Morphic Therapeutic's MORF-627, an orally available αvβ6 integrin inhibitor, has been shelved due to unacceptable oncogenic toxicity despite promising preclinical results. The drug was being developed as a potential treatment for idiopathic pulmonary fibrosis (IPF) by targeting and blocking the TGFβ pathway, a key driver of fibrosis.
The development of MORF-627 involved sophisticated structure-based drug design (SBDD) and free energy perturbation (FEP+) techniques to optimize the molecule's permeability and selectivity for the αvβ6 integrin isoform. A key design element was the focus on inhibiting the "bent-closed" conformation of αvβ6, a novel approach to modulating integrin activity. The molecule also featured a linker design that conferred "chameloenicity," enhancing its drug-like properties.
Preclinical studies of MORF-627 demonstrated favorable multispecies pharmacokinetics (PK) and significant in vivo efficacy in relevant disease models. However, these promising results were overshadowed by the emergence of oncogenic toxicity during preclinical safety assessments, precluding its advancement into human clinical trials. The specific mechanisms underlying the observed toxicity were not disclosed, but the finding highlights the challenges in developing integrin inhibitors, particularly concerning off-target effects and potential disruption of normal cellular processes.
IPF is a progressive and ultimately fatal disease characterized by scarring of the lungs, affecting an estimated 100,000 people in the United States. Current treatments, such as pirfenidone and nintedanib, can slow disease progression but do not halt or reverse the fibrotic process and are associated with significant side effects. The failure of MORF-627 represents a setback in the search for more effective and safer therapies for IPF.
