Several presentations exploring issues related to the synthesis, scale-up, and purification of peptides designed for use as therapeutic agents were presented at the “EuroTIDES” meeting held in December in Berlin. The conference also featured speakers addressing the challenges inherent to synthetic peptide production, the changing face of the peptides industry, and the growing emphasis on optimization and quality control in process development.
Zelos Therapeutics’ (www.zelostherapeutics.com) presented 12-month Phase II trial data on Ostabolin-C™, a drug designed to stimulate bone formation, at the conference. Treatment with Ostabolin, a cyclic form of parathyroid hormone, was associated with clinically relevant increases in lumbar spine bone mineral density among postmenopausal women with low bone mass.
Ostabolin-C is a cyclized 31 amino acid peptide. Unlike the bis-phosphonate compounds commonly used to prevent osteoporosis such as Merck & Co.’s Fosamax, which inhibit bone resorption and slow bone loss, Ostabolin-C increases bone formation and is intended for use as a therapeutic agent in patients with moderate-to-severe osteoporosis, reported Paul Morley, Ph.D., CSO and cofounder of Zelos.
The lactam bridge that gives the compound its cyclic structure precludes synthesis of the peptide using recombinant technology. Zelos produces Ostabolin using solid-phase chemistry, which can be done cost effectively because of the high potency of the drug, noted Dr. Morely. It is active at doses ranging from 10 to 45 µg/day.
Peptide drugs in development are getting more complex, with more modifications and more unnatural amino acids. They are also increasingly being linked to carrier molecules to enhance their pharmacokinetic properties and drug-delivery options. Liquid- and solid-phase synthesis methods as well as hybrid processes, which exploit the beneficial properties of each method (peptide fragments are produced on a solid support and then combined into the full-length peptide in solution), all continue to be embraced by peptide producers.
Recombinant methods of peptide production continue to evolve as companies strive to improve titers, to explore multicopy gene constructs and novel expression systems, and to focus on optimizing and automating downstream purification.
The increasing complexity of the compounds is only one challenge for the peptide industry. Oleg Werbitzky, Ph.D, head of R&D, peptides, and oligonucleotides, at Lonza (www.lonza.com), identifies several others: increasing emphasis on improving product quality and process control combined with a need to move toward more robust, cost-effective, and environmentally friendly synthesis and purification strategies as well as demand for a greater scale of production as the range of therapeutic targets broadens.
All of these market pressures and internal demands are helping to drive the development and adoption of new synthetic, downstream purification, and analytical strategies and to push process design and optimization efforts to the forefront.
All of this activity, however, and the incremental changes in theory and practice are taking place in an uncertain regulatory environment. Unlike organic small molecule production, no clear regulatory guidance exists to help peptide manufacturers develop or modify chemical, analytical, and separation processes to improve peptide quality and simplify the regulatory review process.
Without defined regulatory guidance, “Peptides now fall somewhere in between small molecules and biologicals,” said Paul Little, Ph.D., senior chemist at 7TM Pharma (www.7tm.com). “There is no safety net for being able to point to a guidance document and determine what test to do at what step, yet there is still the possibility to take a peptide drug to market along a smooth regulatory path.”
This can be done by providing appropriate scientific justification and taking advantage of the opportunity to speak to the regulatory agencies throughout product and process development. “There is a rumor that regulatory guidance for peptides will be coming out soon,” added Dr. Little.