REM-422, RNA Processing, and the Next Wave of Translational Science with Benoît Moreau, Remix Therapeutics

About the Interviewee

Benoît Moreau is the Head of Medicinal Chemistry at Remix Therapeutics.

Benoît Moreau serves as the Head of Medicinal Chemistry at Remix Therapeutics, a groundbreaking biotech company focused on the modulation of RNA processing by identifying small molecules that impact the expression of disease driving mRNAs and proteins. Dr. Moreau holds a Ph.D. in Chemistry from Université de Montréal, following which he completed a postdoctoral fellowship at Harvard University. His graduate and postdoctoral work in synthetic organic chemistry centered on natural product synthesis and development of novel catalytic methodologies.

He has extensive experience in medicinal chemistry across multiple therapeutic areas (oncology, rare genetic disease, virology) from working in both biotech (Remix, Syros, Tarveda) and pharma (Boehringer Ingelheim). He contributed to numerous drug discovery programs and led multidisciplinary teams that delivered several clinical candidates. He strives to take on scientific challenges and embraces the use of new technologies to accelerate drug discovery. He joined Remix to develop their RNA processing platform towards the discovery of clinical candidates that address high unmet medical needs.

The Discussion

Journey to Becoming Head of Medicinal Chemistry at Remix Therapeutics

[PharmaFEATURES]: It’s such a pleasure to have you here with us today, Dr. Moreau. So, Benoît, our background showcases a wealth of experiences in medicinal chemistry from hit finding to lead optimization across diverse therapeutic areas and target classes. Could you elaborate on how your experiences leading multidisciplinary teams successfully to clinical candidates, performing multiparameter optimization, SAR and SBDD on a range of projects have influenced your strategy for guiding the medicinal chemistry efforts at Remix Therapeutics? How did these experiences prepare you for the unique challenges and opportunities of RNA-targeted drug discovery?

[Dr. Benoit Moreau]: Thank you for providing an opportunity to talk about my career and the Remix team’s exciting work tackling disease drivers via modulating RNA processing with small molecules. My experiences in drug discovery taught me that to be successful, teams need to work on solving problems that matter. Since we are often operating in an innovative space, this requires clear alignment with management on how the project can deliver and ensuring it can be impactful for patients. Medicinal chemists work closely with several functions to receive timely insights that can guide SAR analysis and designs, which allows them to perform multiparameter optimization and balance relevant compound properties. You need to efficiently communicate across scientific disciplines to react rapidly to new data and to leverage lessons learned on previous projects. Finally, for optimal execution in medicinal
chemistry, it is key to establish strong partnerships with CROs and to not hesitate to leverage additional medicinal chemists while continuously exploring new CROs to complement the team’s expertise.

I was enthusiastic about joining Remix because of the strong team and innovative science. Remix is working at the cutting-edge in the field of RNA-targeted drug discovery and is committed to building a platform to identify and validate novel chemical matter. The potential for small molecules to modulate biologically validated targets through RNA processing is groundbreaking because it could lead to a new generation of therapies in areas of high unmet medical need.

Engineering Novel Therapeutics for Hard-to-Target Proteins

[PF]: RNA-targeted drug discovery is an exciting and possibly groundbreaking approach to address hard-to-target proteins. From your perspective, what are the opportunities for small molecules, how do these differ from traditional drug discovery targeting proteins?

[Benoît]: Many protein targets that are dysregulated in a disease state are deemed “undruggable”, because they lack the requisite binding features required for engagement with small molecules. Modulating gene expression of these proteins by targeting the mRNA offers new therapeutic opportunities notably in cancer and neurodegenerative disorders. Small molecules and oligonucleotides, also referred to as ASOs, can both be used to interact with RNA, but small molecules offer better tissue distribution properties and allow for oral dosing.

One approach to modulate gene expression is to intervene in RNA processing by stabilizing weak splice sites, resulting in exonization of alternative splice sites. The first example of a small molecule operating through the splicing modulator mechanism is Risdiplam, which is approved for treatment of SMA. Risdiplam favors the alternative splicing of the SMN2 gene through stabilizing the interaction of the 5’ splice site to the U1 snRNP complex, resulting in inclusion of exon 7 and leading to production of functional SMN protein.

Conversely the exonization of alternative splice sites can lead to decreased protein levels through degradation of mRNA transcripts. This occurs when the exonization of an alternative splice site leads to the inclusion of a “poison exon”, in which case, the mRNA transcript will be degraded via the nonsense-mediated decay (NMD) pathway. I would like to point anyone interested in learning more about poison exons to a recent comprehensive review in Trends in Pharmacological Sciences written by my colleagues at Remix.

The power of this approach utilizing poison exons is that it enables modulating gene expression for validated biological targets that would otherwise be challenging to engage at the protein level. To summarize some of the benefits of this approach, drug-like molecules are designed to bind RNA-protein complexes while achieving oral availability and CNS penetration (when required) using standard optimization strategies. The compounds act on RNA processing agnostic of the final gene protein target. With this mechanism, there is the opportunity to lead to protein degradation, enhancement, and rescue.

Challenges to RNA-Targeted Drug Discovery

[PF]: Can you highlight the challenges with drugging RNA relative to proteins? With regards to developing novel RNA-targeted therapeutics that will satisfy unmet medical needs, what advancements do you envision as critical for this emerging field?

[Benoît]: The main challenges in discovering small-molecule therapeutics targeting RNA include accurately predicting targetable genes, developing reliable assays for hit identification and validation, and expanding chemotype diversity. From a chemistry standpoint, RNA druggability is limited by the lack of structural enablement and a narrow range of chemical starting points.

RNA’s flexible, dynamic structure, charged sugar-phosphate backbone, and absence of well-defined binding pockets—unlike proteins—complicate small-molecule binding. Computational tools have poor predictive power when it comes to RNA structure given the scarce amount of structural information available to support the drug discovery efforts. Breakthroughs in this field could enable structure-based drug design and predictive computational modelling to support designs and help rationalize SAR.

Because of this, there are limited chemical starting points. Risdiplam and Branaplam were the first two splicing modulators to be tested in the clinic. They have very similar structural features, with a rod-like shape, flat heterocycles and a cyclic amine. The various tool compounds reported to interact with RNA also share these features, as do the vast majority of splicing modulators reported to date. This highlights the challenges so far to identify chemical matter that falls outside the reported chemotypes, likely because there are limited possible interactions with RNA. The main interactions possible are aromatic stacking with RNA base pairs through pi-interactions, hydrogen bonding with sugar-backbone hydroxyls and electrostatic interactions with the negatively charged phosphate backbone.

Remix Approach to RNA-Targeted Drug Discovery

[PF]: Remix Therapeutics created the innovative REMaster platform, which identifies druggable target sites and active chemical matter that modulates RNA processing to control gene and protein expression. How does Remix’s platform overcome the hurdles associated with the discovery of RNA-targeted therapeutics? Could you provide a detailed overview of how the REMaster platform enables the identification and validation of RNA-modulating small molecules?

[Benoît]: Remix is working on several fronts to address the historical challenges associated with RNA-targeted drug discovery. The goal of the REMaster platform is to enable discovery of therapeutics modulating RNA processing through accurate prediction of targetable genes, building reliable assays to identify and validate hits, and expansion of the diversity of chemotypes available. In short, the REMaster platform leverages our expertise in computational biology, RNA processing biology, novel assay development, computational and medicinal chemistry to address these challenges and hopefully bring new medicines to patients.

Target selection is critical in drug discovery and to initiate programs, we need to figure out if biologically validated targets of interest have potential to be modulated using the Remix approach. We built an integrated database of over 350K internal and external transcriptome datasets, we interrogate the database with proprietary algorithms and use AI/ML to predict weak alternative splice sites with potential for stabilization with a small molecule.

Using a defined set of potential alternative splice sites, we then develop a suite of assays for fit for purpose high-throughput multiplexed screening. For example, we developed multiplex cellular assay formats to interrogate alternative splice site modulation resulting from the formation of mRNA exonized at the predicted alternative splice sites. These multiplexed assays allow Remix to interrogate compounds across a range of targets simultaneously, providing a read on selectivity in the primary dataset. We carefully built a curated compound library focusing on drug-like properties, coverage of chemical space diversity enriched with functional groups that are more likely to interact with RNA.

Some assays are purposefully ‘catch all’ assays, providing the possibility to identify compounds that modulate gene expression through a variety of mechanisms. During the hit validation phase we weed out the hits that proceed through undesired mechanisms, which requires orthogonal assays and tools to deconvolute the mechanism of action during the validation phase. In the end, we want to gain confidence that we have sufficient understanding of the mechanism of action to warrant dedicating resources towards a hit-to-lead effort and subsequently to a lead optimization campaign.

Translating Cutting-Edge Research into Clinical Impact

[PF]: Remix is performing cutting-edge research in RNA processing with the objective of delivering clinical programs with a tangible impact for patients. Could you describe how Remix is leveraging its platform to fuel new programs and build partnerships? Are there differences to the drug discovery workflow given the mechanism of action of these molecules, and how does this impact the criteria for selection of clinical candidates?

[Benoît]: The platform allows us to screen potential poison exons in multiple innovative assay formats, which allows the identification of hits that modulate alternative splicing through novel mechanisms. In some cases, we need to discriminate against hits that are unlikely to lead to candidate molecules, for example demonstrating activity through cytotoxicity or broadly affecting splicing.

We have been able to understand MOA and optimize potency early in the project to set us up for positive outcomes. Subsequently, the lead optimization is performed through workflows that are typical to small molecule programs. We optimize potency, perform SAR and balance the ADME/PK profile to achieve in vivo target modulation and efficacy at tolerated doses.

This approach is already delivering programs with starting points outside of current chemotypes, including targeting MYB, an oncogenic transcription factor and a toxic protein aggregate modifier for the treatment of a neurodegenerative disease. We also work to expand the potential of our platform through collaborations with Johnson and Johnson and Roche.

Highlighting Remix’s Successes

[PF]: One of Remix’s notable achievements is the discovery of REM-422, now in clinical trials, which targets the MYB transcription factor. Could you delve into the drug discovery efforts behind this program? Specifically, how did your team overcome the challenges of designing molecules modulating MYB expression through a RNA-processing approach?

[Benoît]: For the first program and clinical candidate of the company, Remix identified MYB, which is a previously undruggable oncogenic transcription factor driving solid tumors and heme malignancies. An oral small molecule that induces the reduction of MYB mRNA and protein expression offers the potential to treat multiple cancers. One indication is adenoid cystic carcinoma (ACC), for which there are no approved therapy and where ~90% patients have MYB dysregulation. Another indication is acute myeloid leukemia/high risk myelodysplastic syndromes (AML/HR-MDS), where there is potential for broad activity given that the MYB dependency is genetically validated.

We used orthogonal and complementary cellular, biochemical and biophysical assays. This suite of assays demonstrated that our compounds are binding to a reconstituted U1 snRNP complex, degrading MYB mRNA, reducing MYB protein levels and are selectively lethal in MYB-dependent cancer cells. The Remix team effort led to the identification of REM-422, a potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and protein expression resulting in antitumor activity in MYB-dependent human tumor models.

From a medicinal chemistry point-of-view, our compound library delivered a drug-like starting point with good overall properties. We performed a lead optimization campaign modulating ADME/PK and balancing properties within the boundaries of typical small molecule programs. REM-422 is a first-in-class mRNA degrader currently in Phase 1 clinical trials. It obtained orphan drug designation from the FDA for the treatment of ACC and AML. It’s an exciting time at Remix, with REM-422 having the potential to make a difference for patients.

Future Outlook in Medicinal Chemistry and Drug Discovery

[PF]: Dr. Benoît, as the Head of Medicinal Chemistry, how do you anticipate the landscape of drug discovery to evolve in the next decade, particularly in the context of biotechnological advances? How is Remix positioned to adapt to these changes, and what role do you see for RNA-targeted therapeutics in shaping the future of precision medicine and expanding the boundaries of chemical space?

[Benoît]: New technologies and innovative approaches constantly emerge to improve and expand the scope of the practices in drug discovery. With the excitement about AI and machine learning, I expect a greater role for computational methods from complex analysis of large datasets to facilitate the enablement of generative models. This will lead to breakthroughs as increased experimental throughput provides better training sets. Medicinal chemists will leverage new tools to have better predictive power in the drug design, providing new opportunities for therapies.

It is exciting to be part of a team that is leveraging splicing modulation for targeted gene regulation and bringing potential new therapeutics to patients. Success will foster more investment in this space and Remix will be in an ideal position to maximize its growth given its commitment to understanding of the rules governing splice-site selection and to making breakthroughs in RNA-complex structural biology.

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES

Join Proventa International’s Medicinal Chemistry Strategy Meeting at Le Meridien Boston, Cambridge, Massachusetts on the 8th of May 2025 to learn more about Remix Therapeutics masterful reprogramming of RNA processing and bleeding-edge designing of therapeutic solutions.