The Rise of Cyclic Peptides: Bridging the Gap in Modern Medicine
Cyclic peptides, characterized by their unique ring structures, represent an emerging trend in drug discovery due to their ability to bridge the gap between small molecules and biologics.
These "Goldilocks" molecules are not too large like monoclonal antibodies, which require injection, nor too small like traditional oral drugs, which often struggle with complex protein-protein interactions.
For instance, Merck's research highlights the potential of macrocyclic peptides to cover extensive surface areas, making them highly effective in disrupting protein interactions crucial to various diseases.
Protagonist Therapeutics' recent success with JNJ-2113, the first oral IL-23 receptor antagonist, underscores the therapeutic promise of cyclic peptides in treating conditions like moderate-to-severe plaque psoriasis.
The positive results from the Phase 2b FRONTIER 1 trial indicate not only efficacy but also tolerability, paving the way for further development in other immune-mediated inflammatory diseases.
These advancements reflect the growing importance of cyclic peptides in expanding the therapeutic landscape, offering new avenues for oral treatments previously dominated by injectable biologics. As research and development in this field progresses, cyclic peptides are poised to significantly enhance the range and accessibility of treatments for complex diseases.
There are a number of drug discovery startups developing second generation cyclic peptides of second generation, including modified peptides and peptidomimetics. Below we summarized 5 such companies.
Unnatural Products
Unnatural Products is a drug discovery startup combining AI and chemistry to address undruggable targets using macrocycles. It was founded in 2017 in Santa Cruz, California by macrocycle pioneers with strong academic backgrounds.
Unnatural Products (UNP) employs a Machine Learning platform to engineer passive cell permeability into macrocycles, large molecular structures capable of binding to traditionally “undruggable” targets. These macrocycles bridge the gap between small molecules and biologics, combining high potency and selectivity with favorable pharmacokinetic properties such as oral bioavailability. UNP's platform optimizes the design of these macrocycles to enhance their ability to permeate cell membranes without losing their target-binding affinity. By closely integrating prediction with experimentation, the company creates a rapid, intelligent learning loop that accelerates the development process. This approach allows UNP to generate a unique dataset on compound performance, providing insights that are not readily available to others. Focusing initially on oncology, UNP's technology has the potential to be applied to a variety of urgent clinical needs, including inflammatory diseases. Their strategy aims to unlock the therapeutic potential of macrocycles, overcoming the historical challenge of poor cell permeability.
In 2023, Unnatural Products announced a $220 million collaboration with Merck to leverage their macrocycle technology for oncology applications, particularly targeting intracellular protein interactions that are difficult to modulate with conventional methods. Additionally, Unnatural Products has been involved in a research collaboration with BridgeBio Pharma, focusing on developing therapeutics for rare diseases and oncology.
The company secured $32 million in Series A funding in December 2023. This round was led by Merck Global Health Innovation Fund and ARTIS Ventures, with participation from First Spark Ventures, The Venture Collective, Humain Ventures, LongeVC, and Not Boring Capital.
Orbis Medicines
Orbis Medicines is leading a new phase in oral macrocycle drug discovery with its innovative nGen chemistry platform, designed to systematically explore macrocycle chemical space. This platform combines high-throughput chemical synthesis, large-scale assaying, and machine learning to generate and test vast numbers of diverse macrocyclic compounds, known as nCycles.
Macrocycles, defined by their cyclic structures, possess exceptional versatility and the ability to target a broad range of protein targets. Historically, the de novo design of these compounds has been challenging due to difficulties in achieving properties suitable for oral dosing and intracellular targeting. The nGen platform overcomes these challenges, producing up to 100,000 unique nCycles in a single design-make-test-analyze cycle. Leveraging proprietary DNA-encoded libraries containing nearly 100 billion compounds, nGen ensures an effective hit-finding step that informs subsequent nCycle designs.
Using acoustic droplet ejection technology, Orbis generates vast libraries of macrocycle compounds at a picomole scale in nanoliter volumes. This method allows for the efficient synthesis and screening of macrocycles, identifying candidates with desirable pharmacological profiles without the need for purification. nCycles are optimized for oral bioavailability and membrane permeability, designed to be effective against both intra- and extracellular targets.
Orbis Medicines' pipeline initially focuses on developing oral macrocycle candidates that target proteins validated by blockbuster biologic drugs, offering oral alternatives with significant healthcare benefits and the potential to treat a larger patient population. Additionally, Orbis is expanding its exploration to encompass a wide array of therapeutic areas, targeting both intracellular and extracellular proteins.
Founded in 2021 by the Seeds Investment team of Novo Holdings, Orbis Medicines launched with a €26 million seed financing led by Novo Holdings and European life sciences venture firm Forbion. The company was established with Morten Døssing as Executive Chair and João Ribas as interim CBO, building its corporate strategy and team. The scientific foundation was developed by Prof. Christian Heinis and Sevan Habeshian at the Swiss Federal Institute of Technology in Lausanne (EPFL).
Research published in leading journals such as Nature Communications and Nature Chemical Biology has demonstrated the effectiveness of Orbis's chemical methods and the nGen platform in generating orally bioavailable nCycles. These publications highlight the high reaction efficiency, minimal side products, and the ability to directly assay macrocycles without purification, unlocking possibilities for generating leads against any protein target.
Circle Pharma
Circle Pharma is a biopharmaceutical company developing innovative macrocycle therapeutics designed to tackle "undruggable" targets, particularly in precision oncology. Founded in 2012 and headquartered in South San Francisco, California, Circle Pharma leverages structure-based rational design and advanced synthetic chemistry to create intrinsically cell-permeable macrocycles. These therapeutics can address both intra- and extracellular targets and are suitable for multiple routes of administration, including oral delivery.
In 2023, Circle Pharma made strides by presenting data on their first-in-class cyclin A/B inhibitor for breast cancer treatment at the AACR-NCI-EORTC International Conference. Additionally, the company announced the selection of a clinical candidate, demonstrating the practical application of their macrocycle platform in oncology.
Circle Pharma has raised $117.5 million across several funding rounds, with notable investors including The Column Group and Nextech Invest. The latest $66 million in a Series C round was secured in 2021.
Insamo
Insamo is a biotechnology company based in Berkeley, California, and founded in 2022, specializing in discovering orally available macrocyclic peptides. The company utilizes a machine learning-driven molecular design to create membrane-permeable macrocyclic peptides, enhancing drug discovery efficiency. Their platform's pioneering capability lies in its automated process of designing, synthesizing, and testing at an unprecedented scale, leveraging trillions of proprietary experimental data points. This approach enables iteration across an astronomical drug-like chemical space, setting a new standard for scalable machine learning applications in drug design, and developing orally available formulations to replace injectable biologics.
This platform aims to replace injectable biologics with oral formulations, making drug discovery faster and more efficient. Insamo recently secured $12 million in seed funding from investors including Playground Global, venBio, and MRL Ventures Fund.
Nimble Therapeutics
Nimble Therapeutics is a Roche spin-off in the field of peptide-based therapeutics, renowned for its cutting-edge platform that accelerates drug discovery and development. Founded in 2019 and headquartered in Madison, Wisconsin, Nimble Therapeutics has quickly established itself as a leader in the biopharmaceutical sector. The company leverages its proprietary peptide synthesis and screening platform, which utilizes high-throughput, parallel synthesis, and advanced screening technologies to rapidly identify and optimize novel peptide therapeutics.
In 2023, Nimble expanded its collaboration with Genentech to co-develop novel peptide therapeutics, showcasing the strength of Nimble's technology and expertise. Additionally, several peptide candidates in Nimble's internal pipeline have progressed to preclinical development, demonstrating the platform's potential to address unmet medical needs.
Financially, Nimble Therapeutics has raised $10 million in a single funding round from Telegraph Hill Partners.
