生物类似药将使生物制剂成为常规用药

风湿病领域的生物类似药时代已然到来，专家们预测，生物类似药竞争将使目前昂贵的生物制剂价格降低，从而得到更广泛的应用。

2013年下半年进入欧洲市场的一种英夫利昔生物类似药是首个此类药物。2014年初，该药已产生了巨大影响，例如使挪威的英夫利昔价格降低了1/3。挪威可能是迄今受到生物类似药影响最大的国家，原因是该国每年都会对市场上的竞争药物实施竞价，然后强制要求临床医生在启动新治疗时使用价格最低的药物。

美国可能不久就会出现类似的情景。Celltrion和Hospira联合生产和销售英夫利昔生物类似药，商品名为Remsima和Inflectra（在东欧部分国家及其他地区），2014年8月，这两家公司宣布已向美国食品药品管理局（FDA）提交了上市申请。在新闻通告中，Celltrion官员预计FDA有望在1年内批准这项申请。如果事实果真如此，英夫利昔生物类似药Remsima将成为美国市场上的首个生物类似药。（今年7月，诺华的子公司山德士宣布，已向FDA提交了Zarzio上市申请，该药是粒细胞集落刺激因子非格司亭的生物类似药，目前市场上仅有Neupogen这一种版本的非格司亭。Zarzio似乎是目前唯一一种可与Remsima竞争美国头名的生物类似药）

至少还有另外两种生物类似药（第3种英夫利昔版本和一种依那西普）可能将接踵而至，不过风湿病学家们在6月举行的欧洲风湿病大会（ECR）上提醒，还需要对这两种生物类似药开展更多研究。

更低的价格会带来更广泛的应用

接下来的挑战是向临床医生们证明，生物制剂的类似药是安全有效的，患者可以从品牌药改为生物类似药以降低治疗费用。与此同时，支付方和患者均迫切需要生物类似药以降低生物制剂治疗的高昂费用。

“价格的降低将改变生物制剂的使用方式。目前，美国类风湿性关节炎（RA）患者大约有一半接受生物制剂治疗。”斯坦福大学的风湿病学家Vibeke Strand博士指出，实际治疗比例远低于应该接受生物制剂治疗的患者比例。她预测生物类似药将会产生非常大的影响。

Vibeke Strand博士

奥斯陆大学的风湿病学家Tore K. Kvien博士指出：“临床医生正受到来自药企、医院和监管机构的巨大压力，需要尽可能避免使用价格昂贵的药物。如果生物制剂的价格下降，启动生物制剂治疗就会容易得多。”

Tore K. Kvien博士

纽约大学的风湿病学家Bruce N. Cronstein博士表示，更强的支付能力和更高的可及性是驱动生物类似药前行的唯一因素。“费用是使用生物类似药的唯一原因。”除了价格之外，从定义来看，生物类似药与相应的品牌生物制剂之间没有任何有意义的差异。

Cronstein博士指出：“生物类似药将会越来越便宜，但不会像他汀品牌药与仿制药的差异那么大。价格不会降低90%，实际的降幅可能会是30%~40%，不过这样的降幅已经很可观了。这些生物制剂均非常昂贵。但是生物类似药将不会像仿制小分子药物那样带来费用的大幅下降。”

Cronstein博士指出，很难预测价格变化的时间、价格下降的幅度，或者竞争将会如何影响品牌药替代品的定价。Kvien博士在接受采访时介绍了挪威的经验。多年来，挪威一直采用每年与药企协商药品价格的方式。挪威政府会每年邀请竞争关系的药企竞标。Celltrion赢得了竞标，使Remsima成为了2014年挪威强制使用的英夫利昔版本，用于全部6种获得欧洲药品管理局（EMA）批准的英夫利昔适应证：类风湿性关节炎、强直性脊柱炎、银屑病性关节炎、银屑病、克罗恩病和溃疡性结肠炎。

Kvien博士指出：“同事们告诉我，1/3的价格降幅（与2014年类克的价格相比）大大超出了他们的预期。”现在1例类风湿性关节炎患者接受Remsima治疗1年的平均费用约为6,000欧元，而类克治疗1年的费用约为9,000欧元。

Strand博士表示，经济压力在生物类似药获准上市的过程中发挥着重要作用。例如，EMA受到了来自东欧国家的压力，生物制剂由于价格昂贵而在这些国家使用率较低。在美国，FDA同时承受着来自支付方和患者的压力，原因是生物制剂的共同付费额过高。但尽管如此，Strand博士等专家仍然认为，EMA和FDA已经对生物类似药设定了合理的审批标准。

“如果EMA判定某种药物是生物类似药，我就一定认为它就是。可能有微妙的差异，但不是大问题。”某些情况下，品牌生物制剂自身就已与最初时有了实质性差异，就像恩利和美罗华那样。“FDA不能接受哪怕是一个氨基酸序列的微小改变，而且要求开展2项免疫原性研究。”

对安全性的担忧

但是生物类似药可能是个特例，即使是药监部门批准上市也可能无法使部分临床医生完全信服。

Strand博士表示：“目前还是由相当多的人患有疑虑。我认为只要有更多数据显示生物类似药是安全的，怀疑就会逐渐减少。最大的担忧似乎是，假如FDA判定某种药物不仅是生物类似药，还是等效药物，药剂师就可能在医生不知情的情况下改用该药。我认为之所以存在担忧，是因为人们仍不确定生物类似药意味着什么。还需要更多数据来说服一部分人。”

“我认为，证明这些药物以相似方式发挥作用的数据将会说服临床医生。大家担心的是，这些药物在临床试验中的表现似乎良好，但在耐药性和致敏性等方面可能存在微妙差异。”Cronstein博士表示：“我认为临床医生将接受并使用生物类似药，但是会担心临床试验并未显示出其安全隐患。FDA正在尝试找到办法，确定从一种药物改为另一种会不会导致不良反应。”

改用生物类似药治疗的安全性非常重要，以至于挪威政府愿意为此资助一项花费250万欧元的临床试验。这项纳入500例患者的研究预计在2014年秋季启动，正在接受稳定类克治疗的患者将被随机分组，继续使用类克或转为使用Remsima。这项NOR-SWITCH试验将纳入具备EMA批准的6种Remsima适应证中任意一种的患者。

预计该研究将于2016年得出结果，在此之前，挪威不允许对正在接受类克治疗的患者改用Remsima，虽然Remsima是首次启用英夫利昔治疗的患者的选择。尽管如此，NOR-SWITCH的主要研究者Kvien博士指出，一些挪威部门已经在部分患者中进行了药物转换。“他们说现有的科学数据已足以显示药物转换是安全的，但我并不同意。”一些挪威医生现在就想让接受英夫利昔治疗的患者改用生物类似药，这反映出了挪威医生和患者通过Remsima节省费用的强烈意愿。

尽管生物类似药还面临着种种挑战，但其发展趋势却是不可阻挡的。Cronstein博士预测：“生物类似药一定会在10~20年内成为常规用药，它们将会被接受，只是还需要时间。”

英国利兹大学的风湿病学家Paul Emery博士在6月份ECR年会上预测：“生物类似药就在这里，随着各项专利的到期，我们将会看到越来越多的生物类似药出现。”

Kvien博士表示：“我预料生物类似药将占据重要地位。我希望它们较低的价格能改善这类治疗的可及性，使全球更多的患者从这类治疗中获益。”

Strand博士是Hospira、Celltrion、安进、辉瑞、Epirus、百特和默克雪兰诺的顾问。Kvien博士是AbbVie、百时美施贵宝、Hospira、Celltrion、辉瑞/惠氏、默克雪兰诺、默沙东、罗氏、UCB、Orion和武田的顾问。Cronstein博士是辉瑞和默克雪兰诺的顾问。Emery博士是AbbVie、百时美施贵宝、默克、辉瑞、罗氏和武田的顾问。

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By: MITCHEL L. ZOLER, Internal Medicine News Digital Network

The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.

An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.

A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)

At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.

Lower cost broadens use

With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.

 “A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.

 “Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.

Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.

Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.

Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”

While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.

“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.

Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.

“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”

Concerns about safety

But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.

 “There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”

“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”

The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.

Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.

While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.

“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.

 “Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.

“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.

Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.