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The pace of new glaucoma drug development continues, fueled by continuing research into novel mechanisms of action. Three companies, Aerie Pharmaceuticals, Bausch + Lomb, and Inotek Pharmaceuticals, shared their latest results.
The pace of new glaucoma drug development continues, fueled by continuing research into novel mechanisms of action. Three companies, Aerie Pharmaceuticals, Bausch + Lomb, and Inotek Pharmaceuticals, shared their latest results during “New Horizons in Glaucoma Pharmaceuticals” at the 2016 Glaucoma 360 meeting.
Aerie is staking its future on glaucoma, said Tom Mitro, president and chief operation officer. Two products, Rhopressa and Roclatan, are moving toward FDA submission.
“Rhopressa will be positioned as an additive to prostaglandin therapy,” Mitro said. “That market is 16 million to 17 million prescriptions annually in the United States alone. The current market is made up of products 20 to 30 years old that require two or more times daily dosing and can have some serious systemic side effects.”
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Rhopressa is a once-daily eye drop that inhibits Rho kinase (ROCK) and norepinephrine transporter (NET). Both are novel targets for the lowering of IOP and combine three distinct mechanisms of action.
ROCK inhibition increases fluid outflow through the trabecular meshwork and reduces episcleral venous pressure, while NET inhibition reduces production of aqueous. The NET inhibition effect makes Rhopressa helpful in patients with extremely high IOP, Mitro said.
Two phase III registration trials showed Rhopressa used once daily is not inferior to timolol used twice daily in patients with an IOP of less than 25 mm Hg. The company expects to file a New Drug Application in the third quarter of 2016.
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Roclatan is a fixed-dose combination of Rhopressa plus latanoprost. Phase IIb results suggest that Roclatan has the potential to become the most efficacious, IOP-lowering agent in the market, Mitro said.
Roclatan also showed strong effects in patients who had used a prostaglandin prior to clinical trials. After a washout period at the beginning of trials, patients who had previously used a prostaglandin showed the greatest IOP-lower effect compared to all other subgroups. One of two planned U.S. phase III trials is currently enrolling and a second began enrolling during the second quarter. An E.U.-based phase III trial is scheduled to begin during the second quarter of 2017.
Bausch + Lomb, Inotek
B+L has completed phase III trials of latanoprostene bunod (LBN), its novel prostaglandin analogue + nitric oxide donating moiety. The compound is metabolized into latanoprost-free acid and nitric oxide. Latanoprost-free acid increases uveoscleral outflow to reduce IOP, while nitric oxide donors have been shown to lead to relaxation of the trabecular meshwork to increase outflow and reduce IOP.
Phase II Voyager dose-ranging studies versus latanoprost in patients with open angle glaucoma or ocular hypertension showed a statistically significant reduction in mean diurnal IOP at both 0.024 and 0.040 percent doses (p ≤ 0.009), said Megan Cavet, PhD, manager of medical affairs. The 0.024% dose had the largest proportion of patients with a mean diurnal IOP of 18 mm Hg or less at all time points during the 28-day study. Ocular treatment-emergent adverse events were mild to moderate in severity and were similar in both LBN and latanoprost patients.
The more recent phase III Apollo trial compared LBN against timolol in a 3-month efficacy study that was followed by a 9-month safety extension. LBN showed both a statistically and a clinically significant improvement in IOP at all time points during the efficacy study. The IOP-lowering effect was maintained out to 1 year during the safety extension.
“We have seen LBN can result in a statistically significant IOP lowering compared to both timolol and latanoprost,” Dr. Cavet said. “LBN also showed 24-hour, IOP control over a range of baseline IOPs and there were no significant treatment-associated adverse events.”
The company completed a successful phase II meeting with FDA at the end of 2015 for trabodenoson, an agent which appears to treat both the pathophysiology of elevated IOP and the neural damage that can result for excessive IOP.
“We have the opportunity to treat glaucoma in two synergistic ways, the plumbing and electrical pathways,” said Cadmus Rich, MD, vice president of medical affairs and clinical development. “On the plumbing side, we treat the loss of normal IOP regulation at the trabecular meshwork resulting in an increase in IOP. On the electrical side, we treat the pathology common to all glaucoma patients, the neuropathy that disrupts the relaying of the visual signal.”
A trabodenoson-monotherapy program is in phase III with top-line data expected toward the end of 2016. A fixed-dose combination of trabodenoson plus latanoprost is in phase II with top line data expected during the first half of 2017.
Efficacy increases with both dose and time, Dr. Rich said. Trials have not shown any dose-limiting toxicity. The maximum tolerated dose has not yet been determined and there have been no treatment-related dropouts in any clinical trials.