Updated Dose Escalation Results for ReFocus: A First-In-Human Study of Highly Selective FGFR2 Inhibitor, RLY-4008, in Cholangiocarcinoma and Other Solid Tumors
Our DynamoTM platform and approach are creating new possibilities in drug discovery
RLY-4008 is designed to be an oral, small molecule, selective inhibitor of FGFR2, a receptor tyrosine kinase that is frequently altered in certain cancers.
FGFR2 is one of four members of the FGFR family, a set of closely related proteins with highly similar protein sequences and properties. Non-selective, pan-FGFR inhibitors produced by other companies have demonstrated clinical proof-of-concept in patients with intrahepatic cholangiocarcinoma bearing FGFR2 gene fusions. However, these existing FGFR therapies are constrained by a dose-limiting side effects caused by inhibition of FGFR1 and FGFR4.
Interim clinical data support RLY-4008 as the first highly selective FGFR2 inhibitor that has not shown to be limited by off-target toxicities of hyperphosphatemia (FGFR1) and diarrhea (FGFR4). These initial data also suggest RLY-4008 is safe, tolerable and drives tumor regression across multiple tumor types.
The ongoing first-in-human trial for RLY-4008 is designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor efficacy. Following a thorough assessment of the dose escalation data, the expansion portion of the trial has been initiated at a dose of 70 mg once daily.
RLY-2608 is designed to be the first allosteric, pan-mutant (H1047X, E542X and E545X) and isoform-selective PI3Kα inhibitor.
PI3Kα is the central regulator of a signaling pathway that has been linked to a diverse group of cellular functions related to cancer including cell growth, proliferation and survival. Data collected as a part of large sequencing efforts identifies PI3Kα as the most frequently mutated kinase in cancer.
Traditionally, the development of PI3Kα inhibitors has focused on the active, or orthosteric, site. The therapeutic index of orthosteric inhibitors is limited by the lack of clinically meaningful selectivity for mutant versus WT PI3Kα and off-isoform activity. Toxicity related to inhibition of WT PI3Kα and other PI3K isoforms results in sub-optimal inhibition of mutant PI3Kα with reductions in dose intensity and frequent discontinuation. RLY-2608 is designed to overcome these limitations.
We solved the full-length cryo-EM structure of PI3Kα, performed computational long time-scale molecular dynamic simulations to elucidate conformational differences between WT and mutant PI3Kα, and leveraged these insights to support the design of RLY-2608.
The first-in-human trial for RLY-2608 is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity.
RLY-5836 is a chemically-distinct, pan-mutant selective PI3Kα inhibitor. Like RLY-2608, it has been observed preclinically to be active on all of the most common PI3Kα mutations, including H1047X, E542X and E545X, and has shown preclinically to be selective over wild-type PI3Kα.
The first-in-human trial for RLY-5836 is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity.
RLY-2139 is designed to be an oral, small molecule, potent and selective inhibitor of CDK2 that spares other CDKs.
Cyclin-dependent kinases (known as CDKs) are critical regulators of cell division and CDK 4/6 inhibitors have validated targeting the CDK family in breast cancer. CDK2 plays a different role in cell division from CDK 4 or 6 and is activated by a partner protein called cyclin E. Cyclin E is amplified in some tumors, which is believed to lead to tumor dependence on CDK2 for growth and survival. In HR+/HER2- breast cancer, the expression of cyclin E (with or without genomic amplification) is associated with resistance to CDK 4/6 inhibitors suggesting that CDK2 inhibition could prevent or overcome resistance to CDK 4/6 inhibitors in this setting.
The discovery of novel CDK inhibitors has historically been challenged by achieving the desired selectivity for the CDK of interest while avoiding activity against other CDKs. For CDK2, we set out to discover a selective compound that avoided inhibiting other critical CDKs, including CDK1. Conventionally, this would be accomplished with empirical medicinal chemistry, which has resulted in agents with sub-optimal selectivity profiles.
We applied the physics-based computational part of our Dynamo platform to model the interaction of CDK inhibitors with CDK2 and other CDK family members, allowing us to develop a predictive computational model to rationally design selective CDK2 inhibitors rather than engage in a long empiric medicinal chemistry campaign.
We anticipate entering the clinic with RLY-2139 in early 2024.
Our ERalpha Degrader is designed to be an oral, potent, selective, bifunctional protein degrader.
Endocrine therapy has been a mainstay of treatment of hormone-receptor positive breast cancer for decades, and we believe will continue to be a backbone therapy moving forward. Among the emerging next generation anti-estrogens, the early data on bifunctional estrogen receptor degraders is amongst the most promising in our view. These are agents that bind to the estrogen receptor and to components of the E3 ligase system, which tag the estrogen receptor for destruction by the proteasome.
As with other problems to which we have applied the Dynamo platform, the design of bifunctional protein degraders has been largely empiric to date. We can apply tools from the Dynamo platform, including experimental tools like cryo-EM, crystallography and HDX-mass spec integrated with computational tools like long time scale MD to build conformational models of ternary complex formation and triage compound design ideas.
We anticipate nominating a development candidate for our estrogen-receptor degrader program in 2023. Relay Therapeutics and EQRx will equally share in the discovery, development and commercialization costs as well as the net profits from sales of any collaboration medicines, if approved.
GDC-1971 (formerly RLY-1971) is designed to be an oral, small molecule, potent and selective inhibitor of the protein tyrosine phosphatase SHP2 that binds and stabilizes SHP2 in its inactive conformation.
SHP2 promotes cancer cell survival and growth through the RAS pathway by transducing signals downstream from receptor tyrosine kinases (RTKs). As a critical signaling node and regulator, SHP2 drives cancer cell proliferation and plays a key role in the way cancer cells develop resistance to targeted therapies.
We believe that inhibition of SHP2 could be effective as a monotherapy in cancers with specific alterations and could block a common path that cancer cells exploit to avoid killing by other antitumor agents, thus overcoming or delaying the onset of resistance to those therapies.
In December 2020, we entered into a worldwide license and collaboration agreement with Genentech, a member of the Roche Group, for the development and commercialization of GDC-1971. Under the collaboration, Genentech has assumed development of GDC-1971 with the potential to expand into multiple combination studies.
Discovery Programs (5+)
While our initial focus has been on enhancing small molecule therapeutic discovery in precision oncology, protein conformational dynamics are implicated in a wide variety of therapeutic areas. We have also leveraged the power of our Dynamo platform to extend to genetic disease as well.
Our current discovery programs are focused in targeted oncology (3) and genetic disease (2).
We also continue to evaluate potential additional therapeutic areas beyond precision oncology and genetic disease that we could enter in the future.
At Relay Therapeutics, we know that patients need new medicines now. This is the driving force behind everything we do.