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    DRUG:

    risovalisib (CYH33)

    i
    Other names: HHCYH 33, CYH33, CYH-33, HH-CYH33, HHCYH33, CYH 33
    Company:
    HaiHe Biopharma, Otsuka
    Drug class:
    PI3Kα inhibitor
    Related drugs:
    6ms
    PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors. (PubMed, Cell Death Dis)
    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
    |
    EGFR (Epidermal growth factor receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • GAB1 (GRB2 Associated Binding Protein 1)
    |
    risovalisib (CYH33)
    7ms
    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, Haihe Biopharma Co., Ltd.
    New P1/2 trial
    |
    risovalisib (CYH33)
    7ms
    Study to Evaluate the Safety, Tolerate, Pharmacokinetics and Preliminary Efficacy of CYH33 (clinicaltrials.gov)
    P1, N=206, Completed, Haihe Biopharma Co., Ltd. | Recruiting --> Completed | N=100 --> 206 | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Jun 2023 --> Dec 2024
    Trial completion • Enrollment change • Trial completion date • Trial primary completion date
    |
    risovalisib (CYH33)
    over1year
    Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors. (clinicaltrials.gov)
    P1, N=24, Terminated, Haihe Biopharma Co., Ltd. | N=350 --> 24 | Recruiting --> Terminated; Business decision
    Enrollment change • Trial termination • Combination therapy • Metastases
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    PIK3CA mutation
    |
    Lynparza (olaparib) • risovalisib (CYH33)
    2years
    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 • PARP Biomarker
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    PIK3CA mutation
    |
    Avastin (bevacizumab) • risovalisib (CYH33)
    over2years
    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
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CCND1 (Cyclin D1) • CDK2 (Cyclin-dependent kinase 2) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • E2F1 (E2F transcription factor 1) • SKP2 (S-phase kinase-associated protein 2)
    |
    CCND1 amplification
    |
    risovalisib (CYH33)
    3years
    First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors. (PubMed, Nat Commun)
    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.
    P1 data • Journal
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    PIK3CA mutation
    |
    risovalisib (CYH33)
    over3years
    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, Haihe Biopharma Co., Ltd. | Not yet recruiting --> Recruiting | N=228 --> 86
    Enrollment open • Enrollment change
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    PIK3CA mutation
    |
    risovalisib (CYH33)
    over3years
    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
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    risovalisib (CYH33)
    almost4years
    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
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
    |
    MYC expression
    |
    Piqray (alpelisib) • Zydelig (idelalisib) • birabresib (OTX015) • risovalisib (CYH33)
    4years
    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, Haihe Biopharma Co., Ltd.
    Clinical • New P2 trial
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
    |
    PIK3CA mutation
    |
    risovalisib (CYH33)