Faulty manufacturing trips up Nektar's BMS-partnered cancer drug

因药物批次不合格,Nektar公司NKTR-214与百时美施贵宝Opdivo癌症试验受挫

2019-08-13 17:09:00 FiercePharma

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Could a manufacturing mix-up be as detrimental as the fact that a drug simply doesn’t work? Nektar learned the answer the hard way with its Bristol-Myers Squibb-partnered experimental cancer therapy. On Thursday, Nektar CEO Howard Robin went to great lengths to explain why response rates dropped in the second stage of a clinical trial testing NKTR-214 (bempegaldesleukin) in tandem with Bristol's Opdivo. But in a nutshell, some patients received substandard batches of the Nektar drug, he told analysts during a conference call. And unsurprisingly, those bad batches didn't work as well. If you think that would alleviate investors’ concerns, think again. The news wiped out over a third of the biotech’s stock price on Nasdaq in Friday pre-market trading—more than a billion dollars in market value right down the drain. According to Robin, Nektar ran an analysis of all 22 lots of bempeg it had produced and found that two lots—lots 2 and 5—were out of specification, though they had passed release controls under old assays. The team noted correlations between patients who started treatment with the two problematic lots and a lower response rate during the PIVOT-02 trial as compared with the other two lots used in the study. Specifically, newly diagnosed melanoma patients who started with lots 2 and 5 saw 36% of their tumors respond to the treatment at best, with a complete response rate of 27%. The others posted response rates at 75% and 44%, respectively, Nektar’s R&D chief Stephen Doberstein said during the call. In the trial's first-line urothelial cancer cohort and first-line renal cell carcinoma cohort, similar differences were observed. Management attributed the mess-up to a single suboptimal batch of intermediate that was used to produce only lots 2 and 5. The company found that bad batch using new quality control assays, Robin said. And Robin promised that Nektar now has the problem under control. “As a result of this discovery, we have developed a comprehensive control strategy to limit variances in raw materials, intermediates and the final product in our manufacturing, and this is being validated for commercial-scale manufacturing,” he said, adding that the company has also shaken up its CMC leadership. But analysts remain skeptical—and apparently, so do investors. “[I]t’s hard to tell if there’s a legitimate issue with the batches or another creative way to explain away our concerns that bempeg has not been dosed to have meaningful clinical activity,” Evercore ISI analyst Josh Schimmer wrote in a Thursday note to clients. As Doberstein explained, most patients in PIVOT-02 rotated through different lots during the course of treatment. But Nektar only used starting lots for its analysis. “While this might impact early response rates, it’s less clear why the initial treatment would be predictive of longer-term efficacy,” Schimmer said. In a double whammy that further dampened investors’ confidence in bempeg, the company withdrew its already-accepted abstract for first-line non-small cell lung cancer in the upcoming European Society for Medical Oncology meeting in September due to what execs called “immaturity of the data.” That cohort is experiencing slower-than-expected enrollment, and Nektar wants to have more patients on unaffected lots, Doberstein said. Nektar has been targeting the all-important NSCLC data at ESMO since the J.P.Morgan Healthcare conference in January, “discussing this for some time as a key catalyst,” Jefferies analysts said in a Friday memo. They “find it puzzling that the company decided not to present the data at this time,” given that it has presented numerous immature datasets before. Industry watchers have been on the fence about bempeg for some time. In an analysis in March, shortly after Nektar unveiled the bladder cancer data, Cantor Fitzgerald’s Louise Chen ruled that the drug “is not going to be a comeback kid.” Physicians worried that the available data looked “cherry-picked” to appear somewhat positive and that more critical numbers, such as progression-free survival, were long overdue. Moreover, a slowdown in new clinical trial sites “could point to loss of confidence among investigators,” Chen cited one physician as saying. Perhaps the only silver lining that came out of Thursday’s call was that the FDA already knew about the substandard lots, but they didn’t stop the agency from handing the bempeg-Opdivo combo a breakthrough therapy designation in untreated advanced melanoma. BMS, according to Robin, remains “highly committed” to the bempeg development program. For now, the pair plans to focus on five or six key registrational trials, he said.
生产混合是否会像药品根本不起作用那样有害?Nektar 通过与百时美施贵宝( Bristol-MyersSquibb )合作的实验性癌症治疗,很难找到答案。 周四, Nektar 首席执行官 HowardRobin 不遗余力地解释了为什么在临床试验的第二阶段, NKTR-214( bempgaldesleukin )与 Bristol 的 Opdivo 同时降低了反应率。 但他在一次电话会议上告诉分析师,简言之,一些患者接受了不合格的 Nektar 药物批次。不出意外的是,这些坏的批次也不起作用。 如果你认为这会缓解投资者的担忧,再想想。这一消息抹去了生物技术公司在纳斯达克股票价格的三分之一以上在周五的盘前交易-超过10亿美元的市场价值直接流失。 根据 Robin 的说法, Nektar 分析了它所产生的22批 bempeg ,发现两批(第2批和第5批)都不符合规格,尽管它们在旧的检测下通过了释放控制。研究小组注意到,在 PIVOT-02试验中开始使用两个问题批次治疗的患者与其他两个批次相比,反应速度更低。 特别地,新诊断的黑色素瘤患者在第2和第5批患者中发现36%的肿瘤对治疗反应最好,完全反应速度为27%。Nektar 研发总监 StephenDoberstein 在电话会议上表示,其他公司的回应率分别为75%和44%。 在试验的一线尿路上皮癌队列和一线肾细胞癌队列中,观察到相似的差异。 管理层将这种混乱归因于一批仅用于生产2和5批产品的次优中间体。罗宾说,该公司发现使用新的质量控制检测的不良批次。 罗宾还承诺,内克塔现在已经控制住了这个问题。 他表示:“由于这一发现,我们制定了一项全面的控制战略,以限制原材料、中间体和最终产品在我们制造业的差异,这一点正得到商业规模制造业的验证。”他补充称,该公司还改变了 CMC 的领导地位。 但分析师仍持怀疑态度——显然,投资者也持怀疑态度。 Evercore ISI 分析师乔什•希默( Josh Schimmer )在周四发给客户的一份报告中写道:“(我)很难判断这些批次是否存在合理的问题,也不能用另一种创造性的方式来解释我们的担忧,即 bempeg 没有被用于有意义的临床活动。” 正如 Doberstein 所解释的,大多数 PIVOT-02患者在治疗过程中通过不同的方式进行了大量的旋转。但是, Nektar 只用开始批量分析。Schimmer 说:“虽然这可能影响早期反应率,但不太清楚最初的治疗为何能预测长期疗效。” 在即将于9月召开的欧洲医学肿瘤学会( European Society for Medical Oncology )会议上,该公司撤回了已经被接受的一线非小细胞肺癌摘要,这一双重打击进一步削弱了投资者对 bempeg 的信心。 Doberstein 说,这一人群的登记速度低于预期, Nektar 希望有更多的患者不受影响。 杰富瑞( Jefferies )分析师在上周五的一份备忘录中表示,自今年1月摩根大通( J.P . Morgan Healthcare )召开会议以来, Nektar 一直将 ESMO 所有重要的非小细胞非小细胞肺癌(NSCLC)数据作为目标,“在一段时间内讨论这一问题,将其作为关键的催化剂。”他们“感到困惑的是,该公司现在决定不提交数据”,因为它以前曾提供过许多不成熟的数据集。 行业观察人士已经在围篱上等待了一段时间。今年3月,在 Nektar 公布膀胱癌数据后不久, Cantor Fitzgerald 的 Louise Chen 在一份分析报告中裁定,这种药物“不会是一个复出的孩子”。 医生们担心现有的数据看起来“樱桃精选”看起来似乎有些积极,更关键的数据,如无进展生存,早就过时了。此外,新临床试验网站的放缓“可能意味着调查人员失去信心,”陈晓援引一位医生的话说。 也许周四的电话中唯一的一条“银线”是 FDA 已经知道了不合格的地段,但他们并没有阻止 FDA 在未经治疗的晚期黑色素瘤中提供一种突破性的治疗方案。 罗宾表示,百时美施贵宝(BMS)仍“高度致力于” bempeg 开发计划。他说,目前,两人计划集中在五到六个关键的注册审判。

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