Will More Fixed-combination Medications Become Available in the U.S.?

By Desiree´ Ifft, Contributing Editor

While three fixed-combination topical glaucoma medications have been approved by the FDA, physicians outside the United States can choose from several more options, including dipifevrine/guanethidine (Thilodigon, Alcon), dipifevrine/pilocarpine (Thiloadren, Alcon), bimatoprost/timolol (Ganfort, Allergan), latanoprost/timolol (Xalacom, Pfizer), travoprost/timolol (DuoTrav, Alcon), brinzolamide/timolol maleate (Azarga, Alcon) and the triple combination of brimonidine/dorzolamide/timolol (Krytantek, Laboratorios Sophia).

Notably missing from the U.S. armamentarium is a prostaglandin analog (PGA)-containing fixed combination. Three such formulations had been considered for approval by the FDA but were denied. Travoprost/timolol, latanoprost/timolol and bimatoprost/timolol “didn’t meet FDA requirements for additivity in terms of efficacy,” says L. Jay Katz, MD, director of the Wills Eye Institute Glaucoma Service and professor of ophthalmology at Jefferson Medical College in Philadelphia. “FDA wanted to see a certain amount of pressure reduction above and beyond the prostaglandin alone, and these combinations didn’t meet that bar.”

Angelo P. Tanna, MD, vice chairman of the Department of Ophthalmology and director of the Glaucoma Service at the Northwestern University Feinberg School of Medicine in Chicago, says he would welcome a PGA/beta blocker fixed combination. “It would be a once-daily drop, which of course would be ideal.”

Nathan Radcliffe, MD, director of the Glaucoma Service and clinical assistant professor at New York University Langone Ophthalmology Associates, believes other options — such as Azarga, which could serve as a Cosopt alternative with a different carbonic anhydrase inhibitor, and the triple-action Krytantek, “which is powerful yet well tolerated” — would be useful as well. However, he also says, “While there are still some options we don’t have, the ones we do have fit most patient profiles, allowing us to streamline and individualize therapy. For patients needing upgraded or reinforced therapy, an appropriate fixed combination is likely available.”

The U.S. pipeline is not without activity related to fixed combinations for treating glaucoma:

■ Aerie Pharmaceuticals (aeriepharma.com) is evaluating Roclatan, a fixed-dose medication that combines its experimental drug Rhopressa with latanoprost. Rhopressa is thought to lower IOP via three mechanisms of action: increasing outflow through the trabecular meshwork, decreasing fluid production in the eye and reducing episcleral venous pressure, to which latanoprost would add increasing fluid outflow through the uveoscleral pathway. Both Rhopressa and Roclatan are designed for once-daily dosing. In January, the company announced the acceleration of its previously expected timeline for reporting efficacy results from its Phase 3 trial of Rhopressa. Results are expected by midway through the second quarter.

The company reported that in a Phase 2b trial, Rhopressa demonstrated a strong IOP-lowering effect, with mean IOP reductions of 5.7 mmHg and 6.2 mmHg on days 28 and 14, respectively. In addition, it showed a consistent mean IOP-lowering effect irrespective of patients’ baseline IOP.

■ Bausch + Lomb and Nicox recently announced results from pivotal Phase 3 studies evaluating latanoprostene bunod (Vesneo), which is a new molecule, but a combination of nitric oxide and latanoprost. The companies said the studies met their primary endpoint and Vesneo, described as a novel nitric oxide-donating prostaglandin F2-alpha analog and designed to be dosed once a day, reduced mean IOP by 7.5 mmHg to 9.1 mmHg from baseline between two and 12 weeks of treatment, which was statistically superior to timolol in both studies. Bausch + Lomb plans to submit a new drug application to the FDA for the approval of Vesneo in mid-2015. ■