An Overview and Update on the ORBIT Trial

A phase 4 study is under way on the real-world outcomes with ocriplasmin.

MICHAEL A. KLUFAS, MD • JEAN-PIERRE HUBSCHMAN, MD

The internal limiting membrane and posterior vitreous cortex are tightly bound together with extracellular matrix components, including laminin and fibronectin.^1-3 As individuals age, the combination of weakening vitreoretinal adhesion and vitreous liquefaction results most often in posterior vitreous detachment.

However, in select cases, the release of adhesion is incomplete, resulting in abnormal vitreomacular traction.^1,2 When the posterior vitreous face is not completely detached from the macula with focal adhesions on optical coherence tomography, it is known as vitreomacular adhesion.^1,4,5 If the traction persists, consequently causing distortion of the structure of the retina, this results in VMT.^1,5

VMT associated with symptoms may also be referred to as symptomatic VMA. Further, VMA/VMT may be subclassified according to the width of vitreous attachment (broad >1,500 µm vs focal ≤1,500 µm), macular thickening, visual distortion, and reduced visual acuity.¹

Traditionally, pars plana vitrectomy was the only treatment for relieving vitreous traction and restoring the normal retinal anatomy of patients with VMA/VMT.^5-7 In 1998, the term “pharmacologic vitreolysis” was introduced, and it involves the enzymatic breakdown of extracellular matrix proteins at the vitreomacular interface to release adhesion.²

Another treatment option with less robust evidence for its safety and efficacy is “pneumatic vitreolysis,” which deserves mention in an area of soaring medical costs.^8-10

OCRIPLASMIN FOR VMA/VMT

Ocriplasmin is a protease plasmin that has proteolytic activity against laminin and fibronectin and is approved for the treatment of “symptomatic VMA” (VMA/VMT) in the United States.¹⁰ Intravitreal ocriplasmin is a first-in-class pharmacologic agent to manage VMA/VMT without surgical intervention.

Based on the results of two parallel, phase 3, randomized, double-blind, placebo-controlled studies, known as the MIVI-TRUST trials, ocriplasmin was approved for the treatment of symptomatic VMA/VMT.⁸ The MIVI-TRUST trials evaluated the efficacy of 125 µg of intravitreal ocriplasmin in patients with focal VMA. The primary outcome was the resolution of VMA at day 28 postinjection.

The trials treated a total of 652 eyes, with 464 receiving ocriplasmin and 188 receiving placebo (0.1 mL of diluted drug vehicle). The actual injection of placebo was an important and unique aspect of the study design, to better understand whether an intravitreal injection itself could change the vitreoretinal interface regardless of drug effect.

At the primary study endpoint (day 28), VMA resolved more often in eyes treated with ocriplasmin than in those injected with placebo (26.5% vs 10.1%, P<.001). Nonsurgical closure of macular hole occurred more often in the ocriplasmin group vs placebo as well (40.6% vs 10.6%, P<.001). Fewer patients required pars plana vitrectomy at six months in the ocriplasmin group compared to placebo (17.7% vs 26.6%, P=.02).

Overall, ocriplasmin was superior to placebo in achieving nonsurgical full-thickness macular hole (FTMH) closure among patients with FTMH at baseline, ≥3-line improvement in BCVA by ETDRS chart, less need for vitrectomy, and better quality of life scores as measured by the NEI VFQ-25. These findings were seen as early as seven days after ocriplasmin injection and were sustained to the six-month endpoint.

Ocular adverse events occurred in a large proportion of all eyes: 68.4% of ocriplasmin-injected eyes and 53.5% of placebo-injected eyes. The most common ocular adverse event reported was floaters. The incidence of serious adverse events was similar between the two groups (7.7% ocriplasmin vs 10.7% placebo, P=.26). Serious adverse events included retina tears or detachment (1.3% ocriplasmin vs 4.3% placebo, P=.11).

Notably, there were three patients with severe visual loss in the ocriplasmin group, and these cases are now thought to be related to outer retinal abnormalities and electroretinogram (ERG) changes. However, spectral-domain OCT and ERG were not performed in the original MIVI-TRUST trial, so the exact etiology in these cases remains unknown.^11-13

Ocriplasmin was approved by the FDA on October 17, 2012, for the treatment of symptomatic VMA and macular holes ≤400 µm in diameter and became commercially available in January 2013 in the US,⁶ where the cost of a single-dose vial of ocriplasmin is $3,950.¹⁴

DATA SINCE MIVI-TRUST

Since the results of the MIVI-TRUST trials, there have been many retrospective reviews of the real-world experience with ocriplasmin,^7,15,16 but they have been limited by small sample sizes and short follow-ups.

Notably, a recent subgroup analysis by Haller and colleagues reported on the combined data of TG-MV-006 (NCT00781859) and TG-MV-007 (NCT00798317), perhaps providing the strongest evidence-based approach for the use of ocriplasmin.¹⁷ The purpose of the subgroup analysis was to ascertain whether the efficacy of the drug was consistently observed among all of the relevant populations.

The baseline characteristics included a majority of female patients (placebo, 61.2%; ocriplasmin, 67.7%) of white race (placebo, 92.6%; ocriplasmin, 92.2%). The mean age was 70.7 years old (range 24-97) in the placebo group and 72.1 years old (range 18-93) in the ocriplasmin group.

A centralized reading center determined that all of the patients had VMA at baseline, and 23.5% also had concurrent FTMH (23.5%). Other concurrent ocular conditions included epiretinal membrane (38.7%), pseudophakia (34.5%), and diabetic retinopathy (6.9%).

Overall, the baseline demographic and ocular characteristics were similar between the two groups, with the only statistically significant difference being the proportion of pseudophakic patients (placebo, 28.2%; ocriplasmin, 37.1%).

Resolution of VMA was achieved more often in patients younger than 65 years of age, patients without ERMs at baseline, patients with FTMHs at baseline, phakic patients, and patients with VMA diameters <1,500 µm.¹⁷

At the day 28 endpoint, 7.2% of eyes with ERMs achieved resolution of VMA/VMT (OR, 6.20; P=.046) vs 23.1% without ERMs (OR, 3.79; P<.001). Overall, patients with FTMHs at baseline had a four-fold higher rate of closure when treated with ocriplasmin vs placebo (40.6% vs 10.6%; OR 5.94; P<.001) at the day 28 endpoint, and this effect also persisted to the six-month follow-up.

Eyes with FTMHs ≤250 µm achieved hole closure at a rate of 58.3% vs 24.6% in the FTMH ≤250 µm group at the six-month follow-up. No holes ≥400 µm achieved closure at six months. The closure rate for holes >250 µm and ≤400 µm at baseline was 36.8% in ocriplasmin-treated eyes vs 15.8% in placebo-treated eyes.

With regard to VA, the proportion of patients who showed a ≥2-line improvement in BCVA at 6 months was 28.0% in the ocriplasmin group vs 17.1% in the placebo group (OR, 1.91; P=.003), irrespective of vitrectomy. A ≥3-line improvement in BCVA at six months was achieved in 12.3% of patients in the ocriplasmin group vs 6.4% in the placebo group (OR, 2.08; P=0.024), irrespective of vitrectomy. VA gains occurred more often in patients younger than 65 years of age and those with a lower baseline BCVA (<65 letters, Snellen equivalent of ~20/50).

SAFETY CONCERNS

Numerous studies have raised postmarketing safety concerns, particularly with regard to outer retinal abnormalities on SD-OCT, ERG changes, and dyschromatopsia.^11,13,15,18 A recent report outlined the safety profile based on the results of the MIVI-TRUST trials.¹⁹ The authors also reported other adverse events of special interest from eight other completed phase 2 studies, as well two ongoing clinical trials with ocriplasmin.

Most of the adverse events were ocular and mild to moderate in severity, with the majority occurring in the study eye. Adverse events were reported in 76.6% of patients treated with intravitreal ocriplasmin 125 µg and 69.0% of placebo patients. Vitreous floaters, conjunctival hemorrhage, eye pain, and photopsia were the most frequently reported adverse events in the ocriplasmin group.

The adverse events more frequent in the placebo group included incidence of new or worsening FTMH, intraocular pressure increases, and cataract. Regarding serious adverse events, 41 ocular events occurred in 37 patients treated with ocriplasmin, with the majority occurring in the study eye, compared to 24 ocular serious adverse events in 20 patients in the placebo group.

The most common study eye serious adverse events reported in the ocriplasmin vs placebo groups included new or worsening FTMH (5.2% vs 8.6%), persistent VMT or VMA (1.1% vs 0.5%), reduced VA (0.6% vs 0.5%), and rhegmatogenous retinal detachment (0.4% vs 1.6%).

Additionally, the number of patients who had acute loss of vision, defined as ≥2-line decrease in vision within the first seven days, was higher in the ocriplasmin vs placebo group (7.7% and 1.6%, respectively).

Among these patients, 83.3% of ocriplasmin-treated eyes and 33.3% of placebo-treated eyes had visual recovery to within 5 letters of baseline at the six-month follow-up. Overall, the combined safety analysis of the two phase 3 studies demonstrated that intravitreal ocriplasmin was well tolerated.

In this same report, data on adverse events of special interest were analyzed to include additional studies, given the infrequency of these events in the original phase 3 trials.¹⁹ This was achieved by pooling data from ongoing trials to a cut-off date of July 24, 2014, to provide a total cohort of 1,008 ocriplasmin-treated eyes and 351 placebo- or sham-treated eyes.¹⁹

Vision decreases considered serious were reported in nine of 1,008 ocriplasmin-treated eyes, which resolved in all nine cases with a median time to recovery of two weeks (with the exception of one patient with exudative AMD and a rhegmatogenous retinal detachment who required one year to recover to baseline).

Although not formally tested in the phase 3 trials, full-field ERG changes were reported in 10 (1.0%) of 1,008 ocriplasmin-treated patients. ERG changes were described as mild decreases in a-wave and b-wave amplitude, with no cases of isoelectric findings. The ERG changes resolved in six patients with a median time to resolution of six months.

Dyschromatopsia alone was reported in 16 (1.6%) of 1,008 patients and was generally described as “yellowish vision.” All but two cases resolved, and both of these cases were lost to follow-up. One case of lens subluxation was reported in a four-month-old premature male infant who received ocriplasmin 175 µg by intravitreal injection. One patient treated with ocriplasmin at the normal 125-µg dose was noted to have phacodonesis during a vitrectomy performed nearly one year later.

Given there have been postmarketing safety concerns among the vitreoretinal community for approved ocular drugs, including ocriplasmin, the ASRS has formed the Therapeutic Surveillance Committee (TSC) to monitor postmarketing drug-related and device-related adverse events.

A recent study retrospectively analyzed the aggregate safety reports of premarketing or clinical trial data (n=999 injections), as well as postmarketing reports through July 16, 2013 (n=4,387 injections), for ocriplasmin.²⁰ Eight categories of adverse events were identified, including acute reduction in VA attributable to either worsening macular pathology or development of subretinal fluid, ERG changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodenesis, impaired papillary light reflex, retinal vessel findings, and ellipsoid zone (inner segment/outer segment) findings on OCT.

The rates of postmarketing reports were lower than premarketing data; however, the authors noted that the postmarketing analyses were limited by significant underreporting. Another benefit of this study was that, given that ocriplasmin is a first-in-class drug, it offered the advantage of capturing safety events that were novel or not yet identified.

The ellipsoid zone loss abnormalities on OCT are one such example that was not observed during premarketing studies, when time-domain OCT was the imaging standard, and these abnormalities may be more apparent on newer, higher-resolution SD-OCT.²⁰

THE ORBIT STUDY

The ORBIT (Ocriplasmin Research to Better Inform Treatment, NCT02079883) study is a multicenter, prospective, phase 4 study currently under way to expand upon the clinical results of patients receiving ocriplasmin (Jetrea, ThromboGenics, Iselin, NJ) in retina clinics in the United States.

The ORBIT investigators plan to enroll 1,500 patients at 120 sites with the goal of assessing clinical outcomes and safety in the real-world setting of retina specialists using intravitreal ocriplasmin for the treatment of VMA/VMT. A complementary study, INJECT, is also being performed at sites outside the US.

Reports by the ASRS TSC have fueled the need for additional studies, such as ORBIT, so that retinal physicians may have proper expectations of the real-world applications, indications, and outcomes with ocriplasmin.

Several series on real-world experience with ocriplasmin^7,15,16 have been published, but they are limited given their retrospective nature, small sample sizes, and limited follow-ups. The ORBIT trial has been designed and is pending to expand on these preliminary studies. As of February 2015, at least 400 patients have been enrolled in the ORBIT study, marking a significant recruitment milestone.

The ORBIT inclusion criteria include patients 18 years old and older capable of providing consent and diagnosed with symptomatic VMA, who will be treated with ocriplasmin at the physician’s discretion in a manner consistent with the US product label. The exclusion criteria include treatment with ocriplasmin for medical conditions outside the US product label or concurrent participation in a research study that prescribes ocular treatment or other interventions.

Data will be collected over the course of the study with up to 12 months of follow-up and will be entered into an electronic database through secure, Internet-based electronic case report forms.

One unique aspect of the study to facilitate the real-world outcomes with the use of ocriplasmin is that, after the baseline visit (day of ocriplasmin injection), no specific visits, examinations, laboratory tests, or procedures are mandated by the study design. The frequency and timing of visits will be at the discretion of the treating physician.

Baseline factors including age, sex, ethnicity, relevant medical history, and ocular history will also be collected. Treating physicians will provide data collected from ocular examinations in both eyes, reflecting only what would normally be performed for the treatment of VMA/VMT.

The primary clinical outcome measurements include resolution of VMA/VMT on SD-OCT, FTMH closure on SD-OCT, mean change in VA from pretreatment values over time, and occurrence and time to vitrectomy if needed. Images will be uploaded to a central reading center and independently reviewed.

Safety parameters to be collected include types and incidences of adverse drug reactions, changes in VA postinjection, SD-OCT findings, and changes in baseline ocular signs and symptoms over time.

The study is not randomized, which will introduce bias, so to reduce selection bias, the study design includes centers that serve large, heterogeneous patient populations, as well as a spectrum of recruiting centers (private practice, academic, multispecialty clinics). For the final data analysis, careful attention will be paid to confounding factors, including physician experience, treatment practices, and willingness to consent, among other factors.

Preliminary data presented on the first 184 subjects enrolled in ORBIT showed baseline characteristics including a mean age of 71 years old, 63.6% female sex, 70.1% phakic eyes, and 20.9% of patients with concurrent diabetes.²¹

According to a press release of March 24, 2015, among the patients already treated for 24 months, 41.7% achieved resolution of VMA by day 28 vs 6% of control subjects. The safety profile of the drug proved consistent.²²

CONCLUSION

In conclusion, the ORBIT study will continue to provide important complementary data to the phase 3 MIVI-TRUST clinical trials by allowing for an improved risk vs benefit analysis for ocriplasmin across a broader spectrum of patients than included in the original randomized studies.

These real-world data with subgroup analyses from the phase 4 study provide important information to retina specialists to further characterize the safety and efficacy of ocriplasmin, and it may better define patients who will benefit the most from this first-in-class, nonsurgical treatment option for VMA/VMT. RP

REFERENCES