The Turning Point for Oral Biologics: Q&A With Morten Graugaard

In a conversation with Pharmaceutical Executive, Morten Graugaard, CEO, Orbis Medicines, discussed FDA’s approval of Icotyde as an early validation point for oral biologics, describing it as a meaningful step toward translating the efficacy and target engagement of biologics into more accessible oral formats.

In the conversation, Graugaard characterized the milestone as the beginning of a broader industry transition, noting that while first-generation oral biologics demonstrate clinical and commercial potential, challenges such as low bioavailability, formulation complexity, and high costs remain barriers to widespread adoption.

Graugaard also highlighted the dual patient and commercial advantages of oral biologics, emphasizing improved adherence, reduced logistical burden, and the potential to expand access in cost-constrained or infrastructure-limited markets.

A transcript of Graugaard’s conversation with Pharmaceutical Executive can be found below.

Pharmaceutical Executive: Icotyde’s FDA approval has been described as a turning point for oral biologics. From your perspective, does this milestone signal a fundamental shift in how the industry approaches drug delivery?
Morten Graugaard: Icotyde’s approval is an important proof point that the industry can translate the efficacy of biologics as well as their ability to engage challenging targets into an oral format.

This changes the conversation of what is possible in terms of patient accessibility and competition with established therapies centring on injectable biologics.

For many years, oral biologics were viewed as “the holy grail” combining the efficacy of biologics with the commercial attractiveness of a lower-cost orally available modality. However, due to the significant technical challenges involved in designing oral biologics, achieving this goal has long remained elusive. This milestone is therefore especially encouraging, as it clearly demonstrates both clinical validity and market appetite. It also reinforces a broader shift we are already seeing, where route of administration is becoming a tactical advantage by transitioning injectable blockbuster products into even larger oral markets.

At the same time, I would characterize this as the beginning of a transition rather than the endpoint. First-generation oral biologics still come with meaningful limitations, particularly around drug discovery timelines, low oral bioavailability, formulation complexity, fasting requirements and high cost of goods. The real inflection point will come when we can systematically design oral biologics with higher exposure and scalable manufacturing. As those capabilities mature, I believe the industry will increasingly approach drug discovery with the assumption that many injectable therapies can and should be converted into oral medicines, especially in chronic disease settings.

PE: Oral biologics have long been a goal for the industry. What are the most meaningful advantages they offer compared to injectable therapies, both from both a patient and commercial standpoint?
Graugaard: Oral biologics fundamentally reshape how therapies are delivered. By eliminating the discomfort and logistical burden of injections, they make it easier for patients to initiate and sustain treatment over the long term.

They also enable more flexible combination regimens, allowing multiple therapies to be taken together to enhance efficacy. Studies and patient surveys consistently show a strong preference for oral therapies over injectables when efficacy and tolerability are comparable. These gains in accessibility and adherence are especially impactful in chronic diseases, where long-term treatment is essential.

Critically, one of the key factors limiting uptake of biologics is pricing and market access restrictions such as, patients struggling to access treatments due to high price and payer push-back in various forms. A lower priced oral alternative has the potential to provide access to many more patients, including those with mild-moderate and moderate-severe disease, as well as patients in regions of the world that currently lack access to biologics due to supply chain issues or high cost.

From a commercial perspective, oral formulations can offer lower cost of goods and simpler manufacturing compared to injectable biologics, providing a meaningful advantage in competitive markets. Globally, access to biologics is often constrained by the need for a temperature-controlled supply chain from manufacture through administration. In many developing regions, these complex and costly logistics place biologics out of reach. Overall, oral biologics better align clinical impact with real-world usability, creating value for both patients and healthcare systems.

PE: Macrocycles are gaining momentum as a modality. How do they enable the next generation of orally available therapies, and where do they fit within the broader drug development landscape?
Graugaard: Macrocycles are cyclic peptide molecules composed of amino acids arranged in a ring structure. As a goldilocks molecule, they fall between small molecules and biologics in terms of size and combine the strengths of both modalities.

Like small molecules, they can be optimized to be orally bioavailable and cell permeable but also have the capability of antibodies to engage challenging targets including transcription factors, targets without well-defined protein pockets, and protein-protein interactions.

As emerging technologies make macrocycle design and development faster and more reliable, the modality is well positioned to build on the growing momentum of oral biologics, highlighted by therapies such as Johnson & Johnson’s Icotyde, a macrocycle, and Merck’s oral PCSK9 antagonist Enlicitide, which is also a macrocycle. Some assessments predict as high as 85% of the targetome could be addressed by macrocycles, including the huge range of protein-protein interactions integral to many diseases.

Looking ahead, we expect macrocycles to become a new pillar of drug development. The advantages discussed above, improved patient accessibility and stronger market competitiveness, are already driving increased strategic interest among large pharmaceutical companies in building in-house capabilities for oral biologics. This is particularly relevant, as oral biologics offer a unique opportunity to work on clinically validated targets, effectively eliminating a major driver of attrition in pharmaceutical R&D, clinical attrition in Phase II and Phase III, as well as expanding blockbuster injectable markets into even larger commercial opportunities through an oral modality for the same target.

PE: Building on the success of Icotyde, what needs to happen for oral biologics to become a repeatable and scalable approach across the industry rather than a one-off breakthrough?
Graugaard: To date, the development of macrocycles, including Icotyde, has been accomplished through traditional peptide-based macrocycle medicinal chemistry, a high-risk laborious and lengthy process with a low success rate.

To more rapidly and efficiently design the next generation of macrocycle drugs, the field needs to evolve from a low-throughput artisanal process into a programmable, data-driven discipline.

To drive this evolution, we built ⁿGen, a synthetic macrocycle discovery platform at the intersection of physical and digital technologies. Orbis’ macrocycles are synthetic in nature and are in a different chemical space compared to 1^st generation macrocycles and can be optimized for much higher permeability and oral bioavailability. Automated synthesis and high-throughput screening enable us to generate and evaluate macrocycles at an unprecedented scale.

By systematically creating and testing tens of thousands of real molecules, we produce large, high-quality datasets to guide discovery with increasing precision. This continuous, lab-in-the-loop approach ensures each cycle builds on the last, refining designs and accelerating the path to optimized candidates.

This automated platform has already achieved key breakthroughs. For example, exciting work by our scientific founder, Christian Heinis, using a synthesis and screening approach that we have since expanded upon to create our ⁿGen discovery platform, delivered a remarkable proof-of-concept (POC) result: the creation of an ⁿCycle thrombin inhibitor with oral bioavailability nine times higher than the industry standard.