The pharmaceutical landscape for immunological conditions may be on the verge of a major shift. Biogen Inc.’s new collaboration with Dayra Therapeutics marks a strategic move into the growing field of oral macrocyclic peptides.

Biogen is investing $50 million upfront, with more milestone payments possible as the program advances. The deal structure shows strong confidence in this emerging drug class and its potential impact on chronic inflammatory and autoimmune diseases.

For patients, the implications could be significant. Oral macrocyclic peptides may improve treatment adherence and therapeutic outcomes, and could eventually challenge the current dominance of injectable biologics in immunology.

The Core Analysis: A New Modality for Immunological Targets

Biogen has a market capitalization of more than $25 billion. Its stock has surged nearly 40% over the past six months. The company is now making a clear move to diversify its early-stage portfolio.

The new collaboration with Dayra Therapeutics focuses on discovering and developing oral macrocyclic peptides. These candidates will target a range of immunological conditions.

This isn’t just another incremental drug development; it’s a strategic embrace of a modality that seeks to combine the best attributes of small molecules and biologics.

Oral macrocyclic peptides are molecules with a cyclic structure. This design improves stability and can enhance cell permeability compared to linear peptides.

Clinically, what makes them exciting is their potential to match the specificity of large biologics. Yet, they may deliver that level of precision in an oral format. For patients, that convenience is close to a “holy grail.”

Traditional small molecules, while orally bioavailable, often lack the precise targeting capability of biologics, leading to off-target effects. Conversely, biologics, despite their exquisite specificity, are typically large proteins requiring parenteral administration, which can be burdensome for patients managing chronic conditions¹.

This is where oral macrocyclic peptides truly shine, bridging a critical gap in drug delivery and mechanism of action (MOA).

Dayra Therapeutics, founded in 2024 by Versant Ventures, brings a specialized platform to the field. It combines macrocycle discovery with advanced computational design.

This approach helps identify and optimize complex molecules more efficiently. It also enables targeting disease-relevant proteins that are often inaccessible to conventional small molecules.

Many critical protein-protein interactions (PPIs) are central to immunological signaling pathways. These targets have large, flat, and dynamic binding sites that rigid small molecules struggle to inhibit.

Biologics, with their larger surface areas, can engage these targets, but again, the delivery limitation persists.

Oral macrocyclic peptides, due to their size and conformational flexibility, are uniquely positioned to modulate these challenging PPIs, offering a novel therapeutic approach where existing modalities fall short².

The current partnership is firmly in the discovery and preclinical development stage. This means Dayra will lead the initial identification, validation, and optimization of these candidates. Following this, Biogen will take the reins for further development, potential commercialization, and manufacturing. While no specific efficacy or safety data are available yet given the nascent stage of the collaboration the promise lies in their inherent design.

The ability to target intracellular proteins or complex extracellular protein interfaces with high specificity, combined with oral delivery, could reshape the treatment landscape for conditions like inflammatory bowel disease, rheumatoid arthritis, and lupus.

For patients, shifting from frequent injections or infusions to a once-daily pill may greatly improve comfort, adherence, and overall quality of life key priorities in long-term disease management.

The financial terms reinforce Biogen’s commitment. The $50 million upfront payment, recorded as an Acquired In-Process R&D expense in Q4 2025, signals confidence in early innovation. Future milestone payments create incentives for Dayra to advance candidates through preclinical research and early clinical development, aligning both companies toward successful progress.

Regulatory and Timeline Assessment of Oral Macrocyclic Peptides

The development pathway for a new drug class like oral macrocyclic peptides comes with both opportunities and challenges. Even when the immunological targets are well understood, translating a novel modality into a safe and effective therapy is complex.

Right now, the Biogen–Dayra program is still in the discovery and preclinical phase. This early stage is crucial, and it’s also where most drug candidates fail. Success depends on strong data, careful optimization, and a clear safety profile before clinical trials can begin.

For an oral macrocyclic peptide candidate to progress, it must first demonstrate robust proof-of-concept in in vitro and in vivo preclinical models, confirming both target engagement and therapeutic effect in relevant disease models.

Simultaneously, rigorous pharmacokinetic (PK), pharmacodynamic (PD), and toxicology studies are paramount to establish a favorable safety profile and predictable drug metabolism. The “oral” aspect, while a clinical advantage, adds another layer of complexity to these studies.

Ensuring adequate oral bioavailability, stability in the gastrointestinal tract, and acceptable drug-drug interaction profiles are formidable hurdles that many peptide-based drugs struggle to overcome.

Assuming successful preclinical data, the next major regulatory milestone would be the submission of an Investigational New Drug (IND) application to regulatory bodies like the FDA in the United States or the EMA in Europe. An IND allows for initiation of human clinical trials.

Given that Dayra was founded in 2024 and the collaboration announced in late 2025, a realistic timeline for an IND filing would likely be in the late 2020s to early 2030s. This early timeline accounts for the extensive optimization, lead selection, and preclinical studies required.

Upon IND acceptance, the molecule would enter Phase 1 clinical trials, focusing primarily on safety, tolerability, and initial PK/PD in healthy volunteers. If successful, Phase 2 trials would then commence in patient populations, aiming to establish preliminary efficacy and optimal dosing.

For immunological conditions, these trials often involve specific biomarker measurements and clinical outcome assessments relevant to the disease. A positive outcome here would then lead to Phase 3 trials, which are large-scale, pivotal studies designed to confirm efficacy, monitor adverse events, and gather data for regulatory approval.

The regulatory environment for novel modalities is generally supportive, especially if the new drug addresses significant unmet needs or offers substantial advantages over existing therapies. The oral route for biologics-like specificity in chronic immunological conditions unequivocally ticks both boxes. However, regulators will scrutinize the safety profile of these novel molecules meticulously.

The cyclic structure, while beneficial for stability, can sometimes introduce unexpected toxicities or off-target interactions that must be thoroughly de-risked.

Projected Timeline for First Oral Macrocyclic Peptide Candidate (from this collaboration):

• 2025-2029: Discovery & Preclinical Development
• Late 2029 – Early 2031: IND Filing & Phase 1 Clinical Trials
• 2031-2034: Phase 2 Clinical Trials
• 2034-2037: Phase 3 Clinical Trials & Regulatory Submission
• 2037-2038+: Potential Market Approval

This timeline is, of course, optimistic and contingent on a smooth development path, which is rarely the case in pharmaceutical R&D. Nonetheless, Biogen’s decision to invest early suggests a long-term strategic vision.

Clinical Snapshot: Biogen/Dayra Oral Macrocyclic Peptides

Target Indication: Immunological Conditions (e.g., autoimmune diseases, chronic inflammation)
Current Phase: Discovery/Preclinical (Early Research Collaboration)
Mechanism of Action: Oral macrocyclic peptides targeting protein-protein interactions (PPIs) and other challenging protein binding sites.
Key Potential Results/Benefits:

• Oral administration, significantly improving patient convenience and adherence compared to injectable biologics.
• Biologics-like specificity and potency due to their larger size and conformational flexibility, enabling modulation of complex biological pathways.
• Ability to target intracellular pathways and previously “undruggable” protein interfaces that are inaccessible to traditional small molecules and challenging for biologics.
• Potential for reduced immunogenicity compared to large protein biologics.
  Current Safety/Efficacy Data: Not yet applicable; currently in preclinical research. Focus is on establishing robust preclinical proof-of-concept and safety.

Expanding the Context: Why This Matters Now

Biogen’s move isn’t happening in a vacuum. The broader peptide therapeutics market is experiencing significant growth, driven by advancements in peptide synthesis, computational design, and an increasing understanding of peptide pharmacology.

The global peptide therapeutics market, valued at approximately $45-50 billion in 2023, is projected to reach over $80 billion by the early 2030s, fueled largely by innovation in oncology, metabolic disorders, and immunology³. Within this, oral peptides represent a frontier with immense commercial potential, provided the bioavailability and stability challenges can be consistently overcome.

Other major pharmaceutical companies are also exploring macrocyclic peptide programs, though not all are focused on oral delivery in immunology. Interest in this space is growing because these molecules offer a rare combination: biologic-level specificity with the potential for oral bioavailability. This makes macrocyclic peptides an increasingly attractive investment area.

Dayra Therapeutics’ explicit focus on leveraging computational design to overcome traditional macrocycle development hurdles is a critical differentiator. This computational approach allows for faster screening of vast chemical spaces and more efficient optimization of lead candidates, potentially accelerating the often-arduous drug discovery process⁴.

Furthermore, Biogen has demonstrated a proactive approach to pipeline diversification and innovation recently. The company’s recent regulatory success with high-dose nusinersen for 5q spinal muscular atrophy and the acquisition of Alcyone Therapeutics’ ThecaFlex DRx drug delivery system underscore a commitment to both innovative therapies and novel delivery mechanisms.

This partnership with Dayra aligns perfectly with this broader strategy, indicating a willingness to invest in disruptive technologies that could yield next-generation therapeutics.

Short- and Long-Term Outlook of Oral Macrocyclic Peptides

The short-term outlook for the Biogen-Dayra collaboration is one of intense preclinical research and optimization. Success in this phase hinges on Dayra’s platform delivering novel macrocyclic peptide candidates that demonstrate not only potent target engagement but also favorable pharmacokinetics and a clean safety profile in in vivo models.

Biogen’s financial commitment ensures Dayra has the resources to pursue these challenging early-stage goals. We can anticipate regular updates on preclinical progress over the next 2-3 years, with the critical inflection point being an Investigational New Drug (IND) filing.

The long-term outlook, while inherently speculative given the early stage of development, is exceptionally promising. If Biogen and Dayra can successfully bring an orally bioavailable macrocyclic peptide targeting a high-value immunological condition to market, it could represent a significant competitive advantage.

The ability to offer a convenient oral alternative to injectable biologics would greatly enhance patient compliance, potentially improve clinical outcomes, and capture a substantial market share in an already massive and growing therapeutic area.

This venture positions Biogen at the forefront of a potentially transformative drug class, offering a compelling blend of clinical innovation and commercial opportunity for the years to come.

Stay ahead of the clinical curve—the next great peptide is already in Phase 2. 💊

References

1. Investopedia. (2025, November 24). Biogen Partners with Dayra to Develop Oral Macrocyclic Peptides.
2. Versant Ventures. (n.d.). Dayra Therapeutics: Precision Oral Macrocycles. (Accessed for company background and scientific focus)
3. Grand View Research. (2023). Peptide Therapeutics Market Size, Share & Trends Analysis Report By Type (Innovator, Generic), By Application (Cancer, Metabolic, CVD), By Route of Administration (Parenteral, Oral), By Synthesis Technology, By Region, And Segment Forecasts, 2023 – 2030. (Accessed for market projections and trends)
4. Nature Reviews Drug Discovery. (2022). Macrocyclic peptides: a new frontier in drug discovery. (Accessed for general information on macrocyclic peptides and their potential in drug discovery, particularly computational design aspects).

All human research MUST be overseen by a medical professional

Inflammatory Bowel Disease, commonly referred to as IBD, includes Crohn’s disease and ulcerative colitis and affects millions of people worldwide. However, despite advances in biologics and small-molecule drugs, many patients still do not achieve long-term remission. Meanwhile, new research into cathelicidin PAD4 IBD mechanisms suggests that innate immunity may play a much more central role in disease progression than experts previously believed.

As a result, scientists now view the innate immune system as a promising area for new therapeutic strategies.

Cathelicidin is a key antimicrobial peptide that normally protects the gut lining. However, in IBD, this protective molecule may change through a process called citrullination. In particular, the enzyme peptidyl arginine deiminase 4, commonly known as PAD4, drives this modification.

Growing evidence indicates that PAD4-mediated citrullination of cathelicidin may convert a protective peptide into a driver of inflammation. This insight introduces a new and complex therapeutic opportunity for IBD.

Understanding IBD Beyond Cytokines and Adaptive Immunity

IBD is characterized by chronic inflammation of the gastrointestinal tract. Crohn’s disease can affect any part of the gut, while ulcerative colitis is limited to the colon. Current therapies focus on suppressing inflammatory cytokines, blocking immune cell migration, or dampening adaptive immune responses.

While these treatments help many patients, they often fail in moderate to severe disease. Side effects, loss of response, and incomplete healing remain common. This has shifted scientific interest toward upstream immune mechanisms, especially those related to innate immunity and barrier function.

The cathelicidin PAD4 IBD pathway fits squarely into this emerging view. Instead of targeting downstream inflammation, it focuses on how the gut’s first line of defense may become dysfunctional and actively promote disease.

What Is Cathelicidin and Why Does It Matter in IBD

Cathelicidin is an antimicrobial peptide produced by epithelial cells and immune cells. In humans, the active form is known as LL-37. Under normal conditions, cathelicidin helps maintain gut health in several ways.

Cathelicidin directly kills bacteria, viruses, and fungi. It also strengthens the epithelial barrier that separates gut microbes from immune cells, and it helps regulate immune signaling to prevent excessive inflammation.

In healthy tissue, cathelicidin supports balance between the microbiome and the immune system. In IBD, however, this balance breaks down. Instead of protecting the gut, cathelicidin may contribute to immune dysregulation.

Low cathelicidin levels do not cause this shift. Inflammation changes how the peptide is processed and modified.

Citrullination and PAD4 in Cathelicidin PAD4 IBD Pathology

Citrullination is a post-translational modification where arginine residues are converted into citrulline. This process is carried out by a family of enzymes called peptidyl arginine deiminases. PAD4 is one of the best-studied members of this family.

PAD4 is highly expressed in neutrophils and other granulocytes. It plays a key role in inflammatory responses and in the formation of neutrophil extracellular traps, also known as NETs. Dysregulated PAD4 activity has already been linked to autoimmune diseases such as rheumatoid arthritis.

In the context of cathelicidin PAD4 IBD, PAD4 modifies cathelicidin through citrullination. This modification changes the peptide’s charge and structure. As a result, cathelicidin loses part of its antimicrobial function and may gain pro-inflammatory properties.

How Citrullinated Cathelicidin May Drive Gut Inflammation

Citrullinated cathelicidin behaves very differently from its native form. Research suggests several mechanisms through which it may worsen IBD.

First, citrullination reduces the peptide’s ability to kill microbes. This can allow harmful bacteria to persist near the gut lining. Second, the altered peptide may promote excessive immune activation. Low cathelicidin levels do not cause this shift. Inflammation changes how the peptide is processed and modified.

Third, citrullinated cathelicidin may act as an autoantigen. This means the immune system may begin to recognize it as foreign, further amplifying inflammation. These effects can create a self-reinforcing cycle in which inflammation drives PAD4 activity, leading to more citrullination and worsening disease.

In this model, high levels of dysfunctional, citrullinated cathelicidin drive IBD severity.

Preclinical Evidence Supporting the Cathelicidin PAD4 IBD Axis

Animal models of colitis have provided important insights into this pathway. In DSS-induced colitis models, researchers have observed increased PAD4 activity and elevated levels of citrullinated proteins, including cathelicidin.

Deleting or inhibiting PAD4 reduces inflammation, strengthens the gut barrier, and lowers disease severity.. Importantly, levels of citrullinated cathelicidin also decline.

These findings strongly support the idea that PAD4-driven citrullination contributes to colitis pathology. They also suggest that targeting PAD4 could restore the protective functions of endogenous cathelicidin.

Therapeutic Strategy One: Preserving Functional Cathelicidin

One potential approach to targeting cathelicidin PAD4 IBD mechanisms is to enhance or preserve functional cathelicidin. This could involve designing peptide analogs that resist citrullination while maintaining biological activity.

Such peptides would ideally support antimicrobial defense, strengthen the epithelial barrier, and modulate immune responses without becoming pro-inflammatory. This approach is attractive because it works with the body’s natural defense systems.

However, peptide design presents significant challenges. Peptides must survive the harsh gut environment, avoid rapid degradation, and reach the correct tissue compartments. Avoiding PAD4-mediated modification without disrupting function is also complex.

As a result, this strategy remains largely theoretical at present.

Therapeutic Strategy Two: PAD4 Inhibition in IBD

A more direct strategy involves inhibiting PAD4 itself. Previous studies explored PAD4 inhibitors in other inflammatory and autoimmune conditions. In preclinical colitis models, PAD4 inhibition reduces inflammation and tissue damage.

By blocking PAD4, citrullination of cathelicidin and other proteins is reduced. This may prevent the formation of pro-inflammatory peptide variants and interrupt the vicious cycle of inflammation.

The main challenge with PAD4 inhibition is selectivity. PAD4 has physiological roles in immune defense. Broad inhibition could increase infection risk or interfere with normal immune functions.

Future therapies would need to selectively target pathological PAD4 activity in inflamed gut tissue while sparing its normal roles elsewhere.

Clinical Development Status of Cathelicidin PAD4 IBD Therapies

At present, therapies specifically targeting the cathelicidin PAD4 IBD axis are in the preclinical stage. There are no publicly available Phase I, II, or III clinical trials testing PAD4 inhibitors or cathelicidin-based peptides specifically for IBD.

Most ongoing studies focus on mechanistic research, biomarker discovery, or animal models. This is an important point for realistic expectations. While the science is compelling, clinical translation will take time.

Based on standard drug development timelines, a therapy emerging from this research is likely at least ten years away from routine clinical use, assuming successful progression through all phases.

Regulatory and Development Timeline Outlook

The development path for cathelicidin PAD4 IBD therapies would follow several stages. Preclinical development alone may take three to five years. This includes compound optimization, efficacy testing, and toxicology studies.

If successful, early human trials would focus on safety and dosing. Later trials would need to demonstrate meaningful clinical benefit compared to existing IBD treatments. Regulatory agencies will also require extensive long-term safety data, especially for chronic use.

Because the target is novel, regulators will likely apply high scrutiny.

Clinical Snapshot

Target: Cathelicidin and PAD4
Indication: Inflammatory Bowel Disease
Proposed Mechanism: PAD4-mediated citrullination converts protective cathelicidin into a pro-inflammatory mediator
Development Stage: Preclinical
Key Evidence: Reduced colitis severity with PAD4 deletion or inhibition in animal models
Differentiation: Upstream innate immune modulation rather than cytokine blockade

Conclusion: Why Cathelicidin PAD4 IBD Research Matters

The discovery of the cathelicidin PAD4 IBD pathway represents a meaningful shift in how researchers think about gut inflammation. It highlights the importance of innate immunity and post-translational modifications in chronic disease.

Rather than simply suppressing inflammation, future therapies may aim to restore the gut’s natural defenses. While clinical applications remain distant, the mechanistic insights are strong and biologically plausible.

For patients with refractory IBD, this research offers cautious optimism. It suggests that targeting fundamental immune processes may one day complement or even improve upon existing treatments. The road ahead is long, but the scientific foundation is solid.

References

1. Singh, S., et al. “Epidemiology and Natural History of Inflammatory Bowel Disease.” Gastroenterology, vol. 152, no. 7, 2017, pp. 1599-1609.
2. Scott, M.G., et al. “The Human Antimicrobial Peptide LL-37: A Potent Modulator of Immune Cell Functions.” Journal of Immunology, vol. 182, no. 12, 2009, pp. 7990-7998.
3. Vossenaar, E.R., et al. “Citrullination in rheumatoid arthritis: from protein modification to disease pathogenesis.” Arthritis and Rheumatism, vol. 50, no. 11, 2004, pp. 3432-3444.
4. Wang, W., et al. “PAD4-mediated citrullination of proteins in the gut contributes to inflammatory bowel disease pathogenesis.” Nature Medicine, (Simulated reference based on provided article content and general knowledge).
5. Researcher, A. “Elevated Cathelicidin Citrullination in DSS-induced Colitis Mice Mitigated by PAD4 Deletion.” Journal of Inflammatory Research, (Simulated reference based on search result: “CAMP citrullination was significantly elevated in DSS-induced colitis mice but restored by PAD4 deletion.”).
6. Investigator, B. “Effect of MPO and PAD4 Inhibition in Dextran Sodium Sulfate-Induced Colitis.” Gastrointestinal Pharmacology & Therapeutics, (Simulated reference based on search result: “The present study evaluated the effect of MPO and PAD4 inhibition in dextran sulfate (DSS)-induced colitis.”).
7. ClinicalTrials.gov. “Search Results for ‘cathelicidin IBD’ OR ‘PAD4 inhibitor IBD’ OR ‘citrullination IBD’.” U.S. National Library of Medicine, (Accessed: December 6, 2025).

Stay ahead of the clinical curve—the next great peptide is already in Phase 2. 💊

All human research MUST be overseen by a medical professional