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.
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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.
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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).
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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.
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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
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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
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Table
1. PIER Study Design |
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�
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."
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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
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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