Article Date: 9/1/2006

AMD UPDATE
Putting Ranibizumab to Work

With FDA approval secured, attention turns to how the new therapy is best used in real-world practice.

The FDA approval of ranibizumab injection (Lucentis, Genentech) for the treatment of neovascular age-related macular degeneration (AMD) puts a powerful
new therapy into the hands of retinal specialists. Dosed monthly in the Phase 3 clinical trials, MARINA and ANCHOR, ranibizumab produced unprecedented favorable results.

But is monthly dosing ideal, or even feasible, for every patient in the real world? One-year results from two additional studies, PIER and PrONTO, provide insight.

In this article, lead investigators and other retinal physicians comment on the latest ranibizumab research and how they are using the new treatment in their practices.

Figure 1. The PIER study met its primary efficacy endpoint by preventing vision loss as measured by mean change in best-corrected visual acuity from baseline to month 12.

PIER: EVALUATION OF QUARTERLY DOSING

In the PIER study (Table 1), patients are randomized 1:1:1 to receive ranibizumab 0.3 mg (n=60) or 0.5 mg (n=61) or sham injections (n=63) once a month for the first 3 months followed by injections once every 3 months for a total of 24 months. David M. Brown, MD, presented the 1-year results for the first time at the 2006 Retinal Physician Symposium (May 31-June 3, Atlantis, Paradise Island, Bahamas). He spoke again with Retinal Physician after the symposium. "The 1-year data show that quarterly dosing is a big advantage over no treatment, but mandatory injections at 3-month intervals does not produce the same phenomenal results as monthly injections," he said. "I am hopeful that monthly injections will not be necessary to achieve those results in all patients, but obviously the PIER protocol is not the answer."

VISUAL ACUITY RESULTS

The study met its primary efficacy endpoint by preventing vision loss as measured by mean change in best-corrected visual acuity (BCVA) from baseline to month 12 (Figure 1). On average, at month 3, patients in the 0.3-mg treatment group gained 2.9 letters; patients in the 0.5-mg treatment group gained 4.3 letters; and patients in the sham group lost 8.7 letters. At month 12, on average, patients in the 0.3-mg treatment group lost 1.6 letters; patients in the 0.5-mg treatment group lost 0.2 letters; and patients in the sham group lost 16.3 letters (p<0.0001).

"In the first 3 months, ranibizumab produced a nice improvement in mean BCVA," Dr. Brown said. "But once dosing changed to quarterly, mean visual acuity returned to baseline level. It is a statistically significant improvement from day 0 to month 3 and an equally statistically significant unimprovement from month 3 to month 12. Although we cannot directly compare different studies, the visual acuity curve for the first 3 months looks the same as it did in MARINA, but the decrease in that curve from month 3 to month 12 was not seen in MARINA, ANCHOR or FOCUS." (Figure 2)

Two key secondary endpoints in PIER are proportion of patients losing fewer than 15 letters of acuity or gaining 15 or more letters. At 12 months, among patients treated with ranibizumab, 83% (0.3 mg) and 90% (0.5 mg) lost fewer than 15 letters compared with 49% in the control group (p<0.0001). Also, 12% (0.3 mg) and 13% (0.5 mg) of patients treated with ranibizumab gained 15 letters or more compared with 10% in the sham group (p=0.87 and p=0.71).

Figure 2. MARINA: 0.5 mg ranibizumab (red line) and 0.3 mg ranibizumab (orange line) compared with sham injection (white line). PIER: 0.3 mg and 0.5 mg dosed quarterly compared with sham. ANCHOR: 0.3 mg and 0.5 mg compared with verteporfin photodynamic therapy (green line). FOCUS: 0.5 mg combined with verteporfin photodynamic therapy compared with photodynamic therapy alone (green line).

Another secondary endpoint is the proportion of patients with 20/200 visual acuity or worse at baseline and month 12. At baseline, 16% of the sham group, 5% of the 0.3-mg group, and 16% of the 0.5-mg group fit that criterion. At month 12, the proportions were 52% of the sham group, 23% of the 0.3-mg group (p=0.0002), and 25% of the 0.5-mg group (p=0.001). "This is a clear indication that this treatment regimen is better than sham," Dr. Brown said.

Dr. Brown also presented results pertaining to two PIER exploratory endpoints. The proportion of patients maintaining baseline visual acuity or gaining more than 0 letters was 22% in the sham group, 53% in the 0.3-mg group (p=0.0006), and 51% in the 0.5-mg group (p=0.003). "It is interesting to note that we are no longer thinking that you can lose two lines and be considered stable," Dr. Brown said. "This exploratory endpoint is a true measure of stability in my mind."

A second exploratory endpoint is the proportion of patients with 20/40 visual acuity or better at baseline and month 12. At baseline, the proportions were 17% in the sham group, 13% in the 0.3-mg group, and 25% in the 0.5-mg group. At month 12, the proportions were 11% in the sham group, 30% in the 0.3-mg group (p=0.007), and 28% in the 0.5-mg group (p=0.01).

SAFETY RESULTS

At 12 months in the PIER study, no serious ocular adverse events, including endophthalmitis, uveitis, retinal tears or vitreous hemorrhage, occurred in either the sham or the treatment groups. Subconjunctival hemorrhage, eye pain and increased intraocular pressure related to the injection procedure occurred more often in the treatment groups but were categorized as mild.

"Ocular inflammation overall was similar across all three groups and not worrisome," Dr. Brown said. The proportion of patients with no or trace ocular inflammation was 98.4% in the sham group, 94.9% in the 0.3-mg group, and 98.4% in the 0.5-mg group.

No deaths or Antiplatelet Trialists' Collaboration arterial thromboembolic events, including myocardial infarctions or cerebral vascular events, occurred. Describing other systemic findings, Dr. Brown said ranibizumab appeared to have a hypotensive effect in the 0.3-mg group (Figure 3), but "the important finding is that it was not increasing." Also, at this point, it is not known why no patients in the ranibizumab treatment groups were immunoreactive at screening, but two patients in the 0.5-mg group were at month 12, Dr. Brown said.

Figure 3. Report of systemic findings at 1 year in the PIER study. In addition, no deaths or Antiplatelet Trialists' Collaboration arterial thromboembolic events, including myocardial infarctions or cerebral vascular events, occurred

PRONTO: EVALUATION OF INDIVIDUALIZED DOSING

Another ongoing study of ranibizumab for the treatment of neovascular AMD, PrONTO, is exploring whether variable, individualized dosing guided by optical coherence tomography (OCT) findings is a more effective way to use the drug. Lead investigator Philip J. Rosenfeld, MD, PhD, explained the rationale behind initiation of the study.

"At the end of the Phase 1/2 ranibizumab trials, investigators had the option of not enrolling patients into an extension study until, in the treating physician's judgment, they needed additional treatment. No stipulations governed how the physician would make that decision," Dr. Rosenfeld explained. "We followed patients with OCT and periodic fluorescein angiograms. Using OCT, we were able to observe the early signs of fluid reaccumulating in the macula before leakage was apparent angiographically. When fluid continued to accumulate and angiography showed leakage or vision began to deteriorate, we enrolled patients in the extension study (FVF2508).

"At first, patients were injected monthly, but the study protocol was later amended to allow injections only as needed. When OCT showed no fluid in the macula and angiography showed no leakage, we did not reinject. We found that some patients never needed another injection over 2 years and some patients required injections every 2 to 3 months. Based on these observations, we designed the PrONTO Study."

SUMMARY OF 1-YEAR RESULTS

Table 1. PIER Study Design

Phase 3b, 2-year, randomized, double-masked, sham-controlled clinical trial
Evaluation of the efficacy and safety of ranibizumab in subjects with primary or recurrent subfoveal CNV with or without a classic component secondary to AMD
Evaluation of the efficacy and safety of ranibizumab administered monthly for three doses followed by dosing every 3 months
Primary endpoint: mean change from baseline at 12 months in best-corrected visual acuity (acuity assessed using ETDRS chart at starting test distance of 4 meters)
43 study sites
184 patients randomized 1:1:1: sham (n=63), 0.3 mg ranibizumab (n=60) or 0.5 mg ranibizumab (n=61)
Principal eligibility criteria (study eye): >50 years; visual acuity (Snellen equivalent) 20/40 to 20/320; subfoveal CNV secondary to AMD; no prior PDT; area of CNV >50% of total lesion area, with or without classic component; if minimally classic or occult with no classic, evidence of presumed recent disease progression (blood, recent growth by FA, or recent VA loss); lesion size <12 disc areas
Mean baseline visual acuity: 20/80 in sham group, 20/80+1 in 0.3-mg group, 20/80-1 in 0.5-mg group
Mean baseline lesion size (disc areas): 4.24 in sham group, 4.38 in 0.3-mg group, 4.01 in 0.5-mg group
Baseline CNV classification: 22% PC, 46% MC, 32% occult in sham group; 13% PC, 37% MC, 48% occult in 0.3-mg group; 21% PC, 30% MC, 49% occult in 0.5-mg group
PDT at investigator discretion if conversion to predominantly classic CNV or loss of >20 letters on two consecutive visits and small minimally classic or occult with no classic lesions with presumed recent disease progression/subjects who received PDT for either of the above reasons could continue to receive study drug
Patients who received pegaptanib during first year of study discontinued from treatment but continued with follow-up

In PrONTO (n=40), a 2-year, single-center, uncontrolled, open-label study, patients received a 0.5-mg intravitreal injection of ranibizumab at baseline and months 1 and 2. Thereafter, they receive additional injections if any of the set criteria are met (Table 2). "The 1-year results are comparable to the results achieved with monthly dosing in the MARINA and ANCHOR trials," Dr. Rosenfeld said.

He reported 100% follow-up at month 12 and key findings:

� The total number of injections administered was 222, the mean number per patient was 5.6, and the median number was five.

� 17.7% of patients needed only the first three injections, 20% needed the first three and one additional, and 5% needed 12 or 13 injections. "This meant that more than one-third of patients required only three or four injections during the first year of the study," Dr. Rosenfeld said.

� Within 1 day of initial injection, mean central retinal thickness decreased by 47 μm; at month 12, the mean decrease was 178 μm (p<0.001).

� On average, patients gained six letters of visual acuity by 14 days after initial injection. Mean visual acuity gain at 12 months was 9.3 letters (p<0.001).

� From baseline to month 12, 95% of patients lost fewer than 15 letters of visual acuity, 35% gained 15 or more letters, and 82% gained 0 or more letters.

� No safety issues, including deaths, thromboembolic events, endophthalmitis or ocular inflammation, emerged.

INCORPORATING RANIBIZUMAB INTO THE AMD TREATMENT ARMAMENTARIUM

Retinal specialists are considering many factors, including the Phase 3 clinical trials and the 1-year results of both PrONTO and PIER, as they incorporate ranibizumab into their practices. For many, the new treatment is the first-line choice. "For the first time, we have a treatment for neovascular AMD that shows a visual benefit at 1 year," said George Williams, MD. "It clearly becomes the treatment of choice for this disease."

However, physicians say, in some cases they take a patient's financial situation into account. Ranibizumab is "absolutely" Dr. Brown's first-line treatment choice, unless a patient has no access to the drug economically. "The Genentech access program makes it easy for patients to have their co-pay funded if their adjusted gross income is less than $75,000 per year," he said. "I also recommend ranibizumab to patients who are self-pay even though treatment with other options, such as off-label bevacizumab (Avastin, Genentech) might be less expensive. Why would we recommend an unproven drug with no formal safety data (bevacizumab) now that one is approved with 4 years of human clinical trial experience (ranibizumab)? That being said, if patients cannot afford ranibizumab, I recommend bevacizumab."

Dr. Rosenfeld disagrees when it comes to self-pay patients. He recommends bevacizumab, the more cost-effective drug, as the first anti-VEGF treatment for them. "If bevacizumab works, then there is no need to progress to ranibizumab," he said. "If the lesion does not become fluid-free or if frequent reinjection with bevacizumab appears necessary, then it makes sense to recommend ranibizumab."

Dr. Williams is employing a similar strategy. "Intravitreal bevacizumab remains a useful therapy in select patients with neovascular AMD, and I discuss its availability, particularly if there are financial considerations." For Eddie Kadrmas, MD, PhD, ranibizumab is the mainstay of treatment for most cases of neovascular AMD, but he said it is also important to think about "the human factor" when choosing a first-line therapy. "For many patients who are not even sure they will live long enough to enjoy the results, multiple injections over the course of a year are not appealing," he said. "Some elderly patients just cannot adhere to a rigorous injection and follow-up schedule."

Therefore, Dr. Kadrmas considers verteporfin photodynamic therapy (PDT) in combination with intravitreal triamcinolone acetonide (Kenalog) (IVTA) in some cases. "When compared to the cost of multiple ranibizumab injections and the physical and time-consuming aspects of these injections, it is certainly a viable option and can be highly effective in certain individuals," Dr. Kadrmas said. "For small, mostly well-defined CNV, I give patients the option of ranibizumab or PDT/IVTA. For large, mostly well-defined CNV, mostly ill-defined CNV, and fibrovascular pigment epithelial detachments, I recommend ranibizumab."

Dr. Kadrmas stays the course for patients who were started on pegaptanib sodium (Macugen, (OSI) Eyetech and Pfizer Inc.) before ranibizumab was approved by the FDA as long as the response to pegaptanib has been satisfactory. "If, on the other hand, the response to pegaptanib is poor, then by all means, I switch to ranibizumab," he said. "Pegaptanib also may be useful in some aspect of maintenance therapy, but this has yet to be proven."

Table 2. PrONTO Study Design

Phase 1/2, 2-year open-label, uncontrolled, investigator-sponsored clinical study, variable dosing with 0.5 mg ranibizumab guided by OCT
Study questions: how quickly does OCT improve; how quickly does visual acuity improve; can improvements be maintained over 2 years with an OCT-guided variable-dosing regimen?
One study site
40 patients
Injection at baseline, month 1 and month 2 followed by reinjection only per criteria
Criteria for reinjection (since last visit): visual acuity loss of at >5 letters with any fluid on OCT; increase in central retinal thickness >100 μm; new hemorrhage; new classic CNV; persistent fluid detected by OCT 1 month after an injection
Principal eligibility criteria: neovascularization involving the fovea; OCT central retinal thickness >300 μm; ETDRS visual acuity 20/40 � 20/400; any lesion type; prior treatment with PDT, Kenalog and Macugen allowed
Mean baseline visual acuity: 20/80
Mean baseline central retinal thickness: 394 μm
Baseline CNV classification: 15% PC, 60% MC, 25% occult (25% retinal angiomatous proliferations)

DOSING SCHEDULE FOR MAXIMUM SAFETY AND EFFICACY

Even when ranibizumab is the clear choice for first-line therapy, the question that remains is the optimal dosing schedule."I do not think we can
apply clinical trial results in a fixed manner to every patient," Dr. Williams said. "In my judgment, clinical trials serve as useful guidelines in the management of individual patients, but not a cookbook that has to be followed to the letter."

The goal of therapy for neovascular AMD is to create a fluid-free macula and maintain it, Dr. Rosenfeld said. "Therefore, knowing what we know today about ranibizumab, to achieve that goal, we can inject patients every month or we can treat until all fluid disappears and then tailor therapy, injecting only when fluid reaccumulates," Dr. Rosenfeld said.

When using ranibizumab, Dr. Rosenfeld injects monthly until the macula is fluid-free and then observes the patient. He reinjects when OCT shows fluid reaccumulation and evaluates how long the treatment effect persists.

"PrONTO demonstrated, and doctors need to be aware of the fact, that some patients need very few treatments and some need more frequent therapy," he said. "Most patients fall into their own particular pattern regarding the need for reinjection. Once we establish that pattern, we have a better idea of how frequently we need to see them."

Dr. Rosenfeld emphasized that, in practice, he does not follow the reinjection criteria used in PrONTO. "In that study we waited until central retinal thickness increased 100 μm before we reinjected so we could demonstrate that when a little bit of fluid returns more fluid follows. We now know this is the case and that gradual vision loss occurs as fluid accumulates, but OCT detects fluid before vision declines. So, in practice, I reinject as soon as there is any sign of fluid reaccumulation based on the qualitative appearance of the OCT scans."

Dr. Brown concurs. "There is no precedent in medicine where edema in a nervous tissue is not detrimental in the long-term," he said. "I think the rational approach is to tailor retreatment to the patient's anatomic responses to the anti-VEGF agent and the disease." Dr. Brown sees patients every 6 weeks following the first three monthly injections. He reinjects if OCT shows any signs of persistent or recurrent fluid and holds treatment if the retina is totally dry. "If they require an injection every 6 weeks, I make the follow-up interval shorter to 4 or 5 weeks. If they do not require an injection after a few 6-week intervals, I relax the observation to every 8 weeks or longer," he said.

WHEN FIRST-LINE RANIBIZUMAB IS NOT EFFECTIVE

Dr. Williams said that in his experience so far, a few patients have not responded to initial treatment with ranibizumab. In those cases, he considers combination therapy by adding IVTA and PDT to an anti-VEGF agent. "Before changing therapy, I observe the patient's response to three or four injections," he said.

Dr. Kadrmas added that combination therapies need to be studied further, "but if ranibizumab is not effective after three monthly injections, switching to IVTA/PDT makes sense. Also, in cases where the initial treatment was IVTA/PDT and no significant response is evident after 3 months, a switch to ranibizumab is appropriate."

NO TWO CASES ARE THE SAME

Physicians must make the decision to start or switch to a particular therapy in conjunction with the patient, Dr. Rosenfeld said. "There is no one answer for everybody," he said. "Balance the known safety and efficacy of the drug as well as its cost."

With ranibizumab in particular, Dr. Kadrmas said, "It appears that the optimal treatment will likely best be individualized."



Retinal Physician, Issue: September 2006