Good morning, and welcome to the Chemomab Therapeutics Virtual KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the Chemomab website following the conclusion of the event. I'd now like to turn the call over to Adi Mor, Co-founder, Chief Executive Officer, and Chief Scientific Officer of Chemomab Therapeutics. Please go ahead, Adi.
Thank you. Good morning. Welcome to our webinar, Breaking New Ground: Expert Perspectives on Primary Sclerosing Cholangitis. Please note that we will be making forward-looking statements, so please refer to the risk factors in our SEC filings. I'm delighted to introduce our panel of PSC experts, who will share their insights on this rare progressive disease that can be devastating to patients and lacks any FDA-approved therapies. This is an exciting time at Chemomab as we look forward to the top-line data readout from the phase II clinical trial of our first-in-class monoclonal antibody, CM-101, in patients with primary sclerosing cholangitis. CM-101 addresses a unique target and has dual anti-inflammatory and anti-fibrotic activity. Based on extensive preclinical and early clinical data, we believe it may have disease-modifying potential in PSC and other fibroinflammatory diseases.
With us today is our experts with diverse perspectives on PSC. Dr. Christopher Bowlus is a PSC clinical researcher and clinician at UC Davis, who has been active in helping to advance the field of PSC clinical research and in supporting patient advocacy efforts. Ricky Safer is one of those rare individuals who respond to a grim diagnosis by tackling it head-on and creating something amazing. She's the founder and CEO of the PSC patient advocacy organization in the U.S., PSC Partners Seeking a Cure. We're fortunate to have Ricky with us to share her views as a patient and as a PSC activist. Dr. Massimo Pinzani bring us years of experience as a leader in research on PSC and other liver diseases.
Known as the father of ELF, his deep knowledge about biomarkers and other non-invasive endpoints that may improve patients' management and facilitate clinical development and regulatory approval, is very relevant to today's discussion. We also welcome our own Matt Frankel, Chemomab's Chief Medical Officer, who will provide a brief overview of our CM-101 phase II clinical trial. We then will open up the floor to Q&A and urge you to submit your questions to ensure a lively and informative discussion. I will now turn the floor over to Chris Bowlus. Dr. Bowlus?
Thank you, Adi. And thank you to all of you joining us today. I'm gonna give a brief 10-minute overview of primary sclerosing cholangitis or PSC to set the stage for our next speakers. Next slide. So primary sclerosing cholangitis, as the name implies, is a sclerosing or fibrotic disease, and as you can see on the left, that entails fibrosis that occurs around the bile duct associated with inflammation of the bile duct or the cholangitis. It's these features that lead to the stricturing of the bile ducts and the characteristic cholangiographic features of these focal segmental strictures followed by dilations that make the diagnosis of the disease. And while we call it primary, it actually is most often associated with a colitis in 70%-80% of our patients.
There are several variants or a few variants of primary sclerosing cholangitis. Most commonly, we refer to large duct PSC, being those that have the typical cholangiographic features. But in approximately 10% of patients, there are no features on the cholangiogram that suggest PSC, but there are typical findings on liver biopsies, and this is referred to as small duct PSC. And then some patients also have features of autoimmune hepatitis, which we refer to as PSC overlap. Next slide. Now, PSC is a rare disease with about 80,000 patients estimated to be affected in the U.S., Europe, Japan, and other large countries. It's a disease that interestingly is predominantly affects men, about two-thirds being men, and the mean age is about 40 years, though it can be diagnosed in young children.
And in fact, just a few weeks ago, I diagnosed someone in their seventies. There are a myriad of symptoms that these patients experience and as mentioned, there are currently no approved therapies for PSC. Next slide. The exact pathogenesis of PSC is not well understood, but we have some general principles about the disease. First, because of the association with colitis, we believe it's the gut that is driving this disease. And within the gut, there are factors of not only the inflammation and changes in the microbiome, but also changes in the gut permeability, leading to the translocation of bacterial products and metabolites that can activate the immune system in the liver. This involves both innate and adaptive immune responses and importantly, migration of macrophages into the liver.
In fact, a study we did years ago demonstrated that macrophages in PSC are much more abundant compared to primary biliary cholangitis or other liver diseases. This inflammation can lead to damage of the bile ducts, which makes them more susceptible to further injury from cholestasis, as well as activate the cholangiocytes to further augment the immune response. Together, both the immune response as well as the activation of the cholangiocytes, can lead to the activation of fibrogenic cells, including myofibroblasts and hepatic stellate cells. This obviously leads to then the strictures, but also the biliary cirrhosis that we see in PSC. Next slide.
The diagnosis of PSC is not always straightforward, but in the best case, we start with MRI with an MR cholangiogram, and if we see the typical biliary strictures, and there's no secondary cause of sclerosing cholangitis, then we've landed our diagnosis of PSC. But oftentimes, the MRI is equivocal or of low quality, in which further imaging is required, and then sometimes it's actually normal, leading to that liver biopsy and the diagnosis of small duct PSC. Next slide. The symptom burden of PSC on our patients is quite significant. These results from an online registry developed by PSC Partners demonstrated that fatigue, abdominal pain, and itching are the three most common symptoms experienced by the majority of patients. Also, patients often describe sleep disturbances, which was a new finding of this study. Next slide.
The natural history of PSC is somewhat complicated and a little different than other forms of chronic liver disease. So patients with PSC, of course, can develop cirrhosis and as complications of ascites, variceal bleeding, and hepatic encephalopathy, leading to the need for liver transplantation. But in addition, patients with PSC are at high risk of cancers of the bile duct and gallbladder, as well as an enhanced risk of colon cancer above and beyond what patients with colitis are normally at risk for. In addition, with those strictures of the bile ducts, infection of the bile ducts or cholangitis can occur to the extent where liver transplantation is needed. And of course, with the colitis, they're at risk of colectomy due to refractory colitis. Next slide.
So currently, there's no effective treatment for PSC, so management revolves around cancer surveillance and recognizing and treating the complications of PSC. Liver transplantation is the only effective therapy and is recommended for patients with decompensated cirrhosis, refractory cholangitis, and in early cases of cholangiocarcinoma, liver transplantation is an option. However, even with transplantation, PSC recurs in about 20% or more of patients, and not infrequently requires retransplantation. Next slide. So despite the fact there are no effective therapies, it's not for lack of trying. Ursodeoxycholic acid, which is certainly effective in primary biliary cholangitis, has not been demonstrated any effectiveness in PSC. It's been tried at the typical doses we use of 13-15 milligrams per kilogram per day, and while it improves alkaline phosphatase, has not demonstrated any improvements in liver histology or transplant-free survival.
Similarly, at higher doses, the results have been unremarkable, but it should be noted that some of these studies were underpowered and did not meet their target enrollment. Of course, at high doses, in the most recent study, it was terminated due to futility, but in post-hoc analysis, was actually found to be associated with an increased risk of serious adverse events. Next slide. Oral vancomycin has received a lot of attention recently, and in anecdotal and small trials, it has shown some promising results, but the data is actually quite limited. There's only one randomized controlled trial over 12 weeks, which suggested some improvement in Mayo Risk Score. There have been several open-label trials suggesting improvements, though they have been somewhat limited in terms of their study design.
And in a retrospective study, the largest study of oral vancomycin to date, oral vancomycin, and in fact, urso, had no benefit in terms of clinical outcomes compared to just observation in a population of pediatric patients with PSC. Next slide. So currently, in more recent times, a number of targets have been attempted in PSC and shown some promising results. FXR agonists, in particular, obeticholic acid, demonstrated improvements in biochemistries in a phase II study. As many of you are aware, cilofexor, that was in a phase III study, which was terminated due to futility.
Interesting, the FGF19 analog, aldafermin, did not meet its primary endpoint in a phase II study of improvement in alkaline phosphatase, but did show improvements in markers of fibrosis, including the ELF score, which we'll hear a little bit about later. The PPAR agonist, bezafibrate and elafibranor, are currently in trial, and norUDCA, a derivative of ursodeoxycholic acid, is completing up a phase III study, which hopefully we'll hear about in the near future. So those are all targeting the cholestasis. Going to the gut driver of this disease, vedolizumab and other targets of the gut inflammation, including fecal microbial transplantation, really not shown any efficacy in small trials or retrospective analyses.
And most recently, the anti-fibrotic, anti-alpha v beta 6 molecule, bexotegrast, has shown some benefits in terms of serum markers of fibrosis in a cohort of PSC patients with more advanced fibrosis. And then, of course, what we're talking about today is targeting both the macrophage and the fibrosis with CM-101, and we look forward to those results. Next slide. So despite the fact that we don't have an effective therapy for PSC, as we can see from the previous slide, there's no lack of targets. And there is clearly an interest by biopharma in terms of investing in this condition. We are increasingly understanding the physiology or pathophysiology of PSC, and so more targets are likely to be developed in the near future.
We've seen an increase in the coordination of research and advocacy with PSC Partners, the International PSC Study Group, as well as other stakeholders in this area. We've seen an eagerness of patients to participate in clinical trials, so we've seen improved enrollment, even in studies that require liver biopsy. And most recently, and I think most hopeful, is that, FDA and other regulators, are expressing, an openness to new approaches to clinical endpoints so that we can get drugs to our patients. Next slide. And so with that, I'm pleased to pass this on to my friend, Ricky Safer.
Thank you, Dr. Bowlus, and thank you for inviting me to share my patient perspective on life with primary sclerosing cholangitis. Every patient's journey is unique. Mine started unexpectedly without any warning, 21 years ago, while I was leading a life of a health and fitness fanatic. However, one morning, out of the clear blue sky, I ended up in the emergency room with symptoms that did not bode well. High fever, the sickly tint of jaundice, severe right upper quadrant pain, debilitating chills, all signs that pointed to what I would soon learn were those of a cholangitis attack and the devastating diagnosis of primary sclerosing cholangitis, the beginning of an unpredictable life journey. For the next six months, I was in and out of the hospital with repeated cholangitis attacks, ERCPs, and fatigue.
The constant insatiable fatigue was overwhelming, and my anxiety level went through the roof, terrified of what the future held for me. A liver transplant was the only possible treatment for this rare immune-mediated cholestatic disease that had no approved therapies. I was told that the disease was progressive, incurable, and that I probably had five-10 years to live. As if this information weren't enough, I found out that I was also at high risk for cholangiocarcinoma as well as colon and gallbladder cancer. Like all PSC patients, I experienced the shock, fear, and feelings of isolation that come with this dire diagnosis. While forced into dealing with the physical and emotional symptoms of PSC, I had to learn to adapt to an unpredictable lifestyle, forever living with a threatening, dark cloud over my head. I couldn't describe the feeling better.
I'm sorry, one second. Let me get back to where I was. I couldn't describe it any better than one of our community members who described it this way. "It felt like having a ticking time bomb inside me that always has only one second left to explode." In no time, I learned that two of the main symptoms, fatigue and pruritus, now held new meanings for me. I discovered the unquenchable PSC fatigue, which cannot be relieved by sleep. It completely invades the person physically, mentally, and emotionally. PSC pruritus, which we refer to as suicidal itch, is truly indescribable and completely debilitating. For a disciplined person like me, the complete loss of control was bewildering.
I began to consider ways to connect with others with PSC to prevent the loneliness and the sense of loss that come with a PSC diagnosis and to work together to accelerate research. Next slide. In 2020, PSC Partners created Our Voice, Our Voices, a patient survey which had over 800 respondents. Based on the survey responses, the symptoms that patients reported they most struggled with were extreme fatigue, pruritus, liver pain, sleep disruption, brain fog, and nausea. Regardless of the ongoing research, currently, clinicians only monitor disease progression, do cancer surveillance, and treat symptoms, yet the drugs used to manage symptoms are often ineffective. While liver transplant offers the hope for survival, many of us are too sick to get a transplant, and about 25% of post-transplant patients face recurring PSC and the need for another transplant.
To add to our worries, PSC comes with many comorbidities. 75%-80% of us also live with inflammatory bowel disease, mostly ulcerative colitis. We are also at risk at a variety of other inflammatory and autoimmune conditions. With no therapies to slow progression, no approved medications, and no cure in sight, it is no surprise that we also struggle psychologically with anxiety and depression, miss out on activities, struggle to plan for the future, and experience stress in interpersonal, school, or work relationships. Life feels like a constant adaptation to all the lost opportunities and obstacles, an emotional and physical rollercoaster, as described by one parent. I consider myself lucky because I was diagnosed late in life, and so far, my PSC has progressed slowly. However, I still struggle with the constant fear of suddenly worsening disease.
It is difficult to watch our young people at the prime of their lives, burdened with symptoms because they are too sick to work or attend school, yet not sick enough to get a transplant. Our PSC community has an urgent, unmet need for effective therapies and an eventual cure that can crack open the last black box of liver diseases. Patients have clearly expressed that they would rather live with these devastating PSC symptoms if they could have disease progression slow down and cholangiocarcinoma risks reduced. Next slide. Soon after my diagnosis in 2004, it became clear that a patient advocacy group could help unite patients with a strong mission. In 2005, we launched PSC Partners Seeking a Cure, a 501(c)(3) nonprofit organization with a conference that provided education and support for its attendees.
The mission of PSC Partners has grown through the years. Today, our mission is to drive research to identify treatments and a cure for primary sclerosing cholangitis, while providing education and support for those impacted by this rare disease. In 2015, we launched our Canadian affiliate. We are a supportive community that feels like a family for patients and caregivers and offers hope. We have established numerous working partnerships between patients, caregivers, clinicians, researchers, industry, and regulators to help accelerate drug development. Next slide. Here's a brief snapshot of how PSC Partners shares the patient voice while addressing gaps in clinical and in research and regulatory pathways. In 2014, we launched a patient registry in collaboration with the NIH. The registry is reviewed by an IRB and now holds the data of 2,500 patients.
Our mission with the registry is to close research gaps by surveying patients on specific research questions, helping with recruitment for clinical trials and studies, and educating patients on the importance of clinical trial participation. In 2018, PSC Partners obtained a PSC-specific ICD-10 code K83.01, which provides the basis for robust epidemiological and natural history studies and for tracking PSC-specific data. We are developing health equity programs to engage patients from underserved populations and to encourage their participation in clinical trials. We continue our ongoing collaborations with researchers, clinicians, industry, and regulators to ensure that the patient voice is heard. Next slide. Through patient-centered and patient-driven initiatives, PSC Partners continues to address gap, current gaps in research and regulatory pathways.
Since 2007, PSC Partners awarded over $6 million for novel basic science and clinical research in collaboration with leading investigators in the field. These seed grants have led to an increased understanding of PSC, multiple presentations and publications, and future funding opportunities. Two key milestones have elevated PSC Partners to the next level of research activity. Our externally led, patient-focused drug development forum, held in collaboration with the FDA in 2020, focused on identifying patient symptoms and priorities when developing new treatments. This was followed in 2020 by a Chan Zuckerberg Initiative Rare As One grant, which supported the development of our strategic research plan, incorporating key priorities identified by both the patient and research communities.
Under the guidance of our strategic research plan, PSC Partners has moved from sponsoring research to partnering and leading key research initiatives in the hopes of finding new treatments and eventual cure for PSC. The PSC Symptom Assessment Project is a patient-partnered program in collaboration with UNC and Duke, to develop regulatory-grade, PSC-specific, patient-reported outcome measures for key symptoms, which may serve as endpoints for future clinical trials. The WIND PSC Prospective Cohort is a patient-led project working with top global PSC investigators to establish a synthetic comparator cohort, as well as to identify key biomarkers, both of which may support future regulatory filings of new treatments. And lastly, PSC launched the PSC International Collaborative Research Network in 2023, which will annually convene top international PSC researchers, together with the patient community, in a think tank forum to identify and prioritize future research initiatives. Next slide.
Our PSC patient caregiver community will continue to do our part to collaborate with clinicians, researchers, industry, and regulators to find new therapies and eventual cure for our rare and devastating disease. We are delighted with the news that Chemomab SPRING study enrolled early. We look forward to your continued success, which translates into great hope for our community. If you would like to learn more about PSC and about our activities and events, please go to our website at pscpartners.org, or contact me at ricky@pscpartners.org. I would be glad to answer your questions. Thank you. And now it's my pleasure to hand it over to Dr. Pinzani.
Thank you very much, Ricky, and I'm very happy to be here to provide some insights on the assessment, diagnostic, and clinical trial endpoint of primary sclerosing cholangitis. Next slide, please. So just to remind the feature of PSC, it is a very unique liver disease, which is characterized by biliary damage, as seen in the center of this slide, where cholangiocytes are damaged, but at the same time, develop the possibility of secreting inflammatory and fibrogenic growth factors, and they are, for this reason, defined as reactive cholangiocyte. This leads to a fibrotic response, like onion-like, around the damaged bile duct. And next, this is surrounded by next again by an inflammatory infiltrate, which is defined as next, which is defined as self-maintaining, including inflammatory and pro-fibrogenic cells.
So this just to remind what are the main targets, both for diagnostic and therapeutic target in this, rare but very, very, progressive and, and, severe liver disease. Next, please. So these are the three points I will address: diagnosis, risk stratification, and clinical trial endpoint. So in terms of diagnosis, Dr. Bowlus has already, next slide, has already, show a flowchart. So in, in the beginning, the patient, in general, present with an increased alkaline phosphatase, gamma GT, and/or bilirubin. At taking a detailed history, the patient always show, symptoms like pruritus and fatigue. The first approach is, in general, ultrasound, which may reveal gross alteration of the bile duct, but not necessarily. Next, please.
Then, usually an autoimmune screening is performed, and if it's positive for antimitochondrial, antinuclear, the diagnosis is most likely primary biliary cholangitis, which is another rare, you know, but important chronic liver cholestatic liver disease. Next step is to do a magnetic resonance cholangiopancreatography to look at the structure of the bile of the bile duct. And this may actually be sufficient to make a diagnosis of primary sclerosing cholangitis, but this could be still negative. And next, so at this point, it is necessary to refine the diagnosis to do a liver biopsy, which will investigate the nature of parenchymal biliary disease. This could be also still negative.
In this case, is a genetic analysis needed to find out if there is a genetic defect in bile acid transporter, which basically translates into a cholestatic syndrome without very clear anatomical alteration of the biliary tree. So next slide, I want just to dedicate a few words about the indication of liver biopsy in PSC. Although PSC liver biopsy may reinforce the diagnosis of PSC, it is rarely used in clinical practice since it may be not diagnostic, because the disease is very patchy. So depending where the needle enter the liver can actually produce a typical picture of PSC or something that is more like genetic cholestatic.
Also, for the same reason, liver biopsy has a very limited value for staging the disease, so basically to assess the amount of scarring and fibrosis, because this can be variable in different parts of the liver. Having said this, next point is that liver biopsy is, however, always indispensable if there is a suspicion of IgG4 sclerosing cholangitis, which is a special type of inflammatory cholangitis, which is basically can be cured with steroids in a very rapid time. So it's very important to find out if this is present, so we can have a rapid treatment or if there is an autoimmune overlap syndrome, so is a PSC with a very strong autoimmune infiltration. That is very important to know, because this may basically provide some indication to use also steroids.
In 10% of the cases when there is not a clear diagnosis, and we are probably in front of a small duct PSC, liver biopsy may help to refine the diagnosis, but I would say in the majority of cases. Next slide. The magnetic resonance cholangiopancreatography is sufficient to assess PSC in large ducts, but in many cases, also can be helpful with increasing advance in imaging, also to define PSC of small ducts. Next. So next, please. So let's think about stratification and prognostic predictor. Next. So this is a palette of all the possible choices that we have.
However, I will concentrate on blood tests, physical tests, and serum biomarkers, since these are the one that have, had been shown recently, more relevant to, in term of prognostic and, or in addition to diagnostic. Next, please. So let's, so let's talk first about alkaline phosphatase. Alkaline phosphatase has been, you know, up to recently, a gold standard in the diagnosis, but also in the as an, as an, considered as an endpoint of treatment in cholestatic disorders. And, it is true that following treatment, there, there may be a decrease in alkaline phosphatase, and historically, normalization of, persistent normalization had been related to a better prognosis. However, more recent study, particularly this study from 2021, has shown that there is, a fluctuation of PSC independently of the treatment in about 30% of patients.
It is also clear that there is no clear association between alkaline phosphatase level, progression of fibrosis and development of cirrhosis. So basically, either increase or decrease alkaline phosphatase, although it is an alarm bell for a potential cholestatic disease, it is not really very important or useful for as a clinical trial endpoint. And this is, I mean, a strong statement, because for many years, this concept was unmovable, so it was impossible to change it. So why this has changed? Next, next, please. Because, you know, in the past 20 years, there have been introduction of diagnostic, non-invasive diagnostic tool, in particular elastography as a general chapter, that goes from FibroScan, which is a very simple system, can be done by a nurse or by a technician or even by a student.
Then, other systems they use ultrasound, and they need expertise in ultrasound. And finally, magnetic resonance elastography, which is similarly very, very efficient, but obviously has a much higher cost. But all these tools, you know, are now on the table to be used as investigational tools. Next, please. So the first paper about elastography, transient elastography in PSC, was published by Dr. Corpechot in 2014, showing that there was a correlation between the stage of fibrosis, although it was evaluated here with METAVIR, which is not really appropriate for PSC, but just in terms of amount of fibrosis, the more fibrosis, the more stiffness of the liver.
This was also evaluated longitudinally, following patients for several months, and showing that there was a progressive increase in stiffness. Next, in the same study, also, Dr. Corpechot provided cutoff values, particularly 18.5 kPa, you know, higher or lower, which are basically predicting, and they are prognostically relevant for survival rate and liver-related event. So, this, you know, demonstrate that liver stiffness is a potential effective predictor of prognostic predictor. Next, please. This is a recent study done at the Royal Free, and I have to thank Professor Douglas Thorburn, my colleague at the Royal Free, and Davide Roccarina.
This is a study done at the Royal Free, where these two more advanced method of elastography, called ElastPQ point shear wave, where the elastography had been used in the workup of patient with PSC. So basically, liver stiffness, there were two cutoff, below 8.9 kPa, that require follow-up in one year. Instead, in case the stiffness is more than 11.2, the patient is classified with advanced chronic liver disease, and with potential portal hypertension, that can be evaluated by spleen stiffness with the same apparatus. And if spleen stiffness is higher than 40.2 kPa, the patient needs to have urgently an upper GI endoscopy to assess the presence of complication of portal hypertension, like esophageal or gastric varices.
So there is continuous advancement in the technology, and this, I need to recall to you, that these are non-invasive method, they are no harm to the patient, and all the, they have a very low cost. Next, please. Then just to remind to you, the targets of serum markers and therapeutic targets. Can you click three times, please? So it's the bile duct damage, fibrogenesis, and inflammation. Both of these are treasure land, you know, for discovery, and, you know, I think we are still early, but there is a lot of hope. We will know more and more, and this will really help development of more, effective, serum markers and, and therapeutic type. Next, please. So this is the ELF, Enhanced Liver Fibrosis test. Originally, it was called European Liver Fibrosis Test.
It was developed in the late 1990s by a consortium of research, including myself, mostly in interest in fibrosis in the time where nobody was really interested in fibrosis, because it was really the gold time of hepatitis C. But this consortium put together 11 markers, and recruited more than 1,000 patients. And in the end, a score was developed, called the ELF, that includes three marker of extracellular related to extracellular matrix metabolism, hyaluronic acid, procollagen type III, and terminal peptide, and TIMP-1, which is tissue inhibitor of metalloproteinase, in a mathematical algorithm. And this was the first diagnostic direct serum marker of liver fibrosis. And you know, in the beginning, there was no specific correlation to any chronic disease. It was a generic serum marker for liver fibrosis.
And this has been then, you know, confirmed in, you know, the efficacy of this test have been confirmed, then in specific study in viral hepatitis, in metabolic liver disease, in alcoholic liver disease, and so on and so on. Finally, next slide. A study that we performed with data, together with the group, the Norwegian group, led by Mette Vesterhus. Basically accumulating patient cohort from the UK and Norway. The ELF score, compared to another, you know, standard score, like the Mayo score or duration of PSC, was shown to be more, the most effective prognostic score for a prognostication of the evolution of PSC. Next.
This was then validated into another multicenter, large multicenter PSC cohort study, and showing that, you know, the ELF cutoff value, like 7.7, 9.8, and so on and so, are important to define the presence of mild, moderate, and severe fibrosis. And this has confirmed the ELF as an important biomarker for, you know, at and potential endpoint in following treatment of PSC. Next. On the other hand, the concept of the ELF, it was related to our knowledge beginning of the nineties, where we were assuming that extracellular matrix protein were accumulating like bricks over bricks in the fibrotic scar. And basically, they reflect what is synthesized, not what is effectively deposited in the tissue. Next.
Indeed, this protein are continuously remodeled by enzymes, and the end product, it is actually something which is called fingerprint, like, part of the molecule, like in this case, procollagen-III and procollagen-V, like, called PRO-C3 and PRO-C5, which neo-epitopes . And this reflect the final biochemical elaboration of the ECM protein in the fibrotic tissue. So in theory, but also in practical terms, it is a more accurate assessment of what is really in the fibrotic tissue. And this may also be reflected what is circulating in the blood.
So next, this is the first study performed by the company who has developed this biomarker, which is called Nordic Bioscience, showing the prognostic value of the prediction of transplant-free survival in PSC by PRO-C3 and PRO-C5 alone, which is superior to the ELF, at least in this study. And the combination of the two, PRO-C3 plus PRO-C5, has an odds ratio much higher, of 47.3. So there is this is to provide a validation of the value of this new type of marker, although it requires, you know, larger study, which are ongoing, you know, with the collaboration between groups all over the world, that have the highest collection of sample from patients from PSC. So it's still in development, but very promising. Next.
So in summary, a liver biopsy may reinforce the diagnosis of PSC, but is of limited value as a prognostic endpoint. Magnetic resonance cholangiopancreatography, MRCP, is of key value in the diagnosis, but is of limited utility as a prognostic endpoint. Liver stiffness with a different elastography methodology and serum biomarker are non-invasive prognostic endpoint and may be effective surrogate endpoints for clinical trials. And the key serum biomarker include ALP, with all the reservation that I have introduced to you. The ELF score and this fingerprint technology, PRO-C3 and PRO-C5. Thank you very much for your attention. I pass now the word to Matt Frankel, who is the Medical Director of Chemomab.
Thank you, Dr. Pinzani, and good morning. Let me just briefly touch on our phase II SPRING study. We have completed enrollment at this point of the approximate 70 patients. There were two dose groups, two dose cohorts. There's the 10 mg per kg group as well as the 20 mg per kg group. They initially were in a double-blind portion, which we plan on presenting in the mid-year. And then there's also the additional 33 weeks of the open-label extension. The patients who were enrolled at the 20 mg were only allowed subsequent to a data monitoring committee review. The patients all had an alkaline phosphatase of 1-1.5 x the upper limit of normal. We allowed for stable IBD, and if they were on UDCA, it also had to be stable.
We found that, in general, the patient population that we had was quite, representative of the general population. Our primary focus is on safety and tolerability. In addition, from a secondary standpoint, we're evaluating a number of biomarkers, including what you just heard Dr. Pinzani highlight, serum alkaline phosphatase, ELF score, FibroScan data, fibrotic biomarkers, including PRO-C3 and PRO-C5, and then we're also capturing pharmacokinetics and pharmacodynamics. As far as the regions where we collected data and where patients enrolled, about approximately a third of the patients enrolled from Israel, a third from Europe, and a third from the United States. As noted, the top line data is expected, in the middle of this year, and then the open label extension data will be shared at the end of this year or potentially early in next year.
With that, let me hand it over for questions.
Great. Thanks, Matt. So we're gonna begin our question and answer session with all of our speakers. As a reminder to the audience, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. So please hold for a brief moment while we pull for questions. So our first question comes from Jason Wittes at Roth. Please go ahead, Jason.
Great. Thanks for taking my question, and thanks for doing this. I got a few questions here. So first off, if you look at the phase II trial for CM-101, what secondary endpoints would you look to, to declare as the, the trial positive? If I can ask the clinicians that.
So I guess I can start that off. So I think in terms of the secondary endpoints, as Dr. Pinzani was pointing out, I think those serum biomarkers of fibrosis would be most promising to see some trend at least towards improvement in ELF, PRO-C3, PRO-C5. I think biochemical markers in terms of alkaline phosphatase would be nice to see, but I would be hesitant to say something's not effective if we don't see improvements in alkaline phosphatase, because this is a fibrotic disease. I think the length of treatment will be a little bit hard to anticipate or expect that there'll be changes in liver stiffness. But again, if there are improvements in liver stiffness, I would take that as a very good sign, but would not expect to see much change.
Great.
Dr. Pinzani, anything to add?
No, I agree. I totally agree. Because also there is no specific study addressing, since we don't have an effective treatment, we don't know how liver stiffness can change over time after a successful treatment. We know, for example, for hepatitis C, after successful elimination of the virus, how long it takes to improve, but without a treatment, it would be also very difficult to assess if a reduction in stiffness is due to the reduction of fibrosis or reduction of cholestasis, because there is also a factor, cholestasis is also a co-factor in increasing stiffness. So difficult to tell now, but in theory, you know, there should be a decrease in stiffness if we have an effective treatment.
Yeah, absolutely. And I could just reiterate what Dr. Pinzani and Dr. Bowlus has indicated, and maybe to add that we are, given the fact that we have seen CM-101 to work and be and show activity by inhibiting inflammation and fibrosis across many studies over the years, we would very much like to focus on the broadness of the activity of the drug in this upcoming readout. So we'd like to see, as mentioned here, trends of improvements in health, in PRO-C3 and PRO-C5, as well as others. We'll obviously be capturing FibroScan and even patient-reported outcomes.
Maybe one additional mentioning is the fact that since we have two doses of the antibody in this study, we will also be able to evaluate a potential dose response here. So that would be interesting to look at as well.
Sorry, Pinzani, did you have... Dr. Pinzani, you had some other comment?
Pardoning?
So let me ask another question related to this. So which of the potential endpoints discussed today do you think would be accepted by the FDA as primary endpoints for a phase III trial?
Dr. Bowlus, you want to start?
Yes.
The $1 million question.
Yeah. I think that's, that is the big question, and we—I will say that we've heard some, you know, positive comments from the FDA in terms of being flexible on some of these endpoints. And it may be that it's not one endpoint, it may be a combination of endpoints. They, they have suggested they may be open to accepting other endpoints than what we're talking about here, such as events of cholangitis. But I think that there's still some work to be done to clarify exactly what those endpoints are. It could be a combination, for example, of ELF and FibroScan. That's something that's been discussed as well.
There's still some answers that we need to, or questions we need to address in terms of what degree of change it would be required to be acceptable to the regulators.
Yeah, I totally agree with Chris. There is also, we're also witnessing a change in the mentality of, you know, this agency. You know, recently there was a drug that was approved for metabolic for fatty liver without the need of a biopsy. So, I mean, there is a more open kind of there is an opening to non-invasive method or combination of non-invasive method. Also acknowledging that in disease which are not homogeneous within the liver, liver biopsy is not necessarily the best way to make an evaluation. So I think that we are going towards a compromise, histological compromise. And for PSC, as I said before, there has been surrogate alkaline phosphatase for 25 years, and we know that it's not reliable to assess a treatment.
So, yeah, I mean, I think that's clear that biopsies are not very instructive, I mean, they're very variable. But, I mean, how likely is the FDA to require a biopsy for a phase three at this point? Is it... Are they moving away from that, or is that still under consideration?
Honestly, if I were the FDA, I will require a biopsy only if the aim is to select patient with small duct PSC, you know.
Got it.
Because that, you know, it is, you know. But it's just to make a diagnosis, not necessarily to have a biopsy before and after to assess the effectiveness of the treatment.
Mm-hmm.
It's just to refine the diagnosis. You know, I would find very difficult to ask a company to have biopsy as, histology as an endpoint of treatment.
Yeah, I agree. I think that, actually, the PSC Partners at ICRN conference, and they use the example of alpha-1 antitrypsin. They seem to be trying to steer more away from this conditional approval and be more accepting of other types of endpoints, which, especially in a rare disease, they seem to be much more willing. But it, it's... You know, they're not going to say outright what they're going to accept. It's got to be presented to them. But I think that they realize that liver biopsy, number one, is, you know, not favored by patients. As mentioned, it's variable. We see a third of biopsies in placebo groups getting better, a third getting worse, and a third staying the same.
So trying to demonstrate efficacy on a liver biopsy is quite difficult. So what combination of endpoints they would accept is, I think, something that's going to have to be an ongoing discussion with them. I can only say that it's... What we're hearing from them is promising that there will be a path forward with some combination of these, and maybe, you know, it is going to be some fibrotic markers along with, you know, some clinical events such as cholangitis, which is relatively frequent. I will say, you know, ELF has been associated with events of cholangitis on the simtuzumab study, and there is a known change that was associated with events of cholangitis.
And one of the things that we're currently working on is with the PSC forum is develop a standardized definition of cholangitis, because that's been one of the problems we've had. But the FDA seems to be very open to just having the experts come to a consensus that this is what cholangitis is in PSC, and then it can be, you know, measured within a trial as an outcome. And so that, along with, you know, patient-reported outcomes, et cetera, I think there's promise there. But what exactly those endpoints are, combination of endpoints, will depend on.
Mm-hmm.
the drug and what the FDA and/or EMA is willing to accept, and that's still a work in progress.
Very, very helpful. Maybe one last question, and I'll jump back in queue. Do you see IV administration as a challenge to PSC patients? And I guess for CM-101, are you considering doing a sub-Q formulation also for this population?
Ricky, maybe you wanna go first from a patient point of view, and then Matt could address the second part of the question.
Sure. I yeah, I would say not just for myself, but for most of my-- everybody else in our community, other patients, if it would help us, I would say, of course, we'd be very open to this IV infusion. It's certainly not a big price for us to pay. And actually, as an example, for those of us who have IBD, many of us are on biologic, and quite a few of them are IV infusions. I don't hear people complaining about it when it's working for them, so.
Yeah, maybe just to add to that, when you think about these patients, it's a horrible, devastating disease, and if we can get a way to get to a solution or at least reduce the progression, it.
Much like in patients with chronic kidney disease who are on dialysis three times a week. There's really a willingness to undergo something like the IV. The second question about the subcutaneous, we certainly have begun that process. We did a study where we specifically looked at subcutaneous formulation, and we have a drug that could work. From a standpoint of life cycle management, we think that we'll be doing that at a later point in time, and for the expediency of getting into phase three as quickly as possible, we would go forward with an IV.
Makes perfect sense. Oh, sorry, I'll jump back in the queue.
Thanks for the questions, Jason. So our next question comes from Daz Patel at Oppenheimer. Please go ahead, Daz.
Thank you. This is Daz, I'm dialing on behalf of Jeff today. A couple of quick questions around endpoints team. Could you speak to the change in ELF score that is considered clinically meaningful in these patients? And a quick follow-up to that is: What is the next most relevant biomarker after ELF when looking at efficacy in PSC patients?
Dr. Pinzani, you want to start?
No, I didn't understand the second part of the question.
The second part of the question was, what is the next most relevant biomarker after ELF when thinking.
Okay, so basically, ELF in PSC, you know, is relevant as a prognostic score. So that means higher is the score, you know, more likely is the patient is gonna develop liver-related events. So in terms of what is this reduction that you would consider, you know, basically allowing to define the treatment effective, I would say that... If you have a reduction of one stage compared to the one that is predicted by that value, I think it will be already an effective result. But, you know, I stress the fact that ELF is a prognostic score, it's not a diagnostic score of fibrosis for PSC. So you don't make a diagnosis with ELF. You know, ELF is used as a prognostic score.
So if you have a decrease in ELF, you basically reduce the possibility of developing liver-related event and increase the possibility of survival.
If I could add on that, you know, from the simtuzumab study, in terms of change in ELF, there's a cutoff there that we know is associated with clinical events. I think it was 0.19.
Yeah
Was associated. And the clinical events were primarily cholangitis, and I think one of the questions is, would that translate to other outcomes? And then, also from the paper presented from Corpechot, they also showed change in liver stiffness being.
Yes
Associated with outcomes, right?
Yes.
So I think if, you know, if I was to propose something to the FDA, one possibility might be, you know, seeing no progression or change in ELF and FibroScan, in the treatment group.
Yeah.
Since both of those who have been associated with clinical outcomes, and there are thresholds there that could be proposed. Whether they'd be acceptable or to validate is a question.
I was also thinking before, and this may be very relevant from the patient point of view, that there are some attempt of developing a questionnaire to lead to a quality of life score. And you know, the patient that I have experienced, that I have seen with PSC, they have a very poor quality of life, independently of having or not IBD, I mean, you know, or even if they have only PSC. And so I have seen attempt to develop this questionnaire and, you know, although they cannot be primary or secondary endpoint, but it could be tertiary endpoint, improvement in a score, in a quality of life score.
Also, I was thinking that it seems quite, you know, the measurement of spleen stiffness, you know, seems quite sensitive to assess portal hypertension. So, looking at decrease or, you know, how elastography behaves following a treatment, I will consider, you know, separately, liver stiffness and spleen stiffness, just to study if spleen stiffness is more sensitive to an improvement of the liver situation. They could be, actually. But I think we, you know, what we have presented, it shows that there is not very much available, but there is an increasingly change in mentality, and there is good hope that we will reach something, you know, more useful than what we have now.
Thank you. I'll jump back into the queue.
Great. Thank you for the questions, Daz. This concludes the verbal portion of our Q&A session. I'll now turn the call over to Barbara Lindheim, Head of Strategic Communications at Chemomab, to read the remainder of the questions from the webcast.
Thank you, Tara. Are we still good? Do we still have a little time here?
Yeah, I think we still have some time for a few more questions.
Great. Terrific. Next question asks about combination therapies. Do our panelists think that, given the nature of this disease, that combination therapies might make sense going forward? And a related question was about whether you see any potential impact of the GLP-1 class of drugs on PSC itself. Dr. Bowlus, you'd like to start?
Short answer is yes, combination therapy is probably the ultimate place we want to get to, antifibrotic, and cholestatic medications, maybe combinations in both fields. GLP-1s, not likely. They do have some anti-inflammatory immunomodulatory effects, but not likely to be a role here.
I agree that GLP-1 it won't be a competitor in this scenario. Maybe the client compounded their anti-integrin strategy that is likely to be a genetic antifibrotic may come on top of this, together with an anti-inflammatory strategy like the Chemomab. So it is reasonable to have a combination, anti-inflammatory, an antifibrotic, and maybe one day also anti-senescent biliary senescent or reducing the reactivity of cholangiocytes.
Next question. Can you briefly summarize how CM-101 is different from the other products currently in clinical development for PSC?
Yes, absolutely. It's a very good question. So, I would say that overall, CM-101 was shown to have a unique and dual mechanism of action, being able to inhibit both inflammation and fibrosis directly and simultaneously. We have seen across multiple studies, specifically for PSC, that not only CM-101 was able to interfere with inflammation and fibrosis, and we've seen that by reduced numbers of key inflammatory cells, primarily macrophages, reduced collagen deposition in the liver, exactly in the areas surrounding the bile duct. And we've also seen CM-101 to interfere with this aberrant proliferation of the epithelial cells of the bile duct, the cholangiocytes, as Dr. Pinzani just mentioned.
All of this together, kind of seeing CM-101 to interfere with the three core pathways that lead to PSC, led to its potential to serve as a disease-modifying drug in PSC, highly differentiated and potentially have added value for patients.
Okay, thank you. Anyone want to add anything to that?
Mm-mm.
Next question. Do we have any insights into how long a phase III trial under accelerated approval might be required? Have we gotten any feedback on that from those of you working with the regulatory agencies?
Yeah, maybe I'll try and address that. You know, this is really going to be a conversation with the FDA. We don't have any great insight other than historic data, and this is going to be a long-term therapy for patients. So it would does make sense that this is going to be a, at least a one-year, potentially two-year study, and potentially there will be an interim at one year probably, if I were going to estimate, that would be what I'd come forward with.
Next question: What can drug developers do in clinical trials to manage the variability in PSC disease progression? Matt, do you wanna.
Sure. Yeah. I mean, there, there are a number of possibilities and, you know, Dr. Pinzani and Dr. Bowlus as well, please jump in. This is about... Our goal is to, and our aspiration is to treat patients who are suffering from PSC, so we want to include as many patients as possible. At the same time, you have to evaluate, and this is where coming up with entry criteria that are appropriate, so whether it's the alkaline phosphatase greater than 1x the upper, 1.5x the upper limit of normal, the IBD, and as well as stratification, is also going to be important, as we move forward, to ensure that we really, equalize the, the populations and ensure that, we have a good comparison between them. Any feedback from Dr. Bowlus or Dr. Pinzani?
Yeah, I mean, I agree that there is variability in the disease progression, but both ELF and elastography are prognostic markers. So per se, more than, you know, relevant for diagnosis, can indicate what is the fate of the patient in a relatively short period of time. So, you know, if you need to use an entry, you know, entry-level, you know, like, inclusion criteria, I will, I will, I will set a, let's say, I would say, a threshold, you know, in ELF and stiffness, and I will treat all the patient beyond that threshold. To put it simply.
I think you need to, if you want to avoid the variability and have more responsiveness, you need, you need to select patients that are somewhere beyond the most early stage, where you're not going to see much change.
Yeah
T o the natural history. Yeah.
Next question: When do you expect, when you might obtain an approval by the FDA and/or the EMA for CM-101 for PSC? And, generally, what do you think is the market potential globally for this compound, if successful?
Matt, do you want to start?
Yeah. Sure. Well, first, we'd like to see our top-line data, and then we'll go into a conversation with the FDA. If we can, we'll move as quickly as possible to getting the program up and running in a phase III program in the next year and a half from now. So there really is an expectation that we'll be moving quite quickly to get this to patients as quickly as possible.
Yeah. As to the market potential, we are expecting, based on the number of patients to date in the seven major markets, the potential commercial opportunity may exceed $1 billion. It's also worth mentioning that obviously diagnosis to them, and the patients with PSC has no cure, so the diagnosis is also limited there to some extent. We are expecting that once there will be an approved drug for PSC, then diagnosis of PSC would even exceed further together, you know, with patients that most of them are also suffering from IBD. We do expect to see even better diagnosis moving forward.
The next question is actually related to what you just said, Adi, which was asking in around diagnosis. The question of: Do our panelists think that with the advent of effective therapies, potentially like CM-101 and some of the other new drugs in development, that we'd actually see earlier diagnosis of patients and perhaps with the potential for better outcomes by beginning treatment earlier in the disease process?
Yeah. Maybe Dr. Bowlus could initiate and then the others.
Yeah, I think if, you know, once there's an effective therapy for PSC, there'll be, I think, an increased awareness of the disease, increased diagnosis, and, yes, treating patients earlier will have better outcomes for sure. So I think it'd be a tremendous advance.
Yeah. Dr. Pinzani, anything to add?
Well, I totally agree. I mean, the disease that has no treatment is somehow for, you know, a forgotten disease, so there is no much attention. Or in spite of the big work and a fantastic work by the patient association, but it is. It tends to be very niche, you know, cluster between the people with the disease. So obviously, this will give a big hit to the, you know, to the knowledge to the awareness about the disease. And on the other hand, you know, PSC is even more than PBC. It is now a disease that is frequent or has a known agent, like hepatitis C, that you can actually target.
There is no treatment, so basically, if there is a treatment, there would be definitely more, more knowledge about the disease, and the number of diagnoses will increase.
Yeah.
Our last question is actually asking about Europe. We talk a lot about the FDA, but what do we know about in terms of the changing regulatory perspectives out of the EMA?
Matt, do you want to start?
Sure. Yeah, this is in a similar vein, our enthusiasm is to really get this as quickly as possible out to patients. So we will be doing everything possible, that where we're going to be working both with the FDA as well as European agencies as well, because it's our aspiration to get it to out as quickly as possible, and we wanna do it in the most efficacious way. So we will be working both with both agencies to move it quickly. And there is also similarly the belief that it's going to be a conversation with the agencies, because there is a lot of hope and expectations amongst whether it's clinicians, whether it's practitioners, whether it's key thought leaders, whether it's patients and the various agencies.
They all want something in the space, so we're going to be working with all of them.
Before we sign off, does Dr. Pinzani or Dr. Bowlus or Ricky have any insights in terms of movement on the European front?
What did you ask, sorry?
Whether we're seeing some openness among the European regulators as well, as well as here in the U.S. at the FDA.
Well, I know I, I'm not really an expert in regulatory agency. The only thing I know about the EMA, the agency has now reached full maturity. You know, originally it was a bit like a, not a copy, but it was structured in a similar way as FDA. Now, has developed its own, its own feature. You know, one of the main feature that I found, you know, the difference is that EMA deals a lot with countries that have a, you know, a social medicine, so they have a public health system. So One of the preoccupation is if you approve a drug, you know, the system is that they're obliged to, you know, to provide the drugs with huge expenses.
So they try to be careful this way, but there is no difference, in my opinion, the way that they are oriented, you know, in judging and validating endpoints. I mean, there is, it's a science, it's clinical practice. There is a bit of difference in terms of what is the financial outcome of the decision rather than health system. So.
That concludes our questions. Thank you.
Okay.
Thank you. So thank you, all for participating in today's event, we obviously look forward to share some very exciting data in the near future. And just to mention again, that the recording of the webinar will be available on our website. Thank you very much, Dr. Pinzani, Dr. Bowlus, Mr. Ricky Safer. Thank you, and have a nice day.
Thank you very much.