How to Choose the Optimal Battlefield for Cyclic Peptide Drugs?

A Brief Discussion on Target Selection Principles

Over the past century, peptide drugs have gained continuous market recognition due to their significant clinical value, with industry momentum and market scale expanding in tandem. As a cutting-edge approach in this field, cyclic peptide technology plays a key role in the upgrading of the peptide industry. Among the six new peptide drugs approved in 2023, cyclic peptides accounted for 50% (including Rezafungin, Motixafortide, and Zilucoplan), highlighting the importance of cyclic peptides as a core development modality. Industry giants are accelerating their efforts: in January 2024, Merck entered into a $220 million cyclic peptide collaboration with Unnatural Products; in February 2024, Orbis Medicines, incubated by Novo Nordisk, completed a $28 million seed round to advance the development of oral macrocyclic peptide pipelines.

A cyclic peptide is a peptide compound where the amino acid sequence forms a closed ring structure through the connection of the peptide chain's ends or via side chains. As an emerging therapeutic molecule, cyclic peptide drugs exhibit unique advantages in drug development. The key to selecting the optimal battlefield for cyclic peptide drugs lies in accurately identifying clinical needs (especially the unmet demand for oral drugs), aligning target characteristics with the advantages of cyclic peptides, creating differentiated competitive edges, and conducting comprehensive druggability assessments. Successful cases already exist in various disease areas. In metabolic diseases, Merck's MK-0616, an oral PCSK9 inhibitor, addresses the urgent need for convenient treatment options for hypercholesterolemia patients. The ongoing phase III clinical trials, CORALreef HeFH and CORALreef AddOn, have both reached primary endpoints, confirming the efficacy and safety of oral PCSK9 inhibition. In oncology, Roche's oral KRAS G12D inhibitor, LUNA18, successfully overcame the "undruggable" target using cyclic peptide technology, and through structural optimization, LUNA18's oral bioavailability in various animal models was improved to 21-47%. In the immunology field, Johnson & Johnson's collaboration with Protagonist has resulted in JNJ-77242113, the world's first oral IL-23 pathway cyclic peptide inhibitor to enter clinical trials. It has achieved primary endpoints in phase II trials and is currently in phase III trials, showing promising results.

Across various disease areas, there is a high demand for oral drug molecules in immunological diseases, with PPI targets being predominant. These targets interact on flat surfaces, making it difficult for small molecules to achieve high-affinity binding. Antibody drugs, with their high affinity, have shown excellent clinical results, but they are not easily administered orally. Therefore, the immunology field is one of the best battlefields for cyclic peptide drugs. So, how do we select the appropriate targets for cyclic peptide drug intervention in immunology? The following summarizes and provides examples for illustration.

Ideal Characteristics for Selecting Targets for Cyclic Peptide Drug Development

When selecting targets for cyclic peptide drug development, the following characteristics should be prioritized:

• The Indication Requires Oral Drugs

This primarily concerns patient compliance, where there is a demand for oral drug forms. For example, according to research and analysis from Johnson & Johnson's commercial department, 50-70% of patients with psoriasis and inflammatory bowel disease (IBD) are undertreated due to concerns over administration methods and the risk-benefit ratio. Under equivalent safety and efficacy conditions, 75% of current antibody therapy patients would prefer to switch to oral drugs. It is predicted that by 2030, the market share of oral treatments for psoriasis, psoriatic arthritis, Crohn's disease (CD), and ulcerative colitis (UC), all targeting IL-23/IL-23R, will reach $75 billion.

• The Target Has Already Been Clinically Validated with Antibody Drugs

Targets that are validated in clinical settings, particularly those where antibody drugs have shown good efficacy (e.g., with clinical phase II/III data), are ideal for further exploration. For example, TL1A (Tumor Necrosis Factor-Like Ligand 1A) is a member of the TNF family that binds to its receptor, DR3, to activate the TRADD pathway and regulate the secretion of pro-inflammatory cytokines and chemokines, thus promoting inflammation and fibrosis. Currently, all TL1A-targeting clinical pipelines are antibody-based, with the fastest progressing to phase III for IBD indications. TL1A monoclonal antibody clinical trials have shown outstanding results, and non-head-to-head comparisons indicate that TL1A-targeting drugs outperform other targets in the same indications.

• No Small Molecule or Peptide Drugs Are in Clinical Stages for This Target, or the Efficacy of Small Molecule and Peptide Drugs Is Significantly Inferior to Antibody Drugs

Taking TL1A as an example again, there are currently no oral drugs targeting TL1A in clinical development, and only three preclinical small molecules and peptides are being investigated. Other targets like TSLP are also being explored solely with antibody drugs in the pipeline. For such targets, there is an unmet clinical need for oral drugs, and competition is still limited, making it an opportune time to focus on development. These targets can be classified as "antibody oralization" targets, which often lack small molecule binding pockets and are more suitable for cyclic peptide drug development.

• High Market Value

1. Large Patient Population: Targets with large patient populations globally, particularly those with increasing annual cases, indicate significant unmet clinical needs. For instance, IBD affects between 6-8 million people globally, representing a large market opportunity.
2. Long Treatment Cycles: Diseases with prolonged treatment cycles, such as chronic inflammatory diseases, offer even larger market potential. For example, psoriasis patients may require lifelong medication.
3. Existing Market Sales: Evaluating the sales performance of existing drugs in the same indication can provide insights into market potential. For example, Tezepelumab, the world's first TSLP monoclonal antibody for severe asthma, has seen its sales climb rapidly, reaching $567 million in 2023, with Q2 2024 sales already growing to $234 million, approaching blockbuster status.
4. Expandable Indication Range: Some targets have broad potential for expansion into additional indications. For example, TL1A-targeting drugs, currently in clinical development for IBD, also have potential applications in rheumatoid arthritis (RA), atopic dermatitis (AD), pulmonary fibrosis, and intestinal fibrosis, offering substantial market potential.

• Target Should Have Some Structural Information

The clearer the structural information of a target, the easier it is to design drugs. If there are already antibody drugs targeting the same target, it is ideal to have structural data on how the antibody interacts with the target. In the absence of structural data, computational prediction methods can be used for drug design, though this approach may take longer and carry a slightly lower success rate.

Are There Targets That Meet the Above Conditions?

Let's Take a Look at an Example:

TL1A is a member of the TNF superfamily, also known as TNFSF15. It is primarily expressed on the surface of various immune cells such as monocytes, macrophages, dendritic cells, T cells, and non-immune cells like synovial fibroblasts and endothelial cells. TL1A is a type II transmembrane protein that exists in membrane-bound (mTL1A) or soluble (sTL1A) forms. Its extracellular C-terminal domain contains a typical TNF homologous domain (THD), composed of antiparallel β-sheet layers that form a trimeric structure (as shown below). The functional receptor for TL1A, DR3, also known as TNFRSF25, is a type I transmembrane protein primarily expressed on activated lymphocytes, including CD4+, CD8+, and NK cells. TL1A binds to the DR3 trimer in a 3:3 complex, which results in a well-defined structure. Upon binding, TL1A/DR3 activates two distinct signaling pathways that induce inflammation and apoptosis.

The first pathway involves the intracellular death domain of DR3, which recruits the TRADD molecule, followed by the binding of TRAF2, RIP1, and cIAP1/2. The cIAP1/2 molecules polyubiquitinate RIPK1, activating NF-κB, MAPK, and PI3K signaling pathways that induce the expression of pro-inflammatory genes, leading to the secretion of cytokines and chemokines that promote inflammation and cell proliferation. The second pathway occurs when TRADD dissociates from DR3's death domain, and in the cytoplasm, it binds to FADD, RIP3, and caspase-8, activating caspase-3/7 and triggering caspase-dependent apoptosis. Additionally, TL1A/DR3 also promotes apoptosis through the FADD, RIP3, and caspase-8 pathway. When caspase-8 activity is blocked, RIP1 can bind with RIP3 and phosphorylate each other, forming necrosome structures, which eventually lead to necroptosis. Lastly, TL1A can bind to DcR3, which competes with DR3 for ligand binding, thereby reducing the interaction between sTL1A and DR3 and inhibiting TL1A's functional effects.

Market Value of TL1A

The primary indication for TL1A-targeted drugs is inflammatory bowel disease (IBD). IBD refers to chronic, non-specific, and relapsing intestinal inflammation caused by multiple etiologies, with the core pathology being an imbalance in intestinal immune homeostasis. This imbalance results in excessive activation of pro-inflammatory responses and irreversible fibrotic damage, including conditions such as ulcerative colitis (UC), Crohn's disease (CD), and indeterminate colitis (IC). IBD, especially CD, often manifests during adolescence, with its precise pathogenesis still not fully understood. Genetic, environmental, and immune factors likely play a combined role in its onset. TL1A is closely linked to the development of IBD and serves as a crucial regulatory factor. Studies have shown that TL1A/DR3 mRNA and protein levels are upregulated in the inflamed mucosal tissues of IBD patients. In animal models, transgenic mice overexpressing TL1A in lymphocytes developed intestinal inflammation in the ileum, which included inflammatory infiltration in the lamina propria, thickening of the muscular layer, epithelial damage, and increased expression of inflammatory cytokines and chemokine receptors. In contrast, TL1A/DR3 knockout mice showed a significant reversal of the chronic colitis inflammatory phenotype. The mechanism of action involves TL1A binding to the DR3 receptor, inducing signaling that enhances the activity of innate lymphocytes like TH1 and TH17 cells, amplifying the inflammatory cascade and promoting the release of key pro-inflammatory factors such as IFN-γ, TNF-α, IL-6, IL-17, IL-4, and IL-13, which trigger intestinal inflammation.

As of 2024, global IBD patient numbers have reached 7 million. Between 1990 and 2019, the global IBD prevalence increased by 47.45%, with incidence rising annually by 0.9% to 1.5%, particularly in emerging industrialized countries in Africa, Asia, and South America. IBD is characterized by lifelong relapsing episodes, requiring long-term treatment to maintain symptom remission, prevent relapse, and avoid complications. Consequently, the IBD treatment market is substantial. According to GMI, the market size for IBD treatment was estimated at $22.6 billion in 2023 and is projected to reach $38.2 billion by 2032, with a CAGR of 6.1% from 2024 to 2032. Within the IBD treatment market, TNF inhibitors hold the largest market share, with adalimumab, a TNF-α-targeting monoclonal antibody, being the highest-selling biologic drug. However, despite TNF inhibitors showing favorable clinical outcomes, about 40% of IBD patients lose response over time, and 80% experience chronic relapses, with 20%-30% requiring surgical resection of part of their intestines, significantly impacting their quality of life. Additionally, biologics are expensive, imposing a heavy financial burden on most patients. Therefore, there is a significant unmet need in the IBD treatment landscape, highlighting the urgent need for breakthrough drugs.

Moreover, IBD treatment is classified based on administration routes, including oral, rectal, and injectable. Oral drugs are expected to dominate the market due to their convenience and higher patient compliance. A combined analysis of UC patient preferences for treatment showed that for mild symptoms, patients prefer oral drug therapies. Therefore, the development of oral drugs targeting the same pathway will have a significant advantage in the future.

In addition to its role in inflammatory bowel disease (IBD), TL1A plays a crucial role in other autoimmune diseases, such as pulmonary fibrosis and rheumatoid arthritis (RA). Pulmonary fibrosis is a condition characterized by fibroblast proliferation and excessive extracellular matrix deposition, which leads to structural damage in lung tissue. It predominantly affects the middle-aged and elderly population. Upon activation of the TL1A/DR3 signaling pathway, Th1 and Th17-mediated pathways are stimulated, and TL1A can directly activate fibroblasts, promoting their proliferation. This results in the upregulation of osteopontin (a fibrosis marker), increased bronchial smooth muscle mass, and a loss of elasticity in the lungs and airways, contributing to the development of pulmonary fibrosis.

Similarly, in RA, the regulatory mechanism of TL1A is similar to that in IBD. By activating Th1 and Th17 signaling pathways, TL1A promotes the release of inflammatory cytokines, stimulates the proliferation of fibroblast-like synoviocytes, and exacerbates synovial hyperplasia. This leads to joint erosion and cartilage destruction, which ultimately causes RA. For fibrotic diseases, current treatments only provide symptom relief and cannot reverse fibrosis. For RA, most drug therapies primarily target inflammatory cytokines such as IL-6R and TNF-α using monoclonal antibodies. However, these treatments require long-term injections, which often lead to poor patient compliance and the need for combination therapies to reduce the production of anti-drug antibodies.

Current Clinical Development of TL1A-Targeted Drugs

To date, all TL1A-targeting drugs in clinical research are antibody-based. Among these, Pfizer's PF-06480605 (RVT-3101) and Merck's acquisition of Prometheus Biosciences' Tulisokibart (PRA023) have advanced to Phase III trials. These drugs target indications such as ulcerative colitis and Crohn's disease, with Phase II clinical results outlined below:

PF-06480605 (RVT-3101)

RVT-3101 is a fully human monoclonal antibody initially developed by Pfizer and later jointly developed with Roivant through a 2022 partnership. According to Phase IIb clinical results, the RVT-3101 induction group achieved a higher clinical remission rate at Week 14 compared to the placebo group, with effects sustained until Week 56, achieving a remission rate of 39.3%. The endoscopic improvement rate at Week 14 was also higher, continuing through Week 56 at 50%. In biomarker-positive participants, treatment effects were more significant, with a clinical remission rate of 40% and an endoscopic remission rate rising from 40% to 56% by Week 14. RVT-3101 demonstrated good tolerability and safety across all doses and patient groups.

Tulisokibart (PRA023)

PRA023 is a humanized IgG1 monoclonal antibody developed by Prometheus Biosciences. In Phase II clinical studies for treating ulcerative colitis and Crohn's disease, PRA023 showed positive results. At Week 12, 26.5% of patients in the PRA023 induction group reached the primary endpoint of clinical remission, compared to only 1.5% in the placebo group. Additionally, 36.8% of patients achieved the secondary endpoint of endoscopic improvement, while the placebo group showed only 6%. In Crohn's disease treatment, 49.1% of patients in the PRA023 group reached clinical remission at Week 12, with 26% showing endoscopic remission, while the placebo group showed 16% and 12%, respectively. Moreover, in biomarker-positive patients, PRA023 showed a more significant treatment effect, with clinical remission rates of 32% versus 11% for the placebo group, and endoscopic remission rates of 32% versus 11%.

TL1A as an Ideal Target for Oral Cyclic Peptide Drug Development

In summary, TL1A has a clear molecular structure, well-defined signaling pathway, and its effectiveness in clinical trials has been validated as a proof of concept (POC), demonstrating excellent results in the same indications. Additionally, there are currently only three preclinical small molecule/peptide drugs targeting TL1A. Given the high unmet demand for oral drugs in these indications and the large market potential, TL1A represents an ideal target for cyclic peptide drug research. Furthermore, competition for oral TL1A-targeted drugs remains relatively low, making it an opportune time to begin development in this area.

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