The 20th Anniversary PSC Partners Annual Conference took place in Phoenix, Arizona, on October 18-20, 2024. Throughout the conference weekend, more than 360 attendees were reminded of how far PSC Partners has come as an organization in the past 20 years and of the accelerating progress of PSC research. Evidence of that progress included the second gathering of the International Collaborative Research Network (ICRNetwork), which met prior to the general patient/caregiver conference. The ICRNetwork, launched in June 2022, is a group of key stakeholders, including researchers, clinicians, patients, and industry members, that was formed in response to PSC Partners’ focused efforts to forge a strategic research plan. Many of the ICRN members were speakers for the patient/caregiver sessions and presented up-to-date information on PSC management and research advances. One of the general sessions, “Industry Updates: Ongoing PSC Clinical Trials,” included reports by pharmaceutical representatives about several trials for which the Registry has assisted with trial design and/or recruitment, and in which some of you have participated. Presenters sharing updates about their PSC drug trials included Chemomab Therapeutics, Intercept Pharmaceuticals, Ipsen Biopharmaceuticals, Mirum Pharmaceuticals, and Pliant Therapeutics. You can find more information about their trials on the Clinical Trials page. Chemomab and Pliant gave similar presentations a few weeks later at “The Liver Meeting,” an annual global convening of hepatologists and other experts from around the world, sponsored by the American Association for the Study of Liver Diseases. Each presented late-breaking posters about their trial drug results. You can read the news releases and view the posters at the links below. Chemomab/SPRING trial: News Release Chemomab’s AASLD Poster Pliant/ INTEGRIS-PSC trial:  News Release Pliant's AASLD Poster The conference weekend was filled with enthusiasm as both PSC Partners and its Registry celebrated their respective anniversaries amid a growing sense of hope for the future of PSC research and much improved PSC treatments.

Thanks to your active participation in the Registry, significant progress has been made in PSC research. Four publications using Registry data were released in 2024  - two journal articles and two scientific posters. Topics include improving patient-centered clinical trial development, special considerations of pediatric PSC patients, and better understanding PSC-related fatigue and cholangitis. Click on each title to access the abstract and full article/poster (if available). Journal Article: Patient-focused drug development in primary sclerosing cholangitis: Insights on patient priorities and involvement in clinical trials Using the Registry’s 2021-2023 “Our Voices” survey results, researchers looked at patient priorities in drug development and factors/barriers contributing to clinical trial participation. While 61% of patients with PSC reported interest in trial participation, only 26% have ever been asked. Conversations and education with/from hepatologists and gastroenterologists “are vital to closing the gap between trial interest and participation”. Journal Article: Caregiver-reported symptom burden and preferences for therapeutic goals in pediatric primary sclerosing cholangitis Also drawn from the “Our Voices” survey, this study summarizes responses from 51 pediatric PSC patients and caregivers. The responses reveal “a substantial patient/caregiver-reported symptom burden for children with PSC that impacts quality of life and limits access to clinical trials.” Conference Abstract/Poster: Understanding fatigue experiences through qualitative interviews with adults living with primary sclerosing cholangitis (PSC): An essential first step towards customizing a PSC-specific PROMIS® measure A series of in-depth interviews were conducted via recruitment from Registry participants. Analysis of presence, frequency, severity, and distress related to PSC symptoms led to fatigue emerging as a “prominent and distressing symptom.” These interviews inform development of a symptom assessment tool (survey) for use in clinical trials to measure the effectiveness of a treatment in improving patient-reported outcomes, including fatigue. Conference Abstract/Poster: Defining acute cholangitis as a clinical outcomes endpoint in adults with primary sclerosing cholangitis: Results of a multinational patient survey to develop a patient reported outcomes measure Using the “PSC Flare or Cholangitis Attack Patient Survey” , the Registry Team worked directly with an international team of researchers to characterize patient experiences with cholangitis attacks (acute cholangitis). This survey demonstrated a “broad dynamic range of the frequency and severity of symptoms”, and is a first step in developing a precise definition of acute cholangitis for use in clinical trials as a potential outcome of interest. Many thanks again to the Registry participants who have taken the surveys to make these publications possible! The “PSC Flare or Cholangitis Attack Patient Survey” is currently active in the Registry. Log in and complete this survey today! Data is always de-identified and your responses remain confidential while advancing PSC research.

A huge THANK YOU! to everyone who has kept the PSC Partners Patient Registry an active and constantly growing beacon of the patient voice in PSC research! Thanks to your time and effort, 179 new participants living with PSC  joined the Registry, and 416 surveys  were completed between the Registry’s re-launch in March and August 31. As part of the Registry’s 10th anniversary celebration, a drawing for three $100 gift cards was held for anyone who joined as a new participant, logged in and updated their profile information, and/or completed a survey by August 31. The winners of these gift cards have been randomly selected and contacted via email.  To maintain the confidentiality of Registry participants, the Registry will not be announcing their names. Congratulations to the winners, and thank you to each and every person who participated in the Registry to enter this drawing! Each actively engaged Registry participant and each completed survey provides a wealth of information to address pressing research questions and provide a better understanding of the impact of PSC on people living with the disease. There is always more to do – if you haven’t yet updated your profile information or taken the 2024 Clinical Survey, please log in and complete these tasks today! Stay tuned for two new surveys that will be launching in the coming weeks… Together, we are creating a world where a PSC diagnosis comes with a cure.

Issue 5 - October 2022 Welcome! In this issue:  • From the Registry Director • The Clinical Trial Landscape in PSC • Current International PSC Research • The ChiLDRen Study • Gilead's PRIMUS Trial Terminated •  Patient-friendly Clinical Trial Design • Highlights of the 2022 International Liver Congress • Meet PSCP's Ruth-Anne Pai, PhD •  Clinical Trials Are Recruiting From the Registry Director Dear Registry Participants, Whether you are a person living with PSC, or the relative, friend, or caregiver of one, you probably never stop searching to understand how research into PSC treatments is progressing.  In this newsletter, you will find a review of PSC Partners’ recent webinar about current trials; highlights of the annual conference session on the international PSC research landscape; information about a current, exciting study for children and young adults; an invitation to submit ideas and concerns about trials that we can take to those conducting clinical trials; and more. You can also explore trial information at your convenience on the Registry website. The Registry team maintains a list of currently enrolling PSC clinical trials and studies on the “Clinical Trials” webpage and provides links to detailed information about them. On the same page, you can find links to more general information, such as a map of trial locations and an explanation of clinical trial “phases.” A demonstration of how to find the trial page and navigate the map resource is included in a short Registry video tour that can be found here (time stamp 3:40). An important function of the Registry is to assist in connecting PSC patients with clinical trials or studies for which they may be eligible. Based on your answers to the patient surveys, you may receive occasional emails with information about a clinical trial that is recruiting PSC patients. PSC Partners encourages all patients to learn as much as possible when making decisions about joining a study or trial. That is why we created a new Registry feature, the “Publications Related to Clinical Trials in PSC” page , located in the Resources section of the website. Here we suggest ways of evaluating studies, articles, and information related to ongoing clinical trials. Regardless of whether you are interested in or eligible for a trial, staying abreast of PSC research progress will keep you informed about new treatments and discoveries. Your engagement and your input about study design and methods is valued. “Together, we are creating a world where a PSC diagnosis comes with a cure!” On behalf of the Registry team, Rachel Gomel, Director, PSC Partners Patient Registry The Clinical Trial Landscape in PSC - Overview of a PSC Partners Webinar One of the recent PSC Partners post-conference webinars brought together the current clinical trial perspectives in PSC. Numerous clinical trial updates were presented at the September 21 event , “The Clinical Trial Landscape in PSC: Current and New Opportunities for Patients.” A panel of experts discussed ongoing PSC studies and clinical trials. The goal of this webinar was to familiarize the PSC community with what clinical trial participation entails, with the different types of clinical trials that are being conducted, and on ways we can advance towards new treatments and the much anticipated cure. Trials/studies presented were: Brigham and Women’s Hospital (DINER nutrition study) Chemomab Therapeutics (SPRING study of novel antifibrotic, anti-inflammatory, biologic drug CM-101) CymaBay Therapeutics (study of Seladelpar for impact on PSC disease progression) Escient Pharmaceuticals (trial of drug EP547 for pruritus) Gilead Sciences (PRIMIS study of Cilofexor for fibrosis) - This trial was terminated after the webinar; see details below. HighTide Therapeutics (study of HTD180 drug, also known as berberine ursodeoxycholate, with anticipated anti-inflammatory, anti-cholestatic, and antifibrotic properties) Mayo Clinic (oral vancomycin trial) Mirum Pharmaceuticals (VISTAS trial of volixibat for pruritus) Pliant Therapeutics (INTEGRIS-PSC trial of the antifibrotic drug PLN-74809) You are invited to watch the recorded presentations and learn about these ongoing or recently completed trials. Current International PSC Research: Updates from the 2022 PSC Partners Conference An update on international PSC research activity was one of the most popular sessions at the June 2022 PSC Partners conference. Conference co-host Dr. Joshua Korzenik  moderated the presentation, titled “International PSC Research: Updates Across Spectrum – From IBD & Fibrosis to Genetics & Environment.” This informative conference session is online and includes the following three presentations and a question-and-answer segment. “Fibrosis and Fibrotic Mechanisms in Primary Sclerosing Cholangitis,” presented by Richard Green, MD, of Northwestern University Feinberg School of Medicine (time stamp: 3:19 ) “The Norwegian PSC Research Center…an Update from Oslo and Bergen,” presented by Tom Hemming Karlsen, MD, PhD, Norwegian PSC Research Center (time stamp: 20:19 ) “PSC and IBD. A Close Relationship. Siblings or Distant Cousins? What We Can Learn from It,” presented by Joshua R. Korzenik, MD, Brigham and Women’s Hospital (time stamp: 38:57 ) The Q&A portion was moderated by Joel Pekow, MD, of University of Chicago Medicine. Kirsten Muri Boberg, MD, PhD, of the Norwegian PSC Research Center, joined Drs. Green and Korzenik to answer questions submitted by conference participants (time stamp: 58:03 ). You are encouraged to check out what’s new in PSC research and find out the ways in which it is gaining momentum towards developing better treatments for people living with PSC. The ChiLDReN Study: an Opportunity for Children and Young Adults with PSC The Childhood Liver Disease Research Network (ChiLDReN) is a collaborative team of medical professionals, patient support organizations, and the National Institutes of Health (NIH). With clinical sites and research laboratories in the U.S., Canada, and the United Kingdom, ChiLDReN sponsors a number of natural history studies focused on rare cholestatic liver diseases, including a new study on PSC in the pediatric and young adult PSC population. “Primary Sclerosing Cholangitis in Children,” is an observational, 10-year prospective natural history study funded by the NIH.* Study investigators are seeking 700 young PSC patients at nine North American sites. Those aged 2 – 25 at time of screening with a diagnosis of either large-duct PSC or small-duct-only PSC may be eligible if they meet the other specific criteria. Those currently taking ursodeoxycholic acid or oral vancomycin for treatment of their PSC may remain on it. The purpose of the ChiLDReN study is to collect medical and other data to learn more about PSC, how it progresses, and identify factors that may cause the disease to progress more quickly; and to ask questions about how PSC symptoms affect a child's life to learn more about its impact on their daily functioning. Also, participants who are seen at one of the clinical sites will be asked to contribute information, DNA, and other specimens. The information and specimens will be available to investigators to carry out approved research aimed at learning more about the possible causes and long-term effects of PSC. Detailed information about the study and participating sites can be found at clinicaltrials.gov , including site locations, the site’s contact person, and their contact information (scroll down to “Locations”). Please contact them directly for specific study information. Given the rarity of PSC in young people, it is imperative that investigators work together across treatment centers in order to have study cohorts that are large enough to draw statistically sound conclusions. PSC Partners is extremely grateful to the investigators working on this study for their collaborative approach to gathering this important data, and to the NIH for funding the study. *through the National Institute of Diabetes and Digestive and Kidney Diseases program (NIDDK) Gilead's PRIMUS trial is terminated early On September 27, 2022, Gilead Sciences announced the early termination of the PRIMUS study, its phase 3 study of the investigational drug Cilofexor. Although there were no reported safety issues, the trial evidence to date did not show that the drug was effective for PSC. The decision to stop the trial was based on the results reached after the first 160 participants had completed Week 96 of the trial. The primary endpoint was improvement of fibrosis measured with a biopsy. Investigators saw no benefit to continuing the trial. You can read the Gilead statement here . This is certainly disappointing news. However, a “failed” trial is not a failure if lessons are learned that prove helpful going forward. Especially when a disease mechanism is unclear, such as in PSC, an unsuccessful trial can provide clarity regarding the disease process. Other times, the trial design may prove faulty even though carefully planned; such mistakes are informative to future trials and may even provide new information about the disease itself. PSC Partners continues its collaboration with Gilead and hopes that they will persist in seeking a treatment for PSC. If you took part in the PRIMUS study, you are deeply appreciated. The research process is lengthy, difficult, and sometimes disappointing; however, without study participants, it would go nowhere. Patients willing to participate in clinical trials are key to the ultimate goal of treatments and a cure for PSC. For more information, please contact Gilead Public Affairs at public_affairs@gilead.com . How can clinical trials become more patient friendly? Your input is needed! PSC Partners frequently communicates with PSC researchers and drug developers about patient-friendly trial design. Too often, the burden of travel, invasive testing, too-stringent inclusion/exclusion criteria, and more, limit the number of patients willing to enroll in a trial, which naturally slows the pace of research. Have you ever participated in a clinical trial? Wanted to but didn’t meet the inclusion criteria? Met the criteria but found the requirements too burdensome or the potential risk too high? We want to hear from you! Some of you may have participated in a trial and had a positive and rewarding experience. We would love to hear from you, too. It would help to know what the trial team did right. Your comments about both positive and negative trial experiences as well as concerns or limitations that may keep you from enrolling in a clinical trial are valued. You can contribute to the patient voice in shaping patient-friendly trials. You can share your thoughts by email at registrycoordinator@pscpartners.org OR, if you prefer to be anonymous, you can fill out this two-question Google Survey . If you email, Sharon or Rachel will be responding to you. Some points you may want to address:                         Considerations about inclusion and exclusion criteria, which are meant to ensure trial safety and uniformity in testing Thoughts on the trial drug Thoughts about frequency and type of testing Logistics such as travel frequency and time spent at the trial site Comments on health impact incurred by the trial Communication quality regarding consent documents, your role in the trial, and/or availability of the trial team to answer questions Compensation for expenses incurred or payment for your time Access to study results Fears, concerns, and/or positive experiences The chart below shows the percentage of Registry Clinical Survey respondents who were currently participating in a clinical trial related to PSC at the time they completed the survey (blue bar) or who had previously participated in a PSC clinical trial or donated a biospecimen for PSC research (red bars). The green bars signify the percentages of respondents who indicated that they are willing to be contacted in the future about PSC trials and biospecimen donation for PSC research. Receiving information about trials and studies does not obligate participants to enroll or donate.  The relatively low figures for current or past participation raise some questions: Are too many patients not a match for clinical trials? Are researchers unable to reach those who could be a match? Are clinical trials not easily accessible to people with PSC? No matter what the reasons are, these figures show that people with PSC are very willing to participate in research. Thank you for taking a few minutes to email us at registrycoordinator@pscpartners.org OR respond to the anonymous Google survey with your comments. The PSC community has been sharing thoughts and concerns through surveys and discussions. PSC Partners brings your de-identified input to the attention of researchers and trial developers when reviewing trial protocols, with the intent of helping them design trials that are as patient friendly as possible. Highlights of the 2022 International Liver Congress PSC Partners Board Member Jesse Kirkpatrick, PhD, has chosen to pursue a career focused on PSC, following a family member's PSC diagnosis. Now a Harvard medical student and postdoctoral researcher at the Massachusetts Institute of Technology, Dr. Kirkpatrick is conducting PSC research with the goal of answering key unsolved questions in PSC. He recently attended the 2022 International Liver CongressTM (ILC), which was hosted in London by the European Association for the Study of the Liver (EASL), and shared a few of the highlights with the Registry team. Dr. Kirkpatrick described the recently updated EASL Clinical Practice Guidelines* on sclerosing cholangitis as “one of the most relevant” topics discussed. The EASL PSC guidelines  were published in the Journal of Hepatology in September 2022 and a brief summary, i ncluding EASL's strong recommendations, can be found here . Dr. Kirkpatrick also noted that the conference included a symposium on bile acids featuring three cholestatic liver disease experts. He particularly highlighted Dr. Binita Kamath’s talk about the work being conducted around ileal bile acid transporter (IBAT) disruption. IBATs are molecules involved in the reabsorption of bile acids from the intestine, and novel drugs targeting IBATs show promise for treating the itch associated with liver disease. “It sounds like relief is coming for PSC patients with pruritus,” he said. A poster about a multinational pruritus study in which PSC Partners participated was presented at the ILC by Dr. Kris Kowdley of Washington State University. PSC Partners CEO Ricky Safer, Registry Director Rachel Gomel, and Medical Liaison Joanne Hatchett are among the co-authors. You can find a link to the poster abstract on the Registry’s new “Publications Related to Clinical Trials” page , which is accessible to both Registry participants and other patients with PSC interested in joining clinical trials. Look under the Mirum trial heading for the link to the 2022 Kowdley article in the Journal of Hepatology . The 6th Biennial Meeting of the International PSC Study Group (IPSCSG) also took place at the 2022 ILC. The IPSCSG’s aim is to coordinate PSC research projects between leading institutions worldwide. Jesse Kirkpatrick is a member of the IPSCSG, as is Ruth-Anne Pai of PSC Partners. Dr. Kirkpatrick is an integral part of PSC Partners’ efforts to expand its global reach through the International Collaborative Research Network initiative and informational webinars featuring international research and advocacy partners. *The American Association for the Study of Liver Diseases (AASLD) has also recently published a PSC Guidance, which can be found here . PLEASE NOTE: While meetings such as the recent EASL ILC are for scientists, professional organizations are increasingly becoming more accessible for patients. If you are interested in following EASL and accessing its scientific publications and online resources, EASL has announced a new patient membership option at a cost of €25 (Euros, about $24 US). Visit their membership page for more information. If you are interested in attending scientific meetings, the AASLD is hosting The Liver Meeting® in Washington, DC, November 4-8, 2022, and registration for patients/caregivers is available for both in-person and virtual attendance at a very reduced rate of $50. Most of the content is aimed at researchers and clinicians, but there is a patient/caregiver track as well. The sessions cover all things liver-related; cholestatic liver disease is a small part of the agenda. Register here . Meet Director of Research Strategy Ruth-Anne Pai, PhD When doctoral candidate Ruth-Anne Pai was matched with PSC Partners as a scientific advisor through the Chan Zuckerberg Initiative’s Rare As One (RAO) project, little did she know that she had found her next professional home. After advising the organization for a few months, Ruth-Anne discovered that PSC Partners was planning to hire a director of research strategy.  “The role aligned so well with what I hoped to do after my PhD [studies] and I was thrilled when offered the opportunity to position my scientific training to support the PSC community,” Ruth-Anne said. She joined the PSC Partners staff in April 2021. A native of eastern Pennsylvania, Ruth-Anne earned a BA in Biological Sciences at Cornell University and a PhD in Immunology from the University of Pennsylvania. Her doctoral dissertation included identification of two new treatments for an idiopathic form of Castleman disease – another rare disease with liver involvement. Her mentor at UPenn, Dr. David Fajgenbaum – himself a Castleman patient – was the keynote speaker at the 2022 PSC Partners annual conference. “I’ve had the amazing honor of working with Ruth-Anne Langan Pai over the years on Castleman’s Disease,” he said in his conference address , “and I’m just so thrilled that she is the research director for PSC Partners doing such important work.” Ruth-Anne’s focus at PSC Partners is on several new initiatives. She has a leadership role in crafting a Strategic Research Plan and launching the International Collaborative Research Network ( ICRNetwork ); and she is integrally involved developing the Worldwide Integration of Natural History Databases ( WIND ) project and a new PSC-specific patient-reported outcome measure (PROM). “Having Ruth-Anne Pai among us has been a game changer!” said Registry Director Rachel Gomel. “She has led the PSC Partners leadership team to embark in patient-driven research and has helped us bring the patient voice to the forefront." Ruth-Anne’s dedication to research was inspired by her ninth-grade biology teacher, who instilled in her “a love for scientific exploration through science fair.” Ruth-Anne developed a specific interest in immunology at Cornell, where she decided to focus on human disease. As a new PhD student at UPenn, Ruth-Anne was offered a lab rotation opportunity working with Dr. Fajgenbaum on Castleman disease research. “Dr. David Fajgenbaum taught me to always remember the needs of the patient community I serve and to work with urgency and purpose every day,” she said. When asked what insights into PSC her background in immunology provides, she replied, “There are many parallels between the work and skills I gained during my PhD [studies], and the research landscape in PSC, from the challenges of studying a heterogeneous rare disease to the importance of utilizing a multiomic approach to study early disease mechanisms.” “At PSC Partners, my ultimate goal is to provide all of the support I possibly can to accelerate the discovery and development of treatments and a cure for PSC,” said Ruth-Anne. “While one aspect of this is to develop key research projects and collaborations, I aim to support the PSC community in any way that leads to improved quality of life and outcomes.” Ruth-Anne Pai presented a poster illustrating PSC Partners' Roadmap Initiative at the CZI Rare As One meeting in June 2022.  As a researcher, Ruth-Anne understands the significance of the PSC Partners Registry. “Participation from the patient and caregiver community is so critical in that it enables the completion of clinical studies and is an incredible resource for PSC researchers,” she said. “We are so grateful to current and future participants in the Registry, who are active and crucial contributors to our quest for a cure for PSC.” Ruth-Anne presently lives near Seattle, Washington, with her husband, where they enjoy trail-hiking and traveling to visit family. Don't forget to check the Registry Clinical Trials page for updates on active clinical trials! Click image or  here to visit the Registry list of PSC ongoing clinical trials. “Together, we are creating a world where a PSC diagnosis comes with a cure!” Established in collaboration with the Office of Rare Diseases Research ( ORDR ), the National Center for Advancing Translational Sciences (NCATS), and the National Institutes of Health (NIH) © 2022 PSC Partners Seeking a Cure

A new survey is available in the Registry: the PSC Flare or Cholangitis Attack Patient Survey . Why take a survey about PSC flares/cholangitis? Though those who live with PSC may know what a cholangitis attack feels like, surprisingly, the medical world has not agreed on a definition. That is why researchers need information from adult PSC patients about their experience with PSC flares/cholangitis. We request that patients, not caregivers, take this survey. If you have ever experienced a PSC flare or cholangitis attack, whether your symptoms were mild or severe, please log in today to complete this survey! Note: If you have never experienced a flare, or if you have previously completed this survey via Google Forms (see below), you don’t have to take this survey. If in the first few questions you respond that you took the survey before, or that you’ve never had a flare/cholangitis attack, the survey will stop there. If you are a Registry participant, by taking a couple of minutes to let us know that you have taken the survey already, we will know not to send you reminder emails to complete the survey. If you’re not sure whether you previously took this survey, here is what the start of the survey looks like in Google Forms. If you are not a Patient Registry participant, you are encouraged to join today  and take this survey in the Registry after completing your account setup. If you do not wish to at this time, you can instead complete the PSC Flare or Cholangitis Attack Patient Survey  through Google Forms. No identifying information (such as name, phone number, address, date of birth) is collected. Click on the SINGLE USE SURVEY button above to leave the Patient Registry site and complete the PSC Flare or Cholangitis Attack Patient Survey   outside the Registry . About the Survey The survey will capture your symptoms before, during, and after your most recent PSC flare/cholangitis attack. This information will help characterize the prevalence and frequency of symptoms and the impact of these episodes on people living with PSC.  The survey will also include questions about the treatment and care you received, if sought, during your most recent PSC flare/cholangitis attack. Understanding your symptoms through your first-hand experience and from treatments you received during these episodes will help inform clinical trial design and is an important first step in establishing a better standard of care for those living with PSC. To access the survey, log into the Registry here  and find it on the Dashboard or in the Surveys tab on the left menu. Again,   patients should complete the survey for themselves. Caregivers should not complete it on behalf of their patient. This survey has been developed by PSC Partners  (based in the U.S.) and PSC Support  (based in the U.K.) as part of their work with the PSC Forum Acute Cholangitis Working Group. Thank you for your participation, which is critical in advancing PSC research.  Rachel Gomel, Patient Registry Director Together, we are creating a world where a PSC diagnosis comes with a cure!

Three Recent Announcements from: Pliant, NGM, and Chemomab PSC Partners is encouraged by the initial positive data from the CM-101 Phase 2 SPRING Trial which brings hope to our community that an effective treatment may be on the horizon. Of great importance to our community was the news that there were very few side-effects and no safety issues observed in PSC patients treated with CM-101. The decreases in measures of liver injury and fibrosis, as well as the improvement in itch, suggest a potential for improving liver health and symptoms, hopefully slowing the progression of this life-threatening disease. According to Chemomab Therapeutics, their plan is to discuss the SPRING trial results with the FDA later this year. The goal is to conduct a larger clinical trial that could possibly lead to an approved therapy for people with PSC. Given there are no approved therapies for PSC, it is important to study drugs with unique mechanisms such as CM-101 which targets both inflammation and fibrosis differently than other investigational drugs. We now have announcements from three companies with investigational PSC drugs that may move forward into larger studies with longer treatment.  PSC Partners has been actively engaged with all three companies, supporting these future studies and communicating updates with the PSC patient community. Our team is carefully reviewing the results from these new studies and will continue to share information through our regular channels.  News releases from the sponsors: Bexotegrast  (Pliant Therapeutics) Aldafermin  (NGM Bio) CM-101  (Chemomab) Ricky Safer, MA CEO and Founder, PSC Partners Seeking a Cure Stephen Rossi, PharmD CSO, PSC Partners Seeking a Cure Rachel Gomel, MA Registry Director, PSC Partners Seeking a Cure

The repurposing of approved medications with potential new efficacy in rare diseases is challenging, as these medications are unlikely to be studied and be approved by the FDA for their potential new indication. In PSC, the use of oral vancomycin (OV), an approved and repurposed drug, remains an area of debate in both the clinical and patient communities. There is growing evidence of a clinical benefit with OV treatment for certain PSC patients, especially those with active IBD symptoms. However, there is no definitive study to determine the best approach for using OV in PSC, including which patients will most benefit from OV and what treatment time frame will be most effective. Although there are several randomized clinical trials (RCT) underway, it is unlikely that these will provide a timely answer or address many of the questions that remain about how to best use OV. Because of the lack of RCT data, access to OV remains a significant challenge for many patients. A recent publication in Digestive Diseases and Sciences (1) provides a rational scientific framework using an “adaptive treatment strategy” for OV in PSC patients. The article highlights an approach that considers current information, presents an algorithm for OV treatment while also acknowledging the risks and challenges. The treatment approach outlined is “adaptive” in two important ways. First, the treatment decisions are based on an individual patient's response. Second, the definitions of response to OV can be adapted and refined as new data become available. A similar approach was taken with the use of UDCA in PSC which led to an adaptive treatment algorithm that was incorporated into most of the clinical guidance and guidelines, despite the lack of a definitive RCT. There is still work that needs to be done to define treatment response for broad acceptance by the clinicians and payors. However, the authors propose a cogent starting point that can help support access to OV for patients who may benefit from it. We thank the authors for suggesting a practical approach to decision making in treating rare diseases with repurposed drugs such as OV for PSC. (1) Shah A, Tabibian J, Buness C, Holtman G. An “adaptive treatment strategy” for oral vancomycin in patients with the orphan disease primary sclerosing cholangitis. Digestive Disease and Sciences https://doi.org/10.1007/s10620-024-08497-4

On July 15, 2024, Pliant Therapeutics announced positive results from their Phase 2a INTEGRIS-PSC trial for bexotegrast in treatment of PSC. In this randomized controlled study of bexotegrast, the 320 mg arm showed the following key findings (as stated by the sponsor): The 320 mg cohort demonstrated improvement in liver stiffness by transient elastography at Week 24 compared to placebo Statistically significant improvement observed in alkaline phosphatase (ALP) levels over 24 weeks compared to increased levels on placebo Continued improvement in hepatocyte function and bile flow by contrast MRI imaging was observed from Week 12 to Week 24 FDA guidance provided clarity on next steps of PSC development program Bexotegrast at 320 mg was well tolerated up to 40 weeks of treatment with no treatment-related severe or serious adverse events The 320 mg cohort demonstrated improvement in liver stiffness by transient elastography at Week 24 compared to placebo Statistically significant improvement observed in alkaline phosphatase (ALP) levels over 24 weeks compared to increased levels on placebo Continued improvement in hepatocyte function and bile flow by contrast MRI imaging was observed from Week 12 to Week 24 FDA guidance provided clarity on next steps of PSC development program Read the full press release on Pliant’s website . This news comes as a follow-up to the preliminary results at 12 weeks from the same INTEGRIS-PSC trial . This marks the completion of the Phase 2a trial; the Registry will continue to provide updates as more information becomes available. Thank you to everyone who has participated in this trial and all clinical trials! More information about all PSC clinical trials can be found on the PSC Partners Patient Registry website .

The following is a message from Mirum Pharmaceuticals regarding their VISTAS study for volixibat, a possible new treatment for PSC-related pruritus (itch). They have recently expanded their inclusion criteria for this trial to include children with PSC ages 12 and older, and people who also have autoimmune hepatitis (AIH). If you are interested in participating, please contact the research team at this Mirum Pharmaceuticals link.   They will have answers to your questions. The Registry team can answer general questions or concerns but cannot answer specific questions or screen you for eligibility. Your participation is essential for the success of clinical trials for PSC. Thank you! Rachel Gomel, Director, PSC Partners Patient Registry, and the Registry Team Together, we are creating a world where a PSC diagnosis comes with a cure. registrycoordinator@pscpartners.org www.pscpartnersregistry.org Message from Mirum: LIVING WITH ITCH DUE TO PSC? You may be eligible for the VISTAS PSC Study if you: · Are 12 years of age or older · Have a confirmed diagnosis of Large Duct or Small Duct PSC · Are currently affected by itch caused by PSC · Have PSC with or without AIH Study participation will last 7~8 months with the option to continue in the long-term extension phase, where eligible participants will receive the investigational medication, volixibat for an indefinite amount of time. The study now includes a “decentralized” option in the US where all participants can enroll in the trial from the comfort of their home: all study activities will be performed at home by health professionals and supervised by a study physician using virtual visits. Participants who prefer to participate via the traditional hospital- or clinic-based approach may continue to do so. To learn more about the study please visit us at https://mirumclinicaltrials.com/pscstudy/

Exciting news about the Pliant Therapeutics PSC clinical trial preliminary results from their global INTEGRIS-PSC Phase 2a trial for Bexotegrast. Key findings (stated by the sponsor) include: “Bexotegrast was well tolerated over 12 weeks of treatment for participants with PSC.” “Bexotegrast demonstrated antifibrotic activity in a PSC population with suspected moderate to severe liver fibrosis.” “Bexotegrast showed a dose-dependent trend of reduction in ALP relative to placebo.” Phase 2 studies are designed to discover drug dosing and safety. More information from the sponsor about these positive interim results can be found at  Developing Novel Treatments for Fibrotic Diseases ( pliantrx.com )  and  https://pliantrx.com/pln-74809/ . Thank you to each of you who participated in this trial, and thanks to all of you who are active in the PSC Partners Patient Registry, PSC studies, and clinical trials! More information about this and other PSC clinical trials can be found on the PSC Patient Registry at  https://www.pscpartnersregistry.org/clinical-trials/ongoing . Original post from Facebook Open Support Group

Dear Registry Participants (Current and Future),  This year is the 10th anniversary  of the PSC Partners Patient Registry, a perfect time for renewal, for the upgrade you can experience when you log into the Registry. What you will experience is   only the tip of the iceberg . The Registry is fulfilling a PSC Partners dream transformed into the tangible goal of facilitating and speeding up research towards PSC treatments and a cure.  This progress could only take place thanks to all of you participating in the Registry. With your enthusiasm to embark on this journey, you’ve helped open many new paths leading to patient-centered research, advocacy for our unmet needs, and empowerment of our 2,500 voices. Thanks to all 2,500 Registry participants, the Registry is thriving.  A New Registry Experience I will start with the tip of the iceberg, what you will experience when you enter your new space in the Registry and its website. (Please check out the Registry website  for the short video tutorials created to help you log in and navigate through the new features.) The platform has multi-language capabilities for our international participants or for those whose native language is not English. (The Registry platform supports English, Spanish, French, Italian, and German. The surveys are in English at this time but will be translated into these languages in the near future.)  You can now securely share your experience with your physicians and family members. You will be able to upload medical documents, MRIs, school forms, genetic reports, and more. You can track your symptoms and activities and share them with your physicians. The Registry has the capability to keep track of your adherence to medications and adverse events. You can create journal entries to describe the care you are receiving or the symptoms you are experiencing. The Registry website  is regularly updated with news on clinical trials, physicians treating Registry participants (Physician Map), the impact you are having on PSC research, and general news. To access your new Registry home, go to www.pscpartnersregistry.org  and select “Join Now” if you are NOT an existing participant. However, if you are an existing Registry participant, Select “Log In'' from our home page at pscpartnersregistry.org , enter your email address, and click on “Forgot your password?” in order to create a new password. (You must create a new password, even if you remember your previous password.) There are video and written tutorials  on the website to help you. Your Collective Impact Matters The above features are what you can  see. Below are a few of the PSC Partners initiatives that lie beneath the visible tip of the iceberg. They were each enabled by your participation in the Registry.   Your de-identified responses to Registry questions have helped shape the PSC Partners Strategic Research Plan . Over 800 people with PSC responded to Our Voices Survey  and expressed their priorities, which PSC Partners scientists and PSC thought leaders translated and transformed into a research plan. An in-person inaugural meeting brought together the PSC Partners International Collaborative Research Network ( ICRNetwork ) in 2023. Patients, clinicians, researchers, data analysts, and regulators (FDA representatives) formed working groups to discuss your research priorities and ways of implementing them with scientific rigor. Projects are already ongoing. WIND-PSC  was created in response to your research priorities and unmet needs. You let us know that your top research priority was to slow down disease progression.  Gaps were identified, one of which is the absence of dependable and solid PSC biomarkers, which are a requirement to determine whether a PSC drug is effective and can be approved. Over 10 medical centers and 2,000 people with PSC will be participating in this massive initiative. We will ask you for your participation.    Registry data informed us about the PSC symptoms that affect your quality of life, and, in response, a Symptom Assessment Program  (SAP) was created. Two experts interviewed some of you to listen to your description of your PSC symptoms. They are currently translating what they heard from you into validated tools that can be used in clinical trials to objectively measure changes in your symptoms. It is only through your participation and engagement that these tools can be developed and be used to determine the success of a new PSC drug.   Joining a rare disease registry is a powerful act that goes beyond simply providing data. It’s about building community, advocating for change, and actively participating in research. By adding your voices to the Registry, you are powerful partners in the quest for a cure. Patients are moving mountains, and the decision-makers are clearly hearing us. Please know that each email we send you is tied to our collective mission. Please do your very best to respond if you possibly can.  The Registry Team sending you these messages is comprised of three Moms whose children have PSC and two people with close connections to PSC. All of us together are passionately working towards treatments and a cure.  JOIN THE RACE! YOUR JOURNEY MATTERS. Together we are creating a world where a PSC diagnosis comes with a cure! Rachel Gomel  Director, PSC Partners Patient Registry The 3 Unstoppable PSC Moms who Believe in the PSC Community’s Unshakable Power! THE PSC PARTNERS REGISTRY TEAM Rachel Gomel , Director Sharon Nanz , Registry Curator Mary Vyas , Registry Strategist Susan O’Dell , Registry Analyst Brian Thorsen , Registry Webmaster We’re together in the fight, whatever it takes!

Health equity is the state in which everyone has a fair and just opportunity to attain their highest level of health*. The mission of PSC Partners is to drive research to identify treatments and a cure for PSC while providing education and support for those impacted by this rare disease. Why are we surveying our community about health equity topics? PSC can affect anyone. We need a better understanding of who is impacted by PSC and the barriers that can impede your care. PSC Partners’ goal is to facilitate ways to reduce these barriers. PSC Partners needs your help. Please complete this brief survey. Your participation will make a difference in the care of people living with PSC, as well as provide vital information in the search for treatments and a cure. This survey can be completed by a PSC patient or a caregiver on behalf of the PSC patient. In this survey, the PSC patient is referred to as the “participant.” Please be sure that this survey is completed JUST ONCE for each participant.  Are you...  A PSC Partners Patient Registry participant?  Please complete the Health Equity in PSC Survey through the Registry. Click REGISTRY PARTICIPANT LOGIN   to get started now. Log in to your registry account, complete the Health Equity in PSC Survey , and also update your Clinical Survey . This option saves you time: the Health Equity in PSC Survey in the Registry has fewer questions because you won't be asked to provide information that has already been collected in the Registry. --OR-- Not yet a PSC Partners Patient Registry participant?  If you are not a participant in the Patient Registry, you are invited to join today and complete the Health Equity in PSC Survey through the Registry. Benefits of doing so include: Provides a more complete picture of your PSC diagnosis and experience because your response to this health equity survey within the Registry will be one among other surveys.  You can update your information over time. You will receive information about opportunities to participate in research, clinical trials, medical advances and other news from the Registry Continues to strengthen the power of the Registry by demonstrating Registry engagement of the PSC community. Click on JOIN REGISTRY NOW   to set up your account, complete the NEW Clinical Survey and the  Health Equity in PSC Survey . --OR-- Not interested in PSC Partners Patient Registry participation at this time?  You can complete the Health Equity in PSC Survey without being a Patient Registry participant. With this option, your responses will fulfill a single-use purpose as no identifying information (such as name, phone number, address, date of birth) is collected. Registry team will not be able to contact you directly to give you future survey results or to let you know about opportunities to participate in research. Click on SINGLE-USE SURVEY button above  to leave the Patient Registry site and complete the Health Equity in PSC Survey outside the Registry. Each of these three options will support the purposes of this survey! For questions or clarification, please email  registrycoordinator@pscpartners.org . Thank you! *Centers for Disease Control and Prevention https://www.cdc.gov/healthequity/whatis/index.html