Relay Therapeutics Provides Business Update
Taking a Look at Relay Therapeutics (RLAY) Business Update.
Relay Therapeutics (RLAY) released a business update Wednesday after-hours, and it was more interesting than usual. Typically, these updates are non-events, especially for pre-revenue biotech companies that rely on interim or final clinical trial (CT) data readouts to drive investor interest. These readouts are critical for assessing progress, but RLAY does not have any major data releases scheduled in the near future.
One notable takeaway from the update was the lack of results from their triplet combination (RLY-2608 + Fulvestrant + CDK4/6 inhibitor *Ribociclib or Atirmociclib*). At first, this raised some concerns, but after further review, it became clear that RLAY is not abandoning the triplet—rather, they are delaying its release while adjusting their dosing strategy. The company is prioritizing its doublet combination (RLY-2608 + Fulvestrant) for Phase 3 and implementing new dosing regimens before finalizing triplet data. More details on this below.
Please refer to my most recent RLAY article in my archive, as most of the key points, particularly on valuation, remain unchanged. The main updates in this article focus on R&D expenses and dosing regimens.
Financial Results (Q4 & FY 2024)
Revenue & Net Loss:
Revenue: $10M for the full year, down from $25.5M in 2023 due to timing of milestone payments under the Genentech collaboration.
Net loss:
Q4 2024: $76M ($0.45 per share) vs. $83.5M ($0.67 per share) in Q4 2023.
Full year: $337.7M ($2.36 per share) vs. $342M ($2.79 per share) in 2023.
R&D & Opex:
R&D expensesd:
Q4 2024: $68.1M, down from $77.5M in Q4 2023.
Full year: $319.1M, down from $330M in 2023, reflecting pipeline prioritization.
G&A expenses:
Q4 2024: $16.9M vs. $16.8M in Q4 2023.
Full year: $76.6M vs. $75M in 2023.
Cash & Liquidity Position:
Cash, cash equivalents & investments: $781M as of Dec 31, 2024, up from $750M in 2023.
Expected to fund operations into the 2H 2027.
Pipeline Updates & Clinical Developments
Lead Program: RLY-2608 (PI3Kα Inhibitor for HR+/HER2- Breast Cancer)
Key Clinical Data from ReDiscover Trial:
Median PFS: 11.4 months in second-line (2L) patients with PI3Kα-mutated, HR+/HER2- metastatic breast cancer.
ORR: 39% (12 of 31 patients with measurable disease).
CBR: 67% (32 of 48 evaluable patients).
Safety: Mostly low-grade treatment-related adverse events (TRAEs), low discontinuation rate, and mild hyperglycemia (only two Grade 3 cases).
Upcoming Phase 3 Trial (ReDiscover-2) - Mid-2025 Initiation
Randomized, open-label, multicenter study.
Comparator: Capivasertib + Fulvestrant.
Target enrollment: 540 patients.
Primary endpoint: PFS.
Secondary endpoints: OS, response rate, duration of response, quality of life.
Phase 3 Dose: 400mg BID (fed), providing equivalent exposure to 600mg BID (fasted).
Expansion of RLY-2608 Program:
Ongoing triplet combinations:
RLY-2608 + Fulvestrant + Atirmociclib (Pfizer’s selective CDK4 inhibitor).
RLY-2608 + Fulvestrant + Ribociclib.
Future next-gen oral endocrine therapy combinations planned.
Other Pipeline Updates
Vascular Malformations (PI3Kα Target) - RLY-2608 clinical trials begin in Q1 2025.
NRAS-Selective Inhibitor (RLY-8161) - First-in-class NRAS-selective inhibitor targeting NRAS-mutated cancers while sparing KRAS and HRAS. IND-enabling studies ongoing.
Fabry Disease Program - First investigational non-inhibitory chaperone therapy designed to stabilize αGal enzyme without inhibiting activity.
Lirafugratinib (RLY-4008 - FGFR2 inhibitor) - Exclusive global licensing agreement with Elevar Therapeutics, which now leads development and commercialization.
Future Outlook & 2025 Key Milestones
Mid-2025: Phase 3 ReDiscover-2 trial initiation (RLY-2608 + Fulvestrant in HR+/HER2- breast cancer).
Q1 2025: Start of vascular malformations trial with RLY-2608.
NRAS and Fabry Disease Programs: Advancing toward IND filing, with trial start dates phased for optimal resource allocation.
Additional Phase 1b RLY-2608 Data: Expected in 2025.
My Take
This was actually a very exciting business update from RLAY, and it’s clear the company is going all-in on the RLY-2608 + Fulvestrant doublet as it moves into pivotal Phase 3 trials with a planned enrollment of 540 patients. However, there were a few things I needed clarification on, including the lack of a triplet combo data release, R&D expenses, and the updated dosing regimen for the doublet.
What’s Going On with Relay’s Triplet Strategy?
What RLAY was originally testing was two triplet combinations—RLY-2608 + Fulvestrant + Ribociclib (Novartis’ CDK4/6 inhibitor) and RLY-2608 + Fulvestrant + Atirmociclib (Pfizer’s selective CDK4 inhibitor). While both were designed to improve treatment outcomes for HR+/HER2- metastatic breast cancer, the company has not yet released triplet data, which has raised questions about its status. At first, I wondered if the triplet results were so poor that the company might abandon it altogether, but that’s not the case here. They are not abandoning the triplet but rather delaying its release while it refines its dosing strategy and focuses on ensuring the right combination partner.
The core issue revolves around how the triplet was initially dosed. The ribociclib combination was dosed in a fasted state, meaning patients took the drug on an empty stomach, while the atirmociclib combination was dosed in a fed state, meaning patients took the drug with food. RLAY later determined that fed-state dosing is preferred due to better drug absorption and fewer side effects. This created a complication—the ribociclib triplet was tested in a way that no longer aligns with RLAY’s preferred dosing approach. At the same time, the atirmociclib triplet was already designed for a fed-state regimen, making it the more likely choice moving forward.
Since RLAY changed its dosing strategy after initial triplet testing, it really means that the company is now re-evaluating the best triplet partner before making any public data disclosures. If the ribociclib combination no longer aligns with the fed-state approach, they may need to adjust its triplet study before sharing results to avoid inconsistencies. This is likely why the company has been delaying the release of triplet data while it refines its approach. But they are also being strategic about when to release its triplet data, considering recent developments in the biotech space. After Eli Lilly acquired Scorpion Therapeutics’ PI3Kα inhibitor (STX-478) for up to $2.5B, it created a spotlight on PI3Kα inhibitors. RLAY may be waiting to ensure that its triplet data is as competitive as possible before making it public, especially since the atirmociclib triplet could become a major differentiator.
Dosing Mismatch – The ribociclib triplet was tested in a fasted state, but they later decided that fed-state dosing is preferred, creating an inconsistency.
Potential Partner Switch – Atirmociclib was already tested in a fed-state regimen, making it a better fit for their updated dosing strategy and a stronger candidate moving forward.
Regulatory Considerations – They may be waiting to refine its triplet study before submitting data to regulators, ensuring it aligns with its overall treatment approach.
Competitive Positioning – With Eli Lilly’s recent moves in the PI3Kα space, they may be timing its triplet data release to maximize its impact in the market.
I want to make something very clear because there seems to be a lot of confusion—the triplet combination strategy does not matter right now. Even if the triplet ends up being a failure, it won’t change the bigger picture. The doublet has already set an incredibly high bar against competitors, thanks to its data. That’s why RLAY is making a strategic pivot, temporarily shifting resources away from the triplet and doubling down on the doublet, which remains its most valuable asset.
Phase 3 Doublet Trial (RLY-2608 + Fulvestrant)
RLAY's decision to change the dosing strategy for RLY-2608 + Fulvestrant in its Phase 3 trial from 600mg BID fasted to 400mg BID fed was not made arbitrarily. This shift was based on pharmacokinetic (PK) studies (how the body reacts to the drug and what the drug does in the body), regulatory discussions with the FDA, and strategic considerations around safety/efficacy. PK data demonstrated that taking 400mg BID with food provided similar drug exposure to the original 600mg BID fasted dose, while also reducing gastrointestinal toxicity (less nausea and appetite loss), lowering the pill burden, and making the treatment more compatible with future combination therapies.
Dose changes in CTs require regulatory approval and scientific validation to ensure they maintain efficacy while improving safety. RLAY presented its PK data to the FDA during its End-of-Phase 2 meeting, demonstrating that a fed-state regimen enhances drug absorption without compromising effectiveness. The agency accepted this data, clearing the change for Phase 3 (this is not necessarily normal). They also conducted a formal food-effect study and a dedicated PK study, which included a diverse set of patients across various tumor histologies. This allowed the FDA to confirm that the 400mg BID fed dose was equivalent in drug exposure to the original 600mg BID fasted dose.
But another reason the FDA likely signed off on this dosing switch is that fed-state dosing tends to be more patient-friendly in real-world settings. Many oncology drugs require fasting before administration, which can be burdensome for patients already struggling with appetite loss, nausea, and treatment fatigue. Particularly when it’s targeted specifically.
The Role of Fasting in Cancer Treatment
I actually talked about this in my previous article, because it’s actually very interesting. Fasting has been explored as a potential complementary approach in cancer treatment, particularly in targeting cancer metabolism. Some studies suggest that starving cancer cells of glucose and nutrients through fasting or calorie restriction can make them more vulnerable to targeted therapies. This approach gained attention with Petra Pharma (mentioned in previous write-up, Eli Lilly asset now), which developed a PI3K inhibitor strategy that incorporated fasting-like conditions to enhance drug effectiveness.
While it's unclear if Lilly will implement this method with its recently acquired Scorpion PI3Kα inhibitor (STX-478), the idea behind it is compelling. PI3K signaling plays a critical role in cell growth and survival, and cancer cells often rely on this pathway for energy. By inducing a fasting state, the theory is that normal cells can adapt by switching to alternative energy sources, whereas cancer cells, which rely heavily on glucose, become more stressed and susceptible to PI3K inhibition. Though this approach sounds extreme or barbaric, the research suggests that fasting could enhance the efficacy of PI3K inhibitors by making cancer cells more vulnerable to therapy. I’m not sure if this is a smart move here by RLAY, but I think Lilly may combine its two assets, incorporating a more intense fasting-state strategy with STX-478. Even if Lilly ultimately doesn’t take this approach—it’s still speculative at this point—I guess RLAY shifting away from fasting was a strategic decision that makes sense regardless.
For more clarity on this, the decision to move away from a fasted-state regimen for RLY-2608 seems to be based more on practical and clinical considerations rather than an intent to exploit fasting-driven cancer metabolism. Unlike Lilly’s potential strategy with Scorpion, RLAY is optimizing drug exposure and patient convenience rather than attempting to starve cancer cells. However, this highlights an important difference in how companies approach PI3Kα inhibition—some prioritize patient compliance and drug absorption, while others may explore metabolic vulnerabilities of cancer cells. Either way, RLAY is far ahead of peers with their asset.
R&D Control
The company reported having $781M in cash and equivalents, enough to comfortably fund operations into the 2H 2027. This solid financial position is thanks to focused cost-cutting—including a notable 12% QoQ reduction in opex—and strategic financing raised in Q3 2024 on the heels of strong Phase 2 results for RLY-2608. By adopting a disciplined approach to R&D spending, the company has been able to shift resources to where they’re needed most without losing momentum on its core clinical programs.
A key part of this strategy involves fine-tuning R&D expenses so they’re aligned with top-priority agents, such as the RLY-2608 Phase 3 doublet trial, while still somewhat supporting early-stage pipeline work. Instead of spreading its resources too thin across numerous experimental trials, they are funneling its budget into late-stage programs with a clearer path to regulatory approval. The 12% reduction in opex clearly shows that the company is scaling back on lower-priority programs.
That said, they are pushing ahead with its Phase 3 ReDiscover-2 trial for RLY-2608 plus fulvestrant, set to begin enrolling 540 patients in mid-2025. Participants will be randomized in a 1:1 ratio against capivasertib (both in combination with fulvestrant). This study introduces a 400 mg BID fed-state dosing regimen, a switch from the 600 mg BID fasted regimen used in Phase 2. So, resources will heavily be targeted here.
Other targeted programs that will receive a sliver of the R&D pie as follows:
1. Vascular Malformations Trial (RLY-2608) – Kicking Off in Q1 2025
They are expanding the use of RLY-2608 beyond oncology, with plans to initiate a vascular malformations trial in early 2025. Vascular malformations are abnormal blood vessel formations that can cause pain, swelling, and functional impairments, and PI3K pathway mutations have been implicated in some of these conditions. This expansion represents a new clinical avenue for RLY-2608, but it also means additional preclinical studies, trial site activation, patient recruitment, and regulatory expenses—all of which will add pressure to R&D budget.
2. NRAS-Selective Inhibitor Program – IND Filing & Trial Readiness
Company is working on a first-in-class NRAS-selective inhibitor (RLY-8161), which is designed to selectively target NRAS-mutated cancers while sparing KRAS and HRAS, avoiding off-target toxicity issues seen with pan-RAS inhibitors. The company is advancing this program toward an Investigational New Drug (IND) filing, which means they will need to finalize preclinical safety and efficacy studies, manufacture clinical trial material, and complete regulatory documentation before the drug can enter clinical trials. Once cleared by the FDA, they will have to initiate a Phase 1 trial, which adds more costs related to trial site activation, patient monitoring, and safety evaluations.
3. Fabry Disease Program – IND Filing & Clinical Development Costs
They are also advancing its Fabry disease program, which targets a rare lysosomal storage disorder caused by a deficiency in the α-galactosidase A (α-Gal) enzyme. The investigational therapy is a non-inhibitory chaperone designed to stabilize α-Gal without interfering with its enzymatic function, potentially offering a novel approach to treating Fabry patients. Like the NRAS program, the Fabry disease candidate is also moving toward an IND filing, which means significant spending on preclinical validation, regulatory submissions, and clinical trial preparation. If it progresses into human studies, manufacturing and patient recruitment costs will further strain on R&D budget.
Other than that, their main goal/priority is RLY-2608 doublet. But it is indeed certain, that the company is doing an excellent job managing their cash. They are doing what they have told us by prioritizing later-stage assets, which I think everyone should be happy about.
Valuation
Please reference my previous article for a detailed look at RLAY’s valuation—that remains unchanged, just with a slightly lower discount now. Let’s be real: biotech has been a brutal market lately. There’s even a half-joke going around that if you tell people you invest in biotech, they instantly feel sorry for you (sarcasm/joke). It’s that rough out there. But in my view, the companies that execute well, have strong data (and therefore less uncertainty), and can keep the lights on financially will eventually see their valuations catch up to their true worth. There will also be an inevitable sector rotation coming into this arena, when that is? Nobody knows, it could be years. But when it does, you’ll be glad to have some skin in the game. I’m planning to add to my RLAY position when I can, because I see it as a great long-term opportunity, despite all the turbulence in this sector right now.