OR WAIT null SECS
A review of glaucoma drugs in various clinical study phases reveals that at least seven new glaucoma drugs were in trials and two others were approved by the FDA in 2017. Many drugs that have progressed the most act on prostaglandin receptors, though some combine this with other mechanisms of action.
At least seven new glaucoma drugs were in clinical trials and two others were approved by the FDA in 2017, according to Gary D. Novack, PhD.
Many drugs that have progressed the most act on prostaglandin receptors, though some combine this with other mechanisms of action, explained Dr. Novack, professor of pharmacology, University of California, Davis. He highlighted the status of several glaucoma drug developments (as of May 2017) during the most recent meeting of the American Academy of Ophthalmology.
Dr. Novack began his search on www.clinicaltrials.gov, looking under glaucoma as an indication and excluding devices and adjuncts. He then looked at all drugs in clinical trial phases I, II, or III submitted between Jan. 1, 2010 and May 31, 2017.
He found 341 trials, and restricted these to “open” status, leaving him with 53 trials, and winnowed these down by using the criterion “new.” He also looked at applications for glaucoma drugs that were before the FDA as either new drug application (NDA) or biological licensing application (BLA).
The newly approved drugs are latanoprostene bunod ophthalmic solution 0.024% (Vyzulta, Bausch + Lomb and Nicox) and netarsudil ophthalmic solution 0.02% (Rhopressa, Aerie Pharmaceuticals).
Latanoprostene bunod won approval from the FDA on Nov. 2. It is metabolized in the eye to latanoprost acid and butanediol mononitrate.
An F2-alpha prostaglandin analog, latanoprost acid increases outflow of aqueous fluid primarily through the uveoscleral pathway. Butanediol mononitrate releases nitric oxide, which is reported to induce relaxation of cells in the trabecular meshwork and Schlemm’s
canal, increasing outflow through them.
Netarsudil won approval Dec. 18, 2017. According to Aerie, the drug inhibits both Rho-kinase (ROCK) and noreprinephrine transporters (NET). Inhibiting ROCK relaxes the trabecular meshwork cells, while inhibiting NET reduces production of aqueous fluid.
Aerie has also announced plans to file an NDA for a combination of netarsudil and latanoprost 0.02%/0.005% in the second quarter of 2018.
Also on the horizon is latanoprost in a new formulation using swollen nanocellular microemulsion, Dr. Novack said.
As for the others, “some have full papers out, some abstracts, some we don’t know but we can assume they all tried to meet the minimum that the FDA requires,” he said.
That minimum standard is 3 months’ efficacy at least as good as a marketed product, usually timolol or latanoprost, and superiority to vehicle, Dr. Novack said. The drug also has to have been administered to at least 300 patients-100 of them for at least 12 months.
FDA approval is not the only criterion for making drugs available. They must also be adopted by ophthalmologists and find their way into insurance companies’ formularies, he noted.
“Also in the United States, the FDA is explicitly prohibited from considering pricing, but that’s not true in Europe and Japan,” he added. “So we will see, as these products are developed there, what happens.”
Turning next to phase III drugs as of May 2017, Dr. Novack mentioned trabodenson, a selective adenosine A1 receptor agonist that increases the expression, secretion, and activation of several matrix metalloproteinases (MMPs). These MMPs remodel the extracellular matrix of the trabecular meshwork and restore its mechanosensitivity to increase aqueous outflow and lower IOP.
Trabodenoson failed the primary endpoint of the first phase III trial in ocular hypertension and primary open-angle glaucoma, MATrX-1. The drug’s maker, Inotek Pharmaceuticals (which recently merged with Rocket Pharmaceuticals), has separately explored a combination of trabodenoson and latanoprost in a phase II trial.
In other phase I and II trials, he found:
Dr. Novack noted he was not able to find much information about the last two.
None of the drugs on the horizon provides neuroprotection, he said, pointing out the difficult regulatory hurdles for such a drug to clear.
“So, Gary, where are the rest?” he asked, anticipating his audience’s question. “That’s as many as I could find.”
It takes about 10 years from invention of a molecule to its approval, he said. The past 3 to 4 years of that time span are the phase III studies and the approval.
“By definition if something is not in phase III now it’s going to be at least 4 years before it’s available to you and your patients,” he said.
The problem is not a lack of good ideas. Rather, Dr. Novack believes complex financial incentives are in play.
Still, glaucoma physicians should not give up hope of improving patient care, he noted.
As Millennials take over from baby boomers in drug development, they may bring new approaches, he added.
“I think they’d take a drug reservoir, have a computer-controlled release of that drug, measure efficacy however you want-IOP, visual fields-then have a feedback on the release of the drug, probably through a phone app,” he said.
Another rho kinase inhibitor, ripasudil 0.4% (Glanatec, Kowa), received approval in Japan in 2014. Gene therapy is also being researched.
Gary D. Novack, PhD
This article was adapted from Dr. Novack’s presentation at the 2017 meeting of the American Academy of Ophthalmology. Dr. Novack disclosed financial relationships with Achillion, Aerie, Aldeyra, Allergan, Allysta, Aurinia, Chengdu Kanghong, CloudBreak, CoDa, CXLO, DSM, Envisia, Eximore, Graybug, JCyte, Kala, Lexitas, Lung, Ocugenix, Panoptica, Peregrine, Qooqoo, SunPharma, Sylentis, Tyrogenex, and Viewpoint.