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

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 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

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

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

Statement From Gilead Sciences on September 27, 2022 Early Termination of Gilead-Sponsored Study GS-US-428-4194: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects with Primary Sclerosing Cholangitis (PSC) On Monday, September 26, 2022, Gilead announced to clinical investigators plans to discontinue the Phase 3 PRIMIS study (GS-US-428-4194) of cilofexor (GS-9674), an investigational FXR agonist, in adults with non-cirrhotic large-duct primary sclerosing cholangitis (PSC). This decision followed the review of data from a planned interim futility analysis. This analysis was based on the primary endpoint after the first 160 participants had completed Week 96 or Early Termination (ET) assessments in the Blinded Study Phase. The results indicated the futility criterion was met, triggering the data monitoring committee to recommend stopping PRIMIS study. An internal committee at Gilead, who is external to the PRIMIS study, evaluated the futility analysis and unblinded data, confirming the DMC’s recommendation. The committee determined that there is no benefit to continuing the trial and exposing patients to the study drug or, certain procedures required for the study, such as liver biopsies. As such, the PRIMIS study is being terminated. Importantly, neither the DMC nor the internal unblinded Gilead committee identified any safety concerns associated with cilofexor. We are disappointed by this outcome of cilofexor in PSC. We are deeply grateful to the investigators and their PSC patients for their contributions to the PRIMIS trial and to clinical research in PSC, a disease with great unmet need for safe and efficacious therapeutics. Inflammatory and fibrotic diseases are a key focus of our work to bring forward 10+ transformative therapies over the next decade, and we remain committed to developing treatments for patients with liver disease. Importantly, this decision does not affect our ongoing Phase 2 study (GS-US-454-6075) evaluating the safety and efficacy of semaglutide, and the fixed-dose combination of cilofexor and firsocostat, alone and in combination, in patients with compensated cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH). This trial will continue without modification; we remain confident in cilofexor’s safety profile and its potential contribution to efficacy in NASH.   For more information, please contact Gilead Public Affairs at public_affairs@gilead.com .

A proof-of-concept Phase 2 trial conducted by Mayo Clinic and sponsored by Immunic has shown very early positive results. We hope that the early evidence gathered from 11 people will lead to a full clinical trial and prove to be promising in treating PSC. For more information: Press release by Immunic can be found here . ClinicalTrials.gov listing can be found here . Summary: Quoted from 20210218_Immunic_Inc_IMU-838_PSC_IST_Results_Presentation  found on this page at immunic-therapeutics.com: IMU-838 in PSC: Outlook: Feb/18/2021 As an Orally Available DHODH Inhibitor With a Prominent Influence on Th17 Induced Inflammatory Processes, IMU-838 is a Promising Approach for the Treatment of PSC. The encouraging results regarding biochemical parameters and safety suggest that IMU-838 merits further clinical testing in PSC. Immunic is in discussions with investigators and leading clinical experts to further evaluate the data set and to explore potential next steps. Immunic believes that dose optimization would be needed for potential future trials, which would also require assessment of pharmacokinetics in hepatic impaired patients. All rights reserved © PSC Partners Seeking a Cure

The clinical trials resources page has been updated on 1/27/21 to reflect two clinical trials currently recruiting. PLN 74809: Phase 2a Evaluation of Safety, Tolerability, and Pharmacokinetics of PLN-74809 in Patients With Primary Sclerosing Cholangitis (PSC).  Pliant Therapeutics's PLN 74809 is an antifibrotic drug. It is in Phase 2a trial for PSC. The clinical trial is taking place in 22 centers throughout the U.S. The drug received Orphan Drug Designation for PSC. For more details on the trial, please see the  clinicaltrials.gov listing  and the  Pliant Therapeutics site . Volixibat: A Study to Evaluate Efficacy and Safety of an Investigational Drug Named Volixibat in Patients With Itching Caused by Primary Sclerosing Cholangitis (VISTAS).  The purpose of this clinical research study, sponsored by Mirum Pharmaceuticals, is to learn more about the use of the study medicine, volixibat, for the treatment of pruritus* associated with Primary Sclerosing Cholangitis (PSC), and to assess the possible impact on the disease progression of PSC. For more details on the trial, please see the clinicaltrials.gov listing , the Mirum Pharmaceuticals site , and the businesswire article .  * Localized or generalized itching, a prevalent and distressing symptom of cholestasis.

On October 6, 2020, the PSC Partners Registry team sent out an email alert regarding a Harvard Brigham and Women’s Hospital nutrition study that urgently needed more participants. This appeal was sent to adult U.S. registry participants and urged all who were interested to contact the Harvard researchers to find out more. Recipients responded in droves with emails and phone messages to the researchers – to the extent that the Harvard team had to add additional staff! They are working hard to reply to everyone, so please be patient if you are one of those awaiting a return call or email. Dr. Josh Korzenik, lead researcher, has assured us that they will get back to everyone. The excellent response to our appeal is exactly what we need to demonstrate to PSC researchers that our community is active, engaged, and willing to step up when called upon. Thank you for this very positive show of support! To learn more about this nutrition study and for contact information, please visit  https://sites.google.com/pscpartners.org/pscnutrition2020 All rights reserved © PSC Partners Seeking a Cure

Check out this video invitation from PSC nutrition study Principal Investigator Dr. Josh Korzenik to participate in a diet and nutrition study. Enrollment is open and ongoing. The study will be conducted remotely; patients can participate from anywhere in the USA. The PSC Collaborative at the Brigham and Women’s Hospital is recruiting adult patients with PSC for a pilot research study to investigate the role of diet and nutrition in the development and treatment of PSC. Please contact the study team to see if you are eligible to take part in this research study if you are living in the US. Click here for more information: https://sites.google.com/pscpartners.org/pscnutrition2020 Brigham and Women's Hospital Harvard Medical School

Joanne Hatchett, PSC Partners Medical Science Liaison, sat down for a Zoom interview with Dr. Gideon Hirschfield. Dr. Hirschfield is the Lily and Terry Horner Chair in Autoimmune Liver Disease Research at the Toronto Centre for Liver Disease, Toronto General Hospital and Professor of Medicine in the Division of Gastroenterology at the University of Toronto. He also serves on the PSC Partners Scientific Medical Advisory Committee. The discussion focused on the Our Voices survey, clinical trials, and the value of the patient-led PSC Partners Patient Registry. Enjoy, and thank you Dr. Hirschfield!   "The more people that speak, the better!" Why taking surveys through the patient registry is important: Linking messages with the clinical records helps researchers! Enables patients to possibly be the catalyst for a good idea! The Our Voices Survey and the PFDD ... "is a well-timed, important initiative!" "Each piece of the puzzle keeps people excited." To find the survey, please JOIN NOW or LOGIN to your registry account at www.pscpartnersregistry.org . Navigate to the PROFILE tab and you'll see the Our Voices survey listed. While you are there, please take or update your Clinical Survey!  All rights reserved © PSC Partners Seeking a Cure