Imogen Pryce, COO of R&D at Relay Therapeutics, on the Dynamo™ Platform and Portfolio Strategy

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Dr. Imogen Pryce, COO of R&D at Relay Therapeutics

In this episode, we chatted with Dr. Imogen Pryce, Chief Operating Officer of R&D at Relay Therapeutics.

Relay Therapeutics (Nasdaq: RLAY) is a clinical-stage precision medicines company that integrates disparate technologies to push drug discovery. Specifically, its Dynamo™ platform integrates leading-edge computational and experimental approaches designed to drug previously-intractable protein targets.

Imogen manages all operational aspects of R&D, from budgeting to recruiting to program and portfolio management. Prior to Relay, Imogen worked in corporate strategy at Shire Pharmaceuticals, and prior to that, was a Principal at the Boston Consulting Group where she focused on healthcare. Imogen holds a B.S. from the Ohio State University and a Ph.D. in chemical engineering from the California Institute of Technology.

In our conversation, Imogen and I discussed:

• Her journey to Relay Therapeutics
• Relay Therapeutics’ scientific strategy and Dynamo™ platform
• Portfolio strategy and Relay’s competitive differentiation

1:30 to 8:20: Imogen’s journey to Relay Therapeutics

• On the guiding principles behind her career transitions: The two elements that have driven Imogen’s career throughout have been (A) the application of technology to solving problems to improve the world, and (B) working with people who energize her in this pursuit. Her journey began in college and PhD in nanotechnology. The integrated, team-based approach of her research team transitioned her well as a consultant for BCG, where she spent 5 years focused on healthcare. Realizing she wanted to build something, Imogen moved to Shire in corporate development and Relay Therapeutics in 2019, right as Relay was seeking to scale following their Series C!
• On leveraging her consulting skills in biotech building: Imogen views consulting as an excellent training ground for biotech. That includes learning how to: structure ambiguity and shift plans nimbly (e.g., research timelines); tell a compelling story based on the audience (e.g., investors vs. employees); and adapt to different working styles across a diverse set of stakeholders and peers (e.g., research experts to finance).

8:20 to 20:20: Relay Therapeutics’ scientific strategy and Dynamo™ platform

• On the Relay Therapeutics strategy: A new “breed of biotech” at the intersection of computational and experimental approaches, Relay Therapeutics creates precision medicines for protein targets that are well-validated disease-drivers (e.g., PI3Ka).

“We focus on proteins [targets] where there are clear proof points, where there is some sort of translational de-risking that has happened, where we know that drugging them [effectively] will lead to [the desired] effect”

• On how Relay goes after these targets — the Dynamo™ platform: The integration of experimental and computational approach is actualized in three steps. (1) The platform visualizes the protein via motion-based drug design to identify a binding pocket. (2) Next, chemical starting points (to bind to this pocket) are defined. (3) Then, the novel compositions of matter are evolved for drug-like properties (e.g., ADME and toxicity) to ultimately bring into the clinic.
• On the clinical proofpoints of the approach: Founded in 2016, Relay has validated the platform and brought three oncology programs into clinical trials. First, their SHP2 inhibitor is partnered with Roche-Genentech. Second, RLY-4008 is a FGFR2 inhibitor in phase 1/2 clinical trials. Finally, Relay has most recently entered the clinic with a mutant-selective inhibitor of PI3Ka, RLY-2608.
• On deep-diving on Relay’s approach and the FGFR program: For background context, traditional drug discovery retains two key limitations: (A) using static images of protein fragments to understand binding (which does not represent the dynamic, multi-domain, multi-conformation, ‘wiggly’ nature of protein interactions in the cell), and (B) the ability to only test molecular candidates that you could chemically synthesize (not all candidates can be!). By contrast, the Dynamo™ platform integrates genomic data, experimental insights (e.g., cryo-EM for protein visualization), and computational increases for ML/modeling to create protein “movies” to fully understand the disease target. Once the target has been fully explored, Relay can screen billions of compounds in silico to test which candidates could work. As an example, FGFR1/FGFR2 are undifferentiated in static images, but dynamic ‘movies’ uncovered a key difference in protein motion between FGFR1 and FGFR2 that was exploited to yield a highly-selective FGFR2 compound, RLY-4008. At ESMO 2022, Relay presented interim clinical data for RLY-4008 that demonstrated a safe and tolerable profile with an interim ORR of 88% in a cohort of patients with FGFR2-fusion cholangiocarcinoma (CCA).

This picture depicts the Relay approach, where they use dynamic models to better understand a protein’s motion, with the goal of developing novel hypotheses to inhibit the target. This example demonstrates how differences in the motion of FGFR1 and FGFR2 could lead to novel hypotheses to selectively modulate the target. Source: 2023 Relay Therapeutics Corporate Presentation

• On the training data and experimental loops of the Dynamo™ platform: Dynamo’s models are trained on the relevant regions of chemical space, completing additional assays on any ‘blind spots’ of chemical space. This creates a cycle of computation (e.g., molecular dynamics, free-energy calculations) and experiment (e.g., DNA-encoded libraries for ultra-high throughput screening). For example, active learning is used to virtually search databases of multi-billion molecules to fit into a binding site, that then drives the next round of experiments for candidate selection.

“This is analogous to searching through billions of keys to find one that will fit into a lock”

20:20 to 29:30: Portfolio strategy and Relay’s competitive differentiation

• On portfolio prioritization in a large program portfolio: Imogen believes that the more work Relay does, the better the platform becomes. Despite the diversity of programs underway, Relay continues to focus on well-validated proteins that are drivers of disease. This ensures that (A) patients are easily identified (via genomic data), (B) translation risk remains low, (C ) a path to clinical proof-of-concept is well-defined, and (D) clinical indicators read-out quickly (i.e., understand whether the drug is working). Criteria such as these drive portfolio prioritization and resource allocation decisions!
• On balancing different kinds of risks in Relay’s approach: Imogen views two kinds of risks: translational risk and platform risk. By pursuing targets that are genetically well-validated disease drivers, Relay seeks to minimize translational risk. This creates a trade-off in creating technically more challenging therapeutic candidates, that require greater ‘lift’ of the platform.

“You want to minimize [translational risk] as much you can. That can be a very expensive risk to get wrong — it can take a lot of money and years to understand in the clinic whether or not [the medicine] is working”

• On fast-followers pursuing similar disease targets: Though Imogen agrees that other biotechs may be pursuing the same compelling, well-validated disease targets (e.g., PI3Ka), she feels confident in Relay’s ability to drug these targets more effectively than others given their integration of computational and experimental approaches — thus far borne out in Relay’s clinical data!
• On Relay Therapeutics’ competitive differentiation: Relay’s differentiation lies in three elements. First, Relay was founded in 2016, and its greater experience in computational drug discovery means they are a leader in the space, validating their platform and translating it into innovative medicines. Second, Relay remains hyper-focused on validated protein targets and drugging them in its unique motion-based drug design approach. Finally, Relay is a leader in truly integrating computational and experimental approaches across each stage of target modulation hypothesis, hit-finding, and lead optimization.

The Relay Therapeutics approach (slide 47, January 2023 corporate presentation)

29:30 to End: Advice to budding bioentrepreneurs

• On advice to early bioentrepreneurs: Imogen recommends four pieces of advice: (1) spend time building relationships with the right people, (2) stay humble, (3) be okay with a non-linear career path, and (4) don’t be afraid to ask for help along the way!