A Low-Risk, High-Potential Approach to Next Generation Therapeutics
In our industry, we constantly search for the “next generation” of therapeutics through the use of novel approaches that overcome the limitations of existing technologies. However, testing therapeutics based on novel technologies is an undeniably risky process. Cutting-edge siRNAs and gene therapies offer a significant opportunity, but also carry greater risk than current technologies. Some companies have employed an alternative strategy: re-examining and upgrading existing molecules using novel technologies, thus mitigating some risk associated with drug development.
One type of molecule that has been at the center of this movement is peptides. Peptides have always been noted for their selectivity, potency, and rapid optimization. Despite the potency and diversity of peptides, the industry has had limited success in turning peptides into therapeutic products due to their extremely short half-life. With new approaches coming to the forefront, sophisticated, long-acting therapeutics have been developed that re-open the opportunity to create peptide-based therapeutics.
One early approach to extending the half-life of peptides—thereby modifying existing molecules to create commercial opportunities—was through depot formulations. Once thought to represent a durable solution to extending the duration of action of peptides, depot formulations have unfortunately only seen limited success in niche applications. While these polymer-based therapeutics often have good safety and highly predictable pharmacokinetic profiles, the timing of their delivery method and injection site reactions have lead to dissatisfaction among patients and physicians. For example, due to the necessary formulation modifications, depot formulations often require a larger needle size and injection volume, which can result in patient discomfort and non-compliance.
Another example of upgrading existing molecules that has experienced greater commercial success is pegylation. Enzon Pharmacueticals (Bridgewater, N.J.) and Nektar Therapeutics (San Carlos, Calif.), for example, have both created viable drugs by chemically attaching polythethylene glycol (PEG) polymers to large macroproteins (e.g. interferon). Second generation, site-specific pegylated molecules are now being developed with even greater potential. For example, Ambrx Inc. (San Diego), using its novel approach to pegylation, is conducting a Phase 1/2 clinical trial in conjunction with Merck Serono (Darmstadt, Germany ) with its long-acting human growth hormone product. Pegylation also has its limitations in that it generally does not work well with smaller peptides. As a result, the search for an alternative mechanism has brought forth an emergence of novel protein scaffolds, which promise to deliver powerful drugs: peptide-based drugs that are both therapeutic and commercial successes.
Protein scaffolds began with genetically expressed fusion molecules with peptides attached to carrier proteins such as albumin, antibody Fc fragments, and other large protein structures. Protein scaffolds have demonstrated the ability to generate very successful products, exemplified by Enbrel (etanercept) marketed by Amgen Corporation (Thousand Oaks, Calif.) and Wyeth Pharmacueticals (Philadelphia, Pa.), a TNF receptor:Fc fusion for the treatment of arthritis. There are also numerous protein scaffold molecules in clinical trials from Amgen (Fc fusion peptibodies) and Human Genome Sciences (Rockville, Md.) (albumin:interferon fusion), among others.
While these approaches successfully increase half-life, they have limited alternatives for displaying the peptide within their structures, which may result in a suboptimal product profile.
More recently, a conceptually new approach to novel protein scaffolds has emerged through chemical fusion of peptides with particular proteins. These fusion scaffolds can provide the same half-life but with greater freedom to display peptides in various orientations across the surface of their carrier. In contrast to genetically expressed fusions, these technologies allow peptides to be linked throughout their sequence, providing a way to optimize the potency and pharmacokinetic profiles of the therapeutic.
To this end, scaffold proteins incorporating genetically or chemically fused peptides, hold the promise to effectively and economically produce bi-functional therapeutics. The ability to efficiently use peptides may lead to a therapeutic that incorporates three desirable qualities in drug development: highly efficacious, cost-effective molecules that are capable of addressing a diverse range of targets.
About the Author
Rodney Lappe, PhD, chief scientific officer of CovX (San Diego), has advanced drug discovery portfolios and promoted multiple therapeutic candidates through pre-clinical and clinical development at companies such as Pharmacia and Wyeth Laboratories.
Filed Under: Drug Discovery