Peptide Drug Development: Delivery, Conjugates and Scale

The Future of Peptide Drugs

Peptide therapeutics are changing in how they are delivered, how they are designed and how much of them must be made. The approvals of oral semaglutide and octreotide have demonstrated that oral delivery is clinically feasible. Conjugate architectures are extending the modality further: receptor-targeted radionuclide therapies are already established clinically, while peptide-drug conjugates are being explored to deliver other payloads. Conformationally constrained designs, such as cyclic peptides, are opening new approaches to better delivery and less off-site toxicity. Across the broader pipeline, these strategies are being pursued in oncology, immunology and rare diseases, while metabolic disease is pushing peptide manufacturing toward a commercial scale the modality has rarely seen.

"Peptide-based medicines are transforming treatment approaches in metabolic diseases, while sophisticated peptide conjugates and other targeted delivery technologies are expanding the possibilities for precision medicine," said Yu Lu, Senior Vice President, WuXi TIDES, part of WuXi AppTec.

The opportunity is expanding faster than the development infrastructure around it. As chronic-dosing indications push peptide programs toward oral delivery, more complex molecular architectures and larger volumes, discovery chemistry, drug-product engineering and process development have to keep pace, turning a broader design space into medicines that can be manufactured reliably at scale.

Keeping pace depends on decisions that chemistry, formulation and process teams make at different stages. These include a medicinal chemist selecting a scaffold, a formulation scientist assessing whether an oral presentation is feasible and a process team determining whether a discovery route can withstand scale-up. Three shifts are bringing those decisions closer together and forcing development questions to be addressed earlier than before.

Oral peptide delivery: absorption routes and API volume

For many therapeutic peptides, oral bioavailability without specialized formulation or molecular engineering is well below 1%, according to a March 2026 review in Frontiers in Drug Delivery. One exception is cyclosporine, which showed that oral exposure was possible for a macrocyclic peptide, but its unusual structural properties proved difficult to generalize.

Two approvals helped broaden the field's view of what oral peptide delivery could look like. Oral semaglutide combines the peptide with salcaprozate sodium, or SNAC, which raises the local gastric pH, reduces pepsin-mediated degradation and promotes predominantly transcellular absorption across the gastric epithelium. Oral octreotide uses a different strategy: sodium caprylate, delivered in an enteric-coated capsule, is understood to modulate intestinal epithelial tight junctions and may also perturb cell membranes, thereby enhancing absorption across the small intestine. Together, they showed that clinically viable oral peptide delivery can be achieved through more than one absorption pathway, which gives other programs more than one strategy to explore.

When oral bioavailability is low, however, the amount of peptide active pharmaceutical ingredient (API) that must be produced for each patient can far exceed the amount that ultimately reaches systemic circulation. The rest of the peptide still has to be synthesized, purified and released to specification. As oral peptide therapies move into large chronic-disease populations, that low oral bioavailability can translate into a substantially higher API requirement per patient and, at scale, a significant manufacturing burden.

Peptide conjugates and cyclic peptides add process and analytical work

Beyond acting as the therapeutic agent itself, peptides can serve as targeting ligands, carry therapeutic or diagnostic payloads, extend the circulating life of a molecule, or be constrained into defined three-dimensional structures capable of engaging difficult biological interfaces.

Peptide-drug conjugates link a targeting peptide to a pharmacologically active payload, typically through a linker designed to control stability and release. They apply a targeting strategy similar to antibody-drug conjugates, but in a substantially smaller molecular format. That smaller size can favor tissue penetration and reduce immunogenic potential, while chemical synthesis offers considerable control over the composition of the construct. Their pharmacokinetics create a different constraint. Peptides generally clear much more rapidly than antibodies, placing greater demands on target affinity, linker stability, payload potency and the timing of payload release.

Lipidation extends circulation time by attaching a fatty-acid moiety through an appropriately designed linker, which promotes reversible binding to serum albumin, reduces renal clearance and prolongs systemic exposure. Together with sequence modifications that improve enzymatic stability, these albumin-binding strategies helped enable longer-acting peptide therapeutics. Similar pharmacokinetic engineering is now being explored across a broader range of peptide therapeutics.

Peptides can also act as highly selective delivery ligands for radionuclides. Peptide receptor radionuclide therapy combines a receptor-binding peptide with a linker, a metal chelator and a therapeutic radioisotope. Lutetium-177 dotatate, used in somatostatin receptor-positive neuroendocrine tumors, is an established example.

These molecules carry a manufacturing problem of their own. A chelator selected to bind the intended radionuclide can also bind trace metals from solvents, reagents and container surfaces. The resulting complexes are hard to separate and identify for three reasons: they are structurally similar to the product, they can co-elute during purification and they resist assignment by mass alone. They have to be controlled from the start of process development because they are hard to remove downstream. Solvent systems, order of operations, and container and closure materials are selected against a metal budget, and the analytical method has to resolve species that differ only in which metal occupies the chelate.

These architectures also make development more chemically demanding. Cyclization, stapling, lipidation, chelator installation and payload conjugation introduce transformations beyond linear peptide assembly, along with new process-related impurities and analytical requirements. Metal-catalyzed reactions may require residual-catalyst controls. Chelators introduce sensitivity to trace metals, while potent payloads add their own impurity and containment requirements. As architectures become more specialized, the control strategy must be designed around the chemistry of the individual construct rather than transferred unchanged from one peptide to the next.

Peptide manufacturing scale-up: raw materials, purification and drug product

Peptide synthesis has advanced substantially in scale, speed and efficiency, and program speed now depends on the entire manufacturing chain. As sequences become longer, architectures more complex and commercial demand greater, the critical path runs through raw materials, purification, isolation and drug-product manufacturing.

Hybrid synthesis combines solid-phase and solution-phase chemistry, so selected fragments can be prepared separately and joined convergently instead of building the entire sequence one residue at a time. This reduces the number of coupling and deprotection cycles performed on the full-length chain and lowers the material, solvent and time burden of large-scale synthesis where the sequence allows it.

Biocatalysis is also expanding the route-design toolkit. Enzyme-mediated peptide bond formation and fragment ligation can provide highly selective alternatives to conventional chemical coupling for suitable substrates, while reducing reliance on some stoichiometric coupling reagents and the waste they generate. Advances in enzyme discovery, screening and engineering are making these approaches relevant to complex peptide and peptide-like molecules.

Building-block supply has become a development decision. Many of the unnatural amino acids, linkers and chelators these molecules depend on are either unavailable commercially at the scale a clinical program needs or available from only one supplier, with lead times that can run for months. For specialized components, the building-block route may need to be developed in parallel with the peptide itself.

Downstream, technologies such as tangential flow filtration, continuous or semi-continuous chromatography and other intensified operations can improve solvent use, throughput and product recovery for appropriate peptide processes. Drug-product technologies add another layer, since formulation, drying and fill-finish capacity must ultimately scale with the API they support.

Beyond synthesis, a peptide program can stall when a specialized building block cannot be supplied reproducibly, when purification capacity is not available at the time the program needs it, or when the drug-product process cannot handle the volume the molecule will ultimately require. Securing those elements early is increasingly part of making the molecule developable at all.

Peptide developability starts at molecular design

Oral delivery, conjugation, molecular constraint and large-scale manufacturing can each be treated as separate development disciplines. However, the decisions made in one area often determine what is possible in the others. For complex peptide therapeutics, developability is therefore shaped not only by what the molecule does biologically, but also by how it will be synthesized, purified, formulated, analyzed and supplied.

A macrocyclic scaffold selected to improve permeability may require specialized amino acids and a particular ring-closing chemistry, which in turn creates its own process and impurity-control requirements. If that chemistry relies on a metal catalyst, residual-metal control may also need to be considered during route and analytical development. Lipidation illustrates the same principle from another direction. A modification introduced to prolong systemic exposure can also change hydrophobicity, solubility, self-association and aggregation behavior, with consequences for purification, formulation and drug-product development.

Once a development candidate has been nominated, changing its sequence, site of modification or conjugation strategy can require substantial additional characterization and biological evaluation. If analytical, process and formulation teams enter only after molecular design is largely fixed, they have less opportunity to influence the properties that ultimately drive impurity formation, manufacturability, stability or solubility. Bringing developability considerations into optimization earlier allows those risks to be identified while the molecule can still be changed.

In practice, that means planning these capabilities together:

Molecular and conformational design, including macrocyclization, to balance target engagement with permeability, stability and manufacturability during optimization.
Specialized building-block development and supply so that nonstandard amino acids, linkers or other critical components have scalable and reproducible routes before the candidate depends on them.
Conjugation chemistry, including lipidation, linkers, chelators and payload attachment, with the resulting effects on physicochemical properties and impurity profiles considered during design.
Formulation and drug-product development to translate molecular properties into a stable and reproducible dosage form, including the specialized requirements of oral peptide delivery.
Analytical development and impurity control capable of distinguishing closely related sequence variants, conjugation products, process-related impurities and, where relevant, metal-containing species.
Process development and manufacturing to convert increasingly complex chemistry into robust processes that remain reproducible as programs move from discovery quantities to clinical and commercial supply.

"By connecting chemistry development, manufacturing, and supply within a unified system, teams can operate in parallel, anticipate challenges, and maintain consistent quality across regions," Yu Lu added.

Peptide candidate selection: six questions for the design team

Each question below can be answered during lead optimization. Early answers do not eliminate development risk, but once a candidate is fixed, reopening any of them can delay the program and raise its development cost.

Does every nonstandard component have a scalable, reproducible supply route? Source or route-develop unnatural amino acids, linkers and chelators before the candidate depends on them. A building block available from one supplier, with a lead time of several months, belongs on the program risk register.
What does each modification do to the molecule's physical behavior and impurity profile? Lipidation, conjugation and chelator installation change hydrophobicity, aggregation and the species an analytical method must resolve. Review those effects at the design stage, before they surface in a deviation report.
Is an oral presentation feasible, and what API quantity does it imply? If the target product profile calls for oral dosing, estimate the permeation-enhancement strategy, the achievable bioavailability and the API demand per patient during optimization. Those numbers set the manufacturing scale the program will eventually need.
Can the analytical method distinguish the species that matter? Closely related sequence variants, conjugation products, process-related impurities and, where relevant, metal-containing species all have to be resolved and assigned. When analytical teams develop the method alongside the chemistry, they can find a co-eluting species the method cannot resolve before they set the control strategy.
Will the discovery route survive scale-up, and if not, what replaces it? A route built to supply discovery quantities may need redesign for kilogram scale. Decide early whether the program will move to a hybrid solid- and solution-phase route, a biocatalytic step or intensified downstream processing, so process development does not restart at the first scale jump.

Avoidable delays in complex peptide development

Several of these development delays trace back to early planning decisions.

Sourcing specialized building blocks after the candidate is fixed. When an unnatural amino acid or linker turns out to be single-source or unavailable at scale, the program faces a long wait or a redesign that reopens biology. Qualify or route-develop every nonstandard component during optimization.

Planning synthesis capacity without downstream capacity. Programs that secure chain-assembly capacity, but not purification, isolation, formulation or fill-finish capacity, find the constraint at the first commercial-scale campaign. Plan the whole chain, from raw materials to drug product, as one process.

Bringing the analytical team in last. If analytical development begins after the route is locked, co-eluting species and unassignable peaks turn into schedule delays. Run analytical development in step with route development so resolution problems surface while the chemistry is still open.

Peptide drug development trends: open questions

Question: How far can oral peptide delivery extend into chronic disease?

Answer: Oral delivery is already clinically viable for chronic treatment, but not for every peptide. Oral semaglutide and oral octreotide reach useful exposure through different permeation-enhancement strategies: SNAC supports predominantly transcellular absorption of semaglutide across the gastric epithelium, while octreotide's sodium-caprylate formulation transiently modulates intestinal tight junctions to support paracellular absorption. Oral dosing can offer advantages in convenience and patient preference for long-term treatment, but those benefits have to be weighed against dosing requirements and absorption variability.

Question: Which peptide conjugates are already in clinical use?

Answer: Multiple approaches already have established clinical use. Lipidated peptides, which bind serum albumin to extend circulation, support weekly dosing for several metabolic-disease drugs. Radionuclide conjugates such as lutetium-177 dotatate use a peptide ligand to target somatostatin receptors in neuroendocrine tumors. Peptide-drug conjugates carrying other potent payloads are still being explored, with rapid clearance, linker stability and payload release as the main development challenges.

Question: How do peptide-drug conjugates differ from antibody-drug conjugates?

Answer: Both use a targeting molecule to carry a payload, but peptide-drug conjugates do it in a much smaller format. The smaller size can favor tissue penetration and reduce immunogenic potential, and chemical synthesis gives considerable control over the construct's composition. Peptides also clear from the body much more rapidly than antibodies, which places greater demands on target affinity, linker stability, payload potency and the timing of payload release.

Question: Is peptide manufacturing capacity keeping up with demand?

Answer: Synthesis investment is following demand, but the rest of the supply chain has to keep pace. Metabolic-disease products are pushing peptide API requirements toward volumes the modality has rarely reached and driving investment in metric-ton-capable infrastructure. Supply of specialized amino acids, linkers and chelators is less mature than supply of standard raw materials, and purification, isolation, formulation and fill-finish capacity have to grow with synthesis. The next constraint may appear wherever one of those links falls behind.

Question: What could define the next era of peptide therapeutics?

Answer: The defining challenge may be translation: how quickly new chemistry can become a medicine that is characterized, sourced, manufactured and formulated consistently. Semaglutide and octreotide showed that different absorption pathways can produce viable oral products. Conjugation and conformational constraints are extending peptides into new forms of targeting, half-life control, payload delivery and difficult biological interfaces. Manufacturing capacity is growing to meet larger demand. Chemical design space can expand faster than medicines move through development, which is why the next era may be defined by how early developability is built into design.

How Oral Delivery, Peptide Conjugates and Manufacturing Scale Are Changing the Future of Peptide Drug Development