Can you talk about what you’ll be covering in your speech?
Despite many patients having been identified with glaucoma, and treated with various medications and surgeries to lower pressure, many of them will still progress. This explains the “need” of the keynote title. We know that pressure control is important, but it's not the whole story. As we start to need to lower the pressure more and more – for example, in normal-tension glaucoma – you have to be more and more aggressive, and so the likelihood of having issues increases.
If you think about it more globally, one medicine can handle a lot of ocular hypertension. But to get the pressure down really where it needs to go, you need two or three medicines, and patient compliance is a huge problem – especially if they’re older and if they have any difficulties with memory or the physical ability to put the drops in. The current therapies are wonderful on one hand, but clearly inadequate on the other.
What kind of scientific advances have fueled this renewed interest in neuroprotection for glaucoma?
The resurgence has come from several key researchers in the field – from Johns Hopkins University, Stanford University, and other places – which have basically discovered molecules and genetic pathways that are highly protective of glaucomatous damage.
One of those pathways we’re particularly focused on is the DLK/LZK (Dual Leucine Zipper Kinase/Leucine Zipper Kinase) pathway. This is a signaling pathway that’s very active early on in development, and then basically is not needed. When it’s activated, this pathway kills cells – and when you're growing, you have to kill almost as many cells as you make to make things work. But then, particularly in neural tissues, this is a pathway that needs to be turned off, because you don't want to kill these neural cells.
In glaucoma, this is one of the first signaling pathways that are activated when you have axonal damage at the optic nerve. The research from Johns Hopkins determined that this pathway was the primary, earliest, and strongest pathway identified with optic nerve axonal damage.
From a company standpoint, we decided to start helping the Johns Hopkins team develop this further. The company is called Perceive Pharma, and it has done animal experiments that show almost complete protection of retinal ganglion cells in the presence of this drug. We're now trying to develop it for sustained release so you don't have to use drops. You just go ahead and see the doctor, get an injection, and months later you come back and get another injection. When Derek Welsbie (now at UC San Diego) – who has been studying this for years – saw the primate results, he said he got goosebumps. It really was that dramatic.
Given that glaucoma progresses slowly, what trial designs will finally allow us to test neuroprotective strategies efficiently?
For cost and other reasons, these trials need to show improved outcomes within a year and within a reasonable number of patients. Historically, there's been no way to do that with visual fields. But now with artificial intelligence (AI), you can select a group of patients that are progressing and show that they are likely to progress because of multiple reasons, as well as where the visual field loss will be. You can be more precise and predictive in determining progression.
The Glaucoma Research Foundation has been investing in this research to get the experts together to identify the best patients and best protocols for visual fields. For example, in terms of imaging, OCT can now see individual ganglion cells – it's amazing. Losing a ganglion cell is not going to show up on a visual field test, it's not going to decrease your vision, and so I think this type of data will act as an important indicator for regulators but most regulatory agencies still need to show a visual benefit of the drug, not just an anatomic benefit.
In the future, I think that the regulatory agencies will say, “Well, if you lose this many ganglion cells over this period of time, then that’s indicative of visual loss and we can approve this drug, depending on how safe it is.” I think that'll eventually happen, but that’s not today.
Which investigational neuroprotective agents do you believe are close to clinical viability?
There are several companies looking at a variety of different neuroprotective agents. Interestingly, for example, topical insulin has been shown in primates to slow damage in the retina. Neurotrophins might also have a role to play.
Three or four other companies are looking at mechanisms of damage. For example, also vascular – trying to increase blood flow so you don't damage the axon. One company is Perfuse Therapeutics. All of these companies are trying to prevent progression with these drugs. So, it's all the same in terms of the trial design.
Patient compliance is still a huge issue in glaucoma treatment – will neuroprotective strategies address this issue?
In some places in the US, less than half the patients even pick up their drug. Even when you've lost a lot of your vision from glaucoma, you may not even be aware of it. Half the patients with glaucoma in the US don't even know they have it! These are huge areas that need to be addressed as well. The good thing is that we have better drugs, better diagnostics, and my guess is that there’ll eventually be an app that is able to diagnose glaucoma.
If an effective neuroprotective therapy does become available, how do you think this would reshape how ophthalmologists manage early glaucoma?
Everything is benefit-risk, and changing practice patterns is a huge issue. I'm an older doctor and I tend to use medicines that I know very well, and so changing people from IOP lowering and interventional therapies to neuroprotective strategies will, I think, take some time. It'll probably be focused initially on the more severe cases, but I do think that very rapidly these types of strategies will go up the therapy chain.
When they train, surgeons learn only one way of doing it. You know, it's kind of like: how do you hit a golf ball or a tennis ball? It's the way you learn how to do it and it's hard to change how you’ve initially been taught. The same goes with practice patterns – unless they are dramatic, they take a while to change.
Are there specific patient groups that would benefit most from early neuroprotective intervention?
The obvious answer is in those patients that are progressing despite current treatments. There are a large number of these patients. Also, I think normal-tension or low-tension glaucoma would really benefit. We don't really understand fully the mechanism of that disease. It may not be exactly the same as high-pressure glaucoma, but we know that medical therapies are not as effective and so those will be groups that are explored, because the medical therapies are not as good, and the pressures are already low so getting the pressures even lower is hard and risky.
Other forms of optic nerve damage – ischemic optic neuropathies or other types of optic neuropathies – might well be involved in early treatment.
People are also exploring neuroprotection for things like geographic atrophy and retinopathy. All of these are important and are needed because we currently don't have good enough therapies for many of these conditions.
