Sustained-release topical rings promising for glaucoma

Take-home: A single bimatoprost topical ring has been shown to be effective and safe for lowering IOP over six months, according to results from a phase II study.

Topical rings (Bimatoprost Ring, ForSight Vision5) that release bimatoprost continually for up to six months have safely lowered IOP in a phase II clinical trial, according to researchers.

“It was very well tolerated by the patients,” said James D. Brandt, MD, director of Glaucoma Service, UC Davis Eye Center, Sacramento, CA.

“While patients who used the inserts had slightly less reduction in IOP than patients taking timolol eye drops, the pressure reduction was significant and the rings promise to provide substantial benefit to the many patients who have trouble taking eye drops – whether due to memory issues or the simple physical challenge of using drops correctly,” Dr. Brandt said.

Results of the phase II study were recently published in Ophthalmology (2016;123:1685-1694) Dr. Brandt will present 19-month data at the 2016 annual meeting of the American Academy of Ophthalmology in Chicago.

The ring is designed to address a key problem in the management of glaucoma, he said. While eye drops can effectively lower IOP, patients struggle with understanding glaucoma, remembering to take the eye drops on a regular schedule, and often lack the physical dexterity to apply the eye drops correctly. As a result, patients often do not administer the drops as often as they are needed. Recent literature has shown only 15% of patients remain consistently adherent to their glaucoma eye drops over a 4-year period.¹

Solving adherence problems

Solving adherence problems

Because the ring is replaced at the regular office visits by a patient’s eye care provider, the patient does not need to struggle with taking or remembering to take daily drops. The bimatoprost ring contains 13 mg of bimatoprost mixed into a silicone matrix over an inner polypropylene ring ranging from 24 to 29 mm in diameter; the different diameters allow a custom fit for each patient based on their measured intercanthal distance. The ring elutes a continually declining dose of bimatoprost starting at about 35 µg/day at day 0 (day of insertion) and reaches about 6 µg /day at day 180. To place a ring, the eye care provider gently uses his or her fingers to retract the eyelids and places the ring circumferentially in the upper and lower fornices.

“The ring has been designed so that a doctor would size and apply the rings to start treatment, then replace them every six months at a regularly-scheduled follow-up visit,” Dr. Brandt said.

To understand whether the rings could provide a better alternative for patients who face adherence challenges, the phase II study examined the safety and efficacy of the bimatoprost ring and compared them to eye drops as a control. Dr. Brandt and the investigators at nine additional clinical sites recruited 169 people with open-angle glaucoma or ocular hypertension.

During the eye drop washout period at the start of the trial, each patient wore non-medicated rings bilaterally to assess comfort and fit. Of the 169 participants who wore the non-medicated rings, approximately 90% found the inserts comfortable. After the washout period, the investigators removed the non-medicated inserts from all the participants, then randomly assigned 64 patients to receive the medicated inserts and 66 to the control arm.

This was a double-masked study – patients in the control arm wore non-medicated rings and used non-preserved timolol 0.5% ophthalmic solution twice a day; patients in the medicated group wore rings containing bimatoprost but also used non-medicated eye drops (packaged identically to the timolol to preserve masking) twice a day. Timolol was used in the control arm since it is the most frequently used comparator in regulatory studies of IOP-lowering drugs.

Effectiveness

The two study arms were well-matched demographically. The mean age was 65.6 years; 41%  were male. Sixty-four percent of the bimatoprost patients and 60.6% of the timolol patients had glaucoma; the remainder had ocular hypertension. Mean central corneal thickness was 552.9 µm at baseline in the bimatoprost patients and 564.4 µm in the timolol patients. Inclusion criteria specified a mean IOP (after washout) of 23-34 mm Hg at 8 a.m. and 20-34 mm Hg 2 and 8 hours after the first measurement.

The investigators compared the bimatoprost rings to timolol using a statistical model of noninferiority. The test criterion for the non-inferiority test was that the upper limit of the 95% confidence interval of the difference between the mean reduction in IOP for the bimatoprost ring arm as compared to the timolol arm should be within 1.5 mm Hg. This statistical test was conducted at three time points (8 a.m., 10 a.m., 4 p.m.) at weeks 2, 6, and 12 (and was calculated, but not formally tested, at months 4, 5, and 6).

A single administration of the bimatoprost ring provided sustained IOP reduction for six months. The statistical test was successfully met at most but not all of the time points; however, the study was underpowered relative to the treatment effect observed in this phase II study. In phase III studies, the statistical confidence intervals will be smaller due to the larger sample number of patients enrolled. The smaller confidence intervals will make it easier to meet the statistical non-inferiority test described above. “We anticipate in a much larger study that bimatoprost ring and timolol eye drops will be statistically very close to each other if not the same,” Dr. Brandt said.

The bimatoprost insert appeared less effective than one might expect with bimatoprost eye drops, even though the dose delivered by the ring is similar to the total dose delivered by once-daily drops of 0.03% bimatoprost ophthalmic solution. This finding was consistent with an earlier finding that bimatoprost (and other prostaglandins) becomes less effective the more frequently it is administered, as was demonstrated in the phase III bimatoprost (Lumigan, Allergan studies.²To provide additional IOP-lowering, a ring may be developed that can elute more than one IOP-lowering drug.

The vast majority of the patients kept the rings in their eyes without the aid of their physician for the duration of the study. At 12 weeks the bilateral retention rate was 93.1% and at six months it was 88.5%.

Adverse events

The bimatoprost group had a higher percentage of ocular treatment-emergent adverse events than the timolol group. The difference in ocular adverse events was 45.3% versus 34.8%. The most common adverse event was eye discharge, followed by conjunctival hyperemia and punctuate keratitis. Ten patients withdrew from the study due to adverse events, nine from the bimatoprost group and one from the timolol group. All of the adverse events resolved.

Researchers are also working on another alternative treatment for glaucoma – injectable, sustained release drugs. Still, the topical rings are less likely to cause severe adverse events, Dr. Brandt said.

“There is a very good safety record of injections being done for patients with macular degeneration,” he said. “But the vast majority of patients with macular degeneration receiving regular injections are likely to lose vision quickly without the injections, so the small risk of injections is acceptable. In contrast, in someone with early glaucoma, the risk of going blind during their lifetime is relatively small, so any intervention in these patients must be very safe. The bimatoprost ring has demonstrated a safety and efficacy profile that fits the needs of an early stage glaucoma patient.”

Earlier this year, Allergan announced it will acquire the company that makes the bimatoprost ring, ForSight Vision5. “The acquisition of this ring technology demonstrates our commitment to advancing products that can profoundly change the way patients receive treatment – through innovation that helps address non-compliance, increases adherence and improves tolerability,” Brent Sunders, chief executive officer, Allergan, said in a statement.

References:

1          Newman-Casey, P.A., et al., Patterns of Glaucoma Medication Adherence over Four Years of Follow-Up. Ophthalmology, 2015. 122(10): p. 2010-21.

2.         Brandt, J.D., et al., Comparison of once- or twice-daily bimatoprost with twice-daily timolol in patients with elevated IOP - A 3-month clinical trial. Ophthalmology, 2001. 108(6): p. 1023-1031.