At Ferring Pharmaceuticals, Peptides And Proteins Make Significant Advances

By Ed Miseta, Chief Editor, Clinical Leader

Keith James, president, Ferring Research Institute and SVP of R&D, Ferring Pharmaceuticals

Dr. Keith James joined Ferring Pharmaceuticals as VP of Therapeutic Innovation in early 2012. In December 2012 he was promoted to president of the Ferring Research Institute and SVP of R&D for Ferring Pharmaceuticals. Prior to joining Ferring, Dr. James spent 29 years working for Pfizer, with significant time spent in discovery research. At the 2013 Oligonucleotide & Peptide Based Therapeutics Congress he will speak on recent progress and future prospects in the peptide and protein therapeutic space. I recently spoke with Dr. James to get an overview of the potential in this market.

Ed Miseta: What do we know about the therapeutic benefits of peptides and proteins?

Keith James: Molecules comprised of amino acids are a key and naturally occurring component of all living systems, and a fundamental element of life processes. People need them in order to live.

We have known for a long time that these strings of amino acids are part of living systems. The small ones are typically referred to as peptides and the larger ones are referred to as proteins. These peptides and proteins have very important biological activities. Over the decades, people have tried to use the biological activity that peptides and proteins possess, in order to gain some therapeutic benefit. Insulin is a classic example of a protein that is naturally occurring. It is critical to the control of glucose levels in the blood, and the fact that some people don't produce enough insulin results in diabetes. Therefore, administration of insulin was one of the very first examples of using a protein therapeutic.

Similarly, the body depends on many small peptides in order to function correctly. For example, the peptide molecule oxytocin has an important role in childbirth. In some cases, there are diseases that result from a shortfall or a lack of these natural hormones.  Administering the peptides can therefore, in theory, have a therapeutic benefit.  However, although the therapeutic potential of proteins and peptides has been understood for a long time, the problem is that they're far from ideal drug molecules.

Miseta: What are some of the reasons for that?

James: They are metabolized, or broken into pieces, very rapidly within the body. If you inject a naturally-occurring peptide hormone like oxytocin into the bloodstream, it's cleared from the bloodstream very quickly. It's attacked by enzymes - called proteases or peptidases - and degraded into its original amino acid components, so it loses biological activity rapidly.

If you ingest it orally, then it's even worse, because the gastrointestinal tract is full of enzymes designed to break up the proteins and peptides that occur in our food. The problem we face therefore is how we can use these molecules as therapeutic agents when they're so fragile.

This concern has likely held back the widespread use of peptide therapeutics. Drug designers have invested their time and energy in alternative areas, like synthetics small molecule drugs, where you can design in favorable properties, like metabolic stability, solubility and long-term stability in tablet form. It is understandable that drug designers have gone in that direction, but I would say that in the last decade or so, people have begun to revisit peptide drugs, and also reconsidered proteins as drugs for a couple of different reasons.

Miseta: What are some of those reasons?

James: With proteins, a biotechnology revolution has opened up the way to producing proteins more efficiently than having to extract them from natural resources. You could actually make them on a large scale, using biotechnology pioneered by companies such as Genentech and Amgen.

This has allowed companies to both make naturally occurring proteins, and to explore new kinds of proteins as therapeutics, such as monoclonal antibodies. Not only can researchers now replace proteins that were missing, they've began to introduce new kinds of proteins that have beneficial properties, such as  blocking receptors or activating receptors, or trapping out other, overexpressed proteins.

As a result, we have seen huge growth in the use of proteins as therapeutics over the last thirty years. There are still issues, and certainly room for improvement, because they're expensive to use and have to be given by injection, but they've made a huge difference in many areas of medicine.

With peptides, it has been a slower process to recognize their potential and address some of the problems in using them, but that has also changed over the last decade. People have begun to appreciate how potent and biologically selective they are.

With peptides, we are able to very precisely modulate specific pathways and, crucially, activate receptors within those pathways. And, using peptides, you can switch on receptors in ways that can be very difficult to do using synthetic small molecule drugs. Also, people have begun to appreciate that, because they're selective and don't distribute widely in the body, they are actually safer than small molecule drugs. There have been studies, analyzing success rates of peptides versus small molecules, and peptides clearly have a higher success rate. Recognizing some of these striking features of peptides, researchers are now putting a focus on solving some of the problems associated with their use as therapeutics.

Miseta: Are we making any progress?

James: Yes. There are now peptide-based drugs that you can give once a day, once a week, or once a month. In some cases, even once every three or six months. Because of this progress, there's more interest in the use of peptides as therapeutics.  Another interesting development has been the emerging area of small, engineered proteins, which can also be regarded as large peptides which have a specific secondary structure, or shape.

They are typically domains from large proteins, which can be produced as stable, stand-alone proteins that can be used in novel ways. If they have the right properties, you can make large libraries of them, perhaps ten to the nine or ten to the ten, and then look for members of these very large libraries that have the biological property you're interested in, for example, binding to a particular receptor on a cell.

Because of the power of numbers, using these vast collections of small proteins, people are actually quite successful at finding examples that have the exact properties that they want. Because these proteins are relatively small, and usually quite stable, they're easy to produce in inexpensive expression systems, perhaps using bacteria, rather than mammalian expression systems.

They actually have become very attractive as a new wave of biological agents that might offer some advantages over the monoclonal antibodies that have become an important part of today's medicine cabinet.  Many companies have been formed based upon these engineered, or scaffold, or mini proteins.

One exciting possibility, looking into the future, is that one could design bi-functional molecules, using this approach. That would be a molecule that has two quite distinct biological activities. You might imagine such a molecule, if carefully designed, could be more effective than a molecule that has just one biological activity, because the world of biology is complex and often modulation of a single molecular mechanism is insufficient to achieve a desired therapeutic effect.

There are many, many technical problems to be solved, but a number of companies are now exploring this possibility. The ideal outcome is to have designed a single polypeptide chain that you've produced in a relatively inexpensive bacterial system, like E. Coli, which then folds itself up into this highly organized molecule that has two fully optimized biological activities.

Miseta: Are there certain therapeutics where this will make a large impact?

James: Yes. There have been a significant number of medical advances based upon peptide drugs. Perhaps one of the most significant recent ones has involved the treatment of type-II diabetes with peptides based upon glucagon-like peptide (GLP I). Researchers realized that GLP I could provide a new therapy for diabetes, through helping restore glycemic balance. GLP-1 is a native peptide that is very rapidly cleared. But now, a number of novel modified analogs have been introduced that are very efficacious and represent a very significant contribution to diabetes therapy. The first ones were for administration multiple times a day, but now there are versions available that you can give once a week. In the future, that may become even less frequent. That's a classic example of the progress being made in this area.

Another important area of need is cancer. The standard therapy these days for the early stage of prostate cancer is to give a peptide called GnRH. It stands for Gonadotropin-Releasing Hormone. It is a very potent decapaptide from which many highly optimized analogs have been designed. In this case, you can give an injection of the peptide every three months, or in some cases, six months. Even though the patient has to have an injection, at least it's an injection that's very infrequent.

The peptide shuts down the production of testosterone, and thus starves the prostate cancer of testosterone and stops it from growing. That's become a very important way of treating the early stage of hormone-sensitive prostate cancer.

Miseta: You mentioned peptides having a dual effect. Are we talking about a peptide that will somehow affect a disease protein in two different ways?

James: Yes, although at this time this remains an emerging field, and there are not many successful examples yet. One good example under active investigation is in the treatment of inflammatory conditions, like psoriasis, which is an autoimmune disease that affects the skin. It's been known for some time that you can use antibodies against a protein called TNF-Alpha. That stands for tumor necrosis factor alpha. There are antibodies against TNF-Alpha that are proving very effective in a number of autoimmune disorders, like psoriasis, arthritis and inflammatory bowel disease. But what people have begun to do now is explore the addition of a second biological activity to the blockade of TNF-alpha.

One particular appealing example is Interleukin-17 or IL-17. Blocking IL-17 is known to be useful in the treatment of psoriasis, and so the thinking is, if you have an agent that blocks both these pathways, it would represent a single agent that could be more efficacious.

Miseta: Any other success stories you can share?

James: The only thing that I haven't talked about, which is another frontier that researchers are exploring, relates to the fact that peptides and proteins typically have to be given by injection, and they do not penetrate cells. They are large, polar molecules and therefore tend to remain in the plasma and in the extracellular space, outside the cells. They also do not penetrate the central nervous system, or the brain, because the brain has a barrier protecting it, called the blood-brain barrier. An area of current investigation, that we hope will open up opportunities in the future, is to find ways to enable peptides and proteins to enter cells or cross the blood-brain barrier.

One possibility being explored is to attach the peptide to another molecule which might be recognized by the cell and transported into cells. This would exploit the naturally-occurring pathways that the cell uses to transport either nutrients or key signaling molecules into cells. The thought being that if you could attach your peptide or protein to one of these molecules that is naturally actively transported into cells, or actively transported into the brain, perhaps you could then use that  pathway to enable your peptide to penetrate.

The caveat is, of course, you now might lose some of the safety benefits of peptides and proteins, because they could potentially then interfere with any of the other processes to which they would be exposed inside cells. If they remain outside cells, then they are less likely to generate adverse effects. Exactly how that will play out in the future, we don't know.

For more information on the Oligonucleotide & Peptide Based Therapeutics Congress: http://www.globalengage.co.uk/oligos-peptides.html