Frank Celia, Contributing Writer For years, plaintiffs’ attorneys have hammered away at the doctrine of off-label application, claiming that doctors should face at least some level of increased liability if they administer a drug in ways unapproved by the FDA. Time and again these arguments have been rejected. The government, courts and regulatory agencies have steadfastly supported a doctor’s right to practice medicine as he or she chooses given the clear benefits to medical advancement. Indeed, many drugs and devices approved for one condition are found even more effective at treating another. For example, Topamax (topiramate, Ortho-McNeil) is FDA approved for treating epilepsy and migraines, but psychiatrists have used the drug off-label to treat bipolar disorder. To increase liability would stifle future breakthroughs, the argument goes. Recently, this support manifested itself in the new Medicare Prescription Drug Benefit, which expressly covers some off-label medications. Still, doctors often approach off-label use with caution, especially in the early stages of the new application of the drug. Regardless of legal liability, no practitioner wishes to place patients at risk for serious adverse events that may have gone undetected due to the absence of preclinical studies. And, it is always possible that society as a whole will change its stance on the importance of protecting off-label usage. Thus do those in the medical field speak of the “liability” of off-label prescribing, even though it is a well-entrenched medicolegal principle.1 Anxiety regarding this principle lies at the heart of a controversy occurring in the retina world: the off-label use of Avastin (bevacizumab, Genentech) to treat neovascularization secondary to wet age-related macular degeneration (AMD) and other retina conditions. Originally approved for the treatment of colorectal cancer, Avastin was found last year to be effective at treating a small cohort of AMD patients.2 News spread quickly, and by this spring, several thousand AMD patients had received the off-label therapy. Officials at Genentech probably were less than pleased with this expanded use of their drug, because they planned to launch Lucentis (ranibizumab) this year. Lucentis is similar to Avastin in its mechanism of action, but Lucentis is specifically designed and tested for use on the retina. (The same chemist, Napoleone Ferrara, created both drugs.)
Avastin was in danger of stealing Lucentis’ thunder. Based on the burgeoning popularity of the off-label drug, which is far less expensive than Lucentis, Wall Street analysts downgraded Lucentis’ sales potential from $1.1 billion to $600 million, and Genentech’s stock took a 4% dip. Now, with Lucentis approved by the FDA, the two Genentech drugs are poised to compete against each other. Here are the factors that could determine the winner. No matter which drug prevails, anti-vascular endothelial growth factor (VEGF) drugs, such as Avastin and Lucentis, represent an exciting new age in retina treatment. For the first time, doctors can offer a significant number of AMD patients the chance of improving visual acuity rather than merely stopping or slowing progression of the disease. While current mainstay treatments, namely thermal laser photocoagulation and photodynamic therapy, seek to destroy new vascular growth, anti-VEGF therapies help stem the process of neovascularization itself by blocking the angiogenic factors that cause it. Avastin is a humanized mouse monoclonal antibody directed against VEGF. It received FDA approval for the treatment of metastatic colorectal cancer in February 2004, the first anti-VEGF drug approved by the agency. Avastin came to the attention of Philip Rosenfeld, M.D., Ph.D., an associate professor of ophthalmology at the Bascom Palmer Eye Institute, Miami, during his involvement in early clinical studies of Lucentis, which like Avastin, is a VEGF inhibitor. Positive clinical responses convinced him to look at other anti-angiogenic medications. Dr. Rosenfeld and the institute undertook the Systemic Bevacizumab (Avastin) Therapy for Neovascular Age-Related Macular Degeneration (SANA) study.2 Researchers administered two or three doses of bevacizumab (5mg/ kg) at two-week intervals to 18 eligible patients. Follow-up evaluations revealed rapid improvements in visual acuity, angiographic and optical coherence tomography (OCT) outcomes. At one week, median and mean visual acuity letter scores had increased by eight letters in treated eyes. By two weeks, they had improved by 12 letters. The median and mean central retinal thickness measurements also decreased significantly. Angiography revealed a reduction or absence of leakage from the lesions. Overall, no patient lost a letter of vision, and more than 40% gained three or more lines, the study found. Some patients gained six or more lines. Although patients encountered no serious adverse events, systemic Avastin administered to cancer patients poses a risk of thromboembolic events.3 So, researchers sought to reduce the drug’s dosage. Literature published in the 1990s debunked Avastin’s ability to penetrate the retina via intravitreal injection. Finding the conclusions of various studies to be questionable, Dr. Rosenfeld reduced the dose of the drug by about 400 times and began injecting it into patients’ eyes, with positive results.4
Currently, the drug is most often administered via intravitreal injection. Anecdotal reports indicate physicians use Avastin to treat diabetic macular edema, branch retinal vein occlusion, central retinal vein occlusion, cystoid macular edema and even more rare conditions such as Coats’ disease. While sometimes employed as a first-line therapy, Avastin is usually used after other treatments fail. Experimentation with Avastin drew inspiration in part from what some consider a limited treatment effect of Macugen (pegaptanib, Eyetech Pharmaceuticals/Pfizer).5 Macugen, which was approved in December 2004, is also an anti-VEGF molecule. Macugen has been shown to be an effective therapy for neovascular AMD.6 In two prospective, randomized, studies that involved 1186 patients, efficacy was demonstrated for three doses (0.3mg, 1.0mg and 3.0mg). Seventy percent of patients who took 0.3mg lost less than 15 letters of acuity vs. 55% of patients in the placebo group.6 Further, the researchers found that 33% of patients who received macugen maintained their visual acuity or gained acuity vs. 23% in the placebo group.6 And, as early as six weeks after beginning therapy with the study drug, and at all subsequent points, the mean visual acuity among patients receiving 0.3 mg of pegaptanib was better than in those in the placebo group.6 One difference between Macugen and Avastin, however: Macugen targets only a single splice length of the growth factor, known as VEGF 165.5 After one year of treatment with Macugen, only 6% of patients demonstrated improvement of visual acuity—a significant enhancement over the 2% whose vision improved without therapy but still modest.6 Also, in certain classes of AMD patients, Macugen has not been reported to reduce the rates of moderate visual loss.5-7 Nevertheless, some retinal experts expect Macugen to play a role in adjunctive or prophylactic therapy. Approved this summer, Lucentis is an antibody binding site (Fab) fragment. Lucentis and Avastin both bind to and inhibit all forms of VEGF-A. In June, Genentech released phase III clinical data showing that patients who had wet AMD experienced a 16-letter benefit vs. the control group after one year of therapy. Patients received 0.3mg or 0.5mg injection doses once a month for the first three months, and then once every three months. At three months, treated patients gained 2.9 letters of vision (0.3mg group) and 4.3 letters (0.5mg group), while control subjects lost 8.7 letters. First To Market When word of Avastin’s success circulated, it was quickly embraced by retina subspecialists, who were reluctant to wait for FDA approval of Lucentis when fewer than 10% of their wet AMD patients could expect improved vision. According to the American Academy of Ophthalmology (AAO), as of this spring, some 6,800 Avastin injections had been administered to 5,055 patients at 68 medical centers in 12 countries. A survey conducted by the American Society of Retinal Specialists found that 92% of respondents believed intravitreal Avastin was “somewhat better” or “much better” than other approved or covered therapies. Furthermore, 96% said they thought the off-label application was the same or better in terms of overall safety compared with other FDA-approved or covered therapies. In April, the American Academy of Ophthalmology sent a letter to the Centers for Medicare and Medicaid Services (CMS) calling for Medicare to provide reimbursement for Avastin treatments. At that time, all 17 Medicare carriers covering all 50 states had issued verbal denials of coverage, and seven carriers had issued written denials, according Michael Lachman, publisher of the business publication EyeQ Report.8 In May, however, Pinnacle Business Solutions Inc., a Medicare carrier that operates in several southern states, announced that it would cover off-label use of Avastin when other AMD treatment options have proven ineffective. While ultimately a clinical decision, the choice between these drugs will likely involve economic factors to some extent. The cost of an injection of Avastin is about $40 to $75, while the cost of a Macugen injection is $1,000, and Lucentis is expected to cost as much or more. “There are some people who were using Avastin as a stop-gap measure until Lucentis got approved,” says Jeffry D. Gerson, O.D., of Overland Park, Kan. “But, many people will continue to use Avastin because of the money factor. It’s less costly to the health-care system and potentially to the patient.” The other side of that argument posits that because insurance carriers will likely cover Lucentis, it will have the edge. Says Mark Dunbar, O.D., also of Bascom Palmer, “I think there will be a place for Avastin, but it will probably be among the non-insured or indigent population, or maybe people from other countries who come to the U.S. to get their care.” According to Genentech’s own analysis, 81% of patients have enough insurance (Medicare and a supplemental policy or private insurance with a fixed copay) to bring the cost of Lucentis to $50 or less per treatment, says Genentech spokeswoman Dawn Kalmar. Further analysis, she says, shows that: • Some 3% of patients who have Medicare with a supplemental policy and 5% coinsurance have a copay of approximately $108 per treatment.
Several retina subspecialists publicly stated their intention to switch to Lucentis when it gained FDA approval. Others have said they will stick with Avastin until data convinces them to switch. There are several unknowns regarding both drugs. Researchers are not even clear yet whether some characteristics will end up being positives or negatives. For its part, Genentech has engaged in the unusual endeavor of mounting a public relations campaign against its own product (although Ms. Kalmar says that Genentech will not block off-label use of Avastin). At symposia and in the press, the company has argued that: • The lack of preclinical trials poses the risk that Avastin may end up being toxic in an ocular environment. To date, no large-scale, randomized clinical studies of Avastin in eye disease have been conducted. However, it is uncertain whether all of Genentech’s objections will hold up over time. For example, the increased time in the eye due to Avastin’s longer half-life may prove to be an advantage. Though protocols for frequency of dosing are still being determined for both drugs, Avastin may require less frequent injections, perhaps because of its longer half life. Practitioners and patients see this as an advantage. Anecdotally, doctors report administering Avastin injections every three months, while data from the phase III clinical trials indicate that Lucentis may be most effective when dosed monthly. Nor is the risk of inflammation settled. A recent study on Avastin patients found a “curiously low rate of intraocular inflammation,” when compared with that seen in Lucentis and Macugen, especially given that researchers were anticipating increased inflammation with Avastin.5 As a full-length antibody, Avastin was expected to cause increased inflammation because it contains an Fc portion. “However, not all ligand bound to Fc receptors leads to immune system activation and actually can cause inhibitory effects,” the study notes. Only further research could prove or disprove such a theory, the authors say. There is also the matter of VEGF in general and its role in the eye. Although large multi-center trials with Macugen and Lucentis have raised no safety concerns, it is possible that too much inhibition of VEGF, a naturally occurring and often-beneficial growth factor, could prove detrimental in the long run. One paper cautions, “There is speculation that blocking VEGF may cause an increased rate of apoptosis among ganglion cells and photoreceptors.”9 Thus, Macugen is likely to play a continued role in the treatment of AMD and related disorders—either as an adjunct or prophylactic agent. Because Macugen targets only VEGF 165, pegaptanib may be safer for long-term use. “Macugen may be used in a kind of maintenance fashion,” says optometrist Leo P. Semes, of the University of Alabama at Birmingham. “The Avastin will put out the fire, and the Macugen will quell the embers."
While the advent of anti-VEGF treatments is cause for optimism, a large segment of patients fails to respond to these drugs. “Avastin and Lucentis will probably prove to be better than current treatments, but they are still not perfect,” Dr. Gerson says. “I hope something better comes along at some point.” During the next few years, treatment may evolve into some kind of combination therapy, coupled perhaps with a prophylactic agent. The drug Retaane (anecortave acetate, Alcon) is undergoing study as a treatment for patients who have dry AMD deemed at risk for progressing to the wet form. Evizon (squalamine lactate, Genaera), another anti-angiogenic drug, also is in development. If Avastin and Lucentis prove evenly matched in efficacy, and both retain their current safety profiles, financial considerations will likely have a larger impact on which prevails. In any event, the future of Genentech probably does not hang in the balance. In the wake of the Vioxx product liability lawsuits, biotech firms such as Genentech have replaced pharmaceutical companies as Wall Street’s favored picks, and Genentech is the second largest in the world. The lowered projected sales figures for Lucentis represented only a minor setback in what was a remarkably successful 2005 for the company. Financial experts predict Genentech’s earnings will increase 43% this year. Avastin’s off-label status will undoubtedly work against it, especially considering the unapproved method of drug delivery. Above all, though, anti-VEGF therapy has given retina subspecialists and their patients cause for enthusiasm. “This is the first treatment where we are actually seeing improvement in visual acuity, as opposed to patients slowly getting worse,” Dr. Dunbar says. “That is the most important thing.”
2. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005 Jun;112(6):1035-47. 3. Rajpal S, Venook AP. Targeted therapy in colorectal cancer. Clin Adv Hematol Oncol 2006 Feb;4(2):124-32. 4. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2005 July-Aug;36(4):336-9. 5. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006 Apr;26(4):383-90. 6. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004 Dec 30;351(27):2805-16. 7. Schachat AP. New treatments for age-related macular degeneration. Ophthalmology 2005 Apr;112(4):531-2. 8. Arons IJ. Avastin: A New Hope for Treating AMD Available at: http://irvaronsjournal.blogspot.com/2006/01/avastin-new-hope-for-treating-amd.html (Accessed October 2, 2006) 9. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006 Mar;113(3):363-72. 近日，英国国家卫生和临床医疗优选研究所推荐Lucentis（雷珠单抗注射液）作为治疗所有湿性老年黄斑变性（AMD）的有效方法，湿性老年黄斑变性是50岁以上人群主要致盲原因。诺丁汉大学医学院眼科副教授Winfried Amoaku说："湿性AMD是一种退行性病变，它能导致患者视力迅速下降，患者会因此丧失自理能力，生活质量也会因此下降。Lucentis能帮助那些有维护或改善视力需求的患者。" Lucentis是专门针对眼科疾病研制的药物，是唯一获得批准的能提高绝大多数湿性老年黄斑变性患者的视力和视力相关功能的治疗药物。7000多名患者参与的临床实验表明，接受Lucentis治疗的患者比未接受治疗的患者视力提高4行（21个字母），这种状况可稳定2年。 玻璃体腔注射Lucentis治疗血管样条纹一例
方法：确诊血管样条纹并发CNV患者一例，连续三次玻璃体腔注射Lucentis 0.5mg治疗，观察视力、ETDRS表字母数、眼压、眼底、FFA、ICGA、OCT等情况。 结果：第一次注射4周后随访视力提高右眼4行，提高15个字母，左眼3行8个字母；眼压正常无前节反应；OCT示黄斑中心凹厚度下降右眼15um、左眼49um；FFA示黄斑部荧光渗漏减少。二次注药术后三个月随访视力提高右眼3行，ETDRS表提高10个字母，左眼3行， 10个字母；OCT示黄斑中心凹厚度下降右眼82um、左眼112um；FFA示黄斑部荧光渗漏减少。行三次Lucentis玻璃体注射，仍在观察中。 结论：应用玻璃体腔注射Lucentis治疗血管样条纹短期内具有视力提高、黄斑水肿减轻的作用和较好的安全性，但其长期疗效及安全性仍有待进一步的随访和大样本研究。
Lucentis黄斑水肿第二项3期试验获肯定结果 Genentech公司表示Lucentis(ranibizumab)注射剂在一项三期试验中达到了试验终点，这项名为Cruise的试验表明其与基线相比该药使用6个月后可改善由于视网膜分枝静脉堵塞引起的黄斑水肿患者的视力。Lucentis已批准用于湿性老年性黄斑病变。试验中出现的副作用与此前试验一致，没有出现新的副作用，此前公司于7月初也表示一项名为BRAVO的3期试验获得了肯定性结果。公司表示很高兴这两项试验都获得了肯定结果，显示该药可尽早的与持续的改善黄斑水肿患者的视力，这两项试验结果将成为递交上市申请的资料。
OCT对玻璃体腔内注射Ranibizumab（Lucentis）治疗渗出性年龄相关性黄斑变性效果观察 师燕芸1 Usha Charkrovarthy2 杨自权3 杨继红1 【摘要】 目的 本研究回顾性调查利用光学相干断层扫描（OCT）对璃体腔内按需注射ranibizumab（Lucentis）治疗渗出性黄斑变性的效果。方法 确切诊断为渗出性年龄相关性黄斑变性的患者，使用2m ETDRS（early treatment diabetic retiopathy study）表检查视力， OCT检查分析黄斑区形态变化，包括中央1mm区域视网膜神经上皮层平均厚度值（central retinal thickness, CRT），视网膜神经上皮层的最大厚度﹑神经上皮层内囊样改变的最大直径﹑视网膜下积液（sub-retina fluid，SRF）最大高度及中心凹处视网膜神经上皮层的厚度。患者玻璃体腔内注射0.5mg（0.05ml）ranibizumab后每月定期随访，根据OCT检查结果决定给予第二次或随后治疗。结果 49人（49眼）共接受玻璃体腔内ranibizumab注射116次，随访5~14月（平均8.18±3.52月），除4眼（8.16%）最好矫正视力降低外，余45眼（91.84%）最好矫正视力保持不变或有所提高，其中21眼（42.48%）提高2行以上。OCT检查CRT值和视网膜神经上皮层最大厚度，黄斑中心凹厚度与治疗前相比较都有显著降低并具有统计学差异（p<0.001）。但最好矫正视力所读取字母数目提高的量与黄斑中央区域CRT减少的量，神经视网膜的最大厚度减少的量及黄斑中心凹厚度均无统计学相关。结论 Ranibizumab是治疗渗出性年龄相关性黄斑变性十分有效的药物，治疗后患者的视力得到保持甚至提高，视网膜结构显著恢复，视网膜水肿明显吸收。 原产地英文商品名: 产地国家: 美国 |
