risovalisib (CYH33) / HaiHe Biopharma - LARVOL DELTA

HaiHe Biopharma's Selective PI3Kα Inhibitor was Granted Orphan Drug Designation in Japan (Haihe Biopharma Press Release) - "Haihe Biopharma Co., Ltd. ('HaiHe') announced that its highly selective PI3Kα inhibitor (development code: CYH33) has been granted orphan drug designation by Japan’s Ministry of Health, Labour and Welfare (MHLW) for the treatment of advanced or recurrent ovarian clear cell carcinoma (OCCC) harboring PIK3CA gene mutations that has progressed after chemotherapy."

Orphan drug • Ovarian Cancer

PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors (EACR 2025) - "In conclusion, we found that PI3Kα-selective inhibitor CYH33 displayed potent activity against HNSCC, which was associated with inhibition of Akt signaling as well as attenuation of PI3K-dependent GAB1/Erk phosphorylation. Simultaneous inhibition of GAB1 phosphorylation independent of PI3K potentiated the anti-HNSCC activity of CYH33. These findings revealed the insight mechanism of CYH33 against HNSCC and provided rational combination regimen for HNSCC."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • GAB1 • MAPK1 • PIK3CA

PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors. (PubMed, Cell Death Dis) - P1 | "Concurrent inhibition of EGFR synergistically potentiated the activity of CYH33 against HNSCC. These findings revealed the insight mechanism of CYH33 against HNSCC and provided rational combination regimen for HNSCC treatment."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • GAB1 • PIK3CA

Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of CYH33 in Patients With PIK3CA-related Overgrowth Spectrum (PROS) and PIK3CA-related Vascular Malformations (PRVM) (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: Haihe Biopharma Co., Ltd.

New P1/2 trial

PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors (AACR 2025) - P1 | "Simultaneous inhibition of GAB1 phosphorylation independent of PI3K potentiated the anti-HNSCC activity of CYH33. These findings revealed the insight mechanism of CYH33 against HNSCC and provided rational combination regimen for HNSCC."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR • GAB1 • MAPK1 • PIK3CA

Study to Evaluate the Safety, Tolerate, Pharmacokinetics and Preliminary Efficacy of CYH33 (clinicaltrials.gov) - P1 | N=206 | Completed | Sponsor: Haihe Biopharma Co., Ltd. | Recruiting ➔ Completed | N=100 ➔ 206 | Trial completion date: Mar 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2023 ➔ Dec 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Solid Tumor

A phase Ib study of PI3Kα inhibitor risovalisib mesylate in combination with fulvestrant in patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer. (ASCO 2024) - P1 | "Alpelisib (PI3Kα inhibitor) + fulvestrant has been approved for pts with PIK3CA-mutated HR+/HER2- ABC following progression on/after an ET-based regimen...A multicenter, open-label, phase Ib study of CYH33 in combination with ET ± Palbociclib (CDK4/6i) is ongoing (NCT04856371)... CYH33 + fulvestrant exhibited a manageable safety profile and encouraging preliminary anti-tumor efficacy in pts with PIK3CA-mutated, HR+/HER2- ABC who progressed on/after ET ± CDK4/6i treatments."

Clinical • Combination therapy • Metastases • P1 data • Breast Cancer • Dental Disorders • Diabetes • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Stomatitis • HER-2 • PIK3CA

Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=24 | Terminated | Sponsor: Haihe Biopharma Co., Ltd. | N=350 ➔ 24 | Recruiting ➔ Terminated; Business decision

Combination therapy • Enrollment change • Metastases • Trial termination • Breast Cancer • Endometrial Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Prostate Cancer • Solid Tumor • MUC16 • PIK3CA

An Attempt to Develop a New Treatment Strategy for Rare Refractory Gynecological Malignancies: The Japanese Gynecologic Oncology Group. (PubMed, JMA J) - "Even with the recently developed maintenance therapies using molecular targeted inhibitors for ovarian cancers, such as bevacizumab or poly (ADP-ribose) polymerase (PARP) inhibitors, the prognosis of non-HGSC ovarian cancers is unsatisfactory. Through C-CAT database analysis, we estimated that approximately 40% of the patients with OCCC harbored at least 1 of the 17 PIK3CA hotspot mutations designated in the CYH33-G201 trial. JGOG will continue the challenge of establishing novel treatment strategies for rare refractory cancers that will benefit patients suffering from gynecological malignancies, especially those who do not receive satisfactory standard treatment and care."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kα inhibitors. (PubMed, Signal Transduct Target Ther) - "Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • CCND1 • CDK2 • CDKN1A • E2F1 • PIK3CA • SKP2

Study to Evaluate the Safety, Tolerate, Pharmacokinetics and Preliminary Efficacy of CYH33 (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Haihe Biopharma Co., Ltd. | Unknown status ➔ Recruiting | Trial completion date: Aug 2021 ➔ Mar 2024 | Trial primary completion date: Apr 2021 ➔ Jun 2023

Enrollment open • Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Targeting PI3Kα overcomes resistance to KRas inhibitors mediated by activation of EGFR and/or IGF1R. (PubMed, Acta Pharmacol Sin) - "Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRAS-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRas inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRas inhibitors for therapy of KRAS-mutant cancers in future clinical trials."

Journal • Oncology • EGFR • KRAS • PIK3CA

First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors. (PubMed, Nat Commun) - P1 | "Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations."

Journal • P1 data • Diabetes • Fatigue • Oncology • Solid Tumor • PIK3CA

A Study to Evaluate the Efficacy and Safety of CYH33 in Patients With Recurrent/Persistent Ovary Clear Cell Carcinoma (clinicaltrials.gov) - P2 | N=86 | Recruiting | Sponsor: Haihe Biopharma Co., Ltd. | Not yet recruiting ➔ Recruiting | N=228 ➔ 86

Enrollment change • Enrollment open • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3Kα inhibitors in oesophageal squamous cell carcinoma. (PubMed, Clin Transl Med) - "We performed genome-wide gain-of-function screening with a CRISPR-SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3Kα inhibitor CYH33...Taken together, our study demonstrated that an EZH2-p21-RB axis remodeled cell cycle regulation and rendered resistance to PI3Kα inhibitors in ESCC. Simultaneously targeting PI3Kα and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CDKN1A • EZH2 • PIK3CA

[VIRTUAL] A phase I study to evaluate safety, pharmacokinetics (PK), and preliminary efficacy of CYH33, a phosphatidylinositol 3-kinase α (PI3Kα) inhibitor, in patients (pts) with advanced solid tumors (TAT 2021) - P1 | "Conclusions CYH33 demonstrates a manageable safety profile and linear pharmacokinetic characteristics. An encouraging preliminary anti-tumor efficacy in certain tumor types harboring PIK3CA mutation was observed."

Clinical • P1 data • PK/PD data • Breast Cancer • Cervical Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

Intact regulation of G1/S transition renders esophageal squamous cell carcinomas sensitive to PI3Kα inhibitors by blocking SKP2-mediated p21 degradation (AACR 2022) - "PI3Kα inhibitors including CYH33 and the marketed alpelisib displayed highly variable activity against the proliferation of a panel of ESCC cells, reflecting the heterogeneity of ESCC. CYH33 arrested sensitive ESCC cells at G1 phase via inhibiting the ubiquitination and degradation of p21 by SKP2, which further resulted in decreased activity of CDK4/6 and CDK2 as well as Rb phosphorylation. These findings revealed the insight mechanism of the differential activity CYH33 against ESCC and provided potential candidate biomarkers for the treatment of ESCC."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CCND1 • CDK2 • CDK4 • CDKN1A • PIK3CA • SKP2

Repressing MYC by targeting BET synergizes with selective inhibition of PI3Kα against B cell lymphoma. (PubMed, Cancer Lett) - "A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC • PIK3CA • PIK3CD

[VIRTUAL] A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors. (ASCO 2020) - P1 | "The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Research Funding: Shanghai HaiHe Pharmaceutical Co.,Ltd"

Clinical • P1 data • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

A Study to Evaluate the Efficacy and Safety of CYH33 in Patients With Recurrent/Persistent Ovary Clear Cell Carcinoma (clinicaltrials.gov) - P2; N=228; Not yet recruiting; Sponsor: Haihe Biopharma Co., Ltd.

Clinical • New P2 trial • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8T cells and promoting fatty acid metabolism. (PubMed, J Immunother Cancer) - "CYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment."

Journal • Preclinical • Breast Cancer • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor • PIK3CA

Study of CYH33 in Combination With Endocrine Therapy With or Without Palbociclib in Patients With HR+, HER2- Advanced Breast Cancer (clinicaltrials.gov) - P1; N=228; Not yet recruiting; Sponsor: Haihe Biopharma Co., Ltd.

Clinical • Combination therapy • New P1 trial • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • KRAS • PIK3CA • PTEN

Promising Efficacy, Manageable Safety Are Observed for CYH33 in Solid Tumors (Targeted Oncology) - P1, N=100; NCT03544905; Sponsor: Haihe Biopharma Co., Ltd; "A PI3Kα inhibitor, CYH33, demonstrated positive clinical activity in an ongoing phase 1a trial (NCT03544905) at the European Society for Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021...'Objective tumor responses were observed in 5 patients, including 1 complete response (CR) in 1 patient with ovarian cancer and 4 partial responses (PRs), 1 each in patients with colorectal cancer, breast cancer, ovarian cancer, and gastric cancer'"

P1 data • Breast Cancer • Colorectal Cancer • Gastric Cancer • Oncology • Ovarian Cancer • Solid Tumor

Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells. (PubMed, Cell Death Dis) - "Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • HRAS

Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors. (clinicaltrials.gov) - P1; N=350; Recruiting; Sponsor: ShangHai HaiHe Pharmaceutical

Clinical • Combination therapy • New P1 trial • Breast Cancer • Endometrial Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Prostate Cancer • Solid Tumor