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Barriers challenge development of aqueous outflow drugs
Despite these challenges, however, the novel class of drugs holds promise for improving trabecular outflow.
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Among the top challenges in developing new aqueous outflow drugs, the first is determining whether there is an unmet medical need; the second is raising the funds needed to develop those drugs, according to a physician.
Even though there are already a number of useful glaucoma drugs, the need for new drugs that work on the outflow system still exists, Barbara M. Wirostko, MD, told colleagues at the Glaucoma 360 New Horizons Forum in San Francisco.
“Upwards of 75% of patients can be on more than one IOP-lowering agent, so there is definitely a need for new, innovative medications,” Wirostko told Ocular Surgery News in a subsequent interview.
With regard to payer reimbursement, as recently as 5 to 10 years ago, one needed only to demonstrate superior or non-inferior efficacy in relation to standard of care to achieve regulatory approval. However, this is no longer the case, according to Wirostko.
“Today we have to demonstrate not only equal efficacy, but an added advantage, as well. Otherwise, a new product will not be reimbursed at a favorable price point,” she said. “These drugs will ultimately be compared to a generic prostaglandin and be priced as such.”
The current reimbursement landscape, coupled with efficacious and relatively safe generic prostaglandins, presents a challenge for anyone attempting to develop innovative IOP-lowering agents — and one that is not soon likely to change, Wirostko said.
Barbara M. Wirostko
Additional challenges
The current preclinical models used to move drugs from the research stage to the clinic are suboptimal for these classes of outflow drugs, according to Wirostko.
“Millions of dollars are spent on efficacy and safety work in animal models,” she said. “Unfortunately, the animal models for trabecular meshwork outflow modulation are not ideal. They are not translatable because they cannot mimic the true underlying pathology in the outflow system of the human aging glaucomatous eye.”
Another obstacle in developing new drugs is the need to evaluate what the overall greater benefit of this new compound is from both a partnering and marketing perspective.
“We always think of IOP agents being used as monotherapy, but we truly don’t know how to value, or even ideally design, clinical trials to show true additivity that drives the value proposition,” Wirostko said. “What is the additional value of another 1 mm Hg to 2 mm Hg of IOP lowering?”
Lastly, it can be difficult to separate the safety of a new drug from its efficacy, providing a wide enough therapeutic index that allows the compound to move forward in development, she said.
Drugs in development
As a glaucoma specialist, Wirostko said she welcomes another IOP-lowering agent but feels true innovation will come from non-IOP-lowering mechanisms that focus on retinal preservation, such as neuroprotective, blood-flow modulators and anti-apoptotic agents.
According to Wirostko, the best tissue to target for new IOP-lowering drugs is within the trabecular meshwork/outflow system, which is also the area of increased resistance for aqueous outflow.
“Ideally, these drugs would have a synergistic effect with other medications currently marketed like aqueous suppressants and prostaglandins,” she said.
Among the drugs currently in development, Wirostko is enthusiastic about two eye drops from Aerie Pharmaceuticals: molecule AR-12286, a Rho-kinase (ROCK) inhibitor, and AR-13324, a ROCK inhibitor combined with an aqueous suppressant.
“The mechanism of action of a ROCK inhibitor makes sense,” Wirostko said. “This new class of compounds should complement existing drugs. ROCK inhibitors have been shown to improve perfusion in the central nervous system after intracerebral hemorrhages, and Fasudil is approved for such an indication in Japan. They offer anti-inflammatory and anti-apoptic properties that could also be very attractive in managing glaucoma.”
The dual-agent AR-13324 may achieve significantly better efficacy than a ROCK inhibitor alone, Wirostko said.
Based on present efficacy, safety and in many cases frequency of use, most clinicians envision these ROCK inhibitors as second-line or additive therapy.
“A lot of the compounds in development that have not progressed through clinical trials were being dosed twice a day,” Wirostko said. “The ROCK inhibitor AR-12286 alone is currently in phase 2 development as a once-a-day at night.”
Other compounds with unique mechanisms of action are also in phase 2 development, including adenosine-1 receptor agonist, an outflow agent from Inotek Pharmaceuticals that also allows for improved aqueous flow.
“An expected physiologic side effect of many of these novel compounds is vasodilation of the conjunctival blood vessels,” Wirostko said. “This has hindered these compounds as a topical agent because there is too much hyperemia. Although not pathologic, this side effect may well be a commercial barrier. Patients do not like red eyes.”
Neuroprotection
OSN Glaucoma Board Member Louis B. Cantor, MD, told colleagues in his keynote address at the meeting that neuroprotection is becoming a more integral part of the therapeutic strategy for treating glaucoma. Like Wirostko, Cantor is encouraged by the potential of ROCK inhibitors and adenosine-like drugs.
Louis B. Cantor
“We have not had a new class of drug since the 1990s,” Cantor said in a follow-up interview. “These two new classes of drugs are completely different from anything we have available today.”
ROCK inhibitors have the potential to assist uveal scleral outflow or aqueous suppressant-type drugs that affect the ciliary body, according to Cantor, and the adenosine-type drugs have the opportunity to take advantage of improving trabecular outflow.
Advances
Glaucoma is not simply an eye disease; it is also a central nervous system disease, Cantor said.
“As I was reviewing the literature at the end of 2012 and looking ahead to 2013, there were a number of what I thought were very interesting advances that could fundamentally change how we approach, diagnose and ultimately treat glaucoma,” Cantor said.
Changes in the brain occur early in the disease, he said. When the optic nerve is damaged by glaucoma, there is a profound effect on the connections.
“The input throughout the brain changes, so there are a lot of compensatory and other changes going on in the central nervous system,” Cantor said.
Such changes in the eye and brain early on in the disease process reinforce the need to treat glaucoma “earlier and more aggressively,” Cantor said. “We should be trying to prevent, or at least minimize, these downstream changes.” – by Bob Kronemyer