Previously (in the Fall 1997 newsletter), we reported on the work of a private company, IBEX Technologies in Canada, to treat PKU in a way not involving gene therapy. Their approach involves inserting an enzyme into capsules. The enzyme, while not the phenylalanine hydroxylase enzyme missing in PKU, metabolizes phenylalanine. It is called phenylalanine ammonia lyase (PAL) and can be mass-produced by bacteria. Since 1992, IBEX has been developing several general technologies for orally administering enzymes that act in the gastrointestinal tract. As previously reported, the technology is applicable to treatment of PKU and other inborn errors of metabolism where enzymes are needed to reduce excess levels of amino acids. Using microencapsulation techniques, they hope to deliver enzymes intact into the gastrointestinal tract, where they would then act to capture specific excess amino acids like phenylalanine.
Several years ago, IBEX licensed the patent for the gene that will "program" bacteria to make the enzyme. The company is now in the early stages of evaluating the feasibility of this work for PKU treatment. Mr. Paul Baehr, CEO of IBEX, graciously agreed to summarize the obstacles remaining in developing this new treatment. He outlines the various phases of research that are required for all new drugs and technologies, such as gene therapy trials.
In order for Phenylase to move forward as a drug candidate, several immediate problems must be solved in the lab and in animals. First, we must find a reliable method for protecting PAL from degradation in the intestine. Dr. Thomas Chang of McGill University has worked on this problem for over five years; IBEX has been working on it for three years. Although we have made some progress, we have yet to arrive at a workable method. And unfortunately, we have no assurance that we will ever be able to protect PAL in a way that is going to be effective and safe for long-term use. But should we discover a method for protecting PAL from intestinal degradation, we would begin animal trials to gauge effectiveness of our formulation (Phenylase) and to determine what dose in humans might be suitable.
If animal trials show that Phenylase is effective at lowering phenylalanine levels and shows no apparent toxicity, we would step up our efforts to find a way to produce PAL economically, in large quantities, and at a purity level sufficient to use as a drug. This will not be a trivial exercise. And there is no assurance of a positive outcome. The quantities of PAL required relate more to industrial batch sizes than pharmaceutical batch sizes, but industrial production plants are not acceptable to the FDA for drug manufacturing. We could spend several years before we are either successful, or decide that the problem is not solvable.
If we have the good fortune to solve these problems satisfactorily, we could then start what is known in the industry as "formal drug development." First, we would need to produce sufficient drug to perform FDA-standard toxicology trials. These trials are required to ensure that the drug being developed does not create side effects that are disproportionate to its benefits (that is, one might accept a level of liver toxicity in a drug that stopped the progression of AIDS that you would not accept in a drug for the common cold). In the case of PKU, one would need a drug with a very "clean" safety profile. Such studies would take place in multiple animal species, would take about a year to complete, and would cost around $2 million (including producing the drug).
Once we were assured of the safety aspects, we would then request authority from the FDA to study PAL in humans. The first human trials, known as Phase I trials, must be conducted in healthy volunteers (not patients), would take about a year, and would cost about $1 million. In these trials we look at safety, first in single doses and then repeated doses.
When we are satisfied the drug is safe in healthy volunteers, we move into our first study in patients. These are known as Phase II trials, and fall into two sub-phases. In Phase IIa, we again look primarily at safety to ensure the drug is as safe in a patient as it is in a healthy volunteer. If results are satisfactory, we move onto Phase IIb. These are preliminary efficacy studies in patients. Phase II studies would cost about $3 million and would take about two years.
If the effectiveness and safety is satisfactory in Phase II, we would then request permission from the FDA to move onto Phase III trials. These are large-scale safety and effectiveness trials. In this phase, we would be looking at 500-1000 patients over a period of not less than three months. These trials would actually be very complicated in the PKU population because the FDA requires two well-controlled double-blind trials. In other words, one group would receive drug, and one would receive a placebo (a sugar pill which looks exactly the same as the study drug). The protocol for such a trial in this population has not yet been worked out. In any event, such a trial would probably take three years to complete and would cost somewhere around $10 million.
If the results of this phase are positive, a submission is then made to the FDA. In the best of all worlds, they would take about two years to review and approve the drug for commercial use.
The "best-case" scenario looks like this: