Haizexin (risovalisib) / HaiHe Biopharma, Otsuka - LARVOL DELTA

Taiho Pharmaceutical Announces the Launch of PI3Kα Inhibitor HAIZEXIN Tablets 10mg in Japan (Taiho Press Release) - "Taiho Pharmaceutical...announced today that the PI3Kα inhibitor, HAIZEXIN tablets 10mg (generic name: risovalisib mesilate hydrate), has been listed on the National Health Insurance (NHI) reimbursement price list. The launch of this new product in Japan is scheduled for July 28, 2026. In March 2026, Haihe Biopharma...obtained approval to manufacture and market HAIZEXIN in Japan for the treatment of a patient with ovarian clear cell carcinoma (hereinafter 'OCCC') harboring PIK3CA gene mutations that has progressed after chemotherapy."

Launch Japan • Reimbursement • Ovarian Clear Cell Cancer

PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs in Japan; trastuzumab deruxtecan for solid tumors, talazoparib for prostate cancer, sacituzumab govitecan for breast cancer, darolutamide for salivary gland cancer, risovalisib for ovarian cancer, and mosunetuzumab plus polatuzumab vedotin for lymphoma. (PubMed, Int J Clin Oncol) - No abstract available

Japanese regulatory • Journal • Breast Cancer • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Prostate Cancer • Salivary Gland Cancer • Solid Tumor

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

Japan Approves Risovalisib For PIK3CA-Mutated Ovarian Clear Cell Carcinoma (OncoDaily) - "Supported by data from the phase II CYH33-G201 study, this approval introduces a targeted therapeutic option for a historically treatment-resistant subtype of ovarian cancer. Importantly, the approval is accompanied by the authorization of the AmoyDx PIK3CA Mutation Detection Kit, a companion diagnostic designed to identify eligible patients based on tumor PIK3CA mutation status, reinforcing a precision oncology approach to treatment selection."

Companion diagnostic • Japan approval • Ovarian Clear Cell Cancer

A Study to Evaluate the Efficacy and Safety of CYH33 in Patients With Recurrent/Persistent Ovary Clear Cell Carcinoma (clinicaltrials.gov) - P2 | N=93 | Active, not recruiting | Sponsor: Haihe Biopharma Co., Ltd. | Completed ➔ Active, not recruiting | Trial completion date: Jul 2024 ➔ Feb 2026

Enrollment closed • Trial completion date • Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma. (PubMed, Acta Pharmacol Sin) - "Furthermore, CYH33 possessed potent activity against the growth of LUSC with hyperactivated PI3K signaling. Collectively, the dual-targeting of CYH33 that directly blocked PI3Kα in tumor cells and disrupted CAF-mediated pro-metastatic signaling supported PI3Kα inhibitors as a potential therapeutic approach for advanced LUSC."

Journal • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CAFs • HGF • PIK3CA

A Study to Evaluate the Efficacy and Safety of CYH33 in Patients With Recurrent/Persistent Ovary Clear Cell Carcinoma (clinicaltrials.gov) - P2 | N=93 | Completed | Sponsor: Haihe Biopharma Co., Ltd. | Recruiting ➔ Completed

Trial completion • Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • PIK3CA

GLOBAL PHASE II STUDY OF RISOVALISIB, A SELECTIVE PI3Kα INHIBITOR, AS MONOTHERAPY IN PATIENTS WITH RECURRENT/PERSISTENT OVARIAN CLEAR CELL CARCINOMA HARBORING PIK3CA HOTSPOT MUTATIONS (IGCS 2025) - P2 | "Introduction: Recurrent or persistent ovarian clear cell carcinoma (OCCC) is rare and chemo resistant (ORR <8%). As of July 31, 2024, a total of 93 female patients (China 44.1%, Japan 55.9%) were enrolled; median age 49.0 years. All patients had prior systemic platinum-based chemotherapy; 67.7% received ≥2 lines of systemic therapy. Bevacizumab was used by 69.9% of patients."

Clinical • Late-breaking abstract • Monotherapy • P2 data • Clear Cell Carcinoma • Oncology • Ovarian Cancer • PIK3CA

Haihe Biopharma Enters Into Exclusive License Agreement with Taiho Pharma for PI3Kα Inhibitor Risovalisib (CYH33) (Haihe Biopharma Press Release) - "Under the license agreement, Haihe will receive an upfront payment, development and sales milestone payments, and royalties based on sales revenue from Taiho, and Taiho will obtain exclusive rights in Japan to develop, manufacture and commercialize risovalisib."

Licensing / partnership • Clear Cell Carcinoma • Ovarian Cancer

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

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