個人積分：270分
文章編號：70414852
(6446) 藥華藥新一代長效型干擾素P1101(Ropeginterferon alpha-2b)在活性細胞實驗與細胞外實驗中針對PV在JAK2V617F呈現陽性的作用
https://www.nature.com/articles/s41408-018-0133-0
Blood Cancer Journal volume 8, Article number: 94 (2018)
2018年血液期刊第8卷, 文章編號94
Abstract
摘要
Polycythemia vera is characterized by the acquisition of the JAK2V617F mutation. Recommended treatments include hydroxyurea and interferon-alpha. Several groups have reported a reduction in the JAK2 mutant allele burden in interferon-treated patients, but significance of this observation is questioned. We characterized the activity of ropeginterferon alpha-2b, a novel form of interferon-alpha recently shown to be safe and efficacious in polycythemia vera. Ropeginterferon was able to inhibit the proliferation of the HEL, UKE-1, and UT-7 JAK2-mutant cell lines while sparing JAK2-wild-type UT-7 and normal CD34+ cells growth.
PV的特徵在於產生JAK2V617F突變。推薦的治療方法包括HU和干擾素-α。幾個研究小組指出使用干擾素進行治療的病患JAK2突變等位基因負荷減少，但這種觀察結果受到質疑。我們描述了(6446) 藥華藥新一代長效型干擾素(ropeginterferon alpha-2b)的活性，這是一種新型的干擾素-α，最近顯示在PV適應症中是安全且有效的。(6446) 藥華藥新一代長效型干擾素(ropeginterferon alpha-2b)能夠抑制HEL、UKE-1和UT-7 JAK-2突變細胞的增殖，同時讓JAK2-wild-type UT-7和正常CD34 +細胞生長。
In vitro treatment of erythroid progenitors derived from PV patients showed that ropeginterferon could considerably inhibit the growth of endogenous erythroid colonies, a hallmark of polycythemia vera. Finally, we could study in sequential samples the clonal architecture of erythroid progenitors derived from patients included in a randomized study comparing hydroxyurea to ropeginterferon. After 1 year of treatment with ropeginterferon, the ratio of JAK2-mutated to wild-type colonies grown from bone marrow progenitors was reduced by 64%, compared to 25% in patients receiving hydroxyurea. This study shows that ropeginterferon has a potent targeted activity against JAK2-mutant cells and is able to drastically reduce the proportion of malignant progenitors in patients treated with this drug.
來自PV病患的類紅血球祖細胞的體外治療顯示出， (6446) 藥華藥新一代長效型干擾素P1101可以顯著抑制類紅血球細胞的增長，這是PV的特徵。最後，我們在比較HU和 (6446) 藥華藥新一代長效型干擾素P1101的隨機研究中, 研究來自病患紅血球細胞祖細胞的結構。病患接受 (6446) 藥華藥新一代長效型干擾素P1101處理1年後，JAK2突變比例則降低了64％，而接受HU的病患則為25％。該研究顯示出， (6446) 藥華藥新一代長效型干擾素P1101對JAK2突變細胞具有有效的靶向活性，並且能夠顯著降低病患惡性細胞的比例。
Introduction
簡介
Polycythemia vera (PV) is characterized by a deregulated erythropoiesis related to the presence of the JAK2V617F mutation, which induces a constitutive activation of the JAK/STAT intracellular signaling. More recently, additional mutations in various genes have been discovered, including mutations in genes affecting the epigenome (TET2, ASXL1, DNMT3a, or EZH2), or contributing to transformation to acute leukemia (NRAS, KRAS, TP53, or IDH1/2). The presence of such additional mutations may also influence the response to therapy. Current first-line recommended cytoreductive treatment of PV include hydroxyurea (HU) or interferon-alfa (IFNα). The clinical efficacy of IFNα has been reported since 30 years and was improved with the development of pegylated forms. Furthermore, we and others have observed significant reductions of the JAK2V617F allele burden (%JAK2V617F) in IFNα-treated patients suggesting that IFNα is able to specifically target the malignant clone. The mechanism of action of IFNα in myeloproliferative neoplasms is not clearly elucidated, but several studies confirmed a targeted effect against JAK2V617F mutant clones in both patients and animal models. In clinical practice, a significant proportion of patients still experience adverse events leading to treatment discontinuation with current formulations of IFNα. RopegInterferon alpha-2b (Ropeg) is a long-acting pegylated-IFNα-2b, recently shown to be safe and well tolerated in phase 1–2 studies in PV patients. Both hematological and molecular responses have been reported in a phase 2 trial including 51 patients.
PV的特徵在於與JAK2V617F突變的存在造成失調的紅血球生成，並誘導JAK / STAT細胞內信號傳導的組成活化。最近發現各種基因中的其他突變，包括影響表觀基因組（TET2，ASXL1，DNMT3a或EZH2）的基因突變，或促成轉化成急性白血病（NRAS，KRAS，TP53或IDH1 / 2）。這些額外突變的存在可能會影響對治療的反應率。目前一線用藥推薦的PV細胞減滅治療包括HU或干擾素-α（IFNα）。
自30年以來已經報導了IFNα的臨床功效，並且隨著長效型的發展而改善。此外，我們和其他人已經觀察到IFNα治療的患者中JAK2V617F等位基因負荷（％JAK2V617F）顯著減少，顯示出IFNα能夠針對惡性細胞增殖。 IFNα在骨髓增生性腫瘤中的作用機制尚不清楚，但一些研究證實了在病患和動物模型中對JAK2V617F突變基因增殖的靶向作用。在臨床實驗中，仍有相當大比例的病患經歷不良反應，導致停止治療。 (6446) 藥華藥新一代長效型干擾素P1101是一種長效型干擾素α-2b，最近在PV病患的臨床1-2期研究中顯示出安全性且耐受性良好, 該試驗在51名病患中呈現了血液學反應和分子反應。
In this study, we characterized Ropeg activity against JAK2V617F mutated cells. We tested this new drug in vitro against JAK2-mutant and wild-type cell lines and patients’ primary cells. We could also assess the impact of HU and Ropeg treatments in vivo by sequential studies of bone marrow (BM) progenitors of PV patients treated for 12 months with both drugs in a prospective, randomized study.
在這項研究中，我們標示出針對 (6446) 藥華藥新一代長效型干擾素P1101對於JAK2V617F突變細胞的活性。我們在體外測試了這種新藥對抗JAK2突變基因和野生型基因以及病患的初代細胞。我們還可以通過前瞻性隨機研究中透過HU和 (6446) 藥華藥新一代長效型干擾素P1101在治療PV病患12個月後對於PV病患的骨髓祖細胞的連續研究來評估其影響。
Patients and methods
病患和方法學
Cell lines and reagents
細胞系與試劑
Ropeg (provided by AOP Orphan) was used at two different concentrations consistent with assumed exposure in patients (0.5 and 2 µg/ml), and commercially available standard recombinant interferon-alpha-2a (rIFNα-2a) (Roferon, Roche) was used at 700 U/ml as control. The JAK2V617F positive HEL and UKE-1 cell lines were grown in RPMI + 10% FBS + 1% Glutamax, and IMDM + 10% horse serum + 10% FBS and 1% Glutamax, respectively. We also used the megakaryoblastic leukemia UT-7 cell line expressing the EPO receptor in which either a wild type or a JAK2V617F mutant JAK2 were retrovirally transduced. These cells were cultured in DMEM + 10% FBS + 2 U/mL EPO. Drug efficacy was assessed by counting live cells after Trypan blue staining. All cell lines were tested and found negative for mycoplasma contamination.
(6446) 藥華藥新一代長效型干擾素P1101（由AOP Orphan提供）使用兩種不同濃度（0.5和2μg/ ml），標準重組干擾素-α-2a（rIFNα-2a）（Roferon，Roche）以700U / ml作為對照組。
JAK2V617F陽性HEL和UKE-1細胞系分別在RPMI + 10％FBS + 1％Glutamax和IMDM + 10％馬血清+ 10％FBS和1％Glutamax中生長。我們還使用表達EPO受體的巨核細胞白血病UT-7細胞系，其中野生型或JAK2V617F突變體JAK2被逆轉錄病毒轉導。將這些細胞在DMEM + 10％FBS + 2U / mL EPO中培養。通過在台盼蘭溶液染色後計算存活細胞來評估療效。對所有細胞系進行測試，發現支原體污染呈現陰性。
Patients
病患
Normal hematopoietic progenitors derived from cord blood and primary cells from PV patients obtained after informed consent were studied in clonogenic assays with or without EPO according to manufacturer’s instructions (Methocult, Stemcell technologies©). The study was approved by the local ethics committee (IRB0006477).
The presence of endogenous erythroid colonies (EECs) was determined in cultures without erythropoietin (EPO). Genotyping of the colonies (at least 60 colonies were tested in each condition) was performed by picking, extracting the DNA and testing for the presence of JAK2V617Fmutation using the JAK2 Mutascreen kit (Qiagen©). We studied untreated patients and patients included in the PROUD-PV phase 3 clinical trial (NCT01949805) randomly treated with Ropeg or HU. A total of 13 patients have been included in the PROUD-PV study in France for which BM samples were sent to our laboratory before the initiation of treatment and after 1 year. Informed consent was obtained from all subjects.
根據製造商的說明（Methocult，Stemcell technologies©），克隆測定研究源自於臍帶血和來自PV病患的原生細胞，並獲得其同意。該研究得到了當地委員會批准（IRB0006477）。在沒有紅血球生成素的培養物中測試EEC的存在。通過挑選，淬取出DNA並使用JAK2 Mutascreen試劑盒（Qiagen©）測試JAK2V617Fmutation的存在分別對各菌落進行基因分型（在每種條件下測試至少60個聚落）。我們研究了用(6446) 藥華藥新一代長效型干擾素P1101或HU隨機治療的PROUD-PV 3期臨床試驗（NCT01949805）中包括的未治療和已治療病患。在法國的PROUD-PV研究中共納入13名病患，其中骨髓樣本在治療開始前和1年後被送到我們的實驗室。所有受試者都知情並同意。
Mutant allele burden assessment
突變等位基因負擔評估
The allelic frequency of the JAK2V617F mutation was assessed on DNA extracted from whole blood (QiaAmp DNA blood mini kit, Qiagen) using the JAK2 MutaQuant kit (Qiagen) according to the manufacturer’s instruction. Search for additional mutations was performed using a targeted next generation sequencing (NGS) assay as previously described.
根據製造商的說明，使用JAK2 MutaQuant試劑盒（Qiagen），對從血液中（QiaAmp DNA血液微型試劑盒，Qiagen）萃取的DNA評估JAK2V617F突變的等位基因頻率。如前述，使用靶向的下一代測序（NGS）測定尋找其他的突變。
Results
結果
We first intended to evaluate the action of Ropeg on the proliferation of JAK2V617F-mutated cell lines. In both HEL and UKE-1 cell lines Ropeg exhibited a dose-dependent anti-proliferative effect, comparable to that of standard rIFNα-2a (Fig. 1A, B; Supplementary figure 1). Ropeg at 0.5 µg/ml and 2 µg/ml induced 9%, and 41% inhibition of HEL cells proliferation, and 18 and 35% inhibition of UKE-1 cells proliferation, respectively (compared to 38%, and 36% inhibition of HEL, and UKE-1 cells proliferation, respectively, with rIFNα-2a). To test for a more-specific action of Ropeg against the JAK2V617F mutant form compared to JAK2 wild type, we used the UT-7 model in which both forms of the JAK2 gene have been transduced. We observed a modest impact of AOP treatment on the JAK2 wild-type UT-7 cells proliferation (23% of inhibition at day 3) while a marked decrease in the proliferation of JAK2V617F positive cells was observed (40% reduction at day 3 with 2 µg/ml) (Fig. 1C, D; Supplementary Figure 1).
我們首先打算評估 (6446) 藥華藥新一代長效型干擾素P1101對JAK2V617F突變細胞系增殖的作用。在HEL和UKE-1細胞系中，(6446) 藥華藥新一代長效型干擾素P1101顯示出劑量同向性抗增殖作用，與標準rIFNα-2a一樣。 0.5μg/ ml和2μg/ ml的 (6446) 藥華藥新一代長效型干擾素P1101分別產生抑制了HEL9％和41％的細胞增殖，以及分別抑制UKE-1細胞 18％和35％的增殖（相比之下，rIFNα-2a對HEL的抑制為38％，UKE-1細胞抑制率為36％）。為了測試Ropeg與JAK2野生型和JAK2V617F突變體形式中更獨特的作用，我們使用UT-7模型，其中兩種形式的JAK2基因已被轉導。我們觀察到AOP對JAK2野生型UT-7細胞增殖適度影響（第3天抑制23％），同時觀察到JAK2V617F陽性細胞增殖顯著減少（使用2 µg/ml,第3天減少40％）。
We then studied the impact of an in vitro treatment with Ropeg on the clonogenic potential of erythroid progenitors derived from four untreated PV patients. Ropeg reduced the numbers of colonies grown with or without EPO in all samples. The mean reduction of the numbers of EPO-stimulated colonies was 29 and 59% with Ropeg at 0.5 µg/ml, and 2 µg/ml, respectively. A more striking effect was observed on EECs, the number of colonies being reduced by 90% with Ropeg 2 µg/ml (Fig. 2A). In contrast, Ropeg didnot significantly change clonogenic properties of normal (JAK2 wild type) hematopoietic progenitors isolated from three different cord blood samples (Supplementary figure 2), suggesting that Ropeg inhibits JAK2-mutated hematopoietic progenitors while sparing wild-type cells.
然後，我們研究了(6446)藥華藥新一代長效型干擾素P1101針對來自四個未治療的PV病患的紅血球祖細胞在體外實驗群落形成潛力的影響。在所有樣品中，P1001減少了所有樣本中有或沒有血清紅血球生成激素的群落。
在(6446)藥華藥新一代長效型干擾素P1101分別為0.5μg/ ml和2μg/ ml的劑量下, 紅血球生成激素引起的群落數量平均減少為29％和59％，。在EEC上觀察到更顯著的效果，用2μg/ ml的P1001使群落減少90％。此外，(6446)藥華藥新一代長效型干擾素P1101沒有顯著改變從三種不同臍帶血樣品中淬取的正常（JAK2野生型）造血祖細胞的群落形成特性，表明(6446)藥華藥新一代長效型干擾素P1101抑制JAK2突變的造血祖細胞，同時保留野生型細胞。
To confirm this hypothesis we studied the JAK2 mutational status at the clonogenic level by genotyping individual colonies grown after in vitro treatment with Ropeg. Single colonies from the 4 PV patients were picked (at least 60 colonies per condition) and genotyped. The proportion of mutant colonies was reduced in every patient (Supplementary figure 3) with a median twofold increase in the ratio of wild type to mutant colonies. In addition, in two patients with both homozygous and heterozygous JAK2V617F colonies, eradication of homozygous colonies was achieved with Ropeg, suggesting that JAK2V617F homozygous progenitors are more sensitive to Ropeg, in agreement with previous findings in MPN patients treated with pegylated-IFNα−2a.
為了證實這一假設，我們通過對用(6446)藥華藥新一代長效型干擾素P1101體外實驗後生長的單群落進行基因分型來研究克隆形成水平的JAK2突變狀態。挑選來自4個PV病患的單群落（每種條件至少60個聚落）並進行基因分型。每個病患中突變體群落的比例降低，野生型與突變體集落的比例中位數增加兩倍。此外，在具有同型合子和異型合子JAK2V617F群落的兩名病患中，(6446)藥華藥新一代長效型干擾素P1101根除了同型合子，代表JAK2V617F同型祖細胞對(6446)藥華藥新一代長效型干擾素P1101更敏感，這與先前在用長效型IFNα-2a治療MPN病患中的發現一致。
In addition to these in vitro studies, we took advantage of the PROUD-PV randomized study to search for any correlation between the evolution of the %JAK2V617F in peripheral blood and the impact of therapy on malignant clones assessed by clonogenic assays on BM progenitors. Thirteen patients were included in this study in France, who accepted to participate in an ancillary study of the evolution of their BM progenitors before and after 12 months of treatment in both randomization arms. In this group of patients the mean %JAK2V617F at baseline were 39.4% and 46.5% in the Ropeg and HU arms, respectively. Median %JAK2 V617F was reduced to 29% and 25.8% after 6 months, and to 13.8% and 33.2% after 12 months (Fig. 2B) of treatment with Ropeg and HU, respectively. These data suggested a sustained activity of Ropeg, but not of HU, against JAK2V617F mutant cells. Indeed, we observed a difference between the two drugs considering the median reduction of the %JAK2V617F (p < 0.02) and the responses were more homogeneous in Ropeg compared to HU-treated patients.
除了這些體外實驗，我們透過PROUD-PV隨機研究來尋找JAK2V617F的帶來的惡性腫瘤增殖與治療與對骨髓造血細胞影響之間的任何相關性。這項研究納入法國13名病患，在進化的輔助研究中分別觀察於隨機兩組中在治療12個月之前和之後骨髓造血細胞。這組病患中，(6446)藥華藥新一代長效型干擾素P1101和HU組的基準JAK2V617F分別為39.4％和46.5％。在6個月後JAK2 V617F中位數降至29％和25.8％，並且在用(6446)藥華藥新一代長效型干擾素P1101和HU治療12個月後分別降至13.8％和33.2％。這些數據顯示出(6446)藥華藥新一代長效型干擾素P1101對JAK2V617F突變細胞的持續維持有效性，但HU沒有。實際上，我們觀察到兩種藥物之間的差異，包含％JAK2V617F的中位數減少（p <0.02），此外和治療HU的病患相比之下，(6446)藥華藥新一代長效型干擾素P1101的更具同質性。
To better assess the impact of both drugs on JAK2-mutated cells in vivo we performed clonogenic assays on BM mononuclear cells taken before treatment initiation and after 1 year in order to analyze the changes in clonal architecture. As expected in PV, we observed the presence of EECs in every patient. The ratio of JAK2-mutant to JAK2 wild-type colonies decreased in all of the three patients treated with Ropeg (Fig. 2D) while it decreased in only one out of four patients receiving HU (Fig. 2E). Of note, the poorer clonal response measured by %JAK2V617F in the HU arm wasn't explained by the presence of additional mutations. Using targeted NGS4, we could detect additional mutations in only two patients: one TET2 mutation (p.S393Lfs*34; VAF 27%) in a patient randomized in the HU arm, and one DNMT3A mutation (p.S837*; VAF 7%) in a patient included in the Ropeg arm. Interestingly, the only patient in whom the percentage of JAK2-mutant colonies decreased during HU therapy was the patient with concomitant JAK2 and TET2mutations.
為了更好地評估兩種藥物對體內JAK2突變細胞的影響，我們對處理開始前和1年後採集的骨髓單核細胞進行了克隆檢驗，以分析克隆結構的變化。正如我們對PV的預期，我們觀察到每個患者都存在EEC。在用(6446)藥華藥新一代長效型干擾素P1101進行治療的三個病患中，JAK2-突變細胞與JAK2野生型聚落的比例均降低，而在接受HU治療的四個病患中僅有一個降低。值得注意的是，HU治療組中％JAK2V617F測量到較差的克隆反應無法用其他突變的存在來解釋。使用目標次世代定序方法，我們僅在兩名病患中檢測到其他突變；HU分組中的一名病患偵測到TET2突變和而(6446)藥華藥新一代長效型干擾素P1101組中則有一名偵測到DNMT3A突變。有趣的是，使用HU治療發現的JAK2突變體聚落百分比下降的唯一病患同時有著JAK2和TET2突變。
Discussion
討論
IFNα is a cytokine with a wide range of biological properties including antitumor activity used for decades to treat several types of cancers like melanoma, renal cancer, and hematological malignancies, including MPNs9. In this study, we assessed the ability of a new form of IFNα to specifically target JAK2-mutant cells. We first showed that Ropeg has an antiproliferative effect on JAK2V617F mutant cell lines similar to that of standard recombinant IFNα. In the UT-7 cell line model we could further show that Ropeg has a twofold greater inhibitory effect against JAK2V617F-mutated cells compared to their wild-type counterpart. When tested in cultures of primary hematopoietic progenitors derived from PV patients, Ropeg showed an important inhibitory effect on the growth of erythroid colonies, when it had no particular impact on the growth of erythroid colonies when tested at therapeutic concentrations against normal JAK2-wild-type progenitors. Altogether, these results suggest that Ropeg preferentially targets progenitors harboring the JAK2V617Fmutation while sparing wild type cells.
IFNα是具有細胞因子被廣泛使用，包括幾十年來用於治療幾種類型癌症如黑素瘤、腎癌和血癌（包括骨髓增生性腫瘤）的抗腫瘤活性。在這項研究中，我們評估了新形式的干擾素可以針對JAK2突變細胞的能力。首先可以看出(6446)藥華藥新一代長效型干擾素P1101對JAK2V617F突變細胞系具有類似於標準重組IFNα的抗增殖作用。在UT-7細胞系模型中，我們可以進一步證明，與野生型相比，(6446)藥華藥新一代長效型干擾素P1101對JAK2V617F突變細胞具有加倍的抑制作用。從源自PV病患的原造血祖細胞的培養物中進行測試時，(6446)藥華藥新一代長效型干擾素P1101對紅血球細胞聚落的生長顯示出重要的抑制作用，當它在針對野生型的正常JAK2治療濃度下測試時, 對紅血球祖細胞聚落的生長沒有特別的影響。這些結果顯示出(6446)藥華藥新一代長效型干擾素P1101優先針對帶有JAK2V617F的突變細胞，同時保留野生型細胞。
In the subset of patients included in France in the PROUD-PV trial, we observed deeper and more prolonged molecular responses (assessed by the reduction of %JAK2V617F in peripheral blood) in patients randomly assigned to Ropeg versus those receiving HU. In chronic myeloid leukemia, achievement of molecular remission has been clearly associated with better clinical outcome and possible treatment free remissions after discontinuation of tyrosine-kinase inhibitor treatment. Such correlation between reduction of the JAK2 mutant allele burden in PV with IFNα and clinically relevant outcomes has not been demonstrated yet. To better understand the biological significance of sustained circulating mutant allele burden reduction, we studied the evolution of clonal architecture of hematopoietic progenitors in PV patients randomly treated with IFNα or HU in the PROUD-PV study. Clonal studies of bone marrow progenitors of these patients showed that after 12 months of treatment with IFNα the proportion of wild type to mutant JAK2 colonies was clearly increased, an effect not seen in patients receiving HU. This is to our knowledge the first evidence suggesting that a sustained decrease in the circulating JAK2V617F allele burden could reflect a diminution of the proportion of malignant progenitors in the bone marrow. In that perspective, such results suggest that achievement of deep molecular response in PV could result in the exhaustion of MPN progenitors and open the way for safe cytoreductive treatment discontinuation as currently proposed in CML patients achieving deep molecular response.
在PROUD-PV試驗中法國納入的病者群中，我們觀察到隨機分配到接受(6446)藥華藥新一代長效型干擾素P1101治療的病患與接受HU治療的患者中更多的分子反應（根據外周血液中%JAK2V617F的減少來評估）。在慢性骨髓性白血病中，達到分子緩解的通常伴隨著更好的臨床結果這和停止TKI治療後可能無治療緩解相關。PV中的JAK2突變等位基因負荷減少與IFNα之間的這種相關性和臨床相關結果尚未得到證實。為了持續更好的理解突變等位基因負荷減少的生物學意義，我們研究了在PROUD-PV研究中隨機用IFNα或HU治療的PV患者中造血祖細胞的克隆結構演變。這些病患的骨髓祖細胞的克隆研究顯示，用IFNα治療12個月後，野生型與突變型JAK2聚落的比例明顯增加，這是接受HU治療的病患中所沒見到的。
據我們了解，第一個證據顯示出JAK2V617F等位基因負荷的持續減少可能反映了骨髓中惡性祖細胞比例的減少。從這個角度來看，這樣的結果表明，在PV中達到深度的分子反應可能導致MPN祖細胞的衰竭，這為目前在CML病患中提出的安全的細胞減滅治療中斷提出一個新的可能方案實現深度分子反應。
Altogether, these preliminary results obtained in a small subset of patients included in the PROUD-PV study must be confirmed in larger numbers, but they suggest that IFNα could be a good candidate for achieving long-term eradication of JAK2-mutant clones and restoring normal hematopoiesis in PV patients.
總之，在PROUD-PV研究中的一小部分病患中獲得的這些初步結果，仍需更大樣本實驗驗證，但他們認為IFNα可能是長期讓PV病患根除JAK2突變體和恢復正常的良好造血功能候選者。
個人積分：30分
文章編號：70448731
在此，與各位大大分享，Ruben A. Mesa, MD, FACP and Robyn M. Scherber, MD, MPH of UT Health San Antonio MD Anderson Cancer Center三段說明MF、PV及ET相關影片，發佈日期：2018年10月4日還滿新的。
https://www.youtube.com/watch?v=1nMyYPy2mNE MF
https://www.youtube.com/watch?v=SkTIK4zBT24 PV
https://www.youtube.com/watch?v=i9GbMohwHm0&feature=youtu.be ET
個人積分：270分
文章編號：70451712
(2018-10-09 08:57:21)
時報-台北電
藥華藥(6446)接獲歐洲藥物管理局(EMA)指定的AGES通知公司委託試驗單位-財團法人農業科技研究院(簡稱農科院，ATRI)已獲歐洲藥物管理局(EMA)認定通過優良製造規範(GMP)認證書。
藥華藥藥品Ropeginterferon alfa-2b(P1101)於2017年2月進行歐盟新藥上市許可申請後，歐洲藥物管理局(EMA)於2017年9月18至22日來台做實地查廠，共查核了藥華藥台中廠、台北PEG生產廠及ATRI生物安全實驗室三處，其中藥華藥台中廠及台北PEG生產廠獲一次性通過，兩廠均符合歐盟GMP標準並於2018年1月皆獲得歐洲藥物管理局(EMA)GMP認證書，另ATRI生物安全實驗室因符合GLP規範，歐洲藥物管理局(EMA)遂要求將其提升為GMP規範。公司遂立即完成以已獲歐洲藥物管理局(EMA)認證之德國生物安全實驗室為備位實驗室，但為落實公司完整地台灣生產製造的理念，藥華藥感謝ATRI生物安全實驗室積極合作，一同針對各GMP品質系統重新檢視並加以改善，農科院於2018年7月23、24日再次接受歐洲藥物管理局(EMA)進行實地查核，今公司亦接獲通知，ATRI生物安全實驗室已獲歐洲藥物管理局(EMA)認證通過優良製造規範(GMP)認證書，認證號碼為INS-482690-0002-001。
個人積分：531分
文章編號：70472973
個人積分：18分
文章編號：70475887
個人積分：531分
文章編號：70477156
個人積分：270分
文章編號：70531332
https://www.msn.com/zh-tw/money/topstories/%E8%97%A5%E8%8F%AF%E8%97%A5-%E8%BE%B2%E7%A7%91%E9%99%A2%E6%94%9C%E6%89%8B%E6%B7%B1%E8%80%95%E5%8F%B0%E7%81%A3%E8%A3%BD%E9%80%A0-%E7%8D%B2%E6%AD%90%E7%9B%9Fema-gmp%E8%AA%8D%E8%AD%89/ar-BBOuOTB
MoneyDJ新聞 2018-10-17 15:34:14 記者 新聞中心 報導
藥華藥(6446)今(17)日指出，1980年代李國鼎開始籌畫台灣的生技產業，成立「財團法人生物技術開發中心」促進台灣生技發展。當時美國的生技產業也如雨後春筍般的篷勃發展，許多旅美台灣人紛紛參與此盛會。當時藥華藥創辦團隊成員也在美國各大生技藥廠積極參與並奠定重要功蹟，如執行長林國鐘博士在Biogen研發出許多重要成果。而隨著藥華藥創辦團隊創立即期望有朝一日能以台灣為基地建立從事新藥創新發明、試驗發展、生產製造，進而行銷世界的全方位藥廠。
公司亦指出，本著創立初衷，藥華藥在台成功自主研發新一代長效型干擾素（Ropeg）。Ropeg為世界最長效、純度最高且副作用最低的干擾素，可用於多種適應症包含肝病與MPN等多種疾病。Ropeg用於治療真性紅血球增生症（PV）臨床試驗數據證明，Ropeg有更好的療效與安全性，除了停止疾病惡化（disease progression free），更能治癒病人。目前PV仍缺乏一線用藥，Ropeg上市後，可提供病患最佳的治療選擇。除PV之外，Ropeg亦擴大適應症，在治療血小板增生症（ET）與B肝即將進入全球三期臨床試驗，期能造福更多病人，也創造Ropeg更大的市場價值。
放眼台灣製造業的優勢與動能，藥華藥也積極佈局並深根台灣，試圖打造台灣製造品牌。藥華藥表示，公司已陸續設立符合國際規範的台中廠及台北PEG生產廠用於Ropeg生產製造，於2017年歐盟查核時一次性通過並獲得歐洲藥物管理局(EMA) GMP認證。而藥華藥的委託試驗單位-財團法人農業科技研究院（簡稱農科院，ATRI）生物安全實驗室因負責Ropeg產品的關鍵性檢測，遂要求其調整符合EMA的GMP規範。
農科院生物安全實驗室原設計係為GLP認證之檢驗單位，提供國內外生技公司及相關單位的檢測服務。在早期研發階段，農科院GLP認證已足夠符合要求。然而因Ropeg產品的關鍵性檢測委由農科院執行，故EMA明確要求其需調整符合GMP規範。為此藥華藥與農科院積極合作，全面性的展開調整計畫，同仁在日常繁忙工作之餘，仍需額外付出許多努力進行整改。
在硬體方面，藥華藥表示，如調整符合GMP的動線規畫、週遭環境更嚴謹管控與空調系統改為中央控制等；在整改過程中，特別感謝農科院，農科院當時已承接國內外許多委託案件，仍需配合時程常於週末或甚至特別停工進行工程施作，實屬不易。在軟體方面，聘請國外專家指導，舉辦10多場訓練課程，並重新檢視品質系統完成近200份文件修改。
由於過去農科院已遵循GLP規範執行委託試驗，早已奠定良好且深厚的基礎，在此轉型成符合GMP規範的過程中，更是全力配合接受國際最高標準品質概念的洗禮，遂能在很短的時間完成調整。於今年7月23日至24日接受EMA實地查核，查無重大缺失。稽核員在總結時表示，ATRI無論是品質系統或實驗室廠房設施的改進令人印象深刻，符合EMA GMP規範，並於10月8日獲GMP認證，成為台灣第一個獲得歐盟認證的GMP實驗室。藥華藥表示，公司也因此完成在台研發生產製造的最後一塊拼圖，待EMA核發Ropeg藥證後，即可在最短時間內於台灣進行符合歐盟規範的生產製造，進而於歐洲上市銷售。
農科院院長陳建斌表示，本次農科院與藥華藥合作，共同建立國際標準的國家級實驗室，攜手往華人世界級藥廠目標邁進，為台灣生技業產學合作開啟雙贏局面的里程碑；農科院也期待Ropeg上市，能造福更多病患。
藥華藥執行長林國鐘表示，藥華藥用於治療真性紅血球增生症(PV)新藥Ropeginterferon alfa-2b(商品名BESREMI)之新藥上市許可申請，其生產製造廠與委託檢驗實驗室皆已全部通過EMA實地查核，目前已順利進入取得藥證的最後階段。如今在歐洲只待取得藥證後即可上市銷售。未來Ropeg將在美國、日本、中國大陸等地進行藥證申請與行銷，完全由藥華藥自主掌控，所有環節都已完整布局。
藥華藥指出，公司掌握Ropeg生產技術，以台灣作為全球生產基地，從實驗室到藥廠均符合歐盟EMA GMP標準，未來全球Ropeg的銷售全由台灣供應；而藥華藥深耕台灣，落實台灣製造，並布局全球，銷售世界的願景，以台灣為出發點，完整經歷了重磅新藥的誕生，這不僅是台灣生技業的榮耀，也落實了公司創業團隊應邀返國成立藥華醫藥公司的初衷。
個人積分：531分
文章編號：70551807
個人積分：531分
文章編號：70595037
個人積分：270分
文章編號：70616800
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