Peptides play significant roles in modulating the function of our cells, and hence controlling physiological processes. For a long time, the molecules were largely ignored by drug developers, but their potential for addressing a growing range of biomedical conditions is becoming clear. Key commercialised products include somatostatin analogues (acromegaly), glucagon-like peptide-1 (GLP-1) analogues (diabetes), glatiramer (multiple sclerosis), calcitonin (osteoporosis) and desmopressin (bedwetting).

In the 1970s, the average frequency of peptides entering clinical trials was around one a year. By 2020, that number will be close to 20, and six peptides received approval from FDA as new molecular entities in 2012. Around 80 approved peptide drugs are on the market and numbers are increasing dramatically, with a continuous annual growth rate of 10%.

It’s not just the numbers that are striking though; peptide therapies are now addressing a wide range of disease areas from hormonal problems, through to pain and blood disorders.

Hybrid technology

Peptides are classed as hybrids. Too large to be considered small molecules, they are often equated with proteins because of their amino acid content and poor absorption, but they have their own distinct properties. They are mostly produced using step-by-step chemical processes, differentiating them from biologics, which require recombinant methods of production. They’re smaller than proteins, too, and are arbitrarily defined as containing 50 amino acids, or fewer. Insulin lies right on the cusp. Peptides have proved more popular as the chemical era of drug development has faced increasing challenges. Development pipelines, once dominated by small molecules are now characterised by incredibly high attrition rates. In a typical drug development process, more than 90% candidates would fail to reach the market.

"Until now, peptides have been a niche concern, with a relatively small percentage of total drug sales. The market is now growing very fast and there are many products in development. It’s all very promising."

"In the last few decades, the industry has faced a kind of wall, because it has become increasingly difficult to find new leads to coerce into chemical development, due to poor absorption of these new molecules which became more and more complicated," reveals Joël Richard, senior vice-president of peptides at Ipsen.

Best of both worlds

With 25 years’ experience in the pharmaceuticals industry, Richard leads Ipsen’s development (chemistry, manufacturing and control, or CMC) activities of peptides across various sites in Europe and in the US. The company, which is based in Paris, is a leading organisation in the peptide market and focuses on treatments for neurology, endocrinology and urology-oncology.

Among its leading marketed peptide products is Decapeptyl, a formulation used principally in the treatment of advanced metastatic prostate cancer, but also for uterine fibroids, endometriosis, precocious puberty and in vitro fertilisation.

Richard explains that, around the same time as the industry realised it couldn’t rely on small-molecule drugs any more, the biotechnology sector was successfully developing monoclonal antibodies. These biologics represented an ability to generate large revenues because of higher prices, and were markedly less susceptible to competition.

Additionally, side effects were not such a concern with small-molecule therapeutics because the biologic drugs bound to receptors with higher specificity. However, initial investment and manufacturing costs were high. Peptides began to look like they could be the best of both worlds: less complicated to produce than biologics, but able to address interesting targets without causing serious immune responses or accumulating in specific organs resulting in severe toxic side effects.

"Until now peptides have been quite a niche concern, with a relatively small percentage of total drug sales. The market is now growing very fast and there are many products in development. It’s all very promising," says Richard.

There are many different therapeutic areas in which peptides are having an impact. For example, LHRH analogues can be used to treat breast and prostate cancers, while exenatide has proved useful for type 2 diabetes.

While the most successful developments are in diabetes, hypertension and chronic pain, the span of therapeutic fields is growing every year. Richard reckons that there are about 130 peptide drugs in clinical development at the moment, and about 500 in early discovery phases.

Stuck with needles

One snag to the upsurge in peptide development is the administrative route required to get the drug where it needs to go. Injections are the most common means of application for these types of molecules; oral delivery is a major stumbling block. No one likes injections, and taking tablets is far more convenient. Designing oral peptide drugs has been a persistent challenge, though, largely because of the molecules’ unfavourable physicochemical properties, which include large size, susceptibility to enzymatic degradation, short half-life and a tendency to undergo denaturation.

Even if a peptide could survive the harsh conditions of the stomach unassisted, it would have to cross an impermeable membrane in order to be absorbed.

Designing a peptide formulation for delivery through GI (gastrointestinal) tract requires a multitude of strategies. Firstly, the drug must be protected from the extreme acidity and action of enzymes (mainly pepsin) in the stomach. The formulation also needs to facilitate aqueous solubility at neutral pH and lipid layer penetration, or transient tight junction opening, for the peptide to cross the intestinal membrane and enter the bloodstream.

It’s not always a losing battle, though, says Richard. Some marketed oral peptides exist, most of which have a local action with the intestinal tract. Linaclotide, for instance, is a peptide agonist of guanylate cyclase C that inhibits mechanosensitivity of colonic sensory neurons to reduce abdominal pain, while activating secretion of ions and fluid into the intestinal lumen and acceleration of intestinal transit. The FDA approved the drug in August 2012 for the treatment of irritable bowel syndrome with constipation. It is forecast to achieve blockbuster status within the next six years.

"Like most oral peptides, it’s cyclic, which means it probably has higher resistance to peptidase. This shows the importance of peptide design for oral delivery," says Richard.

Mucus pocus

Luckily for drug developers, the last decade has seen a surge in technological approaches to improving the absorption of peptide therapeutics. Oral absorption enhancers are one such means. These formulation components help peptides penetrate the intestinal membrane by favoring endocytosis in the epithelial cells, or by temporarily opening tight junctions between them. Richard reveals there are many products in phase III trials that rely on such technologies.

Elsewhere, companies are trailing conjugate technologies that attach molecules with specific, self-penetrating properties to drugs. Nanoparticles (colloidal carriers 1-1,000nm in size) too are emerging as useful strategies. These create a close carrier that protects the API from destabilising when it comes into contact with enzymes, and also enhances their capture by the surface of the epithelial cells.

"In addition to these approaches, there’s a technique I would call mucoadhesive systems, which make it possible to keep the peptide for longer in the mucus of the intestinal membrane," says Richard. "Also, most of the technologies today are looking to tackle the issue of stability in the gastric environment using enteric-coated capsules."

"Advances in oral-enhancing technologies for peptide-based therapeutics will probably mean peptides become a more significant class of drugs in the near future."

An enteric coating is a polymer barrier applied to oral medicines. It helps to protect drugs from the low pH in areas like the stomachm where it is not soluble, and then dissolves at the intestine pH so the therapeutic drug can reach the small intestine unharmed. There’s no shortage of techniques, and these advances in oral-enhancing technologies for peptide-based therapeutics will probably mean peptides become a more significant class of drugs in the near future.

Richard concludes that we should expect "a lot of oral peptides on the market in the next few years". For example, an oral form of calictonin was developed recently. A tablet was shown to enhance the drug with once-daily oral dosing.

However, current use of the therapeutic product has been hampered, since FDA and EMA subsequently advised against use of calcitonin in osteoporosis treatment.

An absorbing issue

Richard is confident that other, orally administered candidates will soon come through, but stresses that other alternatives to injections are still worth investigating. After all, even if drug developers do use their preferred absorption-enhancing technology, dosage is likely to remain an issue.

Low oral bioavailability means that larger concentrations of drugs in tablet form are required to achieve the same doses as injections, which would increase the cost of goods and pile pressure on manufacturing capacity.

"Oral administration is only one route, after all" says Richard. "You might also consider transdermal, or nasal, where the bioavailability is that much higher. These methods have their respective pros and cons as well, of course, but it’s worth considering a range of routes of administration when developing a peptide product."