What are some of the current barriers or challenges to the development of peptide therapeutics?
Peptides constitutes interesting drugs in many ways. However, there are also challenges associated with peptide drug discovery and development. The synthesis challenges can be addressed. The main issues are associated with the plasma half-life and low bioavailability. Furthermore, nearly 95% of the approved peptide drugs are injectable. The drug product sterile manufacturing is an area requiring special expertise. The drug needs to be reconstituted before the injection to the patient, which usually requires intervention from the physician. Fortunately peptide drug delivery has progressed a lot over the past 15 years.
Can the goal of orally bioavailable peptides be achieved?
Yes absolutely. We are getting very close. Multiple teams and companies across the academia and industry are working on new oral peptide drug delivery tools/platforms. We start seeing in vivo
bioavailability data in the 10-15% range or higher, depending on the peptide sequence and length. This development complements the existing technologies consisting of long-acting release formulation using polymer or liposomal encapsulations. Oral peptide drug delivery will substantially change the face of this already interesting business.
Will macrocyclic peptides be the answer?
Definitely! By constraining the peptide backbone through cyclisation and introduction of non-natural amino-acids, one increases the peptide bioavailability by decreasing the enzymatic degradation. There are multiple orally delivered peptides in clinical trials. Multiple cyclizations are necessary for a peptide to become orally bioavailable. Linaclotide is a good example. Other similar peptides are in clinical trials phase 2 and 3.
Are peptide therapeutics getting more complex (un-natural amino acid substitutions, modifications like PEGylation or lipidation)? What challenges will that pose to manufacturing (chemistry, sourcing raw materials, scale-up)?
Yes, there is a clear increase in product complexity. The chemistry has made it possible for discovery to consider very complex molecules as their target leads. Peptide modifications such as the more commonly used conjugations, (i.e. lipidation, PEG-ylations, glycosylation) and cyclizations, as well as the introduction of un-natural amino-acids in the sequence, are usually meant to increase product stability in the plasma and decrease the dose and side effects.
Sourcing complex raw materials is always difficult. In this context of peptide modifications, sourcing building blocks or intermediates can be a challenge. Usually the sourcing company has to provide a production process to allow the supplier to make the said building block or starting material.
The current challenges in peptide manufacturing are impurities especially in peptide APIs. How are you handling this problem?
Chemistry Manufacturing and Control (CMC) of peptides can be very challenging. The analytical part is absolutely key for a robust CMC. Impurity detection and monitoring, for stability studies for example, usually require more than just an HPLC/UPLC method. Identifying and characterizing the impurities require special skills in mass spectrometry. As regards regulatory issues, batch to batch consistency requires both a robust manufacturing process and robust analytical methods to demonstrate that the impurity profile and impurity level is reproducible. Analytical process technology and understanding the rational for impurity formation is therefore key.
What emerging analytical technologies are you currently using or plan to use to resolve these challenges?
Peptide based impurity can be process-related or associated with peptide degradation. Their characterization involves HPLC-MS, UPLC-MS and MS-MS method for structure elucidation. In some difficult cases the impurity must be isolated and sequenced using standard methods such as Edman degradation. Impurities coming from the racemization during the coupling steps can be determined by GC-MS. In this case the peptide is fully hydrolysed, and the resulting amino acids derivatized (amine as trifluoroacetate, carboxylic function as Isopropyl-ester) and tested by GC-MS.
One of the challenges that require atypical analytical methods for classical peptides is aggregation or gelling. In this case there are multiple methods that can be used such as size exclusion chromatography (SEC), dynamic light scattering, asymmetric field-flow fractionation, and light obscuration.
Read the full article here.
Read the full issue of Chemica Oggi Oligo & Peptide Supplement, April 2015 here.