Lori Birder: Well, thank you, Alan. And as mentioned, well, it's great to be here and to give a chance to give a little bit of update in some of our work in terms of aminopurines and the management of LUTS. So this is just going to be a brief overview, but as you know that there is definitely an unmet need for new medications in functional urology. There are a number of challenges with many of the current therapies. Some have limited efficacy relative to placebo, and there can be systemic side effects, which I'm sure we're all aware. Often that's because they're not really all that selective. So there's a broad action well beyond the urogenital tract. Due to many of these side effects and perhaps even incomplete symptom relief, many patients simply stop taking their medications. So there's really poor patient adherence, and older patients have often a number of comorbidities. So this creates a risk for drug-drug and drug-disease interactions. So we've had an interest for a particular enzyme called purine nucleoside phosphorylase, or PNPase for short, because we really believe that this actually helps to control or regulate cellular functions. The activity of this enzyme, as shown in this little panel below, really determines the balance between protective purines and as one example, that's inosine shown on the left and uro-damaging purines shown on the right.
And the reason they're uro-damaging is because they're a source of free radicals. So any imbalance in this activity, and this enzyme is really found in all of our cells and that can occur in aging or inflammation, really we believe contributes to LUTS. So we have a new treatment approach, and that's called 8-aminoguanine or 8-AG. It is a new drug class. It has a different mechanism of action. It actually inhibits the enzyme PNPase, thereby restoring the purine balance. It can actually correct the underlying pathology so it doesn't just mask symptoms. And by doing so, it can restore cells to their normal healthy function. So these urotoxic purines can certainly damage the bladder via urinary ROS production, bathing the bladder wall with ROS for a number of years. These purines can actually be transported through the bladder wall and they're done so via nucleoside transporters. We have found in preclinical animal models and even in patient biopsies that aging can increase the expression as well as the activity of these transporters. So then this increases cellular damage. So LUTS patients, obviously due to a whole range of causations, can exhibit a number of negative outcomes. There can be an increased bladder volume at first desire to void and impairment of voiding efficiency. Often this is associated with vascular damage. Ischemia, a drop in blood flow, there can be changes in the bladder nerves themselves, changes in density. Certainly sensation can be altered. And this also is accompanied by fibrosis, which can impact or impair bladder compliance.
So any medicine or therapy is usually initially tested in vitro, but legally and ethically, this must also be tested in a suitable animal model before any clinical trials in humans can occur. So 8-AG treatment we find has a number of benefits in our preclinical animal models, both in aging as well as in pain. 8-AG can restore the healthy bladder function, it can reduce ischemia, increase bladder blood flow. It restores the collagen fiber elasticity, which is altered with aging and even with models of pain. It can prevent and even treat bladder pain, for example, cystitis. And it definitely improves the function of the mitochondria, which these organelles are needed for all of us to survive. So our take-home message is that in a number of preclinical animal models, which do exhibit similarities to many patients, these animal models do exhibit a change or an increase in the activity of this enzyme, PNPase. And if we inhibit PNPase with 8-AG, this can ameliorate a number of these cellular and functional lower urinary tract abnormalities. But 8-AG has benefits in multiple indications not only aging and cystitis, but in cases of peripheral neuropathy and even age-related macular degeneration. And we have clinical pathology findings with a contract research organization or CRO, which show no toxicity or safety concerns thus far, or any off-target effects, which is important. We really believe that inhibition of this enzyme with 8-AG can improve storage and voiding symptoms, especially in the older adult. And thank you for your attention.
Alan Wein: Thank you so much. That was a terrific summary. So it's a great example of how to combine basic science findings with clinical applicability. So of the things that you studied, what's the most likely target to go after first? In other words, in the animal models that you've tested, what would seem to be the human analog that you would go after first, assuming that the toxicity issues were worked out?
Lori Birder: Now that's a very good question, and it's probably difficult to answer. It obviously depends on clinical trials as well, in terms of if you want to call it sort of the best patient target. But in terms of what to look for, I would probably highlight chronic pain conditions. At least in the pain world, anything to manage or to benefit patients with chronic pain is definitely an unmet need. And even after decades of research, no matter what the pain condition is, there's really nothing out there to help these patients. So we're talking about cystitis, either hemorrhagic cystitis due to chemotherapy or radiation or interstitial cystitis, and that could even include pelvic injuries. So neuropathies, peripheral neuropathies after pelvic surgery. Even after chemotherapy, where there's very likely still to be damage to the bladder wall, damage to peripheral nerves. So I would probably highlight chronic pain conditions, and that's a number of these either relative to cystitis or peripheral neuropathies.
Alan Wein: So for the clinician, I mean, we see the end product, we don't see the work that's gone into a particular product or series of compounds prior. So what would be the next step? I mean, somebody's going to look at this video and say, wow, I don't understand why this isn't on the market. So first of all, is this given systemically or is this introduced into the bladder?
Lori Birder: So we can do both. So for our preclinical work, we mainly give it systemically. We actually give it in the animal's drinking water. And while many people might say, well, it's a little difficult to control how much you're getting, but we do monitor exactly how much. The nice thing about that is we can control, it's a constant dosing interval, so it's just continuous. But we can also give it as kind of a, if you want to call it a little slurpy, so they can get it once or twice a day, which is kind of the dosing regimen for patients. We've also given it intravesically and it does work. Systemically works a little bit better, but we can give it via both routes of administration. As to why this isn't in the clinic yet, that's a really good question. And so we're probably at what most people refer to as the Valley of Death. So we have a ton of preclinical efficacy evidence and not just in the bladder.
So my collaborator, Ed Jackson, has spent decades in research with this particular molecule. There's a lot of background information in terms of this benefits the cardiovascular system. So it's not just target selective, it really benefits a number of organs. But to get it to where we are now to the clinic, or at least first-in-human, we have to be able to link up with a CRO or a contract research organization for independent testing. And so that's something that the FDA definitely requires. And so what's called IND-enabling studies, it probably would cost about 5 million US dollars to get us there. And that's not something that we can actually use NIH grants for. We would actually need venture capital or to link up with a particular company that can help us get there. So that's really the problem is financial. We do have some CRO data, but it's not nearly enough to actually get us to a meeting with the FDA, unfortunately.
Alan Wein: So someone on the outside would have to see enough promise in this to figure, hey, if this works, my company can really make a profit on this. And so they would be the investor?
Lori Birder: Yes.
Alan Wein: Is that how it goes?
Lori Birder: That's one possibility, certainly, yes. And they definitely could make a profit. We don't see any downsides in all of the years of work, and not just my work, but also with Ed Jackson. So we do see a number of possibilities for an outside investor or for a company that can actually maybe have the resources to do some of these... Many companies already work with CROs to do a lot of their work to get it closer to the clinic. So if they have connections linking up with us, I think that would be fantastic as well, yes.
Alan Wein: So can you monitor the level of this? Can you tell by some kind of test how much is too much?
Lori Birder: Well, so far we've done, again with a CRO, so we've done a minimum and maximum dosing. And so I don't know what's too much, but we've given... I think it's 20 times or the CRO has given 20 times the amount that we typically would propose for an animal or for a patient. And there's no toxic effects. So again, it's not a lot of these IND-enabling studies that were done so far by a CRO, but what we have done with them, it doesn't suggest toxicity. It does suggest a dosing interval once or twice a day for adequate dosing levels, but we don't see any toxicity so far, or even any off-target effects in other organs.
Alan Wein: So that's really exciting. I mean, we really appreciate your being on the channel and telling us about that. But listen, thank you so much again for being on. Really appreciate it.
Lori Birder: Well, thank you for inviting me. I appreciate it very much. Thank you.