-- STX-478 is active in multiple solid tumor types with both PI3Kα kinase and helical domain mutations, achieving a monotherapy overall response rate (ORR) of 23% in breast cancer and 21% in all tumors --

-- Tumor reductions seen in 72% of patients as a monotherapy, with mutant PIK3CA circulating tumor DNA (ctDNA) decline in 86% of patients --

-- STX-478 is well-tolerated and wild-type (WT) sparing in a high-risk, heavily pre-treated patient population, minimizing metabolic dysfunction with no discontinuations due to treatment-related adverse events --

-- Enrollment is ongoing, including in combinations with fulvestrant +/- CDK4/6 inhibitors in breast cancer --

Scorpion Therapeutics, Inc. (“Scorpion”), a pioneering clinical-stage oncology company dedicated to transforming the lives of cancer patients by redefining the frontier of precision oncology, today presented initial, first-in-human clinical results from its Phase 1/2 study of STX-478 in advanced solid tumor patients in a Proffered Paper late-breaking session at the European Society for Medical Oncology (“ESMO”) Congress 2024 in Barcelona, Spain. Initial Phase 1 monotherapy data for STX-478, an oral, once-daily, mutant-selective, allosteric PI3Kα inhibitor, demonstrated potentially best-in-class PI3Kα inhibition, with anti-tumor activity observed in multiple cancer types, including HR+/HER2- breast cancer (BC), gynecological tumors, and other solid tumors. STX-478 was well-tolerated, including in pre-diabetic, diabetic and heavily pre-treated patients and showed no significant wild-type-mediated toxicities.

“We are pleased to report the initial Phase 1/2 trial results of STX-478, which was designed as the first PI3Kα inhibitor to fully maximize the potential of pathway inhibition in patients with solid tumors and is the first program emerging from our next-generation precision oncology discovery engine,” said Adam Friedman, M.D., Ph.D., Chief Executive Officer of Scorpion. “STX-478 demonstrates potent and potentially best-in-class PI3Kα pathway inhibition as established by our early, differentiated signals of monotherapy efficacy, which exceed benchmarks of other pathway inhibitors. We also are encouraged by early safety data that demonstrates minimal evidence of wild-type PI3Kα-mediated toxicities, with no patients discontinuing STX-478 due to treatment-related adverse events. Together, these results suggest that our highly-selective mutant PI3Kα inhibitor could overcome the limitations of currently available pathway inhibitors and, consequently, meaningfully improve clinical outcomes for patients with PI3Kα kinase or helical domain-mutated solid tumors. We look forward to continuing to progress our clinical-stage and discovery pipeline as we work to broaden the reach and impact of precision oncology for patients with high unmet medical need.”

“Approved and investigational non-selective PI3Kα inhibitors, as well as approved AKT inhibitors, have shown clinical benefit in HR+/HER2- breast cancer in Phase 3 studies. However, their therapeutic benefit is limited by PI3Kα pathway inhibition in normal tissues, resulting in dose-limiting toxicities, including hyperglycemia, rash and diarrhea,” said Alberto J. Montero, M.D., affiliated with University Hospitals Cleveland, and trial investigator. “By selectively targeting mutant PI3Kα, one of the most prevalent oncogenes in cancer, STX-478 has the potential to improve clinical outcomes and quality of life for patients during treatment. In the trial, STX-478 achieves exposures capable of driving several-fold deeper target inhibition than other PI3Kα inhibitors, while avoiding their toxicities, even with the majority of patients having prediabetes or diabetes. I am excited about the early results in patients with breast cancer and other solid tumors and look forward to further clinical development.”

Initial Data from the Phase 1/2 Study of STX-478 in Advanced Solid Tumors

In the Proffered Paper presented at ESMO, 61 patients with both kinase and helical domain PIK3CA mutations were treated with STX-478 at doses ranging from 20mg to 160mg daily, as of the data cutoff on June 21, 2024. Of the enrolled patients, 29 patients had HR+/HER2- BC and 32 patients had other solid tumors. Additionally, 54% of patients were pre-diabetic or diabetic, and 41% of BC patients had a prior PI3Kα pathway inhibitor. 97% of BC patients had previously received a CDK4/6 inhibitor. Enrolled patients were heavily pre-treated with a median of three prior lines of therapy (ranging from 1-7).

Pharmacokinetic and Selectivity Profile

Preliminary pharmacokinetic analysis supports once-daily dosing of STX-478, with dose proportional and linear STX-478 plasma exposure and an estimated half-life of approximately 60 hours. At doses ≥ 40mg QD, STX-478 exceeded the average exposures needed for in vivo efficacy in mouse models and achieved target coverage several fold higher than other approved or investigational PI3Kα inhibitors. STX-478 reached a maximum tolerated dose (MTD) of 100mg daily.

Preliminary Safety Data

STX-478 was well-tolerated in a high-risk population, which included diabetics, pre-diabetics and patients intolerant to other PI3Kα pathway inhibitors, populations excluded from other PI3Kα studies. Most treatment-related adverse events (TRAEs) were mild-to-moderate and transient; TRAEs of ≥ 15% included: fatigue (30%), hyperglycemia (23%), nausea (20%) and diarrhea (15%). No Grade ≥ 3 PI3Kα WT toxicity adverse events (hyperglycemia, diarrhea and rash) were observed, and minimal changes in fasting glucose were observed at any STX-478 dose level.

No patients discontinued STX-478 due to a TRAE, and two dose-limiting toxicities observed at 160mg rapidly resolved after a brief dose interruption.

Initial Clinical Activity Data

As of the data cutoff in 43 evaluable patients, the confirmed/unconfirmed overall response rate (ORR) was 23% (5/22) in HR+/HER2- metastatic breast cancer; 21% (9/43) in all tumor types; and 44% (4/9) in gynecologic cancers, which compares favorably to approved PI3Kα pathway inhibitors (monotherapy ORR 4 – 6%). All responses were confirmed following the data cutoff. The disease control rate across tumors was 67%. Tumor reductions were seen in 72% of all patients as a monotherapy agent across all dose levels. Multiple responses were seen in both PI3Kα kinase and helical domain mutant tumors at multiple dose levels, and many responses were sustained and deepened over several months of therapy.

Mutant PIK3CA circulating tumor DNA levels markedly decreased on therapy in 86% of patients (19/22 evaluable patients).

The presentation will be available here on Scorpion’s website following the conclusion of the session.

“Scorpion is dedicated to bringing highly-selective small molecules to cancer patients as quickly as possible, and the presentation of these data is a testament to the team’s exceptional execution and the productivity of our fully-integrated discovery organization,” said Mark Chao, M.D., Ph.D., Chief Medical Officer of Scorpion. “These exciting data bolster our confidence in the profile of STX-478 and in the continued advancement of the trial as we actively enroll patients into ongoing multiple expansion cohorts across a range of solid tumors and in combinations with active standard of care agents including fulvestrant and CDK4/6 inhibitors in HR+/HER2- breast cancer and lay the groundwork for the rapid advancement of this novel treatment. We would like to thank the patients, caregivers and investigators for sharing our commitment to advancing next-generation cancer treatments, and we look forward to providing updates from this study at future medical meetings.”

About STX-478

STX-478 was designed to improve outcomes in patients harboring PI3Kα mutations, one of the most prevalent drivers of cancer, occurring in over 166,000 patients per year with breast, gynecological and other solid tumors in the United States alone. In preclinical models, STX-478 demonstrated robust activity across a range of both kinase and helical domain PI3Kα mutations while sparing wild-type PI3Kα activity in normal tissues; previous generations of non-selective PI3Kα inhibitors have limited patient benefit due to these on-target toxicities. Scorpion’s Phase 1/2 clinical trial is a multi-center, global, open-label study designed to evaluate the safety and tolerability of STX-478 in multiple ascending doses for patients with locally advanced or metastatic HR+/HER2- breast cancer and other solid tumors driven by PI3Kα mutations. The program has rapidly advanced into multiple expansion cohorts across a range of solid tumors and in breast cancer as monotherapy and in combinations with fulvestrant and CDK4/6 inhibitors. To learn more about the first-in-human trial of STX-478, please visit this page.

About Scorpion Therapeutics

Scorpion is a pioneering clinical-stage oncology company redefining the frontier of precision medicine to deliver optimized and transformational therapies for larger populations of patients with cancer. Scorpion has built a proprietary and fully-integrated platform of the most advanced technologies across cancer biology, medicinal chemistry, and data sciences, with the goal of consistently and rapidly creating exquisitely selective small molecule compounds against an unprecedented spectrum of targets. Scorpion aims to leverage its platform to advance a broad pipeline of wholly-owned, optimized compounds across three target categories: best-in-class molecules targeting validated oncogene targets; first-in-class molecules for previously undruggable targets; and first-in-class molecules for novel cancer targets. For more information, visit www.scorpiontx.com.

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