Key Advantages of Irreversible Drugs
Challenges in Developing Irreversible Drugs
Our FUSION™ System
Biomea Fusion is creating a new generation of small molecule irreversible inhibitors that target genetically defined diseases with high unmet need. These diseases all have biomarker-identifiable patient populations that will be targeted via in silico designed small molecules with new mechanisms of action that likely become best in class. The in-silico and preclinical work is designed to produce an optimized product profile of high potency with benign safety (“Clean Drugs”). We believe that the product profile (best in class potency and safety), and genetically defined disease drivers putatively reduce the technical risk of each project. Irreversible drugs provide a new path to address unmet medical needs and through their innovative mechanism of action will have significant clinical and financial value, if successfully developed.
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Since the discovery of aspirin in 1899, irreversible drugs have been known to offer a number of potential safety, tolerability and efficacy advantages over conventional reversible drugs through multiple mechanisms, including:
Fig. 1. Persistent effect of a marketed irreversible inhibitor in the absence of sustained drug exposure
Beyond aspirin and ibrutinib, a number of irreversible inhibitors have been developed to improve patient outcomes including sofosbuvir (marketed as SOVALDI for hepatitis C virus), tenofovir (marketed as VIREAD for hepatitis B virus), osimertinib (marketed as TAGRISSO for NSCLC) and bortezomib (marketed as VELCADE for multiple myeloma and mantle cell lymphoma).
Despite the potential advantages of irreversible drugs, the majority of approved drugs are reversible binders. The inherent challenges in creating irreversible drugs presents significant barriers to entry to discover and develop these molecules. The key challenges in developing irreversible drugs include:
At Biomea, we believe we are uniquely positioned to leverage the significant expertise, foundational knowledge and capabilities that our management team first acquired while developing ibrutinib and that we have expanded and refined over the last three years to create our FUSION™ System discovery platform.
We believe that irreversible small molecules have the potential to address the key limitations of existing reversible therapeutics and treat diseases where targeted therapies are not yet approved. Leveraging our extensive experience developing irreversible drugs and irreversible binding chemistry expertise, we built our proprietary FUSION™ System to enable the design and development of novel irreversible, small molecule therapies against high-value genetic drivers of cancer. Our FUSION™ System discovery platform encompasses:
We aim to leverage our capabilities and platform to establish ourselves as a leader in developing irreversible small molecules in order to maximize the depth and durability of clinical benefit for patients with various cancers.
Fig. 2. The Biomea FUSION™ System
We leverage unique scaffold designs based on crystal structure analysis with our team’s deep experience in irreversible small molecule drug development. The Biomea Fusion team members were involved in creating some of the most exciting compounds in commercial use today. Top of the list is PCI-32765, an irreversible inhibitor of BTK, which achieves precise target inhibition with a benign safety profile. This compound is commercially available as IMBRUVICA with over $6B of yearly sales and a label that shows overall survival benefits.
We also apply rigorous safety assessments as an integral part of our compound selection processes. We use standard receptor screening tools as well as in-vivo single and ascending dosages with multiple schedules to ensure our compounds are safe in all dosing and usage circumstances. We strive to provide patient-friendly and targeted solutions to address complex diseases. Particularly in oncology, many existing therapies often use aggressive toxins in the hope of controlling the spread of the disease which leads to a myriad of side effects. We aim to laser focus on the target and to do so with incredibly effective compounds that have been preclinically tested and shown to have relative benign safety profiles.