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Mechanism of Action
Ocriplasmin has proteolytic activity against protein components of the vitreous body and the vitreoretinal interface (VRI) (e.g. laminin, fibronectin and collagen), thereby dissolving the protein matrix responsible for the vitreomacular adhesion (VMA).
The intravitreal pharmacokinetics of ocriplasmin were determined in a clinical study in patients scheduled for vitrectomy where 0.125 mg ocriplasmin (corresponding to an average concentration of 29 mcg ocriplasmin per mL vitreous volume [approximately 4.3 mL/eye]) was administered as a single intravitreal dose at different time points prior to vitrectomy. The mean ocriplasmin activity levels decreased with time from injection to time of sampling as illustrated in Table 1, according to a second-order kinetic process. At 24 hours post-injection the levels in the vitreous were below 3% of the theoretical concentration reached immediately after injection.
Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in systemic circulation are not expected after intravitreal injection.
Table 1: Mean Ocriplasmin Activity Levels in Vitreous
Samples after Intravitreal Injection of 0.125 mg Ocriplasmin
|Time post-injection (subjects)||5-30 min
|24 hr ± 2 hr
|7 days ± 1 day
|Mean ± SD Ocriplasmin levels (mcg/mL)||12 ±7.6||8.1 ±5.2||2.6 ±1.6||0.5 ±0.3a||< 0.27b|
|a 2 subjects below lower limit of detection, other 2 subjects
at 0.88 and 0.57 mcg/mL
bLower limit of detection
Animal Toxicology and/or Pharmacology
The ocular toxicity of ocriplasmin after a single intravitreal dose has been evaluated in rabbits, monkeys and minipigs. Ocriplasmin induced an inflammatory response and transient ERG changes in rabbits and monkeys, which tended to resolve over time. Lens subluxation was observed in the 3 species at ocriplasmin concentrations in the vitreous at or above 41 mcg/mL, a concentration 1.4-fold above the intended clinical concentration in the vitreous of 29 mcg/mL. Intraocular hemorrhage was observed in rabbits and monkeys.
Asecond intravitreal administration of ocriplasmin (28 days apart) in monkeys at doses of75 mcg/eye (41 mcg/mL vitreous) or125 mcg/eye (68 mcg/mL vitreous) was associated with lens subluxation inallocriplasmin treated eyes. Sustained increases in IOP occurred in two animals with lens subluxation. Microscopic findings in the eye included vitreous liquefaction, degeneration/disruption of the hyaloideocapsular ligament (with loss of ciliary zonular fibers), lens degeneration, mononuclear cell infiltration of the vitreous, and vacuolation of the retinal inner nuclear cell layer. These doses are 1.4-fold and 2.3-fold the intended clinical concentration in the vitreous of 29 mcg/mL, respectively.
The efficacy and safety of JETREA was demonstrated in two multicenter, randomized, double masked, vehicle-controlled, 6 month studies in patients with symptomatic vitreomacular adhesion (VMA). A total of 652 patients (JETREA 464, vehicle 188) were randomized in these 2 studies. Randomization was 2:1 (JETREA: vehicle) in Study 1 and 3:1 in Study 2.
Patients were treated with a single injection of JETREA or vehicle. In both of the studies, the proportion of patients who achieved VMA resolution at Day 28 (i.e., achieved success on the primary endpoint) was significantly higher in the ocriplasmin group compared with the vehicle group through Month 6 (Table 2 and Figure 7).
Table 2: Proportion of Patients
with VMA Resolution in the Study Eye (Study 1, Study 2: Full Analysis Set)
|Study 1||Study 2|
|Difference (95% CI)||Vehicle
|Difference (95% CI)|
|n (%)||n (%)||n (%)||n (%)|
|Day 7||8 (7.5)||54 (24.7)||17.2 (9.6, 24.8)||1 (1.2)||36 (14.7)||13.5 (8.4, 18.5)|
|Day 14||12 (11.2)||57 (26.0)||14.8 (6.5, 23.2)||1 (1.2)||44 (18.0)||16.7 (11.4, 22.1)|
|Day 28||14 (13.1)||61 (27.9)||14.8 (6.0, 23.5)||5 (6.2)||62 (25.3)||19.1 (11.6, 26.7)|
|Month 3||16 (15.0)||58 (26.5)||11.5 (2.6, 20.5)||7 (8.6)||62 (25.3)||16.7 (8.5, 24.9)|
|Month 6||15 (14.0)||60 (27.4)||13.4 (4.5, 22.2)||10 (12.3)||65 (26.5)||14.2 (5.1, 23.2)|
Figure 7: Proportion of
Patients with VMA Resolution in the Study Eye (Study 1 and Study 2)
Total posterior vitreous detachment (PVD) induction in symptomatic vitreomacular adhesion patients was evaluated by B-scan ultrasound. A statistically significantly higher percentage of JETREA treated patients achieved total PVD at Day 28 compared to vehicle treated patients in Study 1 (16% vs. 6%; p=0.014) and in Study 2 (11% vs. 0%; p < 0.01).
The number of patients with at least 3 lines increase in visual acuity was numerically higher in the ocriplasmin group compared to vehicle in both trials, however, the number of patients with at least a 3 lines decrease in visual acuity was also higher in the ocriplasmin group in one of the studies (Table 3and Figure 8).
Table 3: Categorical Change
from Baseline in BCVA at Month 6, Irrespective of Vitrectomy (Study 1 and Study
|Study 1||Study 2|
|Difference (95% CI)||JETREA
|Difference (95% CI)|
|≥ 3 line Improvement in BCVA|
|Month 6||28 (12.8%)||9 (8.4%)||4.4 (-2.5, 11.2)||29 (11.8%)||3 (3.8%)||8.1 (2.3, 13.9)|
|> 3 line Worsening in BCVA|
|Month 6||16 (7.3%)||2 (1.9%)||5.4 (1.1, 9.7)||10 (4.1%)||4 (5.0%)||-0.9 (-6.3, 4.5)|
Figure 8: Percentage of
Patients with Gain or Loss of ≥ 3 Lines of BCVA at Protocol- Specified
Last reviewed on RxList: 10/30/2012
This monograph has been modified to include the generic and brand name in many instances.
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