Pledge Therapeutics is a clinical-stage biopharmaceutical company focused on developing novel therapies for serious diseases where current treatments do not fully address patient needs. The company aims to bring drug candidates with innovative mechanisms of action into clinical development, ultimately seeking to improve the lives of patients suffering from challenging conditions. Headquartered in Greater Boston, with an additional research and development branch located in Leuven, Belgium, Pledge Therapeutics is dedicated to advancing new medicines.
The PLEDGE™ Technology Platform
Pledge Therapeutics employs a sophisticated technology platform, PLEDGE™, which integrates structure-based drug design with biophysics to create treatments for difficult therapeutic targets. This platform emphasizes clinically validated targets, utilizing advanced biophysical and orthogonal technologies to determine the high-resolution atomic structures of drugs when bound to their protein targets. This detailed structural insight significantly accelerates the drug discovery process, allowing for a more precise design of novel compounds.
A primary focus of this platform is on modulating protein-protein interactions (PPIs), which are fundamental to various cellular activities and play roles in both health and disease states. Historically, targeting PPIs for drug development has been challenging because their binding interfaces are often large, flat, and lack distinct pockets, leading them to be considered “undruggable” for many years. Pledge Therapeutics overcomes this by developing “allosteric binders” or modulators.
Allosteric modulators interact with a protein at a site distinct from its primary binding location, inducing a conformational change that influences the protein’s function. This mechanism is analogous to a dimmer switch for a light, where adjusting a separate control changes the light’s intensity rather than simply turning it on or off. This approach allows for more nuanced control over protein activity and can lead to drugs with improved properties. Through extensive screening, Pledge Therapeutics has analyzed over 75,000 cysteine residues on approximately 12,500 proteins, identifying more than 800 novel binding pockets across 250 validated targets. From these, they have identified small molecules that bind to over 100 unique pockets across more than 80 priority targets.
Focus on Fibrotic and Inflammatory Diseases
Fibrosis, also known as fibrotic scarring, represents a pathological process characterized by the excessive accumulation of fibrous connective tissue, primarily collagen, in response to injury or chronic inflammation. This abnormal deposition of extracellular matrix proteins results in the hardening and scarring of affected tissues and organs. As the fibrotic process advances, it can severely impair organ function and, in many cases, lead to organ failure and death.
This condition can impact nearly any tissue in the body, including the lungs, liver, and kidneys. For instance, idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by relentless scarring of lung tissue, which diminishes quality of life and often results in early mortality. In the heart, cardiac fibrosis can stiffen heart valves and muscle, raising the risk of heart failure. Fibrosis is also a common feature in numerous chronic inflammatory diseases, such as scleroderma and rheumatoid arthritis.
Key Drug Candidates in Development
Pledge Therapeutics focuses on developing small molecule drugs that engage specific targets to produce a profound disease-modifying effect. Their strategy involves tackling challenging drug targets that have previously been out of therapeutic reach.
For fibrotic diseases like idiopathic pulmonary fibrosis (IPF), a drug developed using the PLEDGE™ platform would aim to modulate protein interactions involved in the excessive deposition of collagen and other extracellular matrix components. Such a therapeutic approach would seek to intervene in the aberrant wound healing response that drives fibrosis, potentially by targeting specific signaling pathways that activate myofibroblasts, the cells responsible for producing fibrotic tissue. The goal would be to slow or halt disease progression by restoring a more balanced tissue repair process.
Clinical Trial Progress and Collaborations
Pledge Therapeutics operates as a clinical-stage biopharmaceutical company, with a strategic objective to advance drug candidates closer to clinical translation, making them suitable for co-development. The company’s experienced team has a track record of progressing multiple drug candidates into clinical trials.
Pledge Therapeutics also indicates a broader portfolio that includes first-in-class immune-oncology and antiviral medicinal assets, developed through their integrated ventures like Conformation-X and Orthogon Therapeutics. Pledge Therapeutics also manages independent biotech ventures, including Orthogon Therapeutics, which specializes in antiviral treatments, and Conformation-X, dedicated to advancements in immune-oncology. Conformation-X recently secured over $13.5 million in funding, demonstrating progress in its programs. This affiliate has disclosed successful ex vivo and in vivo proof-of-concept studies for its lead immune-oncology assets, including a potent HHLA2-inhibitor and IL18BP programs.