As some of you know, I'm working two jobs to accelerate the launch of Solt DB. Before I head out the door I wanted to share some fresh thoughts on the pipeline update from Relay Therapeutics (NASDAQ: RLAY). I'll come update this post with more fleshed out thoughts later today.

There were really two updates today:

• RLY-4008 (FGFR2) development and regulatory update
• Three new programs targeting three unique genetic targets in a new breast cancer franchise.

We expected the company to disclose a new program today, so updates on four different programs is quite the surprise.

RLY-4008 Update

Let's keep this simple and walk through the press release. Just going down the bullet points at the top.

First, Relay Therapeutics met with the U.S. Food and Drug Administration (FDA) for an end-of-phase 1 meeting for RLY-4008. This is business as usual to discuss next steps.

Regulators agreed to allow the company to run a single arm phase 2 trial evaluating RLY-4008 in cholangiocarcinoma (CCA), a liver cancer commonly driven by FGFR2 alterations. "Single arm" means regulators won't require the company to test the drug candidate against another therapy, such as chemotherapy or an approved FGFR inhibitor. That's great. It saves time, money, resources, and increases the odds of success.

In fact, it's a sign that RLY-4008 could earn accelerated approval, which is something the company acknowledged today. The teased data show why:

RLY-4008 demonstrated an initial partial response rate of 62% (8/13) in individuals with FGFR2-fusion CCA who had never received an FGFR inhibitor ("FGFRi naïve"). All four individuals who received 70 mg daily achieved a partial response.

A few things:

• Zooming out to the competitive landscape, the best partial response rate observed in a study that led to an approval of an FGFR inhibitor was 36%. RLY-4008 has plenty of wiggle room to beat that by a significant margin. It's also worth noting the 62% PR rate was observed in individuals receiving 20 mg to 70 mg doses once-daily.
• The upcoming phase 2 clinical trial will study a once-daily 70 mg dose. This was the highest dose tested, which suggests the company feels comfortable with the overall tolerability profile and safety. This is a sign of the asset's selectivity for FGFR2.
• Zooming out to the commercial landscape, this is a specific patient population. Other populations include those who have received an FGFR inhibitor in the past, those who have FGFR2-mutations and FGFR2-rearrangements, and those who have cancers other than CCA.

Relay Therapeutics expects to publish more results from FGFRi-naive FGFR2-fusion CCA patients in the second half of 2022, full data from the phase 1a study in the first half of 2023, and initial data from the phase 1b study (including patients with cancers other than CCA) in 2023.

For a quick refresher on RLY-4008, revisit pages 12-13 of the June 2022 report (free in our Ko‑fi shop).

Breast Cancer Franchise

I was prepared to update everyone on a single new pipeline program. Relay Therapeutics decided to triple my homework.

I'll need more time to dig into each target, watch the presentation, and contact the company. A few thoughts:

• Turbulence in the PI3K-alpha franchise? The company unveiled the second program in its PI3K-alpha franchise. The first, RLY-2608, is a pan mutant inhibitor (has activity against many mutations). The new drug candidate, RLY-5836, is also a pan mutant PI3K-alpha inhibitor -- but with distinct chemical features compared to RLY-2608. This is likely a sign the company didn't feel comfortable with RLY-2608, perhaps due to tolerability or maybe it increased the rate of mutations in tumors. Or (I haven't seen the slide deck yet) the first asset whacked all but one mutation, so maybe the company found a way to hit all mutations with a single drug candidate. Either way, this is referred to as a "fast follow" approach, which isn't uncommon but suggests the timeline for PI3K-alpha might be pushed back 12 to 18 months. It appears RLY-2608 is still being actively developed in a phase 1 clinical trial. RLY-5836 is expected to enter the clinic in 2023.
• A combo in the wings: Relay Therapeutics unveiled a CDK2 inhibitor program. CDK2 is commonly mutated in individuals who are receiving CDK4/6 inhibitors, which creates a large and underserved market. It may also make sense to study combinations of with the PI3K-alpha franchise.
• Protein degrader: Relay Therapeutics announced it can now use the Dynamo platform to rationally design protein degraders. In simple terms, the company thinks it can design these types of drugs by looking at the protein targets, rather than screening a gajillion chemical compounds in the lab and seeing what works. The first program will be an ER-alpha degrader, with a development candidate expected to be selected in 2023.

Closing Thoughts

The update from RLY-4008 is the most important right now. It suggests the company could get its first approved product on the market sooner than expected and, if the PR rate comes in anywhere near 62%, with less competition than expected.

Now, the company's plans for the PI3K-alpha franchise are more important in the long run. Is Relay Therapeutics abandoning RLY-2608? That would set the overall franchise back by 12 to 18 months. The unveiling of a new pan mutant PI3K-alpha inhibitor comes as a surprise to me.

All right, I'll add another update this evening.

You can watch the update at 8am ET today (or the archived webcast at your convenience).

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