Conjunctivitis, Acute Hemorrhagic

Pictured: A person with an irritated gut/Taylor Tieden for BioSpace Twenty-two years ago, a molecule called TL1A was first discovered and isolated. Today, after two decades of research, therapeutics to calm its activity may usher in a new era for the treatment of immune-mediated diseases like inflammatory bowel disease, psoriasis and rheumatoid arthritis. TL1A (tumor necrosis factor-like cytokine 1A) is part of the tumor necrosis factor (TNF) superfamily, a group of cell-signaling molecules that have potent effects on immune function and which have led to anti-TNF antibodies such as AbbVie’s blockbuster Humira (adalimumab). Against this backdrop, two monoclonal antibodies targeting TL1A spurred major biopharma acquisitions in 2023. In June, Merck completed the purchase of Prometheus Biosciences for $10.8 billion. The company’s lead asset, PRA-023—now MK-7240—has shown clinical evidence of “best-in-class” potential for treating inflammation and scarring in the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease, Nature reported. Then in October, Roche paid $7.1 billion for Roivant subsidiary Televant Holdings and its anti-TL1A antibody RVT-3101, also for IBD. That same month, Sanofi and Teva Pharmaceuticals announced a collaboration worth a potential $1.5 billion to co-develop TEV-’574, a TL1A inhibitor currently in Phase IIb clinical trials for IBD. Stephan Targan, executive director of the F. Widjaja Inflammatory Bowel Institute of Cedars-Sinai, Los Angeles, and colleagues carried out much of the research into TL1A and developed the antibody Prometheus purchased. After giving the keynote presentation about TL1A at the Crohn’s & Colitis Congress earlier this month, Targan told BioSpace, “I have never had an audience response like that. There’s a big buzz about this in our field.” What’s All the Excitement About? In an April 2023 note shared with BioSpace, Jefferies analyst Michael Yee wrote that there is a “high unmet need” in IBD. Current treatment options are limited and with modest benefit, Yee explained. Driving part of the excitement around TL1A inhibitors is the hope that they can break the “efficacy ceiling that we see even with the best drugs out there,” Aileen Pangan, a rheumatologist and therapeutic area head of immunology clinical research at Merck, told BioSpace. “We are not getting the remission rates we’d like. And even after remission, there is a considerable loss of response over time, requiring patients to switch to another drug. . . . Some patients may have to try two or three different drugs before they find one that works. We are simply not where we want to be.” In December 2022, Prometheus announced positive results from two 12-week Phase IIa studies of PRA-023, ARTEMIS-UC and APOLLO-CD, in patients with moderate to severe ulcerative colitis and Crohn’s disease who had failed other therapies. In the ARTEMIS study, 26.5% of patients reached the primary endpoint of clinical remission compared to 1.5% of those on placebo. And in APOLLO-CD, a 49.1% clinical remission rate was achieved, compared with a 16% historical placebo rate. Targan called the results “huge,” highlighting the durability of the treatment as a significant improvement over existing treatments. “The therapeutics available today might offer a 20% increase [in remission] over placebo over a 12-week trial, but at the end of a year, only 40% are maintained. That means, of the entire population of Crohn’s sufferers, a given biologic may offer an 8% remission.” But with Merck’s TL1A inhibitor, he said, “Initial remission rates may be over 50% and durability over time could be as high as 90%,” for an overall remission rate of 45%. “That’s never been seen before.” Similarly, Roche’s RVT-3101 showed positive results in the Phase IIb TUSCANY-2 study in moderate-to-severe ulcerative colitis. The results, released in June 2023, led to clinical remission in 36% of patients after 56 weeks of treatment, with endoscopic improvement reaching 50%. Enabling Targeted Treatment These new antibodies could perform very well in targeted patient populations, Targan said, thanks to a novel diagnostic tool that uses genetic testing as well as other genomic markers to inform physicians about how well the molecule will work in a specific patient. “Right now, physicians and patients have to go through trial-and-error steps before they find the right drug,” he explained. But certain genetic variations, called risk alleles, increase the likelihood the patient will respond to the drug. “Risk alleles are very significantly associated with increased expression of TL1A over time,” Targan said. “I predict the Phase III trials will show people doing very well if their diagnostic tests show a strong genetic association with the presence of the TL1A molecule.” He added that he believes the new companion diagnostic will also identify those patients who will see a durable response. He compared this companion diagnostic, which is yet to be approved by the FDA, to those used in oncology, where “to find out what you need to treat a tumor, you evaluate the characteristics of the tumor.” Pangan said the power of this diagnostic was evident in Prometheus’ Phase II trial. In the ARTEMIS-UC study, all trial participants were tested with the complementary diagnostic and stratified according to the result. Of the 135 enrolled patients, 32 were positive for a SNP-based signature that includes the TL1A risk alleles (16 were on placebo and 16 received the antibody), and a greater proportion who were positive for risk alleles or other biomarkers achieved remission with the antibody compared to those who were negative, Pangan shared. Merck has embarked on a global Phase III trial that will enroll over 1,000 patients. “If we can identify the population that is most likely to get into remission with this antibody, we can help patients and physicians everywhere,” she said. Biotech entrepreneur Andrew Pannu told BioSpace that the biomarker-driven approach being taken by both Merck and Roche reflects a belief that these biomarkers will credibly predict responders and that this will help with reimbursement efforts in a “fairly crowded market.” Beyond IBD TL1A inhibitors also hold potential in other autoimmune diseases. In a 2022 summary review article published in Frontiers, TL1A was found to be was abnormally expressed in IBD, as well as in rheumatoid arthritis, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. And, as the molecule binds to activated fibroblasts, targeting TL1A might offer another novel benefit: the reversal of fibrosis and scarring. “In a lot of our work in animals, we found that, lo and behold, TL1A inhibitors could reverse scarring,” Targan said. That could have applications for strictures in Crohn’s disease—although anti-TL1A drugs can’t ‘fix’ already formed strictures, they might help keep them from forming or re-forming after surgical intervention, he said. TL1A inhibitors might also be helpful in other diseases where fibrosis and scarring are significant such as systemic sclerosis and primary sclerosing cholangitis, Targan noted. And Merck is currently conducting a Phase II study looking at fibrosis in systemic sclerosis associated with interstitial lung disease. Lee also noted the potential durability and success of the class. “Data could get even better over time given the anti-fibrotic potential of TL1A inhibitors,” he wrote in the April 2023 investor note. “Of course, I’m prejudiced,” Targan said, “but I’ve been around a long time. I’ve been working on inflammatory bowel disease for half a century now, and I do believe TL1A inhibitors will be transformational for many immune-mediated diseases.” Jill Neimark is a freelance science writer based in Macon, Georgia. Reach her at jillneimark.com.

– Reported strong efficacy and favorable safety results for PRA023 in ARTEMIS-UC and APOLLO-CD Phase 2 Studies – – Prometheus intends to advance PRA023 into Phase 3 studies for UC and CD in 2023 – – Initiated a third Phase 2 of PRA023 into SSc-ILD, demonstrating pipeline-in-a-product candidate potential for the program – – Expanded clinical pipeline with advancement of PRA052, a potentially first-in-class monoclonal antibody blocking CD30L, into Phase 1 – – Strong cash position of >$700M following full completion of recent financing – SAN DIEGO, Feb. 28, 2023 (GLOBE NEWSWIRE) -- Prometheus Biosciences, Inc. (Nasdaq: RXDX), a clinical-stage biotechnology company pioneering a precision medicine approach for the discovery, development, and commercialization of novel therapeutics for the treatment of immune-mediated diseases, today reported financial results for the quarter and full-year ended December 31, 2022 and highlighted recent corporate progress. "2022 was a momentous year for Prometheus and the IBD community, highlighted by the positive readout in both PRA023 Phase 2 studies in UC and CD, which we believe set a new standard in IBD by combining high efficacy and favorable safety results,” said Mark McKenna, Chairman and CEO of Prometheus Biosciences. “We continue to believe that PRA023 is a potential best-in-class and first-in-class therapeutic candidate for IBD and we intend on carrying this momentum into 2023 by advancing PRA023 into Phase 3 studies.” FOURTH QUARTER AND FULL-YEAR 2022 AND RECENT CORPORATE HIGHLIGHTS CORPORATE HIGHLIGHTS Reported positive results for PRA023 in both ARTEMIS-UC Phase 2 and APOLLO-CD Phase 2a studies. Prometheus reported topline results from the initial cohort of its ARTEMIS-UC Phase 2 trial and results from its APOLLO-CD Phase 2a trial of PRA023, demonstrating strong efficacy and favorable safety results in both studies in the context of very severe and refractory patient populations. The company plans to advance to Phase 3 trials in both UC and CD this year. Prometheus’ Phase 2 ARTEMIS-UC clinical trial was a 12-week, double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of PRA023 in patients with moderate-to-severely active UC who have failed conventional or advanced therapy. PRA023 met the primary and all ranked secondary endpoints including clinical, endoscopic, histologic, and patient-reported outcome measures in the initial cohort (Cohort 1) of the trial. 68/68 (100%) of PRA023-treated patients completed the Cohort 1 study, compared to 60/67 (89.6%) in the placebo group. The topline results were as follows: 26.5% of patients on PRA023 reached the primary endpoint of clinical remission (per modified Mayo Score), compared to 1.5% on placebo, for a placebo-adjusted clinical remission rate of 25.0% on the primary endpoint (p<0.0001)36.8% of patients on PRA023 reached the secondary endpoint of endoscopic improvement (Mayo endoscopy subscore of ≤ 1), compared to 6.0% on placebo, for a placebo-adjusted endoscopic improvement rate of 30.8% on the secondary endpoint (p<0.0001)All secondary endpoints met with statistical significancePRA023 was well tolerated with no safety signal identifiedCohort 1 interim analysis suggests a trend towards increased PRA023 response in CDx+ patients over all comers with clinical remission of 37.5% in Dx+ patients, compared with 25.0% for all-comers Prometheus’ Phase 2a APOLLO-CD clinical trial was a 12-week open-label study that enrolled 55 patients with moderate-to-severely active CD with endoscopically active disease who had failed conventional or biologic therapy. The study enrolled a highly refractory patient population with 70.9% of patients previously treated with at least one biologic therapy and 52.7% treated with two or more biologic therapies. The results were as follows: 26.0% of patients on PRA023 achieved endoscopic response (p=0.002 compared to 12% prespecified historical placebo rate)49.1% of patients on PRA023 achieved clinical remission (p<0.001 compared to 16% prespecified historical placebo rate)PRA023 was well tolerated in subjects with moderately-to-severely active CD with no safety signal identifiedPRA023 showed a significant impact on multiple markers of inflammation and fibrosis Expanded therapeutic investigation of PRA023 into SSc-ILD, a rare autoimmune disorder. Prometheus initiated its third Phase 2 study of PRA023, ATHENA-SSc-ILD, targeting both key fibrotic and inflammatory pathways for the treatment of SSc-ILD. PRA023 received Fast Track Designation from the US Food and Drug Administration (FDA) for the treatment of SSc-ILD. Systemic Sclerosis (SSc) is a rare autoimmune disorder characterized by progressive fibrosis of the skin and internal organs thought to result from inflammation and chronic immune activation. Lung involvement (SSc-ILD) is the leading cause of morbidity and mortality for individuals with the disorder. SSc-ILD has been largely irreversible with current therapeutic strategies focused on slowing progression of the disorder. Topline results from the Phase 2 study are expected in 1H 2024. Advanced second precision program, PRA052, into Phase 1. Prometheus received IND clearance from the FDA and initiated a Phase 1 trial in normal healthy volunteers (NHVs) for PRA052, a potential first-in-class monoclonal antibody blocking CD30 ligand (CD30L). CD30L is a costimulatory molecule that has been implicated in inflammatory bowel disease (IBD) by genetic, preclinical, and human translational data. Prometheus is also developing a companion diagnostic candidate designed to select potential responders for this program. Results from the Phase 1 NHV study are expected in 4Q 2023. Completed upsized $550M public offering of common stock. Prometheus completed an upsized public offering of common stock following the release of its Phase 2 data on PRA023, with net proceeds to the company of approximately $520 million. UPCOMING ANTICIPATED MILESTONES AND EVENTS ARTEMIS-UC expansion cohort (Cohort 2) results – 2Q 2023Initiation of registrational studies for PRA023 in UC and CD – 2023R&D Day Presentation – 2H 2023PRA052 Phase 1 NHV results– 4Q 2023IND submission for PR1100 – 4Q 2023 FOURTH QUARTER AND FULL-YEAR 2022 FINANCIAL RESULTS Cash, Cash Equivalents and Short-Term Investments. As of December 31, 2022, Prometheus had cash, cash equivalents and short-term investments of $695.8 million, compared to $257.3 million at the end of 2021. The increase is primarily due to raising approximately $470.5 million in net proceeds through an upsized underwritten public offering of common stock in Q4 2022. Subsequent to the end of the year, Prometheus raised approximately $50.1 million in additional net proceeds through the exercise of the underwriters’ option to purchase additional shares. Collaboration Revenue. Revenue was $0.7 million for the three months ended December 31, 2022, compared to $1.0 million for the three months ended December 31, 2021 and $6.8 million for the full year 2022 compared with $3.1 million for the full year 2021. The fluctuations were primarily due to revenue generated from Prometheus’ collaboration with Dr. Falk Pharma GmbH. Research and Development (R&D) Expenses. Research and development expenses were $29.9 million for the three months ended December 31, 2022 compared to $23.6 million for the three months ended December 31, 2021 and $112.8 million for the full year 2022 compared with $62.4 million for the full year 2021. The increases in R&D expenses were primarily due to advancement of PRA023 in global Phase 2 clinical trials and PRA052 into Phase 1 clinical trials, as well as advancing our other development programs. General and Administrative (G&A) Expenses. General and administrative expenses were $12.0 million for the three months ended December 31, 2022 compared to $7.4 million for the three months ended December 31, 2021 and $39.7 million for the full year 2022 compared with $28.5 million for the full year 2021. The increases were primarily due to an increase in headcount and stock-based compensation expense. About Prometheus Biosciences Prometheus Biosciences, Inc. is a clinical-stage biotechnology company pioneering a precision medicine approach for the discovery, development, and commercialization of novel therapeutics for the treatment of immune-mediated diseases. The Company’s target discovery engine, Prometheus360™, combines proprietary machine learning-based analytical approaches with one of the world’s largest gastrointestinal bioinformatics databases to identify novel therapeutic targets and develop therapeutic candidates to engage those targets. The company’s lead candidate, PRA023, is a humanized IgG1 monoclonal antibody (mAb) that has been shown to block the tumor necrosis factor (TNF)-like ligand 1A (TL1A), a target associated with both intestinal inflammation and fibrosis. Prometheus is developing PRA023 for the treatment of immune-mediated diseases including ulcerative colitis (UC), Crohn’s Disease (CD), and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Prometheus plans to advance PRA023 into Phase 3 trials in UC and CD later this year. Forward Looking Statements Prometheus cautions readers that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to statements regarding: the potential of PRA023 to improve IBD treatment and to be both a first-in-class and best-in-class anti-TL1A mAb; the potential of PRA052 to be a first-in-class mAb blocking CD30L; the timing of results from Cohort 2 of the ARTEMIS-UC trial, topline results from the ATHENA-SSc-ILD trial, and results from the Phase 1 NHV study of PRA052; plans to advance PRA023 into Phase 3 trials in UC and CD, including the timing thereof; plans to submit an IND for PR1100, including the timing thereof; plans to develop diagnostic candidates; and the potential of Prometheus’ diagnostic candidates to identify potential responders. The inclusion of forward-looking statements should not be regarded as a representation by Prometheus that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: topline results Prometheus reports are based on preliminary analysis of key efficacy and safety data, and such data may change following a more comprehensive review of the data related to the clinical trial and such topline data may not accurately reflect the complete results of a clinical trial; Prometheus’ approach to the discovery and development of precision medicines based on Prometheus360™ is unproven; interim results of a clinical trial do not predict final results and the clinical outcomes may materially change following more comprehensive reviews of the data, as follow-up on the outcome of any particular patient continues and as more patient data become available, including from Cohort 2 of the ARTEMIS-UC trial; potential delays in the commencement, enrollment and completion of clinical trials and preclinical studies; the results of clinical trials are not necessarily predictive of future results; Prometheus’ dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; Prometheus’ ability to develop companion diagnostics for its therapeutic product candidates; unexpected adverse side effects or inadequate efficacy of its product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; planned future trials of PRA023 may not support regulatory registration; regulatory developments in the United States and foreign countries; Prometheus’ ability to maintain undisrupted business operations due to the COVID-19 pandemic, including delaying or otherwise disrupting its preclinical studies, clinical trials, manufacturing and supply chain; and other risks described in the company’s prior press releases and filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in Prometheus’ most recent annual report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Prometheus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Prometheus Biosciences, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(unaudited)(in thousands, except share and per share data) Three Months Ended Twelve Months Ended December 31, December 31, 2022 2021 2022 2021 Collaboration revenue$653 $1,037 $6,809 $3,129 Operating expenses: Research and development 29,942 23,564 112,848 62,427 General and administrative 12,041 7,417 39,739 28,505 Total operating expenses 41,983 30,981 152,587 90,932 Loss from operations (41,330) (29,944) (145,778) (87,803)Other income (expense), net 2,566 26 4,026 (2,392)Net loss$(38,764) $(29,918) $(141,752) $(90,195)Other comprehensive loss: Unrealized gain (loss) on marketable securities, net 22 — (429) — Comprehensive loss (38,742) (29,918) (142,181) (90,195)Net loss per share, basic and diluted$(0.90) $(0.77) $(3.49) $(2.88)Weighted average shares outstanding - basic and diluted 42,950,876 38,916,838 40,617,465 31,334,154 Prometheus Biosciences, Inc.Condensed Consolidated Balance Sheets (in thousands)(unaudited) December 31, 2022 December 31, 2021Assets Cash and cash equivalents$292,423 $257,254 Short-term investments 403,329 — Other current assets 12,399 8,129 Total current assets 708,151 265,383 Other assets 32,622 2,418 Total assets$740,773 $267,801 Liabilities and Stockholders' Equity Current liabilities$22,817 $16,442 Long-term liabilities 41,988 16,204 Total liabilities 64,805 32,646 Total stockholders' equity 675,968 235,155 Total liabilities and stockholders' equity$740,773 $267,801 Contacts:Noel KurdiVP Investor Relations and Communications(646) 241-4400nkurdi@prometheusbiosciences.com Media contact:Juniper PointAmy Conrad(858) 914-1962media@prometheusbiosciences.com

Courtesy Getty Images Findings from Prometheus Biosciences' Phase II ARTEMIS-UC and Phase IIa APOLLO-CD trials show that PRA023, an anti-TL1A monoclonal antibody, is potentially safe and effective in ulcerative colitis and Crohn’s disease. With these promising data, the California biotech will engage key regulatory bodies to advance the candidate into pivotal development next year. The full data sets and analyses will be presented at an upcoming medical meeting. In response to PRA023’s performance, Prometheus stocks surged more than 190%. In an investor call held Wednesday morning, Mark McKenna, chairman and CEO of Prometheus, said that the company will “take the next several months to refine our registrational plans” and collect feedback for regulatory applications for PRA023. “Given these impressive results at hand, we expect to have a number of attractive options to finance our registrational studies” for PRA023, he added. The data will also empower Prometheus to explore other indications for the candidate and continue to advance its precision-guided approach to inflammatory bowel diseases. “We believe these data clearly validate the Prometheus platform and our pipeline and sets us up for future leadership” in this therapeutic space, McKenna said. ARTEMIS-UC was a double-blinded and placebo-controlled trial that enrolled patients with moderately-to-severely active ulcerative colitis who had failed a previous line of therapy. 26.5% of patients treated with PRA023 met the primary efficacy endpoint of clinical remission, as per the Mayo score, as opposed to only 1.5% of the placebo group. Prometheus’ candidate also induced statistically higher rates of endoscopic improvement, the study’s secondary endpoint, with a placebo-adjusted rate of 30.8% in favor of PRA023. In APOLLO-CD, 55 patients with moderately-to-severely active Crohn’s disease were enrolled, all of whom had previously failed biologic or conventional therapies. Treatment with PRA023 led to an endoscopic response in 26.0% of patients, statistically better than a historical placebo rate of 12%. Clinical remission was also significantly higher than PRA023, at 49.1%, as opposed to 16% in prespecified historical controls. Aside from clinical metrics, Crohn’s disease patients treated with PRA023 saw a sharp reduction in biomarkers of inflammation and expression of disease-related genes. In both APOLLO-CD and ARTEMIS-UC, PRA023 showed a favorable tolerability profile, inducing no treatment-emergent serious adverse events or toxicities leading to treatment discontinuations. Bringing a Precision Approach to Inflammatory Bowel Diseases With PRA023, Prometheus seeks to bring a precision treatment approach, most commonly applied in oncology indications, to immune-mediated and inflammatory diseases. The candidate is an IgG1 humanized monoclonal antibody that blocks the action of the tumor necrosis factor-like ligand 1A. This target is a biomarker commonly associated with intestinal inflammation and fibrosis. To go with PRA023, the company is also developing companion diagnostic products to identify patients most likely to respond to treatment. These diagnostic algorithms likewise performed well in both APOLLO-CD and ARTEMIS-UC. Prometheus will also advance these companion diagnostics into registrational studies. Aside from Crohn’s disease and ulcerative colitis, PRA023 is also being assessed for systemic sclerosis-associated interstitial lung disease.