2015年9月6日,诺华旗下抗癌药Farydak(panobinostat，帕比司他)通过欧盟批准，成为首个获得欧盟批准用于治疗多发性骨髓瘤的HDAC抑制剂，须与硼替佐米、地塞米松联合使用，适用于曾接受过硼替佐米和一种免疫调节剂治疗但复发的多发性骨髓瘤患者。
多发性骨髓瘤是一种目前尚无法治愈的B细胞恶性肿瘤疾病。以白细胞入侵骨髓为特征，在欧洲大约有8.4万人受此疾病困扰。
Panobinostat通过抑制组蛋白去乙酰化酶(HDACs)的活性而发挥作用。这一过程可能延缓了多发性骨髓瘤患者体内浆细胞的过度增殖，或导致这些危险细胞死亡。
诺华坚信，此次Farydak在欧盟的获批，是具有表观遗传活性的HDAC抑制剂首次登陆欧洲市场，为进展型多发性骨髓瘤患者治疗提供了更多用药选择。
“目前，多发性骨髓瘤患者临床上易出现复发或者治疗药物耐受等问题，”来自法国南特大学医疗中心多发性骨髓瘤专家Philippe Moreau如是说，“Farydak则从全新抗癌机制出发，提高患者对标准治疗药物的敏感性及药物有效性。”
诺华一直在寻求Farydak在多发性骨髓瘤适应症上获得拓展。最初诺华向FDA提交Farydak申请时，因其良好疗效而获得了FDA授予的快速通道资格，审查周期大为缩短。而后期临床结果显示Farydak具有较高心血管风险，一度被FDA肿瘤药物顾问委员会（ODAC）拒绝批准。随后，诺华通过提交额外分析数据，并修改了Farydak的适应症，FDA审慎考虑后在保留黑框警告前提下方同意其上市。
在Farydak治疗多发性骨髓瘤临床试验中，联合标准治疗组（Farydak+硼替佐米+地塞米松）的中位无进展生存期（PFS）延长至10.6个月，明显优于对照组（硼替佐米+地塞米松，PFS=5.8）。此外，联合标准治疗组中59%患者在治疗后肿瘤缩小或消失，而对照组数据为41%。
当前，多发性骨髓瘤市场新型药物层出不穷，不同治疗靶点衍生出众多候选药物，如武田制药口服蛋白酶抑制剂ixazomib，业界曾预测其前景可能超越此前获得巨大市场成功的Velcade（万珂）；百时美施贵宝的实验性单抗药物elotuzumab，通过直接靶向骨髓瘤细胞、增加NK细胞杀伤骨髓瘤细胞的能力，曾获得FDA授予的突破性疗法认定；Cleave Biosciences公司p97抑制剂CB－5083，最近刚获得FDA授予的孤儿药资格，目前仍处于I期临床阶段。
FARYDAK Rx
Pharmacological Class:
Histone deacetylase (HDAC) inhibitor.

Active Ingredient(s):
Panobinostat 10mg, 15mg, 20mg; capsules.

Company
Novartis Pharmaceuticals Corp
Indication(s):
Multiple myeloma, in patients who have received at least two prior regimens (including bortezomib and an immunomodulatory agent), in combination with bortezomib and dexamethasone.

Pharmacology:
Panobinostat inhibits the enzymatic activity of HDACs at nanomolar concentrations which results in increased acetylation of histone proteins, leading to transcriptional activation. Accumulation of acetylated histones and other proteins induces cell cycle arrest and/or apoptosis of some transformed cells.

Clinical Trials:
The efficacy and safety of Farydak with bortezomib and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in 768 patients with relapsed multiple myeloma who had received 1–3 prior lines of therapy. Patients were randomized to bortezomib and dexamethasone with Farydak or placebo. The primary endpoint was progression-free survival (PFS). A prespecified subgroup analysis (n=193) showed the benefit:risk was greater in this heavily pretreated population than the overall trial population. The median PFS was 10.6 months in the Farydak arm vs. 5.8 months in the placebo arm (HR 0.52; [95% CI: 0.36, 0.76]).

For more clinical trial data, see full labeling.

Legal Classification:
Rx

Adults:
Swallow whole with water. Take at same time on scheduled days. Initially 20mg once every other day for 3 doses/wk in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider 8 more cycles for patients with clinical benefit if no severe or significant toxicity; max 16 cycles (48 wks). Give with bortezomib inj and oral dexamethasone per scheduled day. Hepatic impairment: mild: initially 15mg; moderate: initially 10mg; severe: avoid. Concomitant strong CYP3A inhibitors: initially 10mg. Dose adjustments and modifications for toxicity: see full labeling.

Children:
Not established.

Warnings/Precautions:
Risk of severe diarrhea and cardiac toxicities. Monitor hydration and electrolytes at baseline, weekly during therapy, or more as indicated. Initiate antidiarrheals at onset of diarrhea; interrupt dose if 4–6 stools/day. Do not initiate if history of recent MI or unstable angina, QTcF >450msec, significant baseline ST-segment or T-wave abnormalities, active infections. Perform ECG prior to initiation and repeat during treatment as indicated. Correct electrolyte abnormalities prior to initiation and monitor; interrupt if QTcF ≥480msec; discontinue if QT prolongation does not resolve. Serious hemorrhage. Obtain CBC prior to initiation; monitor weekly during therapy or more as indicated. Monitor for infections; treat and consider interruption or discontinuation if diagnosed. Monitor liver function prior to and during treatment; consider dose adjustments if abnormal tests observed. ESRD or dialysis: not studied. Elderly: monitor for toxicity more frequently (esp. GI, myelosuppression, cardiac). Pregnancy: avoid. Obtain pregnancy test prior to and during treatment. Use effective contraception during and for ≥1 month after last dose; males: use condoms during and for ≥3 months after last dose. Nursing mothers: not recommended.

Interaction(s)
Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, others); see Adults. Avoid star fruit, pomegranate or grapefruit juice. Avoid concomitant strong CYP3A inducers. Avoid concomitant sensitive CYP2D6 substrates (eg, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine) or substrates with narrow therapeutic index (eg, thioridazine, pimozide); if unavoidable, monitor frequently. Concomitant antiarrhythmics or QT prolonging drugs: not recommended. Antiemetics that prolong QT interval (eg, dolasetron, ondansetron, tropisetron): monitor ECG frequently.

Adverse Reaction(s)
Diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, vomiting, electrolyte imbalance, increased creatinine, thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia.

How Supplied:
Blister packs—6

LAST UPDATED:
6/12/2015