Early Solid Form Assessment Supports Candidate Selection for STORM Therapeutics’ DHX9 Inhibitor Program

How did Sygnature Discovery’s Form & Formulation team help de-risk two lead candidates using only 200 mg of material?

Customer Background

STORM Therapeutics is a clinical-stage biotechnology company focused on developing small molecule therapeutics targeting RNA-modification pathways. As part of its DHX9 inhibitor discovery program, STORM collaborated with Sygnature Discovery’s integrated drug discovery teams to rapidly progress novel chemical matter from lead identification to pre-candidate nomination in just 18 months (Figure 1).

As the program entered late lead optimization, two highly differentiated DHX9 inhibitor candidates remained under consideration. Both compounds demonstrated compelling pharmacology, DMPK properties, and developability characteristics, making candidate selection challenging.

At this critical point,

Understanding the solid-state behavior of each molecule became an important factor in reducing downstream development risk.

The Challenge

Although both compounds were routinely isolated as crystalline solids, little was known about their solid-form landscapes.

The project team needed to answer two key questions:

• Are additional polymorphs possible?
• Can solid-state properties help differentiate between the remaining candidates?

Answering these questions presented an additional challenge. As is often the case during lead optimization, compound supply was limited and in high demand across multiple disciplines. Any investigation would need to generate meaningful data without consuming large quantities of material.

Enter Form & Formulation

Rather than waiting until candidate nomination to begin investigating solid-state risk, Sygnature’s Form & Formulation scientists designed an early-stage, fit-for-purpose solid-form screening strategy.

The study was deliberately scoped to use just 200 mg of API per compound, balancing scientific rigor with the realities of a fast-moving discovery program.

Phase 1: Characterization of the Supplied Material

Analytical methods included:

Each compound was initially characterized using complementary analytical techniques to establish a baseline understanding of the supplied solid form.

• X-ray powder diffraction (XRPD)
• Differential scanning calorimetry (DSC)
• Thermogravimetric analysis (TGA)
• Proton NMR spectroscopy

This confirmed that both compounds were being consistently produced in crystalline forms suitable for further investigation.

Phase 2: Solid Form Exploration

To maximize the opportunity for discovering alternative crystal forms, the supplied materials were first rendered amorphous to eliminate any residual crystal seeds that might bias subsequent crystallization outcomes.

This approach enabled rapid exploration of each compound’s solid-state landscape while maintaining a minimal material requirement.

Following confirmation of the amorphous state by XRPD, materials were exposed to a focused panel of ICH Class 2 and Class 3 solvents using slurry and thermal cycling methodologies designed to promote crystallization across a range of conditions.

Phase 3: Comparative Stability Assessment

Multiple new solid forms were isolated and characterized.

• Additional polymorphic forms
• Hydrates
• Solvates

The screen identified:

A competitive slurry assessment was subsequently performed to determine the thermodynamically preferred form under relevant conditions and to assess the relative stability of the isolated forms.

Results

Despite the limited material available, the study generated significant solid-state intelligence that directly informed program progression.

The assessment demonstrated that:

• Both compounds possessed richer solid-form landscapes than previously understood.
• Alternative polymorphs, hydrates, and solvates could be generated under selected conditions.
• The crystalline material routinely produced by medicinal chemistry corresponded to the most stable form identified during the study.

Importantly, the data demonstrated that solid-state properties should not influence candidate selection, allowing the project team to focus on other critical attributes with confidence.

Client Impact

While the study did not identify a clear « winner » between the two lead candidates, it delivered exactly what the project needed at that stage: risk reduction.

By establishing early confidence in the solid-state behavior of both molecules, Sygnature enabled the project team to:

• Eliminate a significant area of development uncertainty
• Confirm the robustness of the crystallization process already being used by chemistry teams
• Avoid unnecessary investment in extensive solid-form studies before candidate selection
• Maintain aggressive project timelines
• Progress the selected lead with greater confidence into preclinical development activities
  
  

Crucially, this information was generated using only a fraction of the material typically required for a comprehensive late-stage polymorph assessment.

The Advantage of Sygnature Discovery

The success of the DHX9 program relied on seamless collaboration across multiple scientific disciplines, including medicinal chemistry, DMPK, biology, translational oncology, and Form & Formulation. The broader program advanced from lead identification to pre-candidate nomination in just 18 months through Sygnature’s fully integrated discovery platform.

For the Form & Formulation team, this meant delivering development-focused insights precisely when they were needed, helping the project team balance scientific rigor, material constraints, and ambitious timelines.

Whether supporting early candidate selection, preclinical development, or IND-enabling activities, Sygnature’s solid-state scientists provide tailored, fit-for-purpose solutions that help clients move promising molecules forward with confidence.

Looking to de-risk your molecule?

Sygnature Discovery’s Form & Formulation team delivers integrated solid-state, pre-formulation, and developability assessments that help identify risks early, accelerate decision-making, and support successful progression toward the clinic. Contact us to find out how we can assist in your project.