Ординатура / Офтальмология / Английские материалы / Textbook of Vitreoretinal Diseases and Surgery_Natarajan, Hussain_2008

Ranibizumab

INTRODUCTION

Choroidal neovascular (wet) age-related macular degeneration is becoming more prevalent

worldwide as life expectancy continues to increase. Ranibizumab (Lucentis(TM) Genentech, South

San Francisco, CA) is a monoclonal antibody fragment (Fab) directed towards all isoforms of VEGF-

A that was specifically designed to target wet AMD. The human antibody fragment is produced by

an E. coli expression system and has a molecular weight of 48kD allowing for excellent retinal

penetration. The actions of ranibizumab result in reduced cell proliferation; reduced formation of

new blood vessels, and minimization of vascular leakage.12 It was approved by the US Food and

Drug Administration (FDA) for the treatment of AMD in June 2006.13

CLINICAL TRIALS

In December 2005, Genentech submitted a Biologics License Application to the FDA for the use of

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ranibizumab in the treatment of neovascular wet AMD based on 1-year clinical efficacy and safety

Vascular Endothelial Growth Factor: Inhibitors in Age-related Macular Degeneration

data from the two pivotal phase III trials, ANCHOR and MARINA, and the phase I-II FOCUS trial.13

The efficacy of ranibizumab has been studied in these clinical trials having the same primary efficacy

end point, the proportion of patients losing <15 letters from baseline at 12 months (Early Treatment

of Diabetic Retinopathy Study chart). The multicenter, Phase III, randomized, double-blind, sham-

controlled, 24-month clinical trial evaluated ranibizumab 0.3 and 0.5 mg with minimally classic or

occult choroidal neovascularization (CNV) associated with ARMD.12-13 Ranibizumab showed loss of

less than 15 letters in visual acuity in 90% of the patients as compared to 53% in sham.

A 2-year, Phase I/II, single-masked (masked patient and visual acuity examiner, unmasked

investigator), multi-center trial evaluated the tolerability and efficacy of the combination of

ranibizumab 0.5 mg and verteporfin photodynamic therapy (PDT) compared with verteporfin PDT

alone with predominantly classic CNV.12 Finally, an international Phase III, double blind, active-

controlled study compared ranibizumab 0.3 and 0.5 mg with verteporfin PDT with predominantly

classic lesions associated with CNV secondary to ARMD.14-6 The results showed loss of less than 15

letters in visual acuity in 64% of patients undergoing PDT compared to 96% of those with Lucentis.

The findings of these 3 large clinical trials suggest that ranibizumab was effective and well tolerated

in patients. The benefits apply to all angiographic subtypes of neovascular AMD and across all lesion

sizes. Although the pivotal phase III trials (MARINA and ANCHOR) used monthly injections of

ranibizumab for 2 years, the ongoing PIER17 PrONTO, and SAILOR trials are investigating less

frequent dosing regimens, and preliminary results from the PrONTO study suggest that fewer

injections will most likely result in visual acuity improvements similar to the results from the phase

III trials. When comparing the ANCHOR results with the FOCUS results, it also becomes apparent

that the combination of ranibizumab with PDT does not necessarily result in better visual acuity

outcomes, and the use of PDT may even reduce the visual acuity benefits achieved with ranibizumab

alone. It seems unlikely that combination therapy provides any significant advantage over ranibizumab

alone unless the combination of PDT and ranibizumab can decrease the need for frequent retreatment.

The results from the PrONTO Study already suggest that less frequent treatment with ranibizumab

is possible by using a variable dosing regimen with OCT.13

SAFETY PROFILE

Ranibizumab also seems to be safe, with the 2-year MARINA12,13 data showing no increase in the

incidence of systemic adverse events that could be associated with anti-VEGF therapy, such as

myocardial infarction and stroke. There was a hint of a safety concern, however, in the pooled 1-

year safety results from the MARINA and ANCHOR trials. Although the combined rate of myocardial

infarction and stroke during the first year of the ANCHOR and MARINA trials was similar in the

control and the 0.3 mg ranibizumab arms (1.3% and 1.6% respectively), these adverse events were

slightly higher in the 0.5 mg ranibizumab arm (2.9%).13 These differences are not statistically significant,

however, and probably do not represent a dose-dependent increase in risk because the 2-year results

from the MARINA trial with the same monthly injection regimen showed no increased risk of

thromboembolic events. The most common ocular complaints of patients receiving ranibizumab

injections in randomized clinical trials were transient conjunctival hemorrhage, vitreous floaters,

intraocular inflammation, increased intraocular pressure and eye pain 12,18 The rates of serious adverse

events such as retinal detachment, cataract and endophthalmitis were similar to those that have

been reported with other intravitreal injections and patients should always be treated under strict

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aseptic conditions to reduce this risk.12

Anecortave acetate (AA) is a new molecular entity currently being evaluated in clinical trials for its

ability to protect at-risk eyes of patients with unilateral CNV from progressing to bilateral CNV and

preserving visual function. AA was created by modifying the chemical structure of cortisol acetate.24

Three modifications were made to cortisol to generate AA. The 11β-hydroxyl group, which is essential

for glucocorticoid activity, was removed from cortisol. A double bond between C9 and C11 was

added to prevent in vivo enzymatic rehydroxylation at C11, and acetate group was added at C21 to

enhance ocular penetration and provide ideal physical chemical properties for the administration of

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a slow release depot.24

Vascular Endothelial Growth Factor: Inhibitors in Age-related Macular Degeneration

MECHANISM OF ACTION

AA inhibits the angiogenic proteolytic cascade by inhibiting the expression of urokinase plasminogen

activator and matrix metalloproteinases and up-regulating the expression of the urokinase

plasminogen activator inhibitor-1. In addition, AA inhibits vascular endothelial cell proliferation

and migration. IGF, insulin-like growth factor; VEGF, vascular endothelial growth factor.24

MODE OF ADMINISTRATION

Although several routes of drug administration have been studied for best delivery of AA to the

retina and choroid to target CNV associated with AMD, a unique procedure was developed to

ensure localized delivery.25 Therapeutic level of the drug is achieved only when AA is placed into

direct contact with the posterior scleral surface. The drug is delivered as a periocular posterior

juxtascleral depot using a specially designed blunt-tipped cannula25 to deliver the drug onto the

outer surface of the sclera over the macula. Re-treatment is necessary after 6 months.

CLINICAL TRIALS

The monotherapy study evaluated the safety and efficacy of AA, 30, 15, and 3 mg, compared with

placebo, in 128 patients exhibiting CNV secondary to AMD. In this study the 15 mg dose was

demonstrated to be an effective primary therapy for the treatment of CNV, as determined by visual

function and lesion growth. The percentage of patients that maintained vision with administration

of the drug every 6 months for 1 year was significantly greater for AA, 15 mg, compared with

placebo (P = 0.0323). This was supported by a statistically significant difference in the percentage of

patients who maintained vision at the 2-year time point (73% versus 47%). Furthermore, AA was

superior to placebo in patients with predominantly classic lesions at baseline, with 80% versus 42%

maintaining vision.26,27

A study of the safety and efficacy of AA when used in conjunction with verteporfin

PDT demonstrated that it is safe to use both treatments concurrently for treatment of CNV. In the

third study, AA (15 mg) was compared with verteporfin PDT in this study of patients with

predominantly classic subfoveal CNV. Five hundred thirty patients were enrolled and randomized

to treatment with AA, 15 mg, or PDT. In the AA group, the drug was administered by posterior

juxtascleral depot initially and at Month 6, along with an initial sham PDT, which was repeated

every 3 months if there was evidence of leakage based on fluorescein angiography. The PDT treatment

group received up to four PDT treatments at 3-month intervals based on leakage by fluorescein

angiography, along with a sham posterior juxtascleral depot at the beginning of the study and at

month 6. The percentages of patients exhibiting less than three logMAR lines of visual acuity loss

from baseline were 44.9% and 48.6%, respectively, in the AA and PDT treatment groups (P = 0.4305)

1 year after initial treatment. AA was statistically equivalent to PDT in terms of preventing vision

losses in this study,28 although the primary non-inferiority statistical outcome was not met. In addition,

patients in the AA group who had no reflux of the drug on administration and had retreatment

within 6 months from the initial treatment showed 57% responders compared with 49% in the PDT

treatment group.

AA suspension (15 and 30 mg) is currently under evaluation to reduce the risk of disease

progression in patients with dry AMD (the AART study). The study’s objective is to determine the

safety and efficacy of AA suspension when used to treat patients with non-exudative AMD who are

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at risk of progressing to exudative AMD.

angiography revealed no signs of retinal or choroidal toxicity.

Study 207

Study MSI-1256F-207 was conducted to assess the pharmacokinetics of weekly infusions of squalamine

lactate in subjects with wet age-related macular degeneration. Subjects were assigned to three

treatment groups and received doses of 40 mg (N = 6), 20 mg (N = 6), or 10 mg (N = 6) of squalamine

weekly for 4 weeks. Plasma drug concentration curves were generated from samples collected during

visits for the first and fourth weekly infusions.

Study 208

Study MSI-1256F-208 was designed as a 45-subject masked, randomized, controlled clinical trial of

three doses of squalamine lactate used in conjunction with photodynamic therapy (PDT) with

verteporfin. were randomly assigned to receive 10, 20, or 40 mg of squalamine on weeks 1, 2, 4, and

5 of the trial, followed by monthly infusions to total study duration of 6 months. PDT was performed

on all subjects during week 3 of the trial, and could then be repeated if needed as often as every 12

weeks if the subject met certain VA or fluorescein angiography criteria. An active control group was

comprised of subjects receiving sham infusions of each of the three squalamine doses, but receiving

PDT as defined previously. As the trial neared its conclusion, the decision was made to extend the

study, allowing an additional 1 year of squalamine use on an open-label basis.

In addition to the trials reported here, there are three additional ongoing studies of squalamine

use in exudative age-related macular degeneration. Study MSI-1256F-209 is a 1-year trial of the drug

in 112 subjects using the 20 and 40 mg doses of squalamine. This trial is designed to evaluate the

safety and efficacy of therapy in a slightly larger and more general age-related macular degeneration

population, without the study-mandated use of PDT as a concomitant medication.

As in study 208, a 1-year, open-label extension of the trial has been initiated. Studies MSI-1256F-

301 and MSI-1256F-302 are large, multinational phase III programs that will enroll over 700 subjects

worldwide. The phase III program was initiated in mid 2005, and is designed to lead to submission

of squalamine lactate to global health authorities for the indication of exudative age-related macular

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