生華 胡定吾 開發膽管癌FDA phaseI & II (CX-4945)

生華抗癌新藥研發有成　擬12月4日登錄興櫃 今富族網記者吳泓駿／報導     2014-10-30 生華生技（6492）目前CX-4945（蛋白激酶CK2抑制劑）及CX-5461（第一型RNA聚合酶抑制劑）兩項抗癌新藥已進入人體臨床試驗，其中CX-5461新藥獲澳洲政府支持，臨床試驗的相關經費全數由澳洲政府提供，顯示該項新藥深受國際肯定。生華甫於10月7日補辦公開發行，暫定12月4日登錄興櫃交易，主辦券商為永豐金證券。 生華生技設立於2012年11月，總部位於台北，並在美國聖地牙哥設有1家100%持股子公司。目前生華股本6.54億元，定位為小分子抗癌新藥開發公司，董事長為胡定吾，主要股東包括定利開發、漢大創投、金昇化學科技、源慶投資、汎球生物藥劑及台耀生技等法人。此外，外資股東也有香港知名生技醫療創投－晨興創投（The Morningside Group Limited）入股，股東陣容堅強。生華生技的核心理念為發掘相關潛力藥，主要以新藥的後續開發為主，提供藥物開發的技術支援。其中CX-4945便是由美國某生技公司收購而來，治療標的瞄準膽管癌，目前在美國Mayo Clinic及US Oncology進行人體二期臨床試驗。公司指出，CX-4945設計為口服形式，並結合現有針劑藥物採用合併療法，此新藥能抑制CK2蛋白激酶的活性，藉此阻止癌細胞自我修復的能力，因而達到抗癌效果。雖然該項新藥列為孤兒藥的範疇，但未來是否會向FDA申請孤兒藥資格，目前公司尚在討論之中。除此之外，生華的另一項新藥CX-5461則是鎖定血液性癌症，現階段已在澳洲彼得麥克林癌症中心（Peter MacCallum Cancer Centre）展開人體一期臨床試驗。此項新藥透過活化可抑制腫瘤的p53蛋白達到治療效果，當癌細胞侵入人體時，p53蛋白會對細胞DNA進行辨識，若發覺細胞受損已不能修復時，p53蛋白便啟動細胞凋亡作用，避免其繼續分裂生長，期間並不傷害任何健康的細胞。 生華指出，CX-5461及CX-4945兩項新藥均是市場首見（First in class）小分子藥物，預計將在2016年分別完成人體二期、人體一期臨床試驗，未來也不排除再擴展至其他領域。根據合併財報，該公司2013年營收2,626萬元，稅後淨損1.13億元，每股稅後虧損2.57元；累計2014年上半年營收1,891萬元，稅後淨損7,719萬元，每股稅後虧損1.24元。

Study of CX-4945 in Combination With Gemcitabine and Cisplatin for Frontline Treatment of Cholangiocarcinoma  Sponsor: Senhwa Biosciences, Inc. 

Protein kinase CK2 is a constitutively active serine/threonine kinase with a long history as a pro-survival, anti-apoptotic kinase. Given the wide spread overexpression of CK2 in multiple cancers and its role in multiple non-oncogenic processes required to sustain the cancer phenotype, a selective inhibitor of CK2 is an attractive targeted approach to treating cancer. CX-4945 is a tetracyclic, small molecule carboxylate acid salt that exhibits potent and highly selective inhibition of CK2. Protein kinase CK2 is also known to play an important role in the DNA damage repair mechanisms of cancer cells, and this study of CX-4945 in combination with gemcitabine plus cisplatin will determine if inhibition of CK2, in conjunction with the use of chemotherapy drugs, will result in improved clinical outcomes for patients with non-resectable cholangiocarcinoma.

Experimental: CX-4945 and cisplatin plus gemcitabine CX-4945 capsules at the combination MTD on Days 0, 1 and 2, and Days 7, 8 and 9. PLUS Cisplatin 25 mg/m.sq. by IV infusion on Days 1 and 8. PLUS Gemcitabine 1,000 mg/m.sq. by IV infusion on Days 1 and 8. On a 21 day cycle.

Active Comparator: Cisplatin plus Gemcitabine Cisplatin 25 mg/m.sq. by IV infusion on Days 1 and 8. PLUS Gemcitabine 1,000 mg/m.sq. by IV infusion on Days 1 and 8. On a 21 day cycle.

Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia Leukemia (2014) 28, 179–182;  Martins1, P Lúcio2, A Melão1, I Antunes1, B A Cardoso1, R Stansfield3, M T S Bertilaccio4, P Ghia4,5, D Drygin3, M G Silva2 and J T Barata1

1Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal /2CEDOC, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa and Instituto Português de Oncologia, Lisbon, Portugal /3Cylene Pharmaceuticals, San Diego, CA, USA /4Istituto Scientifico San Raffaele, Milano, Italy /5Università Vita-Salute San Raffaele, Milano, Italy  Chronic lymphocytic leukemia (CLL) remains a therapeutic challenge. New immuno-chemotherapeutic approaches have had a significant impact, improving overall survival. However, not all patients can tolerate aggressive regimens, high-risk groups continue to have a poor response, and patients still relapse.1 Therefore, novel therapeutic strategies involving molecular-targeting, rationally designed treatments are particularly desirable.2 CK2 is a ubiquitous, constitutively active serine/threonine protein kinase frequently involved in cancer.3 We and others previously showed that CLL cells rely on high CK2 expression and activity for their viability,4, 5 similar to their dependence on PI3K.6 Notably, CK2 has been consistently linked to the activation of PI3K signaling pathway through its ability to phosphorylate and thereby inactivate PTEN, the main negative regulator of the pathway.4, 7 The relevance of CK2 as a molecular target in cancer has led to the development of CK2 inhibitors for clinical use. CX-4945 (Cylene Pharmaceuticals, San Diego, CA, USA) is a potent and highly specific, orally available, ATP-competitive inhibitor of both CK2α and CK2α′ catalytic subunits, with known antitumor efficacy in breast, pancreatic and prostate xenograft mouse models.8 In phase I clinical trials, CX-4945 induced stable disease in 20% of patients with different solid tumors, positioning it for phase II combination trials. Importantly, adverse effects were generally mild to moderate, demonstrating that CX-4945 can be safely administered to humans and exert a pharmacodynamic response.9 Here, we evaluated whether CX-4945 may be a valid therapeutic option against CLL. We found that incubation of MO1043 (Figure 1a) and primary CLL (Figure 1b) cells with CX-4945 resulted in a marked decrease in C-terminal PTEN phosphorylation, which is indicative of PTEN functional inactivation. In agreement, CX-4945 decreased the activity of PI3K downstream targets Akt and PKC, as determined by their levels of phosphorylation (Figures 1a and b). Moreover, Akt phosphorylation on the CK2 direct target site S12910 was abrogated by CX-4945. Constitutive activation of Akt and PKC was previously shown to be essential for the viability of CLL cells.11, 12 In accordance, CX-4945 had significant cytotoxic and anti-proliferative effects on CLL cell lines (Supplementary Figure 1), and elicited a pro-apoptotic effect against all primary CLL cases we analyzed (Figure 1c), in a dose- and time-dependent manner (Figure 1d). Notably, CX-4945 appeared to have an effect even in samples from patients displaying cytogenetic abnormalities associated with poor outcome and resistance to chemotherapy, such as 11q and 17p deletions13, 14 (Supplementary Figure 2).