24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients

Craven, E. Randy; Walters, Thomas R.; Christie, William C.; Day, Douglas G.; Lewis, Richard A.; Goodkin, Margot L.; Chen, Michelle; Wangsadipura, Veronica; Robinson, Michael R.; Bejanian, Marina

doi:10.1007/s40265-019-01248-0

Cited by 72 publications

(104 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The implant provided dose-dependent IOP lowering over the first 16 weeks, with IOP-lowering efficacy similar to that of a topical PGA. 100 Remarkably, 28% of the Bimatoprost SR-treated eyes were controlled without use of any additional treatment (rescue topical medication or implant retreatment) up to 24 months after a single implant administration 111 (Fig. 10).…”

Section: Exploiting Mmps In Glaucoma Therapy: Development Of a Bimatomentioning

confidence: 98%

“…During the first clinical trial of Bimatoprost SR, the phase 1/2 APOLLO study, 100,111 the formulation was modified to optimize the rate of biodegradation and drug release, and 6-, 10-, 15-, and 20-mg dose strengths of a second-generation implant were tested in 75 patients with open-angle glaucoma in the study eye. In APOLLO, patients received 1 or at most 2 administrations of implant and were followed for 2 years.…”

Section: Exploiting Mmps In Glaucoma Therapy: Development Of a Bimatomentioning

confidence: 99%

See 1 more Smart Citation

Matrix Metalloproteinases and Glaucoma Treatment

Weinreb

Robinson

Dibas

et al. 2020

Journal of Ocular Pharmacology and Therapeutics

Self Cite

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect. IOP, intraocular pressure; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; TIMP, tissue inhibitor of metalloproteinase.MMPS AND GLAUCOMA TREATMENT 209 210 WEINREB ET AL.

show abstract

Section: Exploiting Mmps In Glaucoma Therapy: Development Of a Bimatomentioning

confidence: 98%

Section: Exploiting Mmps In Glaucoma Therapy: Development Of a Bimatomentioning

confidence: 99%

Matrix Metalloproteinases and Glaucoma Treatment

Weinreb

Robinson

Dibas

et al. 2020

Journal of Ocular Pharmacology and Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the phase 1/2 trial of Bimatoprost SR, at study completion 2 years after a single administration of implant, 28% of patients still had not required topical IOP-lowering rescue medication or implant retreatment. 25…”

Section: Discussionmentioning

confidence: 99%

Dose–Response of Intracameral Bimatoprost Sustained-Release Implant and Topical Bimatoprost in Lowering Intraocular Pressure

Lee

Dibas

Almazan

et al. 2019

Journal of Ocular Pharmacology and Therapeutics

Self Cite

View full text Add to dashboard Cite

Purpose: To compare the dose–response profiles of bimatoprost sustained-release implant (Bimatoprost SR) and topical bimatoprost in lowering intraocular pressure (IOP) in normotensive beagle dogs. Methods: In 1 study, topical bimatoprost 0.001%, 0.01%, or 0.1% was administered twice daily in the study eye for 5 days. IOP was measured at baseline and up to hour 6 each day. Other studies evaluated the IOP response to a single administration of Bimatoprost SR at dose strengths ranging from 8 to 120 μg. IOP was measured before implant administration and during 3 months of follow-up; IOP in response to topical bimatoprost 0.03% was measured prestudy as an internal control. Results: Mean percentage decrease in IOP from baseline at hour 6 (peak effect) across study days was 15.7%, 36.1%, and 24.8% (2.8, 7.0, and 4.0 mmHg) in animals treated with topical bimatoprost 0.001%, 0.01%, and 0.1%, respectively. After Bimatoprost SR administration, mean percentage decrease in IOP from baseline across 3 months consistently increased with increasing dose strength and was 38.7% (7.2 mmHg) with Bimatoprost SR 120 μg. Mean percentage IOP decrease with topical bimatoprost 0.03% was 27.6% (5.9 mmHg). Conclusions: Topical bimatoprost demonstrated a U-shaped dose–response curve; increasing the bimatoprost concentration to 0.1% resulted in reduced IOP-lowering efficacy. In contrast, the dose–response curve for Bimatoprost SR showed consistently greater IOP lowering as the dose strength increased, with the dose strength producing maximum IOP lowering not yet determined. At 60- and 120-μg dose strengths, Bimatoprost SR produced greater IOP reductions than were achieved with topical dosing.

show abstract

“…This sustained, very high drug concentration may cause long‐lived anatomic or physiological remodeling of the outflow pathway that persists after drug is no longer present 1,21,27,33 . This durable remodeling may explain why in phase I/II and III human clinical trials, 28%‐36% of patients still had not required topical IOP‐lowering rescue medication or implant retreatment 2 years after a single administration of an implant, even though the implant was depleted of drug long ago 1,21,24,34 . Similarly, in dogs a single intracameral Bimatoprost SR implant at dose levels of 8 to 60 μg resulted in a sustained dose‐related IOP decrease for at least 3 months and a greater than 15% reduction in IOP was still apparent at 6 month in eyes administered 15, 30, or 60 μg—even though the implant had been completely depleted by then 21,24 …”

Section: Prostaglandin Devicesmentioning

confidence: 99%

Medical anti‐glaucoma therapy: Beyond the drop

Miller

Eaton

2020

Veterinary Ophthalmology

View full text Add to dashboard Cite

Barriers to effective medical therapy are numerous and include difficulties with effective and sustained control of intraocular pressure (IOP) and adherence to prescribed anti‐glaucoma drop regimens. In an effort to circumvent these challenges, a number of new anti‐glaucoma therapies with sustained effects have emerged. Methods for sustained delivery of prostaglandin analogs are being intensely investigated and many are in human clinical trials. Intracameral devices include the following: Allergan's Durysta™ Bimatoprost SR, Envisia Therapeutics’ ENV515 travoprost implant, Glaukos’ iDose™, Ocular Therapeutix's OTX‐TIC travoprost implant, and Santen's polycaprolactone implant with PGE2‐derivative DE‐117. Other prostaglandin‐based technologies include Allergan's bimatoprost ring (placed in the conjunctival fornix), Ocular Therapeutics’ OTX‐TP intracanalicular travoprost implant, subconjunctival latanoprost in a liposomal formulation, and the PGE2 derivative PGN 9856‐isopropyl ester that is applied to the periorbital skin. Exciting breakthroughs in gene therapy include using viral vectors to correct defective genes such as MYOC or to modulate gonioimplant fibrosis, CRISPR technology to edit MYOC or to alter aquaporin to reduce aqueous humor production, and siRNA technology to silence specific genes. Stem cell technology can repopulate depleted tissues or, in the case of Neurotech's Renexus® NT‐501 intravitreal implant, serve as a living drug delivery device that continuously secretes neurotrophic factors. Other unique approaches involve nanotechnology, nasal sprays that deliver drug directly to the optic nerve and noninvasive alternating current stimulation of surviving cells in the optic nerve. Over time these modalities are likely to challenge the preeminent role that drops currently play in the medical treatment of glaucoma in animals.

show abstract

24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients

Cited by 72 publications

References 34 publications

Matrix Metalloproteinases and Glaucoma Treatment

Matrix Metalloproteinases and Glaucoma Treatment

Dose–Response of Intracameral Bimatoprost Sustained-Release Implant and Topical Bimatoprost in Lowering Intraocular Pressure

Medical anti‐glaucoma therapy: Beyond the drop

Contact Info

Product

Resources

About