I would now like to hand the conference over to your speaker today, Mr. Pete Raymer, SVP, Corporations Affairs.
Please go ahead.
Thank you, operator, and good morning good afternoon, everyone. You can access the press release from this morning, the slides we are reviewing and a replay of this call by going to the Investor Relations section of our website. Before we get started, I'd like to remind you that during this conference call, Relay Therapeutics will make certain statements that are considered forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including our strategy, business plans and objectives. The expected therapeutic and clinical benefits of our product candidates, the potential of our platform and our product candidates and progress and timing and execution of our clinical trials. Such forward looking statements are not guarantees of future performance and therefore you should not put undue reliance upon them.
These statements are subject to numerous risks and uncertainties that could cause natural actual results to differ materially from what we expect. I refer you to our SEC filings for a discussion of risk factors that could cause our actual results to differ materially from those discussed today. Today on the call, Sanjit Patel, our President and CEO, will walk through a summary of the disclosures. Don Bergstrom, Head of R&D, will also take you through additional details. With that, I'll turn the call over to Sanjeev.
Thank you, Pete, for that introduction, and thank you to those of you on the line. Today, we want to share with you key updates on our progress to deliver new medicines to patients. This is the first clinical update since we were founded in 20 16. And as you can imagine, this is a very exciting day for our company. Reflecting back over the last 5 years, we put a very high premium on setting tangible stretch goals for ourselves and executing against them.
We believe we've achieved every goal we've laid out for ourselves at the time of our IPO in July of 2020. For ROI-four thousand and 8, we've achieved our stated goals. As we are showing today, the interim clinical data suggests ROI-four thousand and 8 is the first known highly selective inhibitor of FGFR2, not limited by any off target toxicities. And it shows the potential to reduce tumors across a range of patients and alteration types. For ROI-two thousand 608, our PI3K alpha mutant selective inhibitor, we've achieved our stated goals as we are rapidly advancing to initiate a clinical study in the first half of 2022 for the first of a franchise of therapies.
The foundation and first of these programs has pan mutant activity and we believe has the potential to be among the largest precision oncology medicines opportunities ever. For RY1971, our SHIP-two inhibitor, we've achieved our stated goals as we have determined a strategic path forward for the clinical and commercialization of this program with the world's leading oncology development and commercialization organizations, Roche Genentech. With regards to our platform and capabilities, we've achieved our stated goals as we've continued to evolve our platform, build the team across all the functions required to make new medicines, seamlessly progress multiple clinical trials in the face of a global pandemic, underscoring our world class development group, while all the time expanding the depth and breadth of our scale and research. To summarize, we have met or exceeded every single 1 of the goals we have set for ourselves. During a plenary presentation today given by Doctor.
Lipik Gohar from MGH for the triple meeting, interim clinical data from our 1st in human study for ROI-four thousand and 8 was shared. To summarize the interim data, although early and from a heterogeneous set of patients treated across multiple therapeutic doses, it shows that we believe ROI 4008 has the potential to be highly selective. This shows our platform has the potential to achieve what we set out to achieve, I. E, creating a highly selective FGFR2 inhibitor. We did this using our Dynamo platform, which is a combination of leading edge computational and experimental techniques.
We created a meaningfully selective inhibitor that has been a challenge for conventional approaches to drug discovery. As of the data cut off, our interim data shows that ROI significantly dials out primary off target effects at all dose levels we tested, including FGFR1 related toxicities of hypophosphatemia and FGFR4 related toxicities of diarrhea. At last, we believe our interim data shows that ROI-four thousand and 8 is potentially not limited by these off target side effects and can inhibit FGFR2 at levels that have not been seen with the pan FGFR agents that have received accelerated approval. This is clear validation of our dynamo platform. We are excited about what this means for our other programs in our deep portfolio of precision medicines.
We believe ROI-four thousand H has promising initial safety and tolerability data and expect to select a recommended Phase II dose optimized for safety without compromising efficacy, and we will commence opening expansion cohorts prior to the end of this year. Finally, from this interim data, we believe ROI-four thousand and 8 showing promising early signs of tumor regressions. Note again that this data is early into a first in human trial where we have multiple doses deployed across heterogeneous patient populations. But with all that said, ROI-four thousand and 8 has shown inhibiting FGFR2 above previously known achievable levels can drive tumor regressions regardless of line of treatment, alteration or tumor type. 3 out of 6 of the pan FGFR treatment naive patients showed confirmed partial responses, all were on the once daily dosing regimen at the time of response.
Notably, a 35 year old with ICC had a confirmed This patient was initiated on a once daily dose of 70 milligrams a day and remained on this dose for the duration of his treatment. This is a wonderful outcome so early in our trial and speaks the potential of this medicine. The other 2 responders continue on a once daily dosing regimen. ROI-four thousand and 8 showed early activity against on target resistance mutations, and we've also been able to see early activity of ROI-four thousand and 8 against de novo mutations and amplifications in tumor types within and outside of cholangiocarcinoma. We are encouraged by this data and we look forward to selecting a recommended Phase 2 dose and sharing more in 2022.
The next target on which we deployed our dynamo platform is PI3K alpha. Our goal was to create a meaningfully selective mutant molecule because this is 1 of the last significant precision medicine targets deemed intractable. With a pan mutant PI3K alpha inhibitor, the addressable patient population has the potential to be several fold greater than that of KRAS G12C, and this is over 100, 000 patients annually in the U. S. Alone.
And we believe that this is among the largest ever for precision oncology medicine. The challenge is the industry has struggled to make such a medicine. Non mutant selective inhibitors have shown efficacy, but are limited by on target toxicity. As you can see from this map of mutations on the protein, they are desperately located, requiring a pan mutant approach to prevent on target resistance mechanisms. We believe only a knowledge of Alastairie and the dynamic nature of this protein will unlock this challenge.
As traditional approaches from our industry have tried and failed this task over several decades, we believe Relay Therapeutics is uniquely positioned to solve this challenge. In our recent abstract shown at the triple meeting this week, we highlight some interim data for the first known PIN mutant selective PI3K alpha inhibitor created by Relay Therapeutics Dynamo platform. We are very excited about this program entering the clinic in the first half of 20 22. Key elements to note about this program are it has a novel mechanism of action. There is a mutant selective binding to an allosteric binding site discovered by Relay Therapeutics Dynamo platform.
It's pan mutant selective while sparing wild type. We believe the preclinical data shows it's more tolerable than existing therapies and it is fast approaching the clinic. As I said, we expect the 1st in human study to start in the first half of 20 22. RY-two thousand 608 represents the start of Relay Therapeutics' emerging PI3K alpha franchise. Today's updates allow us to take another step forward in validating our approach and platform.
We have now shown multiple times that we can select a target, use our platform to identify a motion based hypothesis to drug previously intractable precision medicine targets, use our team to create a molecule that generates promising preclinical data, select a development candidate, and today, we've shown for the first time that we can effectively progress a precision medicine clinical trial and generate promising early clinical data to support this. This gives us great confidence that we continue to do this for programs in our pipeline. With each cycle and each additional program, we're able to improve our approach and strengthen our capabilities. We are very well set up to execute against our goals now and in the future. Over the last 5 years, we've grown our team to well over 200.
We have a core research team with leadership that has tenure now well over 5 years as a group, and this experience as a group is clearly paying off. As we have made it clear, we believe there is a steep experience curve to what we do. In addition, we have shown today our development group is excellent in its ability to design and execute precision medicine trials. It is clear, the more we do, the better we get in all fronts. We believe we have a deep precision medicine pipeline, and we are motivated to bring multiple meaningful medicines to patients globally across both.
Firstly, our wholly owned innovative portfolio, which we believe will be Relay's core focus and secondly, our Challenger portfolio, which we will use to build our platform and derive value through development and commercialization partnerships. We've started work on the first of these partnerships with our partner EQRx. I will now hand over to Don Bergstrom, Executive Vice President and Head of R and D to talk in detail about today's updates. Thank you.
Thank you, Sanjeet. I'll start today with an overview of our wholly owned innovator programs. As a reminder, the interim clinical data we will review today shows that ROI-four thousand and 8 is highly selective and validates our approach for drug discovery, shows robust inhibition of FGFR2 with promising initial tolerability and has early signs of activity across a range of alterations in tumor types. Fibroblast Growth Factor Receptor 2 or FGFR2 has all of the hallmarks of a cancer driver oncogene, which makes it an attractive precision oncology target. FGFR2 gene alterations in tumors include gene fusions, focal gene amplifications and gene mutations.
And they're seen across a range of solid tumors, including breast cancer, endometrial cancer and cholangiocarcinoma. We estimate that a highly selective FGFR2 inhibitor could address between 8, 000, 021, 000 advanced cancer patients with FGFR2 alterations annually in the United States. And despite recent progress with FDA accelerated approvals of pan FGFR inhibitors in FGFR2 altered cholangiocarcinoma and urothelial cancer, there remains a broad tumor agnostic medical need for patients with FGFR2 altered tumors. So FGFR2 has been validated as a therapeutic target in FGFR2 altered tumors, but we believe the current generation of non selective inhibitors are limited by off target toxicity. These non selective FGFR inhibitors are potent not only in FGFR2, but also the highly similar family members FGFR1 and FGFR3 and FGFR4 to a varying extent.
So while inhibitors with accelerated approval for FGFR2 altered cholangiocarcinoma achieved 23% to 36% response rates in FGFR inhibitor naive patients, We believe that the dose of these agents is actually limited by toxicity related to off target inhibition, hyperphosphatemia related to FGFR1, diarrhea related to FGFR4. This ultimately limits how completely these agents can shut down signaling through FGFR2. Our therapeutic hypothesis was that a highly selective inhibitor of FGFR2 will be optimized for inhibition of FGFR2, leading to higher response rates and better durability of response in patients with FGFR2 altered tumors. This is a hypothesis that has been proven out many times before us in precision oncology for other targets including ALK, EGFR, HER2, RET, ROS, TRAC and others. Designing a selective FGFR2 inhibitor is a major challenge for conventional drug discovery approaches.
Here you can see a representation of the static 3 d structures of FGFR1 and FGFR2. And as you can appreciate, they are essentially identical. In contrast, our drug discovery teams use dynamic models of our protein targets to generate novel modulation hypotheses. In the case of FGFR2, as is shown in this movie reel to represent motion, we discovered that despite the similarities in static structure, there's a loop on the surface of both proteins that moves differently in FGFR1 compared to FGFR2. Our drug discovery scientists were able to use this insight into differential protein motion to design a compound able to irreversibly interact with the slower moving loop on FGFR2, potently shutting down the protein, while much less efficiently interacting with the analogous loop on FGFR1.
We believe ROY-four thousand and 8 is the first known highly selective and irreversible FGFR2 inhibitor, designed to avoid engagements of other FGFR family members, which as I mentioned leads to clinical toxicities. ROY-four thousand and 8 display selectivity not only within the FGFR family, but across the kinome generally. In contrast to the pan FGFR inhibitors that are all equipotence against FGFR 1, 23 as well as many other off target kinases which further narrow their therapeutic window. Another unique feature of ROY-four thousand and 8 is that it was designed to exhibit broad coverage against the spectrum of FGFR2 resistance mutations, including the gatekeeper position at V565 and the molecular break position at N550. We have specifically designed ROY-four thousand and 8 to potently target activity against these on target resistance mutations.
The grid here shows the potency of RLY-four thousand and 8 versus these mutations. In a panel of tumor models with primary FGFR2 alterations and or resistance mutations, ROY-four thousand and 8 showed in vivo anti tumor activity across tumor models reflecting the spectrum of oncogenic FGFR2 alterations. These data support the broad tumor and alteration agnostic therapeutic potential of ROY-four thousand and 8. We report today on the interim data from the dose escalation portion of the first in human study of ROI-four thousand and 8, which is enrolling patients with FGFR2 altered tumors as determined by local assessment regardless of prior FGFR inhibitor treatment. Today's disclosure includes data on 49 patients enrolled in Part 1 of the study between September 2020 and the data cutoff date of September 9, 2021.
RLY-four thousand and 8 was administered orally on once daily or Q day and twice daily or BID schedules. The primary objectives are to define the maximum tolerated dose, the recommended Phase 2 dose and safety and tolerability of ROI-four thousand and 8. Secondary objectives are to define the pharmacokinetic profile, impact on pharmacodynamic biomarkers and preliminary anti tumor activity. Given resistance to FGFR inhibitors is often mediated by secondary mutations in the FGFR2 kinase domain, we check for these mutations in this trial in circulating tumor DNA at baseline and longitudinally on study. Once the recommended Phase 2 dose is defined in the study, the dose expansion will begin and enroll across the 5 groups in here on this slide.
40 of 49 patients enrolled had cholangiocarcinoma, as you can see on this slide, 80% of these patients had an FGFR2 fusion or rearrangements. This trial allowed prior exposure to an FGFR inhibitor and 76% of the patients with FGFR2 fusion positive cholangiocarcinoma had received at least 1 prior FGFR inhibitor therapy. You will also note that these heavily pretreated patients had large tumor burden with the mean sum of longest diameters of target lesions nearly 10 centimeters across the study population. Pharmacokinetic studies for the once daily and twice daily schedules of ROI-four thousand and 8 showed that both schedules achieved predictable dose dependent increases in exposure. They also showed that the half life of the drug is long at 15 to 30 hours, supporting a once daily dosing schedule.
Notably, PKPD modeling based on the observed human PK and a receptor occupancy model validated in preclinical tumor efficacy models predicts greater than 85% median FGFR2 receptor occupancy across all dose levels tested in both schedules. All doses achieved exposures that were associated with antitumor activity in preclinical models of FGFR2 altered tumors. Now, according acknowledging that our method of calculating receptor occupancy for ROI-four thousand and 8 differs from the ex vivo blood phospho FGFR2 assay utilized to measure pharmacodynamics at pemigatinib, the target occupancy for all doses of ROI-four thousand and 8 tested exceed that achieved by pemigatinib's label dose. To remind you, pemigatinib's label dose of 13.5 milligrams daily achieved 76% inhibition of FGFR2 at trough, assuming continuous dosing. However, the pemigatinib labeled dose calls for 2 weeks on, 1 week off dosing.
And that's what we believe is likely to be an overestimate of true target inhibition over time. These data suggest that ROI-four thousand and 8 can significantly inhibit FGFR2 with all tested doses achieving target coverage associated with activity in preclinical models and reported FGFR2 inhibition levels for pan FGFR inhibitors. The first in human trial is a Bayesian dose escalation, which allows for flexibility to explore and enrich multiple dose levels in parallel. The trial began with a twice daily dosing schedule. At the initial dose of 50 milligram twice daily, we were already achieving approximately 96% of the FGFR2 receptor continuously over the dosing interval.
We believe this speaks to the broad therapeutic window of RLY-four thousand and 8 preclinical species and the favorable drug like properties of RLY-four thousand and 8 in humans. In the early months of the trial, we focused on the twice daily dosing schedule. And as we gathered more experience with the agent, we appreciated that the long half life of ROI-four thousand and 8 in humans was compatible with once daily dosing and the acute and chronic tolerability of the 50 and 100 milligram twice daily doses was challenging, as shown by the rate of DLTs and dose reductions at these doses. We initiated once daily dosing at 50 milligrams and then 70 milligrams in early 2021. Once we gathered more PK information, we're able to model the once daily dose range that we projected would cover the range of exposures associated with efficacy in preclinical models.
The flexible design of the Bayesian protocol with enrichment allowed us to continue to enroll the 50 and 70 milligram daily cohorts, while in parallel enrolling cohorts at 20, 30 and 40 milligram once daily. For protocol, we are continuing to enroll patients across all 5 once daily dose levels. Based on acute and chronic tolerability in PK, the twice daily schedule was deprioritized for further enrollment. The early data across the doses on the once daily schedule show that only 1 DLT of 32 patients treated in the once daily schedule has been identified as of the data cutoff date across all the doses. And this schedule appears to allow for maintenance of greater dose intensity with fewer dose reductions compared to the twice daily dosing schedule.
All of the once daily doses remain in consideration for the recommended Phase 2 dose, which will be identified based on safety and tolerability, PK and early efficacy signals. We feel the comprehensive database we will have on safety, PK and early efficacy across multiple biologically active doses is promising and will enable us to determine the appropriate recommended Phase 2 dose. We have focused on hyperphosphatemia and diarrhea as hallmark toxicities of the pan FGFR inhibitor associated with inhibition of FGFR1 and FGFR4. And diarrhea across all doses in both schedules. The observed hyperphosphatemia was transient and did not require medical management.
Our PK and receptor occupancy data indicate we are exceeding exposure thresholds required for efficacy in preclinical models of FGFR2 driven tumors and the reported target coverage for pan FGFR inhibitors. These interim data suggest we've created a truly selective FGFR2 inhibitor. This speaks to the power of the Dynamo platform as this drug discovery challenge has alluded traditional discovery approaches for several decades now. We believe this high selectivity for FGFR2 now allows us to be the 1st to be able to optimize dose and schedule for inhibition of FGFR2 and not to be limited by toxicities due to off target effects. This slide shows the stability of serum phosphate levels over time for all doses in both schedules tested, further indicating the selectivity of ROI-four thousand and 8 for FGFR2 over FGFR1.
Given our ability to inhibit FGFR2 at levels not previously seen in the clinic, we can now understand for the first time on target toxicity for such an agent. The adverse event profiles of ROY-four thousand and 8 on the once daily and twice daily schedules are shown here. Overall, most treatment emergent adverse events were low grade. No grade 4 or 5 AEs were seen in either dose schedule. The AE profile was consistent with sparing FGFR1 and FGFR4.
These data provide insight into which AEs that are thought to be class effects of FGFR inhibitors may specifically be related to highly selective FGFR2 targeting. The most common treatment emergent adverse events were palmaroplantar erythroid dysesthesia, stomatitis and dry mouth. Both schedules exhibited a manageable safety profile, but the AE profile favored continuing with once daily dosing. This slide summarizes the overall tolerability profile for the small molecule pan FGFR inhibitors has established in single arm Phase 2 datasets in patients with FGFR2 fusion cholangiocarcinoma. The AEs listed here are the most frequent AEs seen across the class.
This slide shows the rate of AEs with once daily dosing of ROY-four thousand and 8 across the spectrum of the most frequent pan FGFR inhibitor associated AEs. While the data are early and still immature, the promising AE profile has been achieved at exposures exceeding our preclinical efficacy thresholds and at all once daily doses inhibiting FGFR2 more potently in humans compared to the pan FGFR inhibitors. We will select an optimal dose for further characterization of safety, tolerability and efficacy in the Part 2 expansion cohorts in the ongoing study. We look forward to learning more about the safety and tolerability profile of ROY-four thousand and 8 over time as the data mature. In patients with fusion positive glangiocarcinoma who are FGFR inhibitor naive, 3 out of 6 patients exhibited a confirmed PR, all on the once daily dosing schedule, all at doses which are under consideration for the recommended Phase 2 dose.
Despite our plot shows that 3 out of 6 patients remain on treatment and a 4th had greater than 80% response and recently underwent surgical resection with curative intent. The pan FGFR inhibitors available under accelerated approval have shown 23% to 36% response rates in this patient population at an optimized dosing schedule in their registrational Phase II trials. All of the patients ultimately ended up being treated on the once daily schedule. You can see the 1 responder who initiated treatment at 100 milligrams twice a day did not achieve response until treatment on a once daily dosing schedule. And this patient remains on treatment with a deepening response at the 30 milligram once daily dose.
These initial early data highlight the encouraging activity of ROI 4008 in FGFR inhibitor naive fusion positive cholangiocarcinoma patients. I will highlight the patient who underwent resection. He's a 35 year old patient with multifocal left sided liver lesions and an enlarged portal lymph node who had greater than 80% response after 6 cycles of ROY-four thousand and 8 treatment. He remained on treatment at 70 milligrams once daily throughout the duration of therapy. Given the market tumor reduction, the patient underwent partial hepatectomy with curative intent.
This is an exceptional landmark in the current management of patients with advanced cholangiocarcinoma and this vignette highlights the potential of ROY-four thousand and 8 in the FGFR inhibitor naive setting. The second subpopulation is patients with fusion positive cholangiocarcinoma who were previously treated with 1 or more pan FGFR inhibitors. These are the same data as presented earlier at the triple meeting, but broken into patients with detectable acquired resistance mutations versus patients without a detectable acquired resistance mutation or for whom mutation status is unknown. As designed, ROI-four thousand and 8 is active against acquired resistance mutations in FGFR2 that arise in response to treatment with pan FGFR inhibitors. In 10 patients with detectable acquired resistance mutations and circulating tumor DNA, the mutant clones were cleared to below the level of detection by cycle 2 day 1 for all mutant clones in 7 out of 10 patients.
This included clearance of both N550 molecular break and V565 gatekeeper mutations. And there was tumor regression in 9 out of 10 patients with detectable acquired resistance mutations at the time of enrollment. These data are consistent with ROI-four thousand and eight's mechanism of action and preclinical activity against FGFR2 resistance mutations. This is not a population we are primarily focused on for further development of ROY-four thousand and 8. We will continue to focus on the FGFR inhibitor naive patients.
But consistent with the experience for other precision oncology targets, we feel the demonstrated activity of ROY-four thousand and 8 against established on target acquired resistance mutations suggest that ROY-four thousand and 8 may have greater durability of response in naive patients through suppression of common mechanisms of acquired resistance. This patient's vignette is a 51 year old woman with recurrent multifocal cholangiocarcinoma in her pelvis, who is treated with foodibatinib for nearly 1 year and then was found to have an FGFR2 kinase domain mutation at baseline prior to starting on ROY-four thousand and 8. The patient has achieved greater than tumor 20% tumor shrinkage on 4008 and her FGFR2E566V mutation was rendered undetectable at cycle 2. The patient is being treated with 50 milligrams once daily and has had no dose interruption or dose holiday and treatment is still ongoing in cycle 7. We're also sharing a vignette today for a patient who achieved a response subsequent to the database block for the triple meeting presentation.
This is a 65 year old male who received prior infogratinib. Circulating tumor DNA at baseline detected polyclonal on target acquired resistance with N550 ks, N550 D and V565 I resistance clones. The patient commenced treatment with ROI-four thousand and 8 at 30 milligram once daily with a 72% reduction in target lesions at the end of cycle 2 scan with complete regression of a manubrium bone lesion associated with symptomatic improvement of chest pain. The partial response is pending confirmation and the patient is tolerating 30 milligram once daily well and remains on treatment. Additional subpopulations that showed evidence of tumor regression on ROI 4008 were patients with FGFR2 oncogenic mutations or FGFR2 amplification.
We notably saw a confirmed partial response in a breast cancer patient with an FGFR2 N550 ks mutation, a difficult to treat mutation in the molecular break of the hinge region of FGFR2 in which most pan FGFR inhibitors lose significant potency. 2 additional breast cancer patients with activating mutations in FGFR2 remain on treatment and cycle 3 at the time of data cutoff. Additionally, a cholangiocarcinoma patient with a C383R activating mutation treated at 40 milligram once daily showed a 72% reduction in target lesions at the first scan and remains on treatment pending confirmation of response. A cholangiocarcinoma patient with low level amplification of FGFR2 and prior treatment with derazantinib started therapy at 100 milligrams twice daily. This patient remains on study with stable disease at cycle 12 and is currently being treated with ROI-four thousand and 8 50 milligrams once daily.
This vignette is in a 60 year old woman who had 12 prior lines of systemic therapy for advanced breast cancer. The patient's tumor has an oncogenic FGFR2 N550 ks mutation. She received prior treatment with palbociclib and emerging data in the literature suggest that FGFR2 alterations are potential resistance mechanisms to endocrine therapy and or to CDK inhibitors. This patient has been treated with 70 milligram once daily and remains on this dose in cycle 5. The patient had a 41% confirmed PR with response deepening between initial response and confirmatory scan.
We believe this is the first response reported for an FGFR inhibitor in a breast cancer patient with an oncogenic FGFR2 mutation and suggest the potential for ROI-four thousand and 8 in the patient population outside of cholangiocarcinoma. This is the swimmer's plot showing the time on treatment according to FGFR2 alteration. The data reflect the early stage of the trial with limited follow-up. However, 54% of patients remain on treatment with duration of treatment ranging from 4 to 45 weeks. The majority of patients who discontinued did so due to progressive disease.
A number of patients with progressive disease were treated initially on the twice daily dosing schedule and did require prolonged which significantly compromised the ability to maintain ROI-four thousand and 8 dose intensity in that schedule. In summary, we believe this investigational medicine is the first known highly selective FGFR2 inhibitor in the clinic that targets driver alterations in the broad spectrum of FGFR inhibitor acquired resistance mutations and oncogenic mutations in FGFR2. We observed robust FGFR2 inhibition with greater than 85 percent receptor occupancy and minimal hyperphosphatemia or diarrhea across a range of doses. The once daily schedule was favored based on both the PK and safety profile, and we now have initial data showing the AE profile of a highly selective small molecule inhibitor of FGFR2. We believe the initial overall tolerability profile is comparable to or favorable to that of the pan FGFR inhibitors across all doses tested in the once daily dosing schedule.
The drug also showed encouraging early anti tumor activity. In FGFR inhibitor naive FGFR2 fusion positive cholangiocarcinoma, 3 out of 6 patients with confirmed partial responses. In the FGFR2 positive cholangiocarcinoma population resistant to prior FGFR inhibitor treatment, clearance of circulating tumor DNA associated with acquired resistance mutations and tumor shrinkage in the majority of patients and early signs of activity in FGFR2 mutant and amplified tumors beyond cholangiocarcinoma. Overall, these results validate selective targeting of FGFR2 and suggest ROY-four thousand and 8 has potential to overcome the most common mechanisms of on target FGFR inhibitor resistance. We will select a recommended Phase 2 dose and open expansion cohorts before the end of 2021 and look forward to updating you on the next set of data for this agent in 2022.
As we mentioned earlier, we also shared at the triple meeting an abstract from our first pan mutant PI3K alpha inhibitor, which I'll walk you through. Key elements to highlight about this program, it's a novel mechanism, it's pan mutant selective and preclinical models, it's more tolerable than existing therapies and it's approaching the clinic. ROI-two thousand 608 represents the start of Relay Therapeutics' emerging TI-three ks alpha franchise. We can see from Novartis alpelasib marketed as Pecre that it is effective when combined with fulvestrant in ER positive PI3K alpha mutant breast cancer. But its tolerability is challenging given the adverse events of hyperglycemia, which limits the dose of abelicid that can be administered acutely and leads to dose reductions and discontinuations with chronic dosing.
Ultimately, the inability of agents like alpelisib to maintain continuous high level of PI3K alpha is efficacy limiting. The hyperglycemia AE is due to inhibition of wild type PI3K alpha in normal tissue. And there are also AEs related to inhibiting other isoforms of PI3K as well. The objective of this field has become to create mutant selective PI3K alpha inhibitors, meaningfully selective for mutant PI3K alpha relative to the other PI3K family members and the kinome generally. We've learned from the experience with mutation specific inhibitors of oncogenes like the KRAS G12C inhibitors that just targeting a single mutation in the context of a RAS driven tumor leads to relatively short duration of response in multiple on target mechanisms of acquired resistance.
Analogously, we know that PI3K alpha mutations are also clear oncogenic drivers that cluster in a number of oncogenic hotspots, the most common of which are H747, and E545. Based on the experience of KRAS G12C mutant specific inhibitors, we would anticipate that mutant mutant specific inhibitors of PI3K alpha, for example, inhibiting only the H1047R mutation, would likewise be subject to the emergence of multiple on target mechanisms of acquired resistance. We used our unparalleled knowledge of PI3K alpha to design the first known pan mutant selective PI3K alpha. All of the current drugs targeting PI3K alpha target the active or orthosteric site, whereas mutations are distal to it indicating the need for an allosteric inhibitor to achieve mutant selective inhibition of PI3K alpha. The dynamo platform gave us novel understanding of the allosteric networks in PI3K alpha that allowed us to design what we believe is the first pan mutant selective PI3K alpha inhibitor.
We are building a franchise of PI3K alpha mutant selective inhibitors where the foundation is exemplified by ROY-two thousand 608, which is potent and mutant selective for all of the PI3K alpha mutant hotspots. We call this a pan mutant selective inhibitor. We will then augment this foundation with mutant specific inhibitors, which are only active against a specific mutation such as H1047R to allow us to potentially double drug specific mutations to maximize mutant PI3K inhibition. We believe we know more about allosteric targeting of PI3K alpha than anybody else in the industry And we'll leverage our insights to build a portfolio of mutant selective and mutant specific PI3K alpha inhibitors that will allow us to inhibit all PI3K alpha hotspot mutations more completely and more durably than any mutant specific approach can achieve on its own. We started by solving the 1st full length structure of PI3K alpha in complex with its regulatory subunit, both for wild type and mutated forms of the protein.
We then use these data to perform long timescale in silicomolecular dynamic simulation of wild type and mutant PI3K alpha to identify potentially druggable differences in the mutant and wild type proteins. We found the novel druggable allosteric pocket in the mutant protein that we thought could provide us an opportunity to develop a pan mutant selective allosteric inhibitor of PI3K alpha. We believe these insights are unparalleled in the field and culminated in the discovery of RY-two thousand 608. We investigated the activity of RY-two thousand 608 in biochemical enzymatic acids. RY-two thousand 608 has potent activity against the 3 most common PI3K alpha mutations and is 8 to 12 fold selective compared to wild type PI3K alpha in these assays.
This is a profile that we have has not been shared by any other PI3K alpha inhibitors. In addition to wild type selectivity, ROY-two thousand 608 is over 500 fold selective against all of the other PI3K eye supports. RY-two thousand 608 is also meaningfully selective against the rest of the kinome. We believe this is the profile of a true precision oncology therapeutic candidate. The selectivity that we observed in biochemical assays translates into signaling assays in cells.
We generated cell lines that express the mutant protein in the absence of wild type to allow us to tease apart mutants from wild type signaling. While orthosteric inhibitors as expected inhibit wild type and mutants with equivalent potency, ROY-two thousand 608 is significantly more potent at blocking downstream signaling the cell lines that express mutant PI3K alpha. When cancer cell lines harboring endogenous hotspot mutations and the kinase or helical domains are incubated with ROI-two thousand 608, we observed potent inhibition of downstream signaling and potent anti proliferative effects on PI3K alpha mutant cell lines. In contrast, ROY-two thousand 608 is markedly less potent at inhibiting proliferation in PI3K alpha wild type cells. Maximum efficacy is observed across different hotspot orthosteric benchmarks, dose to doses above the exposures achievable in the clinic for these agents due to on target toxicity.
In contrast to the ORH hysteric inhibitors, which significantly induced serum insulin levels due to inhibition of wild type PI3 ks alpha, ROY-two thousand 608 shows lower impact on serum insulin levels compared to the benchmark compounds. We believe that this is in vivo proof of concept that ROY-two thousand 608 is selective for inhibition of mutant PI3K alpha. In higher species at exposures that are matched for the efficacy exposures in the mouse models, there is no glucose increase nor do we observe any histopathological or ophthalmic findings associated with hyperglycemia in the reported preclinical studies for the benchmark PI3K inhibitors. ROY-two thousand 608 has properties consistent with moving into clinical development. The projected human bioavailability is approximately 60% and the projected human half life is approximately 16 hours, compatible with once daily or twice daily dosing in the clinic.
We anticipate initiating clinical studies for ROY-two thousand 608 in the first half of 20 22. I'll now pass it over to Pete before opening it up to questions.
Thank you, Don. Beyond this, our partnered programs, what we're calling challengers, also represent a significant opportunity. For RLY-nineteen 71, we have determined a strategic path forward for clinical development and commercialization with 1 of the world's leading oncology development and commercialization organizations, RocheGenentech. In August 2021, we announced a worldwide strategic collaboration with EQRx through which we intend to discover, develop and commercialize a novel medicine against a validated oncology target, which will help us bolster our AIML capabilities. Over the coming year, we have additional meaningful catalysts including ROI-four thousand and 8, where we will select a randomized Phase 2 dose and move to opening expansion cohorts by year end.
We expect to give an update data update next year in 2022 on this program. On ROI-two thousand 608, the clinical start is expected in the first half of 20 22 and we will make an additional preclinical data presentation at the San Antonio Breast Cancer Symposium in December of this year. Our next precision medicine target will be disclosed in the first half of 20 22. For ROI-nineteen 71, as I mentioned, has begun its combination trial with GDC-six thousand and 36, which is being run by RocheGenentech. Over the medium term, we will also build value through advancing our 5 additional innovator programs, pursuing challenger targets through partnerships, continuing to evolve our Dynamo platform, continuing to expand our pipeline scope and scale.
We have $671, 000, 000 in cash on our balance sheet as of the end of 2020 Q2 2021. And in the most aggressive success scenarios, this will take us into 2024. We look forward to executing
on our plans. I hope that
you've seen that execution is something we've been able to do to date and would like to thank you for your support of our efforts over the years. Thank you for joining us today and hearing our progress to change the way precision medicines are created. With that, I'll turn the call back to the operator to open it up for Q and A.
Your first question comes from the line of Yaron Werber from Cowen. Please ask a question.
Congrats on the data. I have a couple of questions. Number 1, the profile of 4, 008 looks very selective on target for FGFR2 and obviously sparing 1 and 4. In the QP dosing, as you go from 20 to 70 mgs, can you give us a little bit of a sense of how do some of the tolerability relate to dose? Do you see more AEs as you go higher?
Because you're still not really seeing VLTs or do you not see necessarily that trend? And then secondly, in terms of efficacy, how quickly do you see onset of activity and onset of resist criteria responses or does it really deepen with time? Thank you.
Yes. So thanks for the question, Yaron. I'll start with the same caveat for both answers, which is it's still early and we're still collecting data. I think on the once daily dosing schedules, the rate of AEs has still been relatively low. So it's been challenging at this point to necessarily assign a dose relationship based on the current data.
Certainly, we have seen a low rate of acute toxicity as measured by DLT as we go through that dose level. And the dose reduction with chronic tolerability is still emerging. We anticipate as we continue to enroll out the 23, 70 milligram once daily cohorts and gather more acute and chronic tolerability data, we'll be able to provide a more complete picture of the dose relatedness to the AE profile as the data mature. With regard to the timing of the onset of response, again, I think the data are early, and I'm going to be extrapolating from a small number of responses here. But we certainly have seen responses that have occurred early in treatment.
I think 4 of the responses that I highlighted today were all responses that were seen at the first scan. But we've also seen patients where the responses come markedly later, where we haven't seen response until potentially the 3rd scan. And what we've seen across the patients with responses in many cases is further deepening of response with continued treatment. So I think obviously as we continue to collect more data and as the data mature, we'll be able to share with you a more precise estimate of the onset of response. But we certainly have seen both fast responses and responses that have seen more time to build to.
Operator, can we move to the next question please?
Your next question comes from the line of Salveen Richter from Goldman Sachs. Please ask a question.
And yet what's the mechanism for disease progression after the drug was administered here for 4008 was for patients?
Chris, could you please Yes, I think
we missed the first part of
the question. Sorry, could you repeat that, please?
I understand that what you think the mechanism for disease progression was here, whether you think it's because of acquired resistance or what's playing out?
Yes. So thank you for the question, Salveen. I think the first thing I'll point out is that amongst our responding patients with confirmed responses, they all remain in response and have not progressed. So we have not yet obviously been able to assess what the mechanism of potential progression might be in those patients. We are in this trial doing circulating tumor DNA profiling, both at baseline and longitudinally on study.
We've shown you data so far showing the early profiling and showing you our ability to clear mutant clones. But obviously, 1 of the questions that we'll be asking is what is the profile in ctDNA with continued therapy with ROI-four thousand and 8. We anticipate that will be the subject of a later disclosure as our data mature.
Got it. Thank you.
Your next question comes from the line of Eric Joseph from JPMorgan. Please ask the question.
Thanks for taking the questions. I was just wondering if you could speak to the level of prior systemic treatment experience in the TKI naive fusion positive, chlangiocarcinoma patients specifically and how those compare to the sort of the prior treatment exposure in the Phase 2 studies with the pan FGFR inhibitors firstly. And then secondly, as it relates to tolerability, among the patients who underwent those reductions with the the patients who underwent those reductions with the QD schedule, I think on Slide 23, can you talk about the specific AEs that led to that prompted dose modification? How quickly and whether they resolve and whether there were any dose interruptions in between?
Yes. Thank you. Thank you for the question, Eric. So with regard to the first question about the profile of the patients who are in our FGFR inhibitor naive population, These are patients who in our study have all received prior chemotherapy for advanced disease. And we anticipate that it's a patient population that likely is reflective in terms of intensity of prior therapy to the data sets that have been reported for the pan FGFR inhibitors.
With regard to your second question about the AEs that are associated with dose modification, what we've seen so far in terms of the on target toxicity that we think is attributable to FGFR2 based on the experience so far has been stomatitis, PPE, retinal AEs. And those have been the AEs that have most commonly required dose modification, especially in the BID dosing schedule.
Okay. That's helpful. And just I also wanted to revisit the activity in the prior panFG far treated cholangiopish population. This is still a focal population in Part 2 of the study, although it sounds like you're going to focus on those where there is a resistance mutation identified at baseline. I guess is the breakdown here that you're I guess the split that you're reporting here in a study reflective
of the
kind of the prevalence of baseline resistance mutations out there in the bottom population, just trying to get a sense of sort of the FGFR or 53 population that might be in scope as you look to develop further in Part 2?
Yes. So our population has been very reflective of what's been reported in literature. At the triple meeting last year, Doctor. Goyle, who was our presenter this year, presented her work on characterizing mechanisms acquired resistance to pan FGFR inhibitors and presented a series of 46 patients treated with pan FGFR inhibitors of which 23 showed evidence of on target resistance mutations and many of those patients had multiple resistant clones, so polyclonal resistance. And consistent with that in our study, roughly half the patients have detectable on target resistance mutations at baseline.
And as we showed today, many of these patients have multiple on target resistance clones with the 2 most common sites of acquired resistance being the molecular break at N550 and the gatekeeper at V565, again very consistent with the data that Doctor. Goyal presented at the triple meeting last year.
Okay, great. Thanks for taking the questions.
Your next question comes from the line of Michael Schmidt from Guggenheim Partners. Please ask a
question.
Hey, guys. Thanks for taking my questions. I just had 1. Don, could you just comment on the DLTs at Burk Saraf Smith study, were they expected to be on target FGFR2 related DLTs? And then a question on the efficacy.
I mean, it looks like the majority of the response is we're seeing at patients who receive doses of 50, 70, perhaps higher doses per day. I was just wondering if that's just a function of still low follow-up at the lower QD dose cohorts because based on your PD data, you would I think you would expect to see responses at dose dose as well or if there or whether there is indeed unexpected dose response with respect to efficacy in the study? Thanks.
Thanks, Michael. I'll start with the second question first. So you are right that we have not, at this point compiled as many scans on patients who are coming on at the lower doses. We have a lower number of patients who are eligible for response evaluation. We expect those data to mature.
With that being said, we have now seen first scan partial responses in patients at 30 milligram, 40 milligram, 50 milligram and 70 milligram once daily. And the patient who was an FGFR inhibitor naive patient who started treatment at 100 milligrams twice a day actually did not go into response until they started on a 50 milligram once daily dose. And they maintain on they remain on therapy with deepening response at a 30 milligram once daily dose. So we feel that any of these and we also shared the vignette stay for the patient whose response came in following the database lock, who also was able to achieve response at first scan at 30 milligram once daily. So we feel these data are consistent with all of these doses being biologically active.
What we're doing right now with the continued enrollment across all 5 of these dose levels is precisely to answer the question you ask and to identify the dose that gives us the best target coverage, the best evidence of early efficacy and the best acute tolerability profile and chronic tolerability profile that would be consistent with being able to maintain dose intensity over the course of chronic therapy. So I would say to really answer the dose response question, stay tuned as we continue to collect data and it matures. With regard to your first question in terms of our understanding of what the AE profile might be going into our trial, This is the first trial that's been run with a selective small molecule inhibitor of FGFR2. We're able to triangulate in from the pan FGFR inhibitors and then from bemarituzumab, the FGFR2 antibody on what AEs might you might expect to be related to FGFR2 inhibition. But of course, we had no way of knowing from clinical experience given that those are imperfect surrogates for small molecule FGFR inhibitor.
But I think with the data that we've generated here, it definitely suggests that PPE, stomatitis, dry mouth and retinal AEs may all be on target FGFR2 AEs. But we think with the once daily dosing schedule, these are well managed and will not impact our ability to identify a dose that will allow us to maintain chronic dose intensity.
Great. Thank you.
Your next question comes from the line of Jason Gerberry from Bank of America. Please ask the question.
Questions. Just to follow-up on the recommended Phase 2 dose between somewhere between 20 mg and 70 mg QD. So just sort
of curious when you look at
the rates of dose reductions in DLT for either the 30 mg BID or 50 mg BID, Thinking about like the total daily dosage, I'm wondering if that was cautionary at all as you guys think about going above like 50 mg QD or 70 mg QD ultimately or do you look at the BID and QD dosing a little bit a tox profile? And then if you can just comment on the baseline ctDNA levels for those 7 patients where you got those levels down to I think they were down to nil at that second scan. Just sort of curious if you can comment on that. Thanks.
Yes. So, I think with regard to the first question of BIV versus CDA, you're right. I mean, the dose may be the same, but what we've seen is with the long half life of 4, 008, the BID dosing even at 20 or 30 BID is giving us high prolonged exposure at roughly 95% receptor occupancy or greater, that we think is associated really with exposure mediated AEs that seem to be ameliorated with going to the once daily dosing schedule. And so far the data would suggest to us with actually more data maturity than we've seen for the BID dosing that the 50q day and 70q day do appear to be better tolerated to date than we saw with the BID dosing schedule. So I think we're comfortable continuing to enroll in the 1570 1570q day doses.
And as I alluded to, we'll continue to enroll these 5 cohorts in parallel. We'll have up to 12 patients per cohort per protocol where we'll be able to look at again the acute and chronic colorability PK and early efficacy to really be able to select the dose to move forward. In terms of the level of the ctDNA alterations, the assay we're using, I believe, has a lower level of detection of a variant allele frequencies we were seeing varied from being in the 1% or less range to being much higher allele frequencies. But the common thread was that we were able to suppress them all to below 0.1%, which was the lower limit detection on the assay we're using.
Got it. Thank you.
Your next question comes from the line of Silvan Turkan from JMP Securities. Please ask a question.
Thank you. Congrats on the data and thanks for taking my questions. I dropped off there for a second, so this might have been asked. But could you comment on or do you know what the average dose per patient is that the patients received in the naive population and the overall population in the QD schedule? And then I have a follow-up.
Yes. So for the patients who have come on, on the Q day schedule and the treatment naive patients, all of them remain on treatment in the Q day schedule on the dose they came in on that they were admitted to the trial on and started dosing on. The exception, the patient with a dose modification was a patient who started at 100 BID that has had to be dose reduced to 30 Q day.
Okay, great. Thank you. And could you comment on the severity of the mouth thores compared to the pan FGFR inhibitors and also on the severity of retinal disorders? Sorry, as I missed, look for them in the trial and could you please comment on what that how that impact the results? Yes.
So for us, stomatitis has predominantly been grade 1 or grade 2. Grade 3 has been rare. In terms of the frequency of what we're seeing, this is 1 of those AEs that is comparable to our favorable compared to what's been reported for the pan FGFR inhibitors. So we're seeing in once daily dosing, 31% stomatitis, again mostly grade 1 or grade 2, whereas for the pan FGFR inhibitors that's gone up to as high as 56% in the case of infobratinib. In terms of the retinal AEs and the once daily dosing overall we've seen 9 percent all grade 1 or grade 2 all reversible.
The 1 caveat that I'll point out is the experience of the pan FGFR inhibitors that first identified this AE as a potential class effect came in the trial of those agents. The trials of those agents did not require screening ophthalmologic exams while patients were on trial. Patients only went to a comprehensive ophthalmology exam if they were symptomatic, if they had visual changes. Our protocol does have scheduled ophthalmology including OCT to look for retinal detachment whether patients are symptomatic or not. So the rate we're seeing of 9% includes a small number of patients who actually had symptomatic retinal toxicity, but the majority of patients were Grade 1 or asymptomatic retinal toxicity picked up on the scheduled exam.
And as such, largely or potentially overestimates the rate compared to what's been reported earlier for the pan FGFR inhibitors.
Okay. Thank you. Thanks for taking my questions.
Thank you, operator, and thanks to all of you for joining us today. We're excited about potential of our programs and appreciate your support of Relay Therapeutics in our mission to transform the drug discovery process with the goal of bringing life changing therapies to patients. Thank you.