Will the AMD Therapies
Now in Clinical Trials Deliver What They Promise?
Two specialists discuss the possible impact on practice management and what we still need to know about the new drugs.
KAY T. ADAMS, MANAGING EDITOR
With three antiangiogenesis drugs in late-stage clinical trials -- Lucentis (Genentech), Macugen (Eyetech), and Retaane (Alcon) -- retinal physicians may soon have another option for treating AMD patients. To determine what impact these treatments might have on future retina practice, I talked with specialists Lee M. Jampol, MD, Northwestern University School of Medicine, and Mark W. Johnson, MD, University of Michigan Kellogg Eye Center. Both agree these clinical trials are a major step forward in finding a treatment modality that will successfully halt the progression of AMD. But, as each emphasized, it will be many years before their efficacy is proven.
RP: Given the preliminary trial results for Lucentis, Macugen, and Retaane, how will these treatments be best used clinically?
Dr. Jampol: It is worth noting that the results available at this time involve patients followed for a relatively short period of time. Much of the data is unpublished, so we don't know all the details of the efficacy of these drugs, and so far all of the data are short-term, 1 or 2 years. Data available on the phase III Macugen trial are complicated because some, but not all, of the patients have been treated with PDT together with the drug. So we are speculating as to which patients will benefit and how they will benefit. There are giant gaps in our knowledge. For each of these drugs, 2 types of trials have to be conducted. One is testing the drug against the current standard of care, PDT. Then the combination of PDT plus the drug should be studied. These drugs then have to be paired off against each other and also against corticosteroids, which may play a role in the treatment of AMD.
RP: What patient population would benefit the most? Will these drugs halt the progression of dry to wet AMD?
Dr. Jampol: The Macugen data suggest that patients with all subtypes of CNV may benefit. With each drug, we need more information on (1) age; (2) status of the other eye; (3) lesion size; (4) duration of CNV; (5) visual acuity; and (6) lesion characteristics, and other baseline findings to determine the effect on visual outcome. It seems likely that patients with recent symptoms (not longstanding), smaller lesions, and better visual acuities would benefit the most.
The anecortave investigators have come up with an interesting idea: to look at high-risk patients who are likely to develop wet AMD and to try to prevent the conversion of dry to wet. That's a novel concept, but we don't know if it will work. We don't know if the stimuli that convert dry to wet AMD will be affected by these various antiangiogenesis drugs -- that has to be tested. It may be these drugs will work on all types of AMD; however, individual studies will have to be done, for example, to see if they work on polypoidal choroidal vasculopathy, retinal angiomatous proliferation, and other variants of CNV.
Dr. Johnson: For patients with dry AMD, no data exist that we should treat them with any of these new drugs. So I don't believe physicians will treat patients to halt progression, although that may change. The Retaane clinical trial is looking at that question, but it will be many years before we know the answer.
AMD patients with relatively recent (several months) onset of neovascular AMD and mild-to-moderate vision loss would benefit most. Given the available data, the realistic goal of treatment will be vision stabilization with perhaps some visual improvement. These drugs may be especially helpful for patients who are not good candidates for PDT, ie, those with large occult or minimally classic lesions. For patients who are PDT-eligible, further experience and clinical trial data should help determine whether any of these treatments are superior to PDT or significantly enhance the effect of PDT when used in combination with it.
RP: Much is being said about improving vision. How would you explain the potential benefits to patients?
Dr. Jampol: Early phase II trial results of antiangiogenic therapies suggested that vision would improve (3 lines of visual acuity or more) in a sizable number of patients. The phase III Macugen trial doesn't confirm this. We need more data on the other single therapies and on combination therapies. Keep in mind that angiogenesis is only one aspect of AMD, and other degenerative changes may be occurring. So until we understand whether the primary abnormality is in the retina (the photoreceptor) or the retinal pigment epithelium, or the choroidal circulation, or Bruch's membrane, we won't understand what the stimulus for angiogenesis is. Is it inflammatory, or hypoxia, or something else? We don't know if AMD is genetic or environmental, so in our ignorance of the pathophysiology, we won't know what the role of these drugs will be until more research is done.
Dr. Johnson: We don't have much information yet. The expectation with all the drugs was for a larger rate of visual improvement. With what we do know, I think we would have to tell patients the same thing we tell patients about PDT. The best we realistically can hope for is that we will stabilize vision at the level it was when we began treatment and try to prevent further loss from that point. There will be a small percentage of patients who with one of these drugs, possibly in combination with Visudyne, will experience noticeable improvement or have reading vision restored. But based on what we know so far, for the majority of patients, we're talking about increasing their ability to read the eye chart by only 2 or 3 lines.
RP: How will the new treatments change the way AMD patients are managed?
Dr. Jampol: There will be pressure on retinal physicians to use the new drugs, which we experienced with PDT, and there will also be pressure to use the drugs off-label. I hope we will be able to exercise restraint. One thing that will undoubtedly have a moderating influence is these drugs will be expensive, difficult to deliver, and difficult to set up.
The time and effort involved on the part of the physician in administering an intravitreal drug is another factor. These procedures have to be done with precision, training, and quality control to avoid complications. How the eyes are prepped and injections are given will be critical, and patients will have to be carefully monitored following injection. This will influence which physicians will be willing to do these treatments, how they will be done, and how many patients will be treated. We also have incomplete information as to how often or for how long the injections have to be given. Will it be for life, 1 or 2 years, every 3 weeks, or every month? We are guessing at this point. Relapses will be a problem because the drugs will not address the underlying abnormality. The angiogenic response with relapses will be common as the medications wear off.
Dr. Johnson: I think there will be little training needed for physicians. Two drugs are intravitreal injection and Retaane is a sub-Tenon's injection. Most physicians are already familiar with these injections. There may be some fine points about sub-Tenon's delivery that would have to be communicated but not much on how to prevent the drug from refluxing.
Retinal physicians will likely require additional slots in their schedules to administer injections and to observe patients. Some practices may have to hire additional physicians or technicians, but most practices will likely absorb the increased activity without significant personnel changes. The number of new patients is unlikely to increase significantly because the drugs will benefit only a small cohort with relatively new, active lesions. It is the nature of the treatment and the frequency of follow-up that will change in the direction of an increased number of procedures and encounters.
RP: How are these investigational drugs performing so far in terms of safety and side effects?
Dr. Jampol: Intravitreal injection delivery is a less than ideal delivery method. The best example is what happened with CMV retinitis in HIV patients and ganciclovir. Initially, patients were given intravitreal injections and faced all the problems we've been talking about. Then an implant was developed, which was superior, and then an oral drug. That is what's going to happen here. Shortly, there will be other techniques that will replace intravitreal injection.
Dr. Johnson: No doubt you must take great care, but most retinal physicians are already doing routine injections of other drugs so the procedure is not new, only the drug is new. There is certainly a substantial risk with any injection into the vitreous. The serious drawback is the need for frequent injections and the risk of infection. If they are shown to be effective, I think there will be some reluctance to use them routinely because of the frequent need for eye injections, which carries a risk with each injection. I would hope there would be some delivery method developed that will deliver the drug into the eye in a safer manner over time, and that is probably the mode of the future rather than oral delivery. For example, there might be an explant that would sit next to the eye and feed in the drug.
RP: What about the cost of care?
Dr. Johnson: There is not a large cost to the physician for doing the injection procedures. There will be some supplies, such as drops to sterilize the eye, and equipment that will be needed, which should be covered by the reimbursement for the procedures. We don't know yet how expensive the drugs will be. They will not be inexpensive. We assume that Medicare or health insurance will cover the cost. But the cost to society and to the patient will increase because there will be more injections in patients who previously did not receive injections; greater frequency of visits; and more patients will be treated who have not been treated.
RP: What information do retinal physicians need to evaluate the appropriateness and value of these treatments for their AMD patients?
Dr. Jampol: Physicians will have to carefully read the literature and determine what's confirmed and what's speculative. They will have to carefully set up their offices to minimize patient complications and exercise great judgment as to who is and is not an appropriate patient. They will have to determine who is benefiting and who is not and, based on their experience and the experience of other specialists, determine how to proceed.
Dr. Johnson: The big question that will remain unanswered for clinicians, at least in the foreseeable future, is that for patients with wet AMD who are eligible for PDT, there is no information now that compares PDT head to head with these drugs. We can't advise patients to choose one over the other based on efficacy, and there is no trial planned to compare them.
Also, we don't know if it is advantageous to do treatments with these new drugs in combination with PDT or to use PDT alone. There is a suggestion in the Macugen trial that adding this drug might increase the success rate of PDT, but the trial was not designed to adequately answer that question, so we don't know if we should recommend Macugen as an adjunctive or additive treatment. With Lucentis there is a trial comparing the drug with PDT, so we will know whether to choose one over the other; however, we won't know about using the 2 together. With Retaane a study is comparing PDT alone and PDT with the drug. The pressing question there is we know which patients would benefit from PDT, but we don't know if we should add Retaane.
RP: Are you taking any steps in your practice at this time to prepare for adopting the new treatments?
Dr. Jampol: We are giving intravitreal triamcinolone, so we are already set up to give intravitreal injections for diabetic macular edema, AMD, and venous occlusions. We use it in selected patients but not unless we feel strongly it's the best treatment available. We are informing our patients about the gaps in our knowledge about their disease and how this treatment might help them. Then with the informed consent of the patient, we give the injections. We will do the same with these new drugs. I suspect that retina specialists will see markedly increased referrals once the new therapies are approved. Many of these will not be eligible for or receptive to the treatments, so it will be time consuming to evaluate them.
Dr. Johnson: No, I'm not taking any specific steps right now. We don't know when these drugs will be approved and it will be some time before they will be approved.
Dr. Lee M. Jampol is the Louis Feinberg Professor and Chair, Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Ill. He is a member of the Independent Data and Safety Monitoring Committee for Photodynamic Therapy, Novartis Ophthalmics, and the Independent Data and Safety Monitoring Board for the fluocinolone implant, Bausch & Lomb. He has served as a consultant to Genentech and Pfizer. Dr. Mark A. Johnson is Retina, Uveitis, and Ocular Oncology professor, Ophthalmology and Visual Sciences, The University of Michigan Kellogg Eye Center, Ann Arbor, Mich. He is a principal investigator in the Macugen and Lucentis trials.