The exploration of peptide therapeutics has yielded many successful drugs that are used in a range of applications, from diabetes and hypertension to angina and chronic pain. What was once a relatively slow journey along the development path – due largely to challenges with stabilisation or delivery and the fact that they are rapidly digested by enzymes in the human body – has greatly accelerated in recent years as these challenges have been overcome, and the benefits of peptide therapeutics come to the fore.

The pharma industry is steadily investing more in the development of new peptide drugs, which have the potential for very high specificity and potency, and low toxicity. The use of these drugs is helping the industry make great strides forward in many therapeutic areas, most notably oncology, metabolic disorders and cardiovascular disease.

"Peptide therapeutics have been on the market for more than 20 years," says Dr Joël Richard, vice-president of peptides at Ipsen. "We are strongly involved in this market, trying to develop new peptide therapeutics and better formulations. It is still a relatively niche market and only accounts for a small percentage of global drug sales, but it has a fast growth rate – well into double digits – and there are many products in development."

Richard leads all of Ipsen’s chemistry, manufacturing and control activities across the development of peptides and small molecules, from pre-clinical development, proof-of-concept and phase III trials through to filing and lifecycle management. Across five sites in the US and Europe, he oversees drug substance development, scale-up and manufacturing of clinical batches; early formulation and the support of research activities; drug product development; process and analytical development; and quality control testing of clinical supplies.

Given that Ipsen is one of the leading companies in what has become a very competitive market, Richard’s responsibilities are central to the delivery of the company’s strategy. Ipsen, which saw its total sales exceed €1.2 billion in 2012, focuses on treatments for neurology, endocrinology and urology-oncology, with much of its R&D efforts centred on peptides and toxins. Among its peptide products is Decapeptyl, a formulation for injection initially developed by Debiopharm, which is used principally in the treatment of advanced metastatic prostate cancer, though also has applications in the treatment of uterine fibroids, endometriosis, precocious puberty and female infertility. Phase III trials are currently assessing Decapeptyl as part of a combined hormonal therapy for premenopausal breast cancer.

Trends in development

Across the industry, peptide drug research is highly visible for its impact in areas such as glucagon-like peptide-1 (GLP-1) analogues for diabetes, and luteinising hormone-releasing hormone (LHRH) analogues – widely used in oncology as hormone-dependent cancer treatments.

The ‘Development Trends for Peptide Therapeutics’ report of 2010, which was based on data from the Peptide Therapeutics Database, showed an increase in approved peptide new chemical entities (NCEs) across the globe and a significant rise in the number of peptide NCEs entering clinical development. Other notable trends were an increase in the size of peptides being developed and the consequent evolution of synthetic manufacturing methods, along with increased diversity of molecular targets and therapeutic areas. Since the report, momentum has built further, in part because of the relatively high development success rates – similar to those reported for biologics.

"The flexibility of peptides in terms of administration and manufacture is a big reason for the industry’s renewed interest in this area of research."

"Of the five top-selling products on the market, which account for around 50% of the total sales of peptide therapeutics, some have been available for a very long time," says Richard. "When you think about what is making this area of research more popular, you must consider that a lot of companies know how to provide peptides in large volumes, in terms of controlling synthesis by the chemical route. The price could be a lot higher if they were entering the market via the biotech route."

The report, put together by the Tufts Centre for the Study of Drug Development (CSDD) between 2000 and 2010, found that the number of new peptides entering clinical testing had
doubled, and half of the 334 peptides that had been subjected to clinical testing had been taken to the stage of human testing. At the moment, there are around 80 peptide drugs on the market, although hundreds more are at the clinical or pre-clinical stage.

These drugs are increasingly focused on metabolic conditions – which, in a distinct shift over the last 20 years, has become the primary target – and cancer. There is also a focus on other clinical fields such as cardiovascular disease, conditions affecting the central nervous system, autoimmune diseases and gastrointestinal conditions.

Why now?

One of the key reasons for the renewed interest in peptide therapeutics is their perceived advantage, in some respects, over biologics.

"In biotech, the market for leading products is very crowded. For instance, there are many monoclonal antibodies under development. Peptides face fewer immunogenicity issues than biologics. In addition, with peptides, all routes of administration, including oral, are possible. Peptides are less complex than biologics," explains Richard.

Peptides have a number of distinct advantages over small molecules because of their greater affinity for targets. Their short serum half-life, and sensitivity to serum and tissue proteases have, however, been big hurdles to the development of drugs reaching the market. Nevertheless, the development of selection methodologies that address protease resistance and various methods to prolong the half-life have gone a long way towards making peptides an accepted drug class in their own right, with great potential for the future.

"As the technical issues that have limited peptide drug development are steadily overcome, some feel that a new superclass of drugs could be unearthed."

Solid-phase methodologies and novel approaches in organic synthetic chemistry have accelerated the drug development phase for peptides, and made research and development more economical than is the case with small molecules. Monoclonal antibody therapy, in which monoclonal antibodies specifically target cells or proteins and potentially drive a patient’s immune system to attack those cells, is a fertile space for biotechnology research. It is leading to treatments for diseases such as rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease and various cancers. One of the advantages that peptides have over such treatments is their ability to be administered by different routes, such as injection or oral delivery.

"The flexibility of peptides in terms of administration and manufacture is a big reason for the industry’s renewed interest in this area of research," notes Richard.

Market potential

The market for peptides has already delivered on its potential to yield high sales. At the time of the CSDD report, four US-approved peptide drugs – multiple sclerosis treatment Copaxone and the hormone-related products leuprolide, octreotide, and goserelin – had seen sales exceed $1 billion, and the global value of sales for around 60 peptide drugs was almost $13 billion. Recombinant osteoporosis therapy Forteo from Eli Lilly and diabetes drug Byetta, from Eli Lilly and Amylin Pharmaceuticals, are among the other drugs achieving high volumes of sales.

As the technical issues that have limited peptide drug development are steadily overcome, some feel that a new superclass of drugs could be unearthed.

"Pharmaceutical companies now realise the strong potential for peptides, in part because they see that they are less complex than treatments that would be produced through the route of biotechnology," says Richard. "There is a much lower cost to enter the peptides market than if a company chose to get into biologics. Those are some of the reasons why Ipsen is focusing a lot on developing peptide-based drugs.

"We are working on new compound discoveries, new formulations and routes of administration, and our principal focus is on endocrinology. We are working on treatments for acromegaly and neuroendocrine tumours, and drugs for uro-oncology and hormone-dependent cancers. So, for us, peptides represent a major, strategic way to bring new products to market that are more efficient and have higher efficacy," he adds.

"R&D in the peptide therapeutics space is highly dynamic, with work being done on oral delivery and new compounds."

Improving the viability of oral delivery for peptides is high on the agenda of major pharmaceutical companies that are moving further into this space. The recent deal between Chiasma and Roche to develop an oral form of the somatostatin analogue octreotide is a key indicator of this trend.

The drug, under the name Octreolin, is currently in phase III clinical trials for acromegaly – a condition where a patient’s pituitary gland produces excess amounts of growth hormone – and phase II clinical trials for neuroendocrine tumours. As of now, the peptide octreotide is commercially available only by injection. Octreolin is an investigational oral regimen that would give patients an alternative to the frequent injections currently required.

"The acquisition by Roche moves it into areas where peptides are effective and it is focusing on oral forms of peptide therapeutics," Richard remarks. "Roche can likely produce peptides in very large volumes at low manufacturing costs, which is very important as the bioavailability of the treatments is low."

A bright future

Research and development in the peptide therapeutics space is highly dynamic, with work being done on oral delivery and new compounds. Researchers at the University of Alberta, for instance, have developed a synthetic version of the peptide apelin, which could help patients with heart disease, high blood pressure and diabetes by targeting pathways in the heart, and promoting blood vessel growth.

Another exciting development is the progress made by Aileron Therapeutics in developing a drug that could affect proteins made by two genes, the effect of which is usually to shut down gene p53 – the tumour-suppressing gene. Every type of known cancer shuts down p53, so if the company’s pre-clinical work with peptides was to lead to a treatment that prevented this, it could mark a big step forward in cancer treatment. From such examples, it is easy to see the potential of peptides to revolutionise drug development, although no one believes that the road ahead will be easy.

"Peptide therapeutics could have a big impact in terms of providing additional routes of administration, as well as safer products. These are both very important motivations for companies to work in this field," says Richard. "Improving the way drugs are administered to the patient is essential as it is important to increase not only compliance, but also quality of life. If we can reduce the frequency of administration, for instance, and achieve longer periods of release for injected products, then we will see better patient outcomes – and that is what this industry is all about."