My dad passed away when he was just fifty-six from acute myeloid leukemia (AML). Even with all the progress we’ve made treating cancer, it’s one of those diseases that still leaves too many people and families with too few options. The outlook can be particularly tough depending on factors like age, other health issues, and genetics. For my dad, it meant just eighteen more months after diagnosis. Now that I’m nearing the age he was when we lost him, I feel an even deeper sense of purpose in the work I do. As Chief Scientific Officer at Remix Therapeutics, I’m part of an incredibly dedicated team focused on a challenge that cuts across some of the toughest areas in medicine, including AML and other cancers like adenoid cystic carcinoma (ACC), neurodegenerative conditions, and genetic disorders. They share something in common: a need to address the intractable drivers of disease. And that’s exactly where Remix is aiming to make a difference.

One of those intractable drivers of disease is what has historically been called undruggable proteins. While proteins are responsible for the processes necessary to sustain life itself, defects within them can ultimately result in disease. Current approaches often focus on binding these defective proteins with small molecules or biologics, modulating the activity to gain therapeutic effect; however, not all proteins have ligandable pockets, and even when they do, binding does not necessarily result in modulating the activity of the target. Although protein overexpression, overactivity, or lack of activity often drives disease, the root of dysfunction typically begins in the genetic code, often through alterations in the DNA.

Occurring upstream of proteins is RNA processing, a fundamental sequence of events that occurs upon transcription and governs messenger RNA (mRNA) maturation, allowing protein translation and expression followed by RNA degradation. Steps in RNA processing can include RNA end-capping, polyadenylation, removal of introns, and splicing of exons to produce mature mRNA transcripts; as such, reprogramming RNA processing represents an exciting therapeutic opportunity to alter gene malfunction and address the root cause of disease. Targeting the different nodes of RNA processing has the potential to degrade disease-driving transcripts, upregulate beneficial transcripts, and correct defective transcripts to allow for the translation of a functional protein. While this can be done using modalities like siRNA or antisense oligonucleotides, small molecules offer a distinct advantage in terms of oral bioavailability and tissue distribution particularly when considering CNS penetrance for neurological disorders.

At Remix, we pioneered the REMaster platform to discover novel small molecule therapeutics that target the cellular complexes that process mRNA. Fundamentally we reprogram mRNA to either enhance protein function or eliminate protein dysfunction. The REMaster platform unifies built for purpose machine learning algorithms that leverage extensive transcriptomic datasets, bespoke, high-throughput, multiplexed cell-based and cell-free screens and a proprietary RNA-targeted small molecule library to generate key insights and drive our pipeline. Our platform doesn't simply identify small molecules that bind mRNA, since binding alone does not necessarily illicit biological function in a cellular context; our assays identify compounds that are cell penetrant and result in the desired modulation of the mRNA transcript, establishing biological relevance early in our discovery process and resulting in quality, promising lead compounds and recent publications.

Our lead asset, REM-422, targets sequences within mRNA called poison exons (PEs); during RNA maturation, the small molecule drives inclusion of a premature termination codon in the mRNA transcript, resulting in degradation of the transcript via a process known as nonsense-mediated decay and the subsequent reduction of the downstream protein. REM-422 targets the mRNA of MYB, a previously undrugged transcription factor implicated in a diverse range of hematological malignancies and solid tumors. REM-422 is the first orally available, small molecule mRNA degrader to enter the clinic for cancer and is currently in Phase 1 clinical studies in both ACC and AML or high-risk myelodysplastic syndrome (HR-MDS) (NCT06297941, NCT06118086).

Ultimately, Remix was the inevitable convergence of both science and people. As CSO of Remix and one of the first employees at the company, I feel privileged to be in a position to represent the work of some of the brightest, most passionate and collaborative colleagues, who all have their own stories of why they feel compelled to dedicate their careers to a completely new approach to treating disease and the patients who will benefit.

Dominic Reynolds | Chief Scientific Officer