Hi, everyone. Thank you so much for joining us today. Before we kick this off, I do want to point out to the audience that we welcome questions. Please post them in the Q&A section at the bottom of your screen. Type them in as they come to you, and we will address those questions at the end of today's discussion. I'd now like to turn this over to Harvey Briggs, FORCE Family Office's Chief Communications Officer. Harvey, the floor is yours.
Thank you, Callie, thanks, everyone, for taking the time to be with us today. I'm really excited to be moderating this discussion with Bob Bitterman, CEO of Phio Pharmaceuticals, and Dr. Jim Cardia, a research scientist who's been instrumental in the development of RNAi technology. Today, in addition to a quick update on Phio's PH-762 development program, we want to focus on INTASYL, Phio's technology platform, its unique mechanism, and its versatility. Bob, it's great to have Jim join us today. I understand he has a long history with Phio, dating back to the predecessor company, RXi. I believe that's where the initial work with RNA interference started.
Before we turn to Jim, though, could you summarize where Phio currently is with its development program with the PH-762? Obviously, a lot of that success in the clinic has to do with the groundwork Jim has done in the discovery phase. We'll get more to that later.
Yeah. Thank you, Harvey. In fact, if it wasn't for a lot of the work that Jim laid the groundwork for, we would probably not be talking today. On that note, for some of you who may be familiar with our company and our program, we are an immuno-oncology company that is specializing in treating various forms of cutaneous carcinomas, which are basically skin cancers. We do that with the infamous technology that you just cited, called INTASYL. We recently completed a phase Ib clinical trial, let me give you the results and status on that. The treatment phase of that study was completed back in January. I know there are some people who actually have been asking what's going to happen next.
After the treatment phase is completed, we still have a number of other things that had to happen in the study, not the least of which was each of the patients who were treated, they had to be followed for 113 days after their first injection. That took us through the observation phase, going out into the end of March. The treatment phase, which was pretty interesting and exciting, because the results of that were pretty fascinating. What they told us is that in this dose escalation trial, which was increasing the concentration of the active ingredient over five different cohorts of patients, that all of those patients actually had no form of serious adverse event, no dose-limiting toxicity, and no form of what you would call immune reactions.
Because what we are dealing with in our technology is making a temporary adjustment to the immune system to stimulate or to reawaken it to treat these patients. Well, in addition to the safety profile that we learned in this, the other factor that was very interesting, it wasn't the primary endpoint, but was the efficacy outcome, were those five cohorts. By the time we got to the fifth cohort, we had a response rate of 85%, of which out of the cohort of seven patients, we had four of those who had 100% pathological clearance of cancer at five weeks after their first injection, one that had greater than 90% at that same time period, one that had greater than 50%. That constituted what was defined in the clinical trial as a response. 85% response rate was actually quite noteworthy.
With that, of course, the next step was to find out, at the end of the period of follow-up, going into the 113th day, was there any recurrence, or was there any progression of the disease, to find out, in which case there was not. Subsequently, we're now in a phase where we're assessing all of the accumulated pharmacokinetic data. This is all the different types of data that represents the drug that was in the blood at different points in time, from injection point, looking at what was the maximum concentration of drug that went into the body, what was the clearance rates, how many days, what was the half-life of the drug.
All of this is now in the process of being summarized and finalized and analyzed, and will become the basis of a significant portion of what we'll be submitting to the FDA in the very near future, as we look to see what our next study will be. At this point, we're in that phase, looking to wrap up the last of the summary of the clinical study report. As I said, the exciting part probably came out back in the early first quarter when we got those top-line results. The rest of this is a lot of blocking and tackling, but it has to be done. Eventually, within another few weeks or so, we should be sending this down to the FDA for review. That's pretty much the status of where we're at this point.
I think probably we may touch on a little more of this later, but, I think this is probably a good time to turn it back to Jim.
Great. Well, thanks, Bob. Jim, you started with RXi after completion of your postdoc at Harvard. Talk about the circumstances that attracted you to work there. Was it the science, the personnel? Did the journey turn out the way you expected?
Thanks, Harvey. During my postdoc, I studied the formation of fat cells, in order to identify different targets for drug therapy for the treatment of metabolic disease, such as diabetes. For this work, I used an exciting new technology called RNA interference, or RNAi for short, to study proteins involved in this process. Importantly, RNAi is a tool which can be used to reduce levels of a messenger RNA in the cell. This messenger RNA, or mRNA, carries information from our cell's DNA and translates it into protein. By using RNAi, you can reduce levels of a specific messenger RNA, resulting in lower levels of that messenger RNA's protein. You can use this to study biological systems.
Jim, back when you were starting at RXi, the predecessor company to Phio, what was the status of RNAi as a tool, as a discovery at that point in time? Because that was pretty early in its development, right?
Correct, Bob. That was around the 2008, 2009 timeframe, where RNA was really positioned as a potential therapeutic breakthrough that could address targets of any disease that small molecules and even monoclonal antibodies could not tackle. However, the issue was that no one knew how to deliver these RNAi compounds across the cell membrane, and into the cell for them to work in a therapeutic setting. I was very excited about the work that was being done at RXi at the time to address this challenge. Really, at the time, I could not pass up the opportunity to work on a potentially revolutionary medicine with a great team of scientists to overcome this major challenge.
From your experiences and perspective, how did RXi/Phio change over the years while you were there, the strategy, the programs, management? Maybe you could comment on some of the noteworthy pivotal inflection points in the company.
Two, Harvey, come to mind. The first shift was when the company moved from an RNAi platform discovery company to clinical development. At that time, the company was really focused on dermatology and ophthalmology fibrosis. For me personally, I learned a great deal about clinical development, and more importantly, manufacturing of siRNA drugs for clinical testing. The next important inflection point really was a shift to immuno-oncology. At the time, the market was very bullish on immuno-oncology, given the recent successes of PD-1 antibodies such as KEYTRUDA and LIBTAYO. These were life-saving therapies. Very importantly, the capital markets were receptive to immuno-oncology, and Phio was in a great position because they had just acquired an approach to potently and specifically target the PD-1 gene using RNAi, and this was really pivotal in making Phio the company it is today.
Bob, you cite INTASYL technology, that it's the shaping force behind the company. How would you describe the Phio value proposition today?
I think when it comes to the driving force, probably it's fair to say that the driving force are the people who are basically pulling all of this together. The tool, if you will, is INTASYL, which has this unique ability to be both selective and precise in targeting different genes, as Jim had just mentioned, the PD-1 gene. This really plays to our tagline, which states that we make immune cells more effective at killing cancer cells. That's really what drives this business. It really is fascinating, the ability to be this precise and to basically have a significant degree of versatility as well because, as I think Jim may explain, depending on how deep he gets into this, we can change the structure of INTASYL in a way that can target other genes as well besides PD-1.
In any event, I think it's probably kind of interesting if we have Jim maybe go in and explain a little bit more detail in terms of the mechanics of how this works. Jim?
Thanks, Bob. INTASYL compounds, they're designed with unique chemically modified RNA sequences that selectively silence the messenger RNA of proteins utilized by tumors to evade the immune system. These proteins are responsible for suppressing the immune system. By reducing these proteins, INTASYL therapeutics can enhance the anti-tumor response of the immune system and support the body's ability to better recognize and eliminate cancer cells.
Can you elaborate on that a little further?
Happy to, Harvey. INTASYL utilizes a naturally occurring process that exists inside the cells, as you mentioned before, Harvey. This is called RNA interference. The body uses RNAi to combat or fight foreign materials such as viruses. First, let me provide a little background and clarification on the roles of the messenger RNA and the DNA in this process. First, the messenger RNA really is an intermediate molecule that carries the genetic information or instructions from the DNA to our cellular machinery responsible for making proteins. The DNA stores the actual genetic information required for the cell to function, and while the mRNA serves as the messenger that conveys these instructions to produce specific proteins. Importantly, these proteins can sometimes be disease-causing, and in certain cases in cells, these proteins can contribute to disease initiation, persistence, and progression.
Really, Phio's goal using RNAi is to turn off or reduce that messaging from the mRNA that is producing the disease-causing protein. INTASYL allows us to selectively target the specific protein we wish to turn off.
It targets these proteins, and you turn them off. Can you talk in simple terms that maybe I could understand how it works on a more granular level?
Happy to, Harvey. On a more granular level, INTASYL siRNA is made up of two short complementary RNA strands of different length that form a double helix. These strands are called a guide strand and a passenger strand. The guide strand is responsible for directing the specific cleavage of the target messenger RNA we want to silence, while the passenger strand, that helps facilitate delivery of the guide strand to its destination, after which the passenger strand is discarded. How this works in the tumor is first INTASYL is injected into the tumor. After it's delivered into the tumor, INTASYL is delivered intact across the cell's membrane and into the cells due to its proprietary chemistry and chemical modifications. This is a very important characteristic of Phio's technology.
The drug or the guide strand, supported by the passenger strand, is deposited or loaded into something called the RISC complex, and RISC stands for the RNA-induced silencing complex. Once there, the RISC complex cleaves or silences the disease-causing messenger RNA, and RISC really acts as a pair of molecular scissors to cut the disease-causing messenger RNA. It does so by matching the sequence of the guide strand from the siRNA to the cancer-causing gene's messenger RNA. This action leads to a reduction in the gene's protein levels and now allows the body to better harness its immune system and fight cancer.
That passenger strand is like a delivery truck dropping off a package at your home, maybe with a robot in it, and it contains electronics that can scope out your perimeter and detect unwanted presence and neutralize it, right? It's like something that it takes care of the invasion, right?
That may be one way to look at it, Harvey.
I think Jim thought that was less than totally sophisticated, but the point, I think, is made that.
Yeah.
This has a unique ability to go where you tell it to go and not to go someplace else, and once it goes there, it knows exactly the job that it has to do without getting mixed up with anything else, and, in the world of drug technology, avoiding any types of collateral damage or side effects, which is another interesting feature what makes this drug what it is. I digress, I'm sorry.
No, that's great. Now that we have a basic understanding, I guess I do anyway. What INTASYL does, can you comment on the manufacturing and what's involved in that process?
Yeah. In order for INTASYL compounds to work as intended, the siRNAs must be manufactured using state-of-the-art chemical synthesis technologies. In addition, we also need to incorporate Phio's proprietary chemical modifications to achieve enhanced stability of the siRNA, enable cellular uptake in the tumor, and also facilitate tissue distribution. These modifications are what imparts drug- like property directly into the siRNA molecule. Very importantly, efficient delivery into a broad range of cell types and tissues without the need for a delivery-enabling vehicle, or what Phio likes to call formulation enhancers. The absence of a delivery vehicle is a very important point of differentiation between Phio's INTASYL platform compared to other siRNA programs.
I mentioned it before, but it's very important, let me emphasize this again. It really is a major challenge to get an siRNA product across the cell membrane intact. Again, this was the major delivery challenge I mentioned in my first response. Other siRNA compounds, to accomplish this, they may add a cell-targeting molecule or formulation enhancement materials. You may have heard of LNPs, which are lipid nanoparticles or viral vectors. These additions to the formulation can facilitate delivery, but they also can carry with them different toxicities, which may go into the bloodstream. Importantly, Phio does not need these delivery enhancements because INTASYL has a unique design to carry the siRNA across the cell membrane intact until it reaches the RISC complex.
Got it. You recently announced that you started commercial scale-up of your drug substance, and that's a critical piece of the overall CMC work, correct?
Correct, Harvey. Really, this is a very critical element that's probably the least understood by outsiders. It's not as glamorous or as exciting as the science and clinical study outcomes, but you can't have a drug without it. CMC is part of an FDA submission package, and without it being complete, the FDA will reject your submission.
CMC stands for Chemistry, Manufacturing, and Controls. The detailed elements of these three components are critical to satisfying FDA in any development program.
What was done to lead up to the commercial scale production then?
Importantly and excitingly, we started commercial scale production manufacturing last week of a batch. We're very excited to kick off that very important milestone for Phio. Really to give you a little background on how we got there. An agreement was signed with the manufacturing company 12 months ago. Over the last 12 months, we spent developing approximately 12 different chemistry processing steps to scale up from the small- scale clinical batches, to production scale and commercial scale levels. At each step, we were required to establish methods to test and characterize the material. We need to validate these test methods to guarantee reliability and consistency to prove to the FDA or other regulatory authorities that the process can be repeated and replicated with precision. All these processes are recorded in about 12 different manuals or records containing over 500 pages.
After the manufacture of the material, we test it and characterize the material using multiple different methods of analysis, followed by validation of the manufacturing process and controls. Importantly, this is all done to manufacturing guidelines from the regulatory authorities, such as the FDA, to be in line with Current Good Manufacturing Practices. These are things which the FDA requires. There's really no shortcuts at all to this, Harvey.
Wow.
Harvey, if I could just interject one point on this. Back when we were putting together our 2025 budget back in the end of 2024, we made a commitment, as a board, that we would make this CMC process as robust as we possibly could so that it would meet any types of requirements that the FDA would require on a CMC basis, in the future, regardless of what stage of clinical development we're in. I think Jim gives you a perspective. It took 12 months in the making to do all this and with very detailed follow-up and with all the documentation and the manuals. I saw this from afar, talking on occasion with the analytical chemists, with Jim, with our tech ops people.
This is not a small task and oftentimes can be the downfall of many companies in the biotech space if they don't have this thing put together right. We actually did this in advance of when we actually had to do it. We'll have this basically complete in another three to four months. Just wanted to add that.
Great. You can't sell a drug if you can't make a drug, right?
I want to shift gears a little bit. We've heard a lot about monoclonal antibodies. How is INTASYL siRNA different from a monoclonal antibody?
I like to think of the difference in terms of three major things. At first, what it is. Next, how does it work? Finally, where does it work? INTASYL is, as we just mentioned about the manufacturing, it's a synthetic drug-like compound that acts inside the T cell to reduce production of the protein at its source. It does this by targeting and degrading the messenger RNA. Again, messenger RNA is a molecule that contains the instructions for making these proteins. With less mRNA available, the cell produces lower amounts of the disease-causing protein. In contrast, monoclonal antibodies, they're biologics. They work on the surface of the tumor cells by recognizing and binding to specific proteins that cause or contribute to disease. They attach to a particular site on the target protein and block that protein from carrying out its normal function.
This interaction occurs on the surface of the cell, the disease-causing protein is still present on that cell, its activity is blocked by the antibody. INTASYL works a bit differently. Rather than blocking the protein after it's been produced, it turns off the protein at its source, inside the cell. Bob likes to mention, you can think of INTASYL like a faucet that turns off the water. Another important difference is the where. Where did this therapy exert its effects? Monoclonal antibodies, you inject them, and they circulate through the entire body. They may bind to their target proteins on disease cells, but they can also bind to the protein targets on healthy cells. This can contribute to unwanted side effects, and sometimes these side effects can be very serious side effects, impacting the autoimmune system.
In contrast, INTASYL compounds are designed to act locally and act primarily at the specific tumor site. This essentially limits the exposure of the healthy tissues. Accordingly, INTASYL has the potential to reduce certain side effects compared with monoclonal antibodies.
That brings up the idea of safety then. Based on your early investigation with INTASYL, are you surprised at the safety profile which emerged from the study?
I wouldn't really say I was surprised by the safety profile of 762, Harvey, that we saw from the clinical study. siRNA, as a class, have demonstrated favorable safety and tolerability profiles across several different clinical programs. In addition, Phio generated a substantial amount of preclinical data supporting the advancement of PH-762 into the clinic. The findings from the human study were consistent with the preclinical observations and provide additional support for the potential of PH-762, as well as the INTASYL platform. These early data reinforce the belief that INTASYL has the potential to be applied, not only in oncology, but across a broad range of other diseases, where targeting gene silencing may provide therapeutic benefit.
That versatility, what makes INTASYL so versatile?
Well, Harvey, the fact that Jim talked about these two asymmetric strands that consist of these various nucleotides, and 762, those nucleotides are arranged, specifically designed in a fashion to shut down the PD-1 protein. You could change the sequencing of those nucleotides to target a different gene to silence. In fact, one of the other programs that's in our portfolio that we're getting close to putting an IND together on is another gene called the BRD4 gene. That was an interesting drug that at one time was tried to be delivered, or they attempted to deliver the silencing of that through a small molecule pharmaceutical, which basically shut down a number of other things in the process and created some rather dire consequences in the study. What makes this versatile is that you can alter the structure of the sequences to basically silence what you want.
We've done this, actually, we've confirmed silencing of over 30 compounds with the work of the scientists going back a long time ago. It's not just changing the sequence there, it's also, if you look at the PD-1, while it silences PD-1, PD-1 affects obviously different forms of skin cancer, but it has implications in other types of squamous cells as well, head and neck cancer, breast cancer, and a few others. The versatility of silencing PD-1 for, say, another company who has a different disease focus, this drug could also be effective in treating other diseases that might be within their purview. That's what basically makes this versatile.
One last point is that it's conceivable that you can use the INTASYL, any of its various compounds, in combination with other drug therapy too, such as a monoclonal antibody, to get maybe an extra beneficial kick, for a particularly troublesome gene or disease that you're trying to cure. It's those elements that really make this as versatile as it is.
Great, thanks. If you had to boil it down to three things, what makes this technology unique?
Well, I guess from my perspective in the company, it's the selectivity and the precision that you can basically go after anything conceivably that you need to downregulate. That makes it unique. I think the other factor, which we've now demonstrated in a human trial, is the safety factor. Having dose escalated 20-fold from the earliest dose concentration to the last, and seeing no types of immune response problems or dose-limiting toxicities. This drug, it'll have to be further tested in more human trials, but it appears to be pretty safe. It's safe not only because it targets the specific gene and not another gene, but the other factor that Jim talked about was the importance of the delivery. He talked about the fact that there are no delivery enhancements in this.
Delivery enhancements in the form of, say, lipid nanoparticles, which are very common in getting drugs transported across the cell membrane. They can have their own toxicities in and of themselves. We don't have to worry about that, so we have no local toxicities in that regard. I think safety is critical. Selectivity, the precision, all of these make this drug very special and very adaptable to many different types of situations.
Great. Well, those are all my questions. Callie, it looks like we have a bunch of questions in the audience. Do you want to handle those?
Sure. Yes, we do. As larger pharmaceutical companies continue to invest heavily in RNA-based therapeutics, where do you believe INTASYL provides the greatest competitive advantage compared to other platforms currently in development?
Well, I know there are a couple of other companies that are in RNA interference in different therapeutic spaces. I mean, Alnylam, which has been very successful, has started to venture off from the liver into cardiac disease. I think a lot of that really depends on how specific these companies want to look at different segments. If you think about heart disease, even if we think about skin cancers, there are so many different forms of it, and depending on what form that takes is probably going to have an impact in terms of what type of variation on RNA interference the company may want to deal with. Which gene is involved, and how is that going to play into it if they're looking to down-regulate?
Where INTASYL, I think fits, is that there's an awful lot of flexibility and adaptability in the technology, and it's up to some of these larger companies if they see that they would like to complement their existing therapies, or supplement their existing therapies with this. They certainly would be able to do that and have the confidence, hopefully, that this is a very safe and adaptable type of concept. Now that we've completed that first study, we have demonstrated that those people did not get 85% clearance by accident. It was because we shut down that PD-1 protein.
Great. Beyond cutaneous squamous cell carcinoma, which additional cancer indications are the highest priority for PH-762, and what factors will determine the order in which you pursue them?
Well, I think the order in which we pursue them will be a function of our relative competence to understand what they are. We're a small organization. We have seven full-time employees and about four to five subject matter experts at any one point in time. We don't have either the luxury on the one side or the bureaucratic castle of a large infrastructure, so we have to pick and choose. I think there's a couple of obvious one. Head and neck is a place that is a squamous cell carcinoma, a place where they appear. That's an area which is reachable by injection easily, although most places on the body now can be guided to an injection.
Head and neck is a place where there's a fair amount of disease, both here and in other parts of the world, where, due to different elements in the environment, smoking, drinking, things of that nature, some of the countries could possibly benefit from that type of an indication. For the most part, there are other areas within skin cancers that we're going to focus on because that's where our expertise as a company has been. When you start to move away from the core of your knitting, so to speak, you can start to get into not knowing what you don't know, even though sometimes we like to think we do. Our focus will probably be to stay within the area that we're in now and to encourage some other potential partners to look at other applications where they may have expertise.
Great. Thank you. How does the new U.S. API manufacturing for 762 de-risk the CMC program and support scalability as you look ahead to registration trials?
That's an interesting question and a fair one. I think it's a good one as well because, as I mentioned earlier, as a company, we took it upon ourselves to take as much of a robust approach to putting CMC in the format that it's currently in. You don't have to have that level of detail and sophistication in your chemistry manufacturing process for a phase Ib trial. We did not. We were able to go in with far less. You can do so with a phase II trial without that level.
We made the decision that we will basically have this thing as tight and wrapped as we can so that regardless of the circumstances that we may face in a future study, that we will be able to meet what's called the cGMP, the Current Good Manufacturing Practices, which the FDA will hold us to, regardless of if it's in a registration trial. I think we've taken the same approach, if I can just expound on that for a moment, with regard to our toxicology. Another major component of what's taken place this year has been the conduct of our three-month non-human primate study. When we entered into the first clinical trial, we had a 30-day window in which we could apply drug demand. We're now in the process of being able to expand that to 90 days.
While we may not change our dosing regimen at our next trial, if there is a potential business development partner who is treating a different disease. Or if they have a requirement for a longer treatment regimen, we will be able to satisfy that with the additional tox work that we are doing now. All of this is about future planning and executing it and getting it in place.
When will your next trial take place?
The exact design of that is still subject to the final review by FDA. But we are still targeting to have that occur in the first quarter of next year. We believe that that is still doable, based on regardless of what type of feedback we get from FDA. We are very involved in the final processing of the protocol to make sure that we can not only get the same results that we got in the first study, but that we can improve on them and also try to discover if there are certain nuances in the data that can maybe point us in a particular subset of direction that could give us additional value added. First quarter of next year is what we are shooting for.
Great. Is Phio getting any acquisition inquiries?
Acquisition, at this point, no one has approached us about acquiring us. That may be after a phase I trial, which basically in theory, it is designed for safety. It may be a little bit early for the bigger companies. They want to see a little bit more data. No one's approached us on an acquisition at this point per se.
Great. As far as an updated corporate presentation, will there be one on your website?
We have a presentation that's taking place tomorrow, there will be an update of some of the information on that. Some of the information that's, let's say, in the process of being gathered, we have to be careful that we don't do selective disclosure for purposes of obvious SEC activity. There's a limit to how much we can declare at a given point in time until we basically release that in a press release so that everybody can hear it at the same time. There will be some updates and twists, I think, in the presentation tomorrow.
Great. Assuming FDA guideline, or sorry, FDA guidance is generally favorable, do you believe Phio has a realistic path to funding both the PH-762 phase IIb trial and the PH-894 phase I trial without raising capital from a position of weakness?
Well, let me qualify that and say that until we know exactly what the scope of the phase II trial will be, and we'll propose something to FDA in the not- too- distant future, and we'll see what their reaction is to that. That will probably determine, not probably, it will determine the scope and the cost of the trial. As I've said in past fireside chats as well as in my presentations, it is likely that we will have to have some level of capital raise at some point in time in and around the first of the year or the first quarter. That's pretty much inevitable, I think.
Okay, great. Well, that concludes the questions. I want to thank the audience, and thank both Bob and Jim for participating today. Bob, I do want to turn it back over to you for any final words before we close out.
Well, okay. Thank you very much. First, I'd like to thank everybody who took the time to listen to the chat today. As one who had a visit to my dermatologist early this morning, I would encourage everybody to do that at least once a year and make sure that your skin is in order, because if these things are left to go and you don't catch them, they can become very problematic for you. It's just a matter of part of your overall good preventive health to see a dermatologist once a year, and particularly if you are exposed to a lot of sunlight. Depending on your skin type, your complexion, the environment that you're working in, it's very important.
Great. Well, thank you so much. Thank you everyone, and have a great day.
Great job, guys.