4

By Nick Lane PhD New VEGF antagonists in AMD – new quandaries abound

predominantly classic CNV most suitable But here is the rub. is a Of course, in both advanced cancer and for treatment with PDT. molecular cousin of a larger antibody, wet AMD, is an important Even so, despite the relatively slow known as (molecular weight factor in determining outcome. disease progression, patients treated with 148 kDa), marketed by Genentech as felt that bevacizumab was too big to ® ffective vascular-endothelial growth- ranibizumab experienced a mean increase Avastin . Engineered on the DNA level, penetrate the by intravitreal factor (VEGF) antagonists have been of seven letters VA at 12 months, while ranibizumab has several specific base injection; and while life-threatening adverse a long time coming, after first being patients in the control group had a mean changes that increase its affinity to VEGF. events (a higher risk of thromboembolic E decrease of 10.5 letters. Some 34% of the The FDA approved bevacizumab for events such as stroke and MI) might be proposed back in the 1970s; but now, like London buses, three have arrived at once 0.5 mg-treatment group experienced a treating advanced colorectal cancer in acceptable in treating advanced cancer, for the treatment of wet AMD. Far from better than15-letter gain in VA, compared February 2004, and it is still in trials for systemic treatment with bevacizumab for being just ‘me-too’ drugs in the same class, with 4.6% in the control group. other forms of cancer. AMD seemed to be using a sledgehammer the VEGF antagonists have called attention On behalf of the MARINA Study Group, to crack a nut.The risk of such adverse to difficult issues relating to cost, efficacy, Joan Miller MD (Massachusetts Eye and Ear quality of evidence, share value, and a Infirmary), told delegates at the ASRS potential split between industry, regulators meeting in Montreal,“These data are very and practicing clinicians.The issues have compelling because, for the first time, we repercussions throughout medicine. have a potential treatment which has been What is a cost-effective drug? The first VEGF antagonist to be shown to improve vision in a significant Many new medicines, such as The advantage of using an ICER, or cost approved for AMD was pegaptanib number of patients with wet AMD as (Macugen, Eyetech/) or indeed per QALY, is that it is a standard measure (Macugen®, Pfizer/Eyetech), which received opposed to just slowing progression of FDA fast-track approval last December. vision loss.” verteporfin PDT (Visudyne, ), that can give a comparison across Despite this good news, it’s fair to say that Another trial (FOCUS, phase I/II) seem prohibitively expensive, with prices different areas of medicine. Should a the results were disappointing, no doubt compared verteporfin PDT plus often in excess of $1000 per treatment. cash-strapped health system fork out for a for the co-developers.While ranibizumab with PDT alone in patients As probably the best treatment so far, new cancer drug, or ranibizumab, and unquestionably effective at slowing the with predominantly classic CNV.The ranibizumab (Lucentis, Genentech) seems when should it refuse to pay? While rarely progression of neovascular AMD, and the results were similarly encouraging (also certain to follow a similar path. But when stated in as many words, a presumed accompanying loss of visual acuity, hopes presented first directly to the press in does it become simply too expensive to ‘threshold’ cost-effectiveness of $50,000 for a treatment substantially better than May): 90% of patients receiving reimburse? per QALY is generally thought worth verteporfin PDT (Visudyne®, Novartis) combination therapy had stable or paying by reimbursement agencies; any were dashed. improved vision (<15 letters loss) Verteporfin PDT has been mired in cost- more may well not get reimbursed. Some 70% of patients receiving compared with 62% of patients receiving effectiveness issues for almost its whole pegaptanib lost fewer than 15 letters VA PDT alone. time on the market, but newer drugs Given a known efficacy and QALY, this compared with 55% of placebo-injected What may be hidden in the small print is rarely face the same problem. Their cost- means that a pharma company can hardly patients at one year; but only 6% or 7% of still unpublished. In September the FDA effectiveness is virtually guaranteed to be get it wrong now. Simply plug in the patients gained more than 15 letters notified Genentech that it would not grant close to the threshold accepted by number of QALYs gained and calculate compared with 2% in the control group. the company’s request for fast-track society. How so? By wielding the weapon the cost effectiveness threshold. A recent These results are similar to verteporfin review, which allows for a rolling BLA of ICERs per QALY backwards. paper by Sanjay Sharma et al (Can J (Biologics Licence Application). However, PDT, both in terms of efficacy and Ophthalmol, 2005), on anecortave acetate Genentech plans to file for approval this treatment cost, no snippet for pegaptanib The term ICER means incremental cost (Retaane, Alcon) shows how it is done. December, and still have the potential to at around $1000 per injection. effectiveness ratio. The most common They calculate that the threshold cost Higher hopes turned instead to obtain priority review status for definition is simply the ratio of cost to ranibizumab. effectiveness for anecortave works out at ranibizumab (Lucentis®), developed by outcome. Outcome is usually given as a $2986 per vial. The producers, Alcon, can Genentech in partnership with Novartis, QALY, or quality-adjusted life-year gained. Genentech in Competition with Itself argue that at that price it is just as cost- and still in phase III trials. In May 2005, QALYs range from 1, for a full additional effective as other products that have been Genentech announced good one-year data So far, so good.The only surprise, a year in perfect health, to zero, for death. reimbursed in the past. directly to the press, two months before positive one, is that ranibizumab looks It’s also possible to score negative giving ophthalmologists a chance to judge substantially better than pegaptanib. Is this QALYs, for fates considered worse than Of course there is still plenty of scope for for themselves at the American Society of a fluke or real? It might well be real.There death. A QALY of, say, 0.5, implies that dispute. One factor is the time span Retinal Specialists meeting in Montreal at are five or six different isoforms of VEGF, lifespan may not be extended, but quality considered. This is a problem that has the end of July. I call attention to this with differing molecular weights and of life is improved; or that lifespan is frustrated verteporfin PDT. In the UK, the properties.The heavier isoforms are deliberately: giving shareholders priority extended, but quality of life is poor. NHS Health Technology Assessment membrane-bound, whereas the lighter over clinicians is a trend that should not calculated an ICER of £150,000-180,000 isoforms diffuse through the vasculature. be encouraged. Because quality of life is subjective, per QALY, but this was based on a two- But the data do seem to be genuinely Ranibizumab is a humanised antibody that QALYs are also obviously somewhat year period (then the limit of RCT data), extremely encouraging. In the MARINA binds to all the isoforms of VEGF, whereas subjective. QALYs are often high in pegaptanib is a ribonucleic aptamer (a during which time the re-treatment costs trial, 95% of patients treated with , because people value molecule that binds with an affinity that are maximum and the benefits are limited ranibizumab maintained or improved their their sight so highly. For example, a depends on its shape), which binds only to to the two-year period. If the treatment vision (defined as <15 letters loss of VA on recent poll (www.costofblindness.org) the ETDRS charts), versus 62% of placebo- VEGF165.While this is thought to play an benefit persists beyond two years (which revealed that 69% of Canadians would injected patients. If the control group important role in AMD, it is nonetheless it does), but fewer treatments are needed rather lose the use of their legs, or their seems to have done particularly well, this just a single isoform. So differences in both (which they are), then the cost per QALY hearing, than their vision; and those is partly attributable to the patient mechanism of action and target could falls. population, who had minimally classic or account for the observed differences in already legally blind were willing to accept occult CNV lesions, which are generally efficacy. a 50% cut in their remaining years to less aggressive than the classic or recover sight.

EuroTimes November 2005 5

events would be virtually eliminated by Ophthalmic Surgery, Lasers and Imaging, in brink of bankruptcy. In other countries, showed that only the smaller antibody intravitreal injection of a smaller antibody July 2005. including much of the EU, reimbursement fragments could penetrate the retina. On that could penetrate the retina, so In an accompanying editorial, Elias is a major issue. that basis, we developed ranibizumab for Genentech developed ranibizumab for Reichel MD, of the New England Eye Verteporfin PDT, for example, has been intravitreal injection.” intravitreal injection. Centre,Tufts University, concluded, stalled at the National Institute for Clinical She noted that in addition to retinal Then in June 2005, Drs Stephan Michels, “Bevacizumab is a readily available drug Excellence (NICE) in the UK for several penetration, the company considered a Philip Rosenfeld and their colleagues at the that costs a fraction of the proposed years, pending the resolution of number of other factors based on pre- Bascom Palmer Eye Institute, University of alternatives.The dramatic findings of interminable cost-effectiveness arguments. clinical studies as it made the decision to Miami, published an uncontrolled case Rosenfeld et al demand that further In the circumstances, a safe, cheap, effective develop Lucentis.These included: the series using systemic bevacizumab for studies be done to assure safety and medication that is widely available, albeit systemic half life which is significantly treating AMD in Ophthalmology.With 12- confirm treatment benefit.” off-label, is a huge boon. But is it safe and shorter for Lucentis (21 days for Avastin week data for only nine patients, they still Rosenfeld and colleagues have now effective? compared to four hours for Lucentis; found that patients receiving bevacizumab treated more than 200 patients with According to Dr Michels, very elimination of the Fc portion of the full- had marked improvements in VA from as intravitreal bevacizumab, but have yet to preliminary results have convinced many length antibody, a portion known to cause early as a week – results that, on the face publish detailed longer-term results; and retina specialists. inflammation; and the 100 times higher of it, were comparable with ranibizumab. the FDA would hardly deem this a clinical “We have tried to get funding from affinity of Lucentis to VEGF enabling use in “There are potential advantages to trial. Even so, more and more pharmaceutical companies to conduct smaller quantities than Avastin. treating AMD systemically. In particular, the ophthalmologists are trying intravitreal clinical trials with ranibizumab, but there treatment effect of two to three initial bevacizumab, ostensibly with very has been no interest. It is very likely that infusions is quite durable, lasting six encouraging results, mainly on patients larger case series with longer follow-up, months in the majority of our patients, so who did not benefit from other treatments including VA, angiography and optical we may not need to treat as often; and such as verteporfin PDT or pegaptanib – a coherence tomography will be the only "The data behind secondly, active AMD is often bilateral, and refractory group. data available for some time.The situation we treat both eyes at once with systemic The trend has become so marked that is to some extent comparable to the off ranibizumab are so treatment.We are seeing improvements in analysts SG Cowen recently revised their label use of intravitreal steroids in good that I think it will VA in the fellow eye as well as the study financial projections for ranibizumab:“Our combination with verteporfin therapy for eye,” Dr Michels told EuroTimes. checks indicate growing demand for neovascular AMD,” he told EuroTimes. certainly be cost intravitreous Avastin for the treatment of For many surgeons, deprived of the wet age-related . double-blind approach, this would also be effective to prescribe it Positive clinical experience and its low enough; how many effective procedures in “The treatment effect cost should enable the drug to rapidly ophthalmic surgery have been adopted, to here.” capture and maintain significant share in the undoubted benefit of patients, without of two to three initial the wet AMD market.We expect Avastin exhaustive and time-consuming clinical Elais Reichel MD and Lucentis to dominate the AMD trials data? infusions is quite market, but have reduced our Lucentis But if clinicians are to prescribe new So what should be done now? According estimates to account for increasing medicines widely on an off-label basis, this to Dr Reichel the cost issue is a non-issue, durable, lasting six competition from Avastin.” is not just vulnerable to the charge of at least in the US. In fact they lowered their projected double-standards – why should only "The data behind ranibizumab are so months in the majority revenues from $1.1 billion to $600 million, pharmaceutical companies go to the good that I think it will certainly be cost anticipating nearly a 50% reduction in the trouble of paying for proper clinical trials – effective to prescribe it here. In the of our patients,” peak sales potential of ranibizumab. but also has the potential to put patients MARINA trial, 75% of patients showed at risk.This would place clinicians at odds some improvement and 40% of patients Stephan Michels MD Cost versus Efficacy with regulators, with price, rather than had excellent vision (20/40 or better) at A 100 mg vial of bevacizumab costs efficacy, a driving force. the end of one year.These are outcomes So far, Dr Michels and colleagues (who around $700, but only 1.0 mg is needed According to Genentech, bevacizumab that society would consider worth paying are continuing their case series at the for intravitreal injection, giving an was never designed for intravitreal for." University of Vienna,Austria) have found estimated treatment cost for AMD of injection. Its safety and efficacy are simply no serious adverse events, beyond a small around $40 to $75.While ranibizumab has unknown.This might sound a little And for the poor relations, who and reversible rise in blood pressure not yet been priced, pegaptanib costs disingenuous, for Genentech did not test simply can’t afford ranibizumab? (about 12 mm Hg); but that is a moot around $1000 per vial, and it’s a fair bet the pharmacokinetics of bevacizumab by “I think it’s very important that we have point. Just this September, Genentech that ranibizumab would cost more. Mike intravitreal injection. Instead they good properly controlled, double-blinded halted a phase II trial of bevacizumab in King, an analyst with Rodman and compared a molecule of similar size data for both safety and efficacy. I can see platinum-refractory ovarian cancer after a Renshaw, estimates that the cost will be in (Herceptin, also of molecular weight148 that pharma companies may not be higher rate of gastrointestinal perforations the order of $1,200 per injection, totalling kDa) against an antibody fragment similar interested in funding this work, but it (5/43 patients enrolled). Safety is certainly $14,000 a year for treatment. to ranibizumab.A cynic might be forgiven seems an ideal opportunity for an issue. for wondering whether Genentech had governments to get involved.After all, they Dr Michels emphasised that systemic nothing to gain and everything to lose could save a lot of money if bevacizumab treatment for AMD is not comparable with from testing bevacizumab directly. really is proved to be equivalent. So cancer treatment. “In treating AMD it’s But the real world is rarely as black and perhaps the NEI, or a European “In treating advanced cancer, white as a good conspiracy theory.When organisation like the MRC in the UK, could bevacizumab is combined with multiple important that patients EuroTimes put this question directly to organise a head-to-head trial,” Dr Reichel chemotherapy regimens and given every Genentech, spokeswoman Dawn Kalmer told EuroTimes.” two weeks for months or even years.This are regularly seen by came back with a reasonable answer. is not the case for AMD, so the risks are “The tests we did were on rhesus very different. Even so, in treating AMD it’s their internal monkeys, because we needed an animal important that patients are regularly seen model that was much closer to the human by their internal specialist.” specialist.” eye than the rabbit.The trouble was, at the In the meantime, however, it seems that Stephan Michels MD time we did not have humanized bevacizumab is also effective by intravitreal antibodies for either bevacizumab or injection. Philip Rosenfeld MD and This raises several major issues, notably ranibizumab – this work was done back in colleagues announced strikingly good, cost, efficacy, and quality of data.The high 1996, before either had been developed. So albeit very preliminary,VA, optical cost of modern medicines is a serious we worked with what we had, humanised coherence tomography and angiographic challenge to health systems, even in the antibodies of differing molecular weights, findings at the same ASRS meeting in US, where Medicare is teetering on the which is the most important parameter of Montreal, and published a case series in retinal penetration.And this work clearly

EuroTimes November 2005