抗-NGF药物治疗髋骨关节炎有效

《关节炎与风湿病》2013年4月1日在线发表的一项Ⅲ期研究结果显示，与安慰剂相比，抗神经生长因子(抗-NGF)tanezumab治疗16周可显著改善髋关节骨关节炎(OA)患者的疼痛、身体功能以及骨关节炎患者疗效总体评分[Arthritis Rheum. 2013 April 1(doi:10.1002/art.37950)]。

Mark Brown博士及其同事报告称，这项纳入621例髋关节OA患者的随机、双盲、安慰剂对照研究还表明，抗-NGF治疗耐受性良好。他们认为，tanezumab“最终或可成为对非阿片类药物不能耐受或无应答的OA患者的有效治疗药物”。


Roy D Altman博士
 
作者指出，抗-NGF是直接对抗神经生长因子的单抗，通过伤害感受器敏化调节疼痛过程和敏感性。NGF水平增加与损伤、炎症和慢性疼痛相关。

Tanezumab是目前正在被研究用于OA或其他慢性疼痛疾病治疗的多个抗-NGF药物之一，也是开发最全面的药物。2010年，美国食品药品管理局(FDA)在收到tanezumab和另一抗-NGF治疗患者出现骨坏死和缺血性坏死病例报告后，暂时中止了抗-NGF的临床试验。这些报告病例中包括非受累关节和无OA史患者。Brown博士指出，部分病例报告出现在髋关节和膝关节OA的Ⅲ期试验完成之后。

2012年3月，FDA外部专家组认可抗-NGF在研究中所显示出的作为镇痛剂的希望，并一致推荐在密切监测关节相关不良反应和充分知情同意的前提下继续开展临床研究。作者称，anezumab临床试验已于2012年8月解禁(FDA发言人表示，鉴于该药物的新药申请正在审评中，FDA不能就此问题发表意见)。

加州大学洛杉矶分校的Roy Altman博士指出，抗-NGF的开发是对目前疼痛缺乏充分控制治疗的有益补充。在他看来，“对于许多疼痛控制不佳的患者来说，这些已知风险或许是可以接受的”。Altman博士没有参与该项研究。

这项研究比较了621例髋骨关节炎患者(平均年龄62~63岁)在基线、8周和16周接受3个不同剂量anezumab(2.5 mg、5 mg和10 mg)与安慰剂的治疗结果。受试者为不能或不愿服用非阿片类镇痛药物、服用这类药物后疼痛没有得到充分缓解和(或)髋关节手术或其他有创治疗候选患者。基线西安大略和麦克马斯特大学OA指数(WOMAC)疼痛和身体状况次级量表评分≥5，患者OA综合评估(PGA OA)为“一般”、“差”或“很差”。近半数患者为有创治疗候选者。

结果显示，与安慰剂组相比， 3个剂量治疗组患者16周WOMAC疼痛和身体功能次级量表评分以及PGA OA 等3个主要疗效终点指标均显示“较大的、有临床意义和统计学显著差异的改善。”2个较大剂量组与安慰剂组差异更为显著。

各组平均基线WOMAC疼痛次级量表评分范围为7.2~7.3，安慰剂组评分改善平均为-1.62，而治疗组随剂量增加评分改善更为显著：2.5 mg、5 mg和10 mg组分别为–2.90、–3.31和–3.37。WOMAC身体功能次级量表评分改善结果也是如此：安慰剂组为-1.39，而2.5 mg、5 mg和10 mg组分别为–2.,57、–2.88和–3.00。

此外，治疗组患者16周达到WOMAC疼痛次级量表评分最少下降30%、50%、70%和90%的比例也显著高于安慰剂组。约2/3治疗组患者完成24周研究(考虑到tanezumab具有较长半衰期，以该时间点作为研究结束点)，而安慰剂组为38%。

总体上，与安慰剂组相比，更多治疗组患者报告不良反应(44% vs. 55~58%)。治疗组严重不良事件发生率为3%~4.5%。

治疗组和安慰剂组全髋关节置换率相似，共有8例患者行全髋关节置换术(安慰剂组3例，2.5mg和5mg组各2例，10 mg组1例)，其中治疗组2例患者的骨坏死被认为与tanezumab有关。但作者指出，外部评审委员会并未确认这2例患者为骨坏死。他们认为8例患者关节置换的原因为炎性关节病、晚期OA、快速进展性OA或OA恶化。

该研究由anezumab制造商辉瑞公司资助，Brown博士及其他5位作者中的3位为该公司全职员工。Altman博士报告曾担任雅培公司顾问，该公司目前已停止抗-NGF药物项目研究。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

Treatment with the anti–nerve growth factor tanezumab was associated with significant improvements over placebo in pain, physical function, and Patient’s Global Assessment of osteoarthritis results, after 16 weeks in a phase III study of patients with osteoarthritis of the hip.

In the randomized, double-blind, placebo-controlled study of 621 patients with painful hip OA, treatment with the anti–nerve growth factor (anti-NGF) was also well tolerated, according to Dr. Mark Brown and his associates. The study was funded by Pfizer, the manufacturer of tanezumab, and Dr. Brown and three of the five other authors are full-time employees of the company.

Tanezumab "may eventually be useful in OA patients who are intolerant of or nonresponsive to nonopioid treatment," the authors concluded. The study was published online (Arthritis Rheum. 2013 April 1 [doi:10.1002/art.37950]).

Anti-NGFs are monoclonal antibodies directed against nerve growth factor, which "modulates pain processing and sensitivity via nociceptor sensitization," and increased NGF levels are associated with injury, inflammation, and chronic pain, according to the authors.

Tanezumab is one of several anti-NGFs being studied for OA and other chronic pain conditions and is the furthest along in development. In 2010, the Food and Drug Administration placed a partial hold on anti-NGF clinical trials after cases of osteonecrosis and avascular necrosis were reported in patients treated with tanezumab and in those treated with another anti-NGF, including cases in nonindex joints and people with no history of OA. Dr. Brown and his coauthors wrote that some of these cases were reported in phase III hip and knee OA studies, after their study was completed.

In March 2012, an FDA advisory panel of outside experts agreed that the anti-NGFs showed promise as analgesics in studies and unanimously recommended that clinical development should continue, with close monitoring of joint-related adverse effects and adequate informed consent. The authors noted that the clinical hold on tanezumab trials was lifted in August 2012. (The FDA could not provide a comment on this issue because it relates to a drug application under review, an agency spokesperson said.)

The development of the anti-NGFs "is an exciting potential addition to our present inadequate control of pain," and research is resuming with a careful review of the risk of bone and joint changes, Dr. Roy Altman said in an interview. In his view, "the known risks would be acceptable to many people with poorly controlled pain." Dr. Altman, professor of medicine, rheumatology, at the University of California, Los Angeles, was not an investigator in the study.

The Pfizer study compared three tanezumab doses (2.5 mg, 5 mg, and 10 mg) administered intravenously at baseline, 8 weeks, and 16 weeks, with placebo, in 621 people with OA of the hip (mean age, 62-63 years) who could not or did not want to take nonopiate pain medications, did not get enough relief from these medications, and/or were candidates for hip surgery or other invasive treatments. Their baseline Western Ontario and McMaster Universities OA Index (WOMAC) pain and physical function subscale scores were at least 5 at baseline and Patient’s Global Assessment of OA (PGA OA) was "fair," "poor," or "very poor." Almost half were candidates for invasive treatment.

At 16 weeks, compared with placebo, treatment with tanezumab, at all three doses, "produced greater, clinically meaningful, and statistically significant improvements" in each of the three primary efficacy endpoints: changes in the WOMAC pain subscale, the WOMAC physical function subscale, and the PGA OA. Differences between placebo and treatment were greatest for the two higher doses.

On the WOMAC pain subscale, mean baseline scores of all groups ranged from 7.2 to 7.3. Placebo patients’ scores improved by a mean of -1.62 points, but in comparison, improvements were significantly better on progressively higher doses of tanezumab: –2.90 for 2.5 mg, –3.31 for 5 mg, and –3.37 for 10 mg. Similar results occurred on the WOMAC physical function subscale scores, with mean improvements of –1.39 for placebo, –2.57 for 2.5 mg, –2.88 mg for 5 mg, and –3.00 mg for 10 mg.

Other findings included a significantly greater proportion of patients on the treatment who achieved at least 30%, 50%, 70%, and 90% reductions in the WOMAC pain subscale, compared with placebo at 16 weeks. About two-thirds of the patients on treatment remained in the study through week 24 (considered the end of the study because of tanezumab’s long half-life), compared with 38% of those on placebo.

Overall, more patients on tanezumab reported adverse effects (55%-58%, vs. 44% on placebo). Serious adverse events occurred in 3%-4.5% of patients in the treatment groups.

The rate of total hip replacements was similar in the treatment and placebo groups, with a total of eight patients who had a total hip replacement (three in the placebo group, two each in the 2.5-mg and 5-mg groups, and one in the 10-mg group). These included two patients on tanezumab who had osteonecrosis thought to be related to tanezumab. The authors pointed out that an outside adjudication committee, however, did not confirm osteonecrosis in either patient, and concluded that the reasons for joint replacements in the eight patients were inflammatory arthropathy, end-stage OA, rapidly progressive OA, or worsening OA.

Dr. Altman said that he has consulted with Abbott and its now discontinued program on anti-NGF drugs.