Good afternoon, everybody, and welcome to our next fireside chat. Again, my name is James Molloy, specialty pharmaceutical and biotech analyst here at AGP. In this next chat, we're talking with GRI Bio. Their lead program is GRI-0621, a type 1 invariant natural killer T cell NKT antagonist in development for the treatment of idiopathic pulmonary fibrosis, IPF. With us today from GRI is President and CEO Marc Hertz. Thank you for joining us here today, Marc.
Thanks, Jim. Happy to be here.
Perhaps you could give us a brief overview of GRI Bio for our listeners, please.
I'd love to. GRI Bio, we're a clinical stage biotech company focused on regulating the activity of NKT cells to treat inflammatory, fibrotic, and autoimmune diseases. NKT cells, these are critical lymphocytes that sit at the apex of the inflammatory cascade, upstream of many of the key therapeutic targets in the fields that we work in. By selectively inhibiting the activity of these cells, we interrupt disease progression at the source earlier in the inflammatory cascade and restore immune homeostasis. Our lead program, GRI-0621, is a small molecule inhibitor of type 1 invariant NKT cells. It's in a phase 2A study for IPF that will report top-line data next quarter, Q3 of this year. In addition, we have other late preclinical stage assets and a pipeline of about 500 compounds in a library to fuel our growth down the road.
Maybe you could walk us, walk the listeners and myself through the mechanisms of action for 621 and why an invariant NKT cell antagonist, excuse me, is the best target for IPF.
Yeah, absolutely. iNKT cells, these are critical lymphocytes in driving chronic inflammation and fibrosis. We've been able to show that by inhibiting the activity of these cells, this is therapeutic across many different preclinical models of fibrosis. From acute to chronic models, from liver, kidney, lung fibrosis, I mean, probably a half dozen or more different models of fibrosis. Showing that iNKT cell involvement is conserved across so many disparate models of fibrosis gives us a lot of confidence that we're addressing biology that's core to fibrotic disease. The smoking gun, if you will, is that these cells are increased in patients with fibrotic disease and track with worsening or progressive disease. As disease worsens, these cells increase in number and activity in patients, and that might make it a useful biomarker for progressive fibrotic disease.
We and others have shown this in patients across several different liver indications, MASH, alcoholic liver disease, others, as well as in IPF. Secondly, there remains a little bit of a controversy over the role of inflammation in driving IPF. However, recent data supports the role of both the adaptive and innate immune response cells from these different arms of the immune system driving fibrosis in IPF. NKT cells have this unique ability to recruit and activate cells of both the adaptive and innate immune system, and they drive what are known as type 1, type 2, and type 3 immune responses. They are kind of uniquely positioned to influence what we think as the key drivers of fibrotic disease. I guess the last thing I'd say is NKT cells act at kind of both ends of the pathways that drive fibrosis.
There's some of the first cells recruited to sites of injury. They're involved in the normal healing process. They're also involved in kind of the very late stages, the activation of the cells, the myofibroblasts that directly form collagen and extracellular matrix and build up fibrotic tissue. It's kind of this idea, I think, we believe to truly modify disease, you have to kind of, to have a chance of being curative, you need to address core biology driving the course of disease. We think NKT cells fall into that category.
Maybe you could walk our listeners through the inflammatory cascade and how NKT cells sort of get in there and regulate that.
Yeah, they're really interesting cell populations. They constitutively express alarming receptors. Like I said, they're some of the first cells recruited to sites of injury as part of the body's normal healing response. However, repeated or prolonged injury, this is what drives that normal healing response to chronic inflammation and ultimately fibrosis. NKT cells, I mentioned, they drive type 1, 2, and 3 immune responses. This allows them to recruit and activate many, many different cells involved in this process, both from the adaptive arm and innate arms of the immune system. Their roles may change in kind of acute and chronic stages of the disease, but ultimately, they're responsible for kind of quarterbacking, for lack of a better term, the immune responses driving this. They recruit things like neutrophils, which is kind of an earlier step in this process. They activate the inflammasome.
They also activate and recruit TH2 cells, TH17 cells. They drive their production of TGF-β, which is a really important cytokine in fibrotic indications, but also TGF-β independent pathways like through IL-13 that can also activate myofibroblasts.
You have an ongoing phase 2A biomarker trial in IPF going on right now. I recently had a positive IDMC recommendation to keep going. Can you walk through the trial design, the end, the sites, the powering, things like that?
Yeah, absolutely. I'd be happy to give an overview. We're evaluating GRI-0621 once daily versus placebo for 12 weeks in 36 patients. It's a two-to-one randomization, so two patients are on our drug, 0621, one on placebo. When I say placebo, these patients can be on background therapy. If they're taking one of the approved antifibrotics, nintedanib or pirfenidone, they can stay on it, same with the 0621 arms. They don't need to stop their background therapy. The primary endpoints are primarily safety. This is a phase 2A study and tolerability, so PK and pharmacodynamics. We're also looking at biomarkers of fibrosis, pulmonary function tests, differential gene expression, and very, very detailed flow cytometry characterizing the immune system in these patients over time. It's being conducted in the U.S., the U.K., and Australia. It's at 16 different sites. We're about 80% enrolled at this point.
There is a lot more information you can find on our website.
You guided to a six-week interim in the second quarter. Is that still on track? Top line in third quarter, is that still on track? Second quarter is nigh upon us.
Yeah, yeah. I forgot to mention, I think you asked me before also, we did have, so we have these pre-planned analyses from the IDMC, the Independent Data Monitoring Committee. We just completed one. That was after 12 patients had completed two weeks. Happy to say drug continues to be safe and well tolerated, as it has been shown in, I think, roughly 1,700 patients that have been treated up through a year at this point. We also saw an antifibrotic signal in these patients looking at ProC3, which we were quite happy to be able to announce. Again, it's only 12 patients after two weeks. It is very early data. I do not want to kind of over-interpret it, but it was nice to see. We do remain on track to report the six-week interim data.
We announced that we had completed enrollment for that interim analysis earlier this month. We're still on track to report it this quarter, towards the end of this quarter. That will be when 24 patients have completed six weeks of treatment. Again, we'll have primarily safety data, biomarkers of fibrosis. We'll have some pulmonary lung function data at that time point as well. The differential gene expression and flow cytometry are coming a little later. The top line.
Oh, sorry.
Sorry, yeah. Just to confirm, we are still on track for top line data in the third quarter. We'll be able to give a more definitive time point when we've completed the full enrollment, but that should be in the not-too-distant future.
When you talk about biomarkers, are there some biomarkers that are better than others? What should we be looking for here?
Yeah, I mean, that's a really good question. I don't know that anybody has the perfect answer to that question quite yet. There's a lot that are being used. ProC3 is being used. I think it's got a better—I don't want to say better track record, but there's a lot more data in liver fibrosis with ProC3. It's used in lung as well. It seems to be a biomarker. Let me just back up. This is a biomarker of collagen turnover. As fibrosis is being formed, collagen is being processed, and these fragments get cleaved off, and they can be detected in serum. ProC3 is one that's responsive rather early in treatment. Like I mentioned, we've seen a good signal there already after just two weeks. We're looking at, I think, about a dozen in total.
Some of them are relatively novel still at this stage, but others like ProC3 and ProC6 have a little bit more of a track record behind them. We're doing a lot of work to really fully understand the pharmacodynamics of our program. Because we have this cell, this NKT cell that we know is upregulated in fibrotic indications, it allows us to really carefully detail NKT cells in these patients, how those change over treatment, and how that correlates with other markers of fibrosis that we're following.
Now, IPF has been a challenging indication. What do you think are some of the key challenges that folks have had trying to treat this disease state, and what does success look like for 0621?
Yeah, it's been a difficult indication for a lot. It's a very active indication. There's a lot of development. I think that's represented in both the M&A that you see in the space and the activity in the clinic. I mean, these patients, they're in their mid-60s, 70s, 80s even. They're not doing great. It's got a median survival of two to five years from diagnosis. That's whether or not the patients are taking either of the two approved drugs. Those two approved drugs help to slow down the decline of lung function, but don't really improve overall survival. They have some significant side effects that can limit their compliance for patients. I think that's been a challenge for the indication.
I think another challenge has been that a lot of drugs in development for IPF focus on this molecule, TGF-β, that, again, it's very important in fibrosis, but it's quite late in the cascade of events. It's involved in activating these cells that I've mentioned a few times, myofibroblasts that are important in developing fibrotic tissue. Our opinion is you want to try to move as far upstream as you can in fibrosis. The higher up in the cascade you can go, the more effect you have on everything downstream of it. It's kind of like, I have a bad analogy I tend to say of you've got a boat that's filling with water. You take a bucket, you can start throwing water out of it.
If you do not actually go plug the hole, you are not going to really stop what is driving the issue at hand. I think that is a challenge that many have had in this indication, focusing on things that are obviously critical in the development of fibrosis, but it is just maybe a little too distal in the process.
That's an excellent analogy. It gets along the lines of when you're up your ass in alligators, don't forget to drain the swamp.
Yeah, exactly.
Where would 0621 fit in the treatment algorithm for IPF? Should it get approved? What would the potential market look like, do you think?
Yeah, so I mean, it's an orphan indication, and yet nintedanib, one of the two approved drugs, sold about $4 billion last year in sales. It's a very sizable market. There are those two approved drugs, nintedanib and pirfenidone. I already mentioned some of the challenges those molecules have. There's another molecule that I just happen to be at ATS right now at a pulmonary conference, and BI recently or this week presented some of their phase 3 data on their PDE4 inhibitor, which is kind of the molecule that's really furthest along, I think, in potentially getting approval for this. The data was a little bit, not to kind of speak out of school, but a little underwhelming, I think, in that these patients, while it did have some improvements in FVC, they still continue to decline. It's, again, slowing but not halting progression of disease.
Unfortunately for patients, this drug, when in combination with pirfenidone, there seems to be a drug-drug interaction where the PK is dropping quite a bit. The trough values are cut in half. I think even the low dose performed worse than placebo in that trial. With the other approved drug, nintedanib, there seems to be an overlapping of some tolerability issues. There is a question of how will patients be able to stay on that combination. This is a long answer to saying it is a little difficult to know exactly what standard of care is going to be by the time we get there. We are looking at it in combination with antifibrotics in our trial. I think what is going to be critical for anybody working in this space is the traditional endpoint has been FVC, pulmonary lung function tests.
That's becoming more difficult as more and more drugs might enter standard of care, right? Now you're looking to look for changes on top of one, two, maybe three drugs. I think what's going to become important is not only slowing down disease, but halting disease progression. I think we're going to need to have strong pharmacodynamic or biomarkers to help pick the best patients. I think with NKT cells, we have a potential to have that. We've been able to show in a number of fibrotic indications that these cells track with progressive disease. They do that with IPF as well in acute exacerbations.
I can even envision a design where we could go beyond just IPF and say, "Okay, pulmonary fibrosis with increased NKT cells could be a biomarker that we use as part of an inclusion in our program." It is a difficult question to answer because I think it is a moving target. What I know is that FVC cannot be everything for these patients. We need to do more. We need to actually potentially halt disease, not just slow it down and give them a better quality of life.
Enforced expiratory capacity is traditional, but perhaps not the best.
Yeah, and it is, and exactly. Like I say, I mean, trials are getting bigger and bigger as we're kind of slowly stacking these drugs on top of each other.
Are there any opportunities for any expedited approval pathways?
This is an interesting molecule. It's been involved in other phase 3 studies as an oral, primarily in psoriasis. There's a lot of safety data. As I mentioned, about 1,700 patients treated for up to a year. Safety is always an issue in any indication. IPF is no different. The more human safety data you have on a program, you have some advantages there. It'll be a conversation with the agency, but there's an opening where we could potentially do a single registration trial as opposed to having to do two. It's too early to know. We haven't had those conversations.
We're down to our last couple of minutes here. Any final remarks or additional pipeline opportunities you want to run through?
Yeah, I mean, I guess just briefly, I mentioned we do have these other clinical stage or soon-to-be clinical stage programs. We have a program called GRI-0803. We're just finishing up some work and hope to file the IND towards the end of this year. It might go into next year. We've wanted to stay focused on the IPF program. It's an interesting program. These target a different subset of NKT cells called diverse or type 2 NKT cells. They're more of a regulatory T cell population, whereas the iNKT that we're targeting for IPF, that's more of an effector T cell population. We're looking at systemic lupus erythematosus as a potential indication for that first indication for that program. Like I said, we have another 500 or so compounds in a library that we can kind of slowly start developing as well.
All right. With that, we've reached the end of our fireside chat. I can't thank you enough, Marc, from GRI, for joining us here today. And for all of you for listening as well.