瑞士製藥巨頭諾華（Novartis）近日收獲重磅消息，經曆大起大落的抗癌新藥Farydak（panobinostat，LBH589）最終獲得FDA青睞。FDA已批準Farydak聯合Velcade（bortezomib，硼替佐米）和地塞米鬆（dexamethasone）用於既往接受至少2種治療方案（包括Velcade和一種免疫調節（IMiD）藥物）治療失敗的多發性骨髓瘤（myltiple myeloma，MM）患者群體。FDA批準Farydak時附帶有一項風險評估及減災策略（REMS），用於宣傳和教育醫療衛生專業人員了解可能與Farydak治療相關的風險。此次批準，也標誌著Faryda成為用於治療多發性骨髓瘤（MM）的首個組蛋白脫乙酰酶（HDAC）抑製劑，該藥的表觀遺傳學活性，可能有助於恢複多發性骨髓瘤細胞的功能。目前，Farydak在全球其他地區的監管審查正在進行中。
Farydak（panobinostat）是一種新型、廣譜組蛋白脫乙酰酶（HDAC）抑製劑，具有一種新的作用機製，通過阻斷組蛋白脫乙酰酶（HDAC）發揮作用，該藥能夠對癌細胞施以嚴重的應激直至其死亡，而健康細胞則不受影響。
Farydak通過FDA的加速審批程序批準。該藥的獲批是基於一項全球III期臨床研究（PANORAMA-1）中一項預定義亞組分析（n=193）的療效和安全性數據。數據顯示，在既往接受硼替佐米和一種免疫調節（IMiD）藥物治療的多發性骨髓瘤（MM）群體中，聯合標準治療方案（硼替佐米+地塞米鬆）治療時，與安慰劑（PFS=5.8個月，n=99）相比，Farydak延長了中位無進展生存期（PFS=10.6個月，n=94）。此外，Farydak治療組有59%的患者在治療後腫瘤縮小或消失，而安慰劑組數據為41%。
不過，值得一提的是，Farydak的監管之路可謂波折。在2014年初，諾華提交panobinostat監管申請時，鑒於其良好的療效，FDA表示將采用快速審批通道審核該藥，使審查周期由通常的12個月縮短至8個月。然而，去年11月底，FDA腫瘤藥物顧問委員會（ODAC）以5:2的投票結果建議拒絕批準panobinostat。該委員會表示，panobinostat針對經治多發性骨髓瘤（MM）患者群體確實有效，但該藥的副作用過於嚴重，要求FDA慎重考慮。這一建議也迫使FDA將原定於12月份的最後期限推遲至今年3月。之後，諾華提交了額外的分析數據，同時修改panobinostat適應症，用於既往接受至少2種標準療法（包括硼替佐米和免疫調節劑）的多發性骨髓瘤（MM）群體。FDA經過仔細審查後，最終批準panobinostat。需要指出的是，Farydak帶有黑框警告，提示該藥嚴重的腹瀉和嚴重及致命的心髒事件、心律失常及心電圖（ECG）變化。
多發性骨髓瘤（MM）是一種無法治愈且複發率很高的血液癌症。在過去的11年中，武田的抗癌藥Velcade（硼替佐米）作為唯一一種已被證明能夠延緩新診和複發性多發性骨髓瘤（MM）總生存期（OS）的藥物，在多發性骨髓瘤（MM）的臨床治療中發揮了重要作用。但該領域仍存在著遠未滿足的巨大醫療需求。 英文原文：Novartis receives FDA approval of Farydak , the first HDAC inhibitor forpatientswithmultiplemyeloma
-Farydak, an HDAC inhibitor with epigenetic activity, approved in combination for patients who received at least two prior regimens including bortezomib and IMiD[1]
-Farydak prolonged median PFS benefit when used with bortezomib and dexamethasone combination versus combination alone (from 6 to 11 months)[1]
-Multiple myeloma is an incurable blood cancer and there is an urgent need for new treatments[2]
-Farydak is approved under FDA's accelerated approval program; regulatory applications are underway in the EU, Japan and worldwide
Basel, February 23, 2015 - Novartis announced today that the US Food and Drug Administration (FDA) has approved Farydak (panobinostat, previously known as LBH589) capsules in combination with bortezomib* and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory (IMiD) agent[1].
"Farydak represents an exciting agent with a new mechanism of action that is part of a promising class of drugs in this setting," said study investigator Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. "Importantly, Farydak has been shown to improve progression-free survival in relapsed multiple myeloma patients who have received at least two prior regimens, including bortezomib and an IMiD, which is an area of particular unmet medical need."
Farydak has been shown to extend the progression-free survival (PFS) benefit of the standard-of-care therapy in this patient population[1]. Farydak is approved under accelerated approval based on PFS[1]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The FDA's accelerated approval program gives patients access to treatments for serious or life-threatening illnesses that provide meaningful therapeutic benefit over existing treatments. The FDA has approved a risk evaluation and mitigation strategy (REMS) for Farydak. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Farydak treatment.
This FDA approval is based on efficacy and safety data in a pre-specified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an IMiD during the Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial, called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA)[1]. The trial found that the median PFS benefit increased in Farydak patients who had received prior treatment with both bortezomib and an IMiD (10.6 months; n=94), as compared to the placebo arm (5.8 months; n=99) (hazard ratio=0.52 [95% confidence interval (CI): 0.36, 0.76])[1].
The most common adverse reactions (incidence >= 20%) in clinical studies are diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia and vomiting[1]. The most common non-hematologic laboratory abnormalities (incidence >= 40%) are hypophosphatemia, hypokalemia, hyponatremia and increased creatinine[1]. The most common hematologic laboratory abnormalities (incidence >= 60%) are thrombocytopenia, lymphopenia, leukopenia, neutropenia and anemia[1]. Farydak can cause fatal and serious toxicities including severe diarrhea and cardiac toxicities. Severe diarrhea occurred in 25% of Farydak-treated patients. Severe and fatal cardiac ischemic events, including severe arrhythmias and ECG changes have occurred in patients receiving Farydak. Serious adverse events (SAEs) occurred in 60% of patients treated with Farydak, bortezomib and dexamethasone compared to 42% of patients in the control arm. The most frequent (>= 5%) treatment-emergent SAEs reported for patients treated with Farydak were pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%) and sepsis (6%). Additional serious adverse reactions included hemorrhage, myelosuppression, infections, hepatotoxicity and embryo-fetal toxicity[1].
"Novartis is committed to developing innovative first-in-class therapies for patients who need treatment options," said Bruno Strigini, President, Novartis Oncology. "Farydak represents a new drug class in multiple myeloma, providing these patients with an important treatment approach for this difficult-to-treat cancer."
Farydak is the first histone deacetylase (HDAC) inhibitor available to patients with multiple myeloma[3]. As an HDAC inhibitor, its epigenetic activity may help to restore cell function in multiple myeloma[4].
Additional regulatory submissions for Farydak are being reviewed by health authorities worldwide.
About multiple myeloma
Epigenetics is the cell programming that governs gene expression and cell development[3]. In multiple myeloma, the normal epigenetic process is disrupted (also called epigenetic dysregulation) resulting in the growth of cancerous plasma cells, potential resistance to current treatment, and ultimately disease progression[5],[6].
Multiple myeloma impacts approximately 1 to 5 in every 100,000 people globally[7]. Multiple myeloma is a cancer of the plasma cells, a kind of white blood cell present in bone marrow-the soft, blood-producing tissue that fills the center of most bones. The cancer is caused by the production and growth of abnormal cells within the plasma, which multiply and build up in the bone marrow, pushing out healthy cells and preventing them from functioning normally[8]. Multiple myeloma is an incurable disease with a high rate of relapse (when the cancer returns) and resistance (when the therapy stops working), despite currently available treatments[2]. It typically occurs in individuals 60 years of age or older, with few cases in individuals younger than 40[9].
