Laser Treatments for AMD: Visudyne Looks Promising for Preventing Blindness
Irving J. Arons
As I reported following the 1999 AAO meeting ("Laser treatments for AMD show promise", OSN, Jan. 15, 2000), Visudyne PDT therapy appeared promising for those afflicted with predominately classic, wet age-related macular degeneration (AMD), along with several other PDT treatments in the pipeline. One of the questions posed by several industry analysts during that meeting was how, when these new techniques came to market, would HCFA handle the reimbursement issues without bankrupting Medicare?
Well, the inevitable has happened, Visudyne therapy (verteporfin for injection, marketed for QLT, Inc. by CIBA Vision) for predominantly "classic" wet AMD was approved for marketing by the FDA in April 2000. Since then, literally thousands of people with AMD have flooded retinal surgeon's offices seeking treatment. The approval was based on the 12-month data from two, 24-month randomized, double-masked, placebo-controlled Phase III clinical trials known as the TAP (Treatment of AMD with Photodynamic therapy) Investigation. The results of the TAP studies were published in the October 1999 issue of Archives of Ophthalmology. Basically, TAP 12 month findings showed that in 243 patients with predominantly classic wet choroidal neovascularization (CNV), vision remained stable or improved in 67% of patients treated with Visudyne therapy compared to 39% of patients in the placebo arm of the study. Additional data released this past summer showed that the beneficial effect and the favorable safety profile of Visudyne therapy, observed at the 12-month time point, was maintained out to two years, with fewer treatments required in the second year (see the clinical results update below).
Market Size and Reimbursement Issues
It is now estimated that some 65,000 U.S. treatments, both primary and retreatments (90,000 worldwide), were done in 2000, producing between $90 million to $100 million in drug revenues for QLT/CIBA Vision. And, if analysts projections continue to hold up, the drug could reach over $200 million in sales in 2001 -- and as high as $500 to $700 million in revenues by 2003.
But the picture isn't all rosy. In November, HCFA issued its revised National Policy for Reimbursement, calling Visudyne therapy a "medically reasonable and necessary treatment". The agency also expanded somewhat, the number of patients who can receive treatment -- those presenting with at least 50% classic symptoms from a fluorescein angiogram; and how often retreatments can occur -- up to 6 treatments over 24 months, although recent field interviews/surveys are showing that fewer retreatments are occurring in practice and/or are over an extended time frame. (The TAP inclusion criteria included having visual acuities between 20/40 to 20/200, and lesions greater in size than 0.5 mm. Also, on average, 5.6 treatments were reported over the two year period.)
However, the agency cut the expected physician reimbursement for the treatment, including infusion, use of the laser, and staff overheads, to $341 from the $500 to $700 reimbursement figure expected (and previously paid for laser photocoagulation). When added to the drug reimbursement ($1458), Visudyne PDT therapy total reimbursement will be $1799 in 2001. Taken against the cost to administer the treatment, according to a Dain Rauscher Wessels analysis, a high volume practice could expect a profit per procedure of about $500, while a low volume practice might only clear $135 -- and that does not include the physician's fee! This total is down from the $900 profit that a high volume practices could have expected under the older laser photocoagulation rates, and about $550 for lower volume practices.
With between 1200 to 1300 practicing retinal specialists in the U.S., we estimate that there are currently about 600 PDT activation lasers (from Zeiss Humphrey and Coherent Medical) in use in the United States (with an additional 600 in use in the rest of the world).
When queried, in a poll of 67 retinal practices undertaken by Leerink Swann & Company in November 2000, 82% of respondents stated that the new level of reimbursement from HCFA was below expectations, and inadequate. At an AMD press conference held during this years Academy meeting, prior to the HCFA announcement, Dr. Mark Blumenkranz noted that Visudyne treatment may end up being offered only at larger medical centers or academic centers if the reimbursement issues are not satisfactorily resolved.
AMD is the leading cause of severe vision loss in the elderly in the U.S. The National Institute of Health (NIH) estimates that nearly 1.7 million elderly Americans, 5% of the total population over 65 years of age, have some degree of vision loss due to AMD.
I have attempted to calculate what the cost to the Medicare system for PDT might be for the year 2000 and beyond. The cost for 2000 depends on how many people actually underwent the treatment, which, in turn, depends on how many of the 200,000 to 350,000 of the current AMD pool met the acceptance criteria. The wet form of AMD accounts for approximately 10%-15% of the total AMD population, or between 1.3-1.5 million people in the United States, plus another 200,000 new cases diagnosed each year (and an additional 400,000 in the rest of the world). The predominately classic form represents approximately 10% to 15% of the total wet form population, or approximately 130,000 to 250,000 people that could now be treated, with an additional 20,000 to 30,000 being diagnosed and entering the potential treatment pool each year, not taking into account additional patients with diseases such as pathological myopia, which should be added to the Visudyne label sometime in mid-2001.
The cost to the Medicare system for Visudyne PDT in 2000 could conceivably have ranged from $160 million to $280 million, assuming that one-third of the current pool had elected for treatment, one-half of those were eligible (many in the pool may have already lost too much vision to be treatable), and the cost to the system is $1799 per procedure ($1458 for the drug plus $341 for treatment) with an average of three treatments needed over the course of the first year. (The actual cost for 2000, based on 65,000 doses, was closer to $115 million.) In subsequent years, with another third of those eligible entering treatment, along with additional retreatments for some of those already started on their initial course of treatment, Medicare costs could average over $250 million a year. And when other eye diseases and treatment modalities are approved, the cost can only go upward. Another factor to consider is the subjective nature of the diagnosis. Those patients with marginal classic symptoms may be included in the treatment class, as this might be their only hope for retaining vision.
However, on a more positive note, Dr. Sanjay Sharma of Queens University in Kingston, Ontario, presented a paper during the Academy meeting on a decision making model for measuring the impact of Visudyne therapy on the quality of life of those with AMD. He concluded that PDT is a very effective treatment for AMD, and that a patient who is still able to drive, could expect a 10.7% improvement in their quality of life if they received the treatment, while patients who were legally blind could expect a 7.8% improvement. This compares to those who have lost significant vision, and who are assessed as having a 40% reduction in their quality of life. With the looming crisis in vision loss as baby boomers advance into their mid- and senior years over the next decade, more than 500,000 people a year will be diagnosed with AMD, and without treatment, will become more dependent on others (and possibly the welfare system). As his model suggests, "For one patient with macular degeneration to obtain one quality of life-adjusted year, photodynamic therapy will cost a managed care organization $86,721. If the treatment proves effective over the entire duration of a patient's life, this cost will fall dramatically." And what is left unsaid, is what the cost to the system would be for legally blind people, not able to avail themselves of the treatment!
Clinical Update - Wet AMD
During the AAO Vitreo-retinal Update pre-meeting, Retina 2000, Dr. Susan Bressler provided the 24 month data for the TAP study. The data re-iterated the significant difference in those eyes treated with PDT versus the placebo control, with 53% of the Visudyne patients losing less than 15 letters (three lines) of visual acuity, compared to 38% for the placebo group. The sub-group results for predominately classic patients showed even better results, but were not as good for those with minimally classic, or non-classic, disease. For those with predominately classic lesions, 59% lost less than 15 lines, versus 31% of the placebo group; in the minimally classic group, 48% fared better than 44% getting the placebo treatment; and 56% versus 30% for the non-classic disease group. Dr. Bressler concluded that the results seen after 12 months were sustained for the 24 months, with even more compelling evidence to use Visudyne therapy for patients with classic wet AMD. The additional benefits of the 24 month TAP trial were limited, but included; slower lesion growth, reduced leakage, and stable contrast sensitivity. The average number of treatments of the group during the second year was 2.2 out of a possible maximum of 4, resulting in the average number of treatments over the two-year period as 5.6 out of a maximum of 8.
Dr. Joan Miller reported on the 12 month results of the Verteporfin in Photodynamic Therapy (VIP) study for pathological myopia, taking place at 28 clinical centers worldwide. In this case, 72% of those treated achieved less than 8 letter loss (less than 1.5 lines) compared to 44% in the placebo group. Dr. Miller concluded that Visudyne treatment resulted in a significantly increased incidence of stability to improved visual acuity, with no evidence of ocular or systemic tissue risk. Compared to the TAP study, the VIP trial was focused on two groups of patients; those with pathologic myopia and those with an earlier stage AMD (i.e. either those with occult lesions or those with classic lesions but better than 20/40 vision). While the VIP trial was intended to expand the population for Visudyne eligible patients, it was less definitive than TAP. There were statistically beneficial benefits experienced among the pathological myopia group, however there was no statistically significant differences/advantages for those with earlier stage AMD treated with Visudyne compared with placebo.
At the Academy's AMD press conference, Dr. Blumenkranz, coordinator for the Pharmacyclics/Alcon Labs Optrin (LuTex) trials, said that the Phase I/II clinical trials had been completed and were being evaluated prior to beginning recruiting patients for Phase III trials. (It was also learned that a Zeiss diode laser is being used for activation, and not the Diomed system as reported in my January 15th article.)
Dr. Edgar Thomas, head of the Miravant/Pharmacia & Upjohn Photopoint (purlytin) trial, said that it was completing Phase III trials, with nothing new to report.
Dr. Elias Reichel reported on the results to date in the ongoing multi-center clinical trial to treat occult wet AMD, the most prevalent form of the disease, with low intensity laser energy, in the Transpupillary Thermotherapy (TTT) for CNV trial. Rather than photodynamic therapy, this trial uses Iridex's Iris Medical's SLx 810 nm diode laser in its unique longpulse mode to treat the lesions without the need for a photoactivatable drug. He reported that after one year, 80% of patients with occult wet AMD treated with the laser experience a halt in new vessel growth and that 70% had stable or improved vision, without any signs of damage to the photoreceptor cells of the retina. The TTT treatment appears to stop the evolution of the exudative process, and may avoid the development of or progression to the classic form. (Traditionally, half of all cases of occult AMD move into the classic form, with profound visual loss.)
Anecdotal evidence indicates that the TTT treatment is doing quite well in the field, but the reimbursement picture remains cloudy. According to Iridex, reimbursements for this treatment, which are left up to the discretion of local Medicare carriers, range from a low of $127, to a high of $700. Until this discrepancy and confusion is cleared up, and published peer-reviewed studies on its success begin to appear, TTT treatment will be slow to be accepted by most retinal surgeons.
Clinical Update - Dry AMD
At the Iridex booth, a number of speakers provided updates on the ongoing work with both therapeutic and prophylactic treatments for the dry form of AMD. Based on a pilot study in which their 810 nm diode laser was used in a grid-pattern therapy of non-exudative soft drusen, with resorption of drusen seen in 68% of treated eyes and visual acuity improvement in 24% of a subset of treated eyes after a single treatment, the company continues to sponsor additional work in both therapeutic and prophylactic trials. In the therapeutic study, the four-year followup of the original pilot study showed continued improvement in 78% of treated eyes, defined as a reduction of equal to or greater than 50% of drusen from baseline, versus only 8% of eyes not treated, but observed. This resulted in vision improvement by two or more lines of visual acuity in 14% of treated eyes, which suggests a therapeutic benefit for patients with dry AMD who have lost two or more lines of VA due to the presence of central soft drusen.
In the ongoing prophylactic study, Prophylactic Treatment of AMD (PTAMD), a total of 35 neovascular events have occurred in the four years in the 22% of non-responsive to treatment eyes, with half occurring in the observed eyes and half in the treated eyes, indicating no treatment harm nor benefit. However, in the 78% of eyes that responded to treatment with a significant reduction in drusen, there was only one eye that developed CNV. The study authors suggest that a prophylaxis treatment that effectively promotes drusen resorption may be effective in reducing or delaying progression to CNV.
It is beginning to appear that the once dreaded age-related macular degeneration disease, and the visual loss accompanying it in its worst case, will become treatable for the vast majority of those who contract it over the next decade.