. And while animal tissue cultures often work best at producing these complex proteins, they are very expensive to maintain.
Plants, on the other hand, are biologically advanced enough to produce many large, complex proteins. And their maintenance is far simpler -- and therefore cheaper -- than animal cell cultures. It's also much easier to scale up production rapidly from proof of concept to commercial manufacturing with plants than with cell cultures. And the costs associated with doubling, tripling, or quadrupling output are tiny compared to doing so with animal cells.
That cost advantage is already important, but it will become increasingly obvious as we move into a future in which more personalized medicine means that treatment options are targeted to smaller and smaller patient populations. Unfortunately, while FDA may be willing to become more flexible with its own approval requirements for drugs that treat rare diseases, the regulatory requirements for genetically engineered plants imposed by the USDA are growing, not becoming more streamlined. So, this may mean that a big chunk of the plant-based "bio-pharming" cost advantage gets eroded by unnecessarily strict regulatory hurdles.
Still, as investment analyst Ritu Baral told the journal Nature, the Elelyso approval is "a huge proof of concept for the entire platform." It shows that human therapeutic proteins can be produced in genetically engineered plants and that those products can be approved for commercialization. That adds one more weapon to the medical treatment arsenal - and an potentially very useful one at that.