Dompe's past developments, continual progress in NGF applications

Flavio Mantelli, MD, PhD, Chief Medical Officer at Dompé, sat down with Optometry Times®' assistant managing editor Emily Kaiser to chat about Dompé's role in nerve growth factor (NGF) applications.

Editor's note: This transcript has been edited for clarity.

Kaiser:

Hi everyone. I'm Emily Kaiser with Optometry Times and I'm joined today by Dr. Flavio Mantelli, Chief Medical Officer at Dompe. He's here to share about Dompe's research and clinical development programs in ophthalmology with a special focus for nerve growth factor—or NGF—applications in ophthalmic diseases. Thank you for being here, Dr. Mantelli.

Mantelli:

Thank you very much, it's a pleasure.

Kaiser:

So first, will you please tell us about these NGF applications?

Mantelli:

Yeah, sure. So, if you don't mind, I'll just take a quick step back and mention that NGF, it's neurotrophin. It's been discovered, actually in the 50s by an Italian scientist, Professor Rita Levi-Montalcini, who was awarded the Nobel Prize for this discovery in the 80s. And it's a polytrophic molecule. It has a huge potential of treatment in human diseases. It was the first of the neurotrophin family to be discovered, and it's a molecule that is present in our bodies, in healthy condition, in healthy states, and it helps drive the differentiation and proliferation of neurons as well as epithelial cells. And that's where the research in ophthalmology started. And it was the end of the 1990s, where a group of researchers—again from Italy actually—talked about bringing NGF as a topical treatment for an ophthalmic disease of the ocular surface, where you have both damage to corneal nerves and damage to corneal epithelium. And that is neurotrophic keratitis.

So as you know, today NGF is a treatment for a condition that is neurotrophic keratitis, and the science behind it goes to the underlying mechanism of disease, which is the damage to corneal innervation. The cornea is a vascular to be transparent, and nerves not only provide sensation to the cornea, and that leads to blinking, that leads to reflex tear secretion, for instance, but it also provides nourishment to the cornea. And when the corneal innervation is damaged, it sort of triggers that detrimental loop.

So what happens is that patients who have damaged their corneal nerves, that can be by very various etiology—could be postherpetic, it could be diabetic, it could be following corneal surgery—then they enter this detrimental loop where they have damage to the corneal epithelium, that instead of spontaneously healing gets worse over time because there is this lack of trophins by the corneal nerves, and there is this lack of protection in those by blinking, and those by reflex tear secretion to protect and lubricate the cornea.

And this is where NGF eye drop treatment enters the paradigm of treatment for these patients. So this was a condition before Oxervate was approved and before the clinical trials that proved Oxervate to be the right treatment for these patients. This was a condition that was chronic, and was a progressive disease that started with minor epithelium damage and progressing towards corneal ulceration, corneal melting and perforation.

Today, with the advent of NGF eye drops, it's a treatment that can be managed. So it really changed the natural history of the disease. It changed the management of the condition by ophthalmologists and optometrists, and it changed the lives of these patients because these are now patients that can have a therapeutic alternative that goes way beyond what was in the past.

In the past, all you could do was try to slow down disease progression. And in case of damage that could lead to corneal perforation and visual loss, undergo surgery to save the eye. So really, what I usually say is that with Oxervate for neurotrophic keratitis, what we see is the tip of the iceberg, because NGF—and the neurotrophins in general—have a huge potential that is not only in ophthalmology, it's also in neurodegenerative diseases, for instance. And what we've done, and we're very proud of what we've done, was to finally bring—after so many decades following the discovery of NGF—we made it to bring NGF to patients, to physicians who actually treat patients with, in this case, a rare condition like neurotrophic keratitis with high unmet medical need. And hopefully in the future NGF will help patients with other conditions as well. And this is why we talk about indications for NGF and not only neurotrophic keratitis that is our current labels for Oxervate.

Kaiser:

Yeah, and what is the future of Dompe's role in NGF applications and other therapeutic areas?

Mantelli:

So [Dompe] is committed to keep working and gaining knowledge—scientific and medical knowledge—on the potential use of NGF to help other patients with other diseases. And this starts, of course, from ophthalmology, where we are already present, and we are expanding knowledge. In the clinical trials that were used for registration of Oxervate, we enrolled the patients with stage 2 and 3 of neurotrophic keratitis—so the more severe forms of the condition—while we've just completed another study on stage 1 of the disease. So it's the same patients, but they're taken a bit earlier. What we're trying to see is if it would be even better to treat patients earlier to reduce the potential visual complications, for instance, in these patients induced by more profound lesions of the cornea and scarring of the cornea.

So we are still working to gain more and more knowledge on the topical ophthalmic use of this drug. We have currently running two phase 3 clinical trials in severe Sjogren's dry eye disease. So that's another population where there is a very high unmet medical need, because these are patients that have a condition that goes beyond just having dry eyes. Some patients with Sjogren's, for instance, have reduced corneal sensitivity. So they have characteristics that are similar to patients with NK stage 1.

So we are working on ophthalmic indications, we are working on also developing formulations that are appropriate to test in clinical studies for indications of the back of the eye—so targeting the preferential targets of nerve growth factor and neurotrophin, hence, the neural retina, the retinal ganglion cells or the optic nerve. So this is something that the company is already doing. And in the future, there is the possibility to open the research and the clinical development, also, to neurodegenerative diseases—so the central nervous system. Of course, there was the dream of scientists and physicians who work with NGF, in the decades before, they actually got involved in building a plant to produce NGF. Because this is not trivial.

I mean, a very important aspect is that we are talking of a complex molecule to produce that we have a dedicated plant in Italy that is cGMP approved by the regulatory authorities. And this was an important step to help patients get an NGF to treat their conditions. And it was a mandatory step, of course, to have the possibility to produce this molecule in an efficient way, and to produce it in the right way. Because NGF needs to have the right 3D structure to bind to the receptor and to work. And this is really not trivial from production standpoint, because we produce it in E. Coli. So in prokaryotic cells, and we induce these bacteria to produce an NGF that has the very same sequence of the human NGF. So it's a human recombinant NGF. But of course, we needed an additional step to make sure that after production, this protein would fall in the right tertiary structure to be effective, to work, to bind to the receptors on the human cells. And this is also part of the technology that we developed just to make this product.

So having all this technology and this ability, as I mentioned, you know, the tip of the iceberg; and I reiterate now, we have a lot to discover, but we have possibility to do it. You know, we are willing to invest—our company is very committed to raise the level of the scientific knowledge beyond NGF. We have a plant that is the only one that is producing NGF and is capable to produce NGFs and other neurotrophins. And so other indications hopefully will come and we are really committed to do research in this perspective.

Kaiser:

Thank you so much for your time today.

Mantelli:

No, thank you, it was the pleasure.

Please see the full Prescribing Information for Oxervate, which is available at www.oxervate.com/prescribing-information.