IL-13

The FDA's approval for resmetirom sets the bar for many other candidates, including drugs leveraging the GLP-1 mechanism. The decades-long wait for an effective treatment for metabolic dysfunction-associated steatohepatitis (MASH) has ended, as the FDA has approved the first drug for the fatty liver disease. After a long and winding drug development path for the common disease, Madrigal Pharmaceuticals’ resmetirom, to be sold under the brand name Rezdiffra, has become the first MASH therapy to clear the FDA finish line. Thursday, the FDA approved the tablet drug for the treatment of MASH, also known as nonalcoholic steatohepatitis (NASH), with moderate or severe liver scarring, or fibrosis, consistent with stage F2 and F3 disease, according to a product label (PDF) posted on the FDA’s website. Rezdiffra emerged successful from a notorious drug development graveyard about four decades after the term NASH was first coined by researchers at Mayo Clinic. Its approval sets the bar for many other companies that are also eying the field, which is estimated to affect about 5% of adults in the U.S. “Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.” Madrigal is pricing Rezdiffra at the wholesale acquisition cost of $47,400 before any discounts. Previously, the influential cost watchdogs at the Institute for Clinical and Economic Review figured the drug would be cost-effective under common thresholds if its net price falls between $39,600 and $50,100 per year. In a major win for Madrigal, the FDA isn’t requiring a liver biopsy to determine a patient’s eligibility for Rezdiffra. Before the approval, a potential biopsy requirement served as a key point of debate among investors because the cumbersome and invasive procedure would have limited access to Rezdiffra.   A clinical feat Rezdiffra was the first drug to have met both goals of MASH resolution and fibrosis improvement in a phase 3 trial. Prior to Rezdiffra’s breakthrough, Intercept’s Ocaliva looked closest to being that first drug for MASH until the FDA struck it down for a second time in June 2023. The vast sea of MASH drug development had previously also sunk ships from the likes of Pfizer, Bristol Myers Squibb, Genfit, NGM Biopharmaceuticals and others. The current approval was based on an analysis of about 900 patients with biopsy-confirmed MASH and liver fibrosis who enrolled in the MAESTRO-NASH trial. In the study, Rezdiffra, given at either 80mg or 100mg once daily, cleared MASH with no worsening of fibrosis in 25.9% and 29.9% of patients, respectively, versus 9.7% for those who received placebo, according to data published in the New England Journal of Medicine. In addition, 24.2% and 25.9% of patients on the two Rezdiffra doses enjoyed fibrosis improvement of at least one stage, with no worsening on a fatty liver disease activity score. The rates were significantly more than the 14.2% seen in the placebo group. In the FDA’s approved label, Rezdiffra’s efficacy for each endpoint was presented by ruling from two pathologists. For improvement in liver fibrosis and no worsening of steatohepatitis, pathologist A found a 13% placebo-adjusted difference for Rezdiffra at 100mg, and the rate was 11% for pathologist B. Under the FDA approval, patients will get different dosages of Rezdiffra based on their body weight. For those weighing less than 100kg (220lbs.), the recommended dosage is 80mg. The other patients are supposed to take the 100 mg strength. Madrigal also provided additional safety data from the MAESTRO-NAFLD-1 trial, which the company believes resembles a real-world situation in which patients’ diagnoses are not confirmed by biopsies but instead noninvasive measures. There, the drug was found to be well tolerated, and offered significant improvements on some biomarkers such as liver fat and triglycerides. Physicians typically feel comfortable diagnosing MASH with noninvasive tools such as the FibroScan and therefore don’t routinely perform biopsies, Madrigal CEO Bill Sibold said in an interview with Fierce Pharma ahead of the approval. Plus, the biopsy procedure isn’t perfect for MASH because it only takes a thin slice of the liver, and it also comes with safety risks. With that considered, Madrigal wasn’t expecting a biopsy requirement from the FDA, or pushback from payers in reimbursement discussions, Sibold said. Based on a sans-biopsy-requirement label, analysts at Evercore ISI recently estimated that Rezdiffra could reach about $2.6 billion in global sales in 2030 and $5.5 billion at peak. That’s based on Madrigal’s estimate that about 315,000 U.S. patients who have MASH with significant fibrosis at stage 2 or 3 (F2 and F3) are currently being treated by specialists. Those F2 and F3 patients—plus about 5,000 to 7,000 high-volume, top-tier hepatologists and gastroenterologists—will be Madrigal’s key focus for the launch of Rezdiffra, Sibold said.    A specialty launch Sibold joined Madrigal in September after spending 12 years at Sanofi, most recently as executive vice president of specialty care and president of the French pharma’s North America business.  Sibold compared Rezdiffra to Dupixent, the blockbuster inflammatory disease drug that he managed, which delivered Sanofi 10.7 billion euros ($11.7 billion) in revenue last year. In Dupixent’s case, the dual inhibitor of IL-4/13 was the first biologic medicine approved for atopic dermatitis. Now, Rezdiffra is the first drug for MASH, another major market opportunity with significant unmet need. “Since there hasn’t been [a drug], we really get to shape the market and shape how you engage with the various stakeholders, and I love doing that,” Sibold said. Because Rezdiffra is the first MASH drug to hit the market, Madrigal has a lot of prep work to do. In a Feb. 29 note to clients, Evercore’s analysts said they expect to see a meaningful sales acceleration in the second year of the launch, after an initial phase for establishing infrastructure. “Just remember, there’s never, in the history of the country, a script been written for NASH,” Sibold said. “So there’s this notion of creating a pathway for patients to get through that.” In one important consideration, doctors will need to figure out how to process their existing patients. Initially, Madrigal will focus on educating doctors on both the disease and its medicine. The company will also work to have reimbursement policies in place and help practices navigate the prescription steps. “That is not a barrier to the ultimate success of the product, but it’s just a prerequisite for getting to that […] more established pathway,” Sibold said. By the CEO's estimate, it will take about 12 months before Madrigal can finish establishing the commercial foundation for Rezdiffra to ensure a “real rapid uptake," he said.   Prospect competitors behind the pioneer While Rezdiffra enjoys its first-mover advantage, other therapies have turned up promising preliminary clinical data in the hope of snatching meaningful market share. An estimated 100 million patients are projected to live with NASH in the U.S., France, Germany, Italy, Spain, the U.K., China and Japan by 2030. But researchers remain uncertain about how the disease’s prevalence will translate into a market for therapeutics, leading to wide variations in market size estimates, ranging from above $10 billion to more than $100 billion by 2030, according to a recent white paper from analytics firm IQVIA. Viking Therapeutics has VK2809, which, like Rezdiffra, is an oral thyroid receptor-beta agonist. In a midstage study, the drug led to an average relative change in liver fat of 51.7% after 12 weeks of treatment. The company has yet to report 52-week data on histologic response.  Meanwhile, both 89bio’s pegozafermin and Akero Therapeutics’ efruxifermin are FGF21 analogs given subcutaneously. Both have shown promising anti-fibrosis results in patients with F2 and F3 MASH, and phase 3 trials are either already underway or about to start.  Just before Rezdiffra’s approval, Ionis on Wednesday said a high dose of its antisense candidate ION224 helped 32% patients achieve a one-stage improvement in liver fibrosis without worsening steatohepatitis at week 51 in a phase 2 trial, compared to just 12.5% who received placebo. And then there’s the GLP-1 agonist class. Lilly in February reported positive phase 2 MASH data for its GIP/GLP-1 dual agonist tirzepatide in overweight or obese people, although the study wasn’t statistically powered to measure improvement in fibrosis. That drug is already approved in diabetes as Mounjaro and obesity as Zepbound. A few days ago, Boehringer Ingelheim touted what it called the best-in-class potential of its Zealand Pharma-partnered glucagon/GLP-1 agonist survodutide for MASH based on a phase 2 win. Detailed trial findings on the drug's statistically significant improvement in fibrosis remain under wraps.   RELATED: Prospective NASH market flips to overcrowded as Big Pharma GLP-1s cast shadow over biotech breakthroughs Sibold touted Rezdiffra’s advantage as a liver-directed medicine versus the more systemic approach with the GLP-1s, especially in patients with significant fibrosis. Madrigal plans to use its lead to establish deep roots in the community “in a way that will make it difficult for others to follow,” Sibold said. Eventually, Sibold expects Rezdiffra to be a foundational therapy which others will want to utilize in combinations rather than replace. While the company recognizes that combination treatments will be the future, it is right now focused on completing Rezdiffra’s existing trials, he said. As part of the accelerated approval, Madrigal has agreed to provide further evidence to confirm Rezdiffra’s benefits. That plan includes running the ongoing 54-month extension of MAESTRO-NASH that will measure disease progression and other outcomes such as liver transplants and development of cirrhosis. In addition, another study called MAESTRO-NASH Outcomes is evaluating Rezdiffra in patients with well-compensated NASH cirrhosis, which is a more advanced stage of the disease. If positive, the study could support the full approval of Rezdiffra and expand its patient base. Sibold said it’s hard to predict an exact timeline for a readout because the trial is event-driven, but he put it as a 2026 or 2027 event. While the long-term follow-up of MAESTRO-NASH lasts for 54 months, Sibold said Rezdiffra is expected to be a chronic treatment that patients continue to take until signs of the patient’s disease are gone and all the contributing factors such as obesity are removed. Editor's Note: The story has been updated with Rezdiffra's price.

Pictured: Woman scratching psoriatic lesions on her elbow/iStock, helivideo Alumis on Saturday posted promising data from the Phase II STRIDE study demonstrating that its investigational TYK2 inhibitor ESK-001 can significantly reduce the severity of lesions in patients with moderate-to severe plaque psoriasis. The results, presented during a late-breaking session at the annual meeting of the American Academy of Dermatology, showed that all dose levels and schedules of ESK-001 resulted in a significantly higher proportion of patients achieving a 75% improvement on the Psoriasis Area and Severity Score (PASI), which is a widely used tool to evaluate the severity of psoriasis. At week 12, 64.1% of patients treated with a 40-mg, twice-daily regimen achieved the endpoint, also known as PASI-75. Meanwhile, 56.4% of those assigned to the 20-mg, twice-daily and 40-mg, once-daily schedules met the same outcome. These data were all significantly higher than in the placebo group, in which no participant achieved PASI-75. Even the lowest dosing regimen of 10-mg, once-daily ESK-001 elicited a significantly higher rate of PASI-75 than placebo. Alumis CMO Jörn Drappa in a statement said that these data “support the potential for a best-in-class pro ESK-001 in psoriasis,” pointing to patients who demonstrated a “high degree of clinical improvement at week 12 that continued to increase over time.” The biotech is now preparing to take ESK-001 into Phase III trials, with an eye toward launching the drug as an oral therapy with a better efficacy pro current treatments on the market, Alumis CEO Martin Babler said in a statement. The company will also advance the candidate in other immune-mediated indications. ESK-001 is a highly selective allosteric inhibitor of the TYK2 protein. The oral drug candidate works by dampening signaling through the IL-12, IL-13 and interferon-α receptors, tempering the body’s immune and inflammatory responses. In STRIDE, this mechanism of action also helped ESK-001 meet key secondary endpoints. At the highest dosing schedule—40-mg twice-daily—38.5% of treated participants achieved PASI-90, while 15.4% reached PASI-100, indicating a 100% improvement in PASI scores. In terms of safety, ESK-001 was overall well-tolerated, inducing no treatment-related serious adverse events. Study dropouts due to side effects were low and the study did not find signs of toxicities associated with JAK inhibition. STRIDE’s open-label extension phase, which followed patients up to 16 weeks, likewise showed that PASI endpoint responses increased even further and that ESK-001 continued to be well-tolerated. Saturday’s readout comes days after Alumis closed its $259 million Series C funding round to help bring ESK-001 into late-stage development. The candidate will help it compete with Bristol Myers Squibb, which owns the TYK2 inhibitor Sotyktu that won the FDA’s approval in September 2022 for the treatment of moderate-to-sever plaque psoriasis. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

TREK-DX, the first randomized, double-blind, placebo-controlled study to be conducted in a dupilumab-experienced atopic dermatitis (AD) patient population, has started enrolling patients in the US under an updated protocol; new European sites are on track to open in the first half of 2024 In a preliminary review of blinded data from 22 patients treated to date, 45% (10/22) of patients saw at least a 90% reduction in their EASI score (EASI-90) and 50% (11/22) of patients achieved a vIGA score of 0 or 1 (clear or almost clear skin) after 16 weeks. Topline unblinded data from the full dataset is expected at the end of 2024 Translational data demonstrates differentiated effects of targeting IL-13R versus IL-4R, suggesting eblasakimab has the potential to be effective in AD patients that do not achieve an adequate response to dupilumab, a significant and underserved patient population with few safe and long-term treatment options SAN MATEO, Calif. and SINGAPORE, March 11, 2024 (GLOBE NEWSWIRE) -- ASLAN Pharmaceuticals Ltd. (Nasdaq: ASLN), a clinical-stage, immunology focused biopharmaceutical company developing innovative treatments to transform the lives of patients, today announced that it has begun to enroll patients in the US under an updated protocol in the ongoing TREK-DX trial, studying eblasakimab in dupilumab-experienced patients with moderate-to-severe atopic dermatitis (AD). TREK-DX is the first randomized, double-blind, placebo-controlled trial to be conducted in AD patients who have been previously treated with dupilumab, a market estimated to reach $10 billion by 20291. Based on findings from the TREK-AD study which highlighted the changing AD patient population in the US, the TREK-DX inclusion criteria have been tightened to enroll patients with a baseline Eczema Area and Severity Index (EASI) score of at least 18, instead of 16. In conjunction with this, independent reviewer confirmation of baseline EASI scores has also been implemented. US sites are now enrolling patients according to the updated criteria and additional sites in Europe are on track to open in the first half of 2024. TREK-DX will enroll approximately 75 patients who have discontinued dupilumab treatment for any reason, including inadequate control of AD, loss of access or an adverse event, and treat them with either 400mg eblasakimab or placebo once weekly for 16 weeks. At the time of the data cut off for this preliminary review of blinded data from 22 patients enrolled under the original inclusion criteria, who were randomized 2:1 active to placebo, 17 patients completed the 16 week treatment period and 5 patients discontinued before the completion of the 16 week treatment period. At 16 weeks or the last visit, EASI score decreased at least 90% (EASI-90) in 10 patients, or 45%, and 11 patients, or 50%, achieved a validated Investigator Global Assessment (vIGA) score of 0 or 1 (clear or almost clear skin). Of the 9 patients who previously had an inadequate response to dupilumab, 5 patients (56%) achieved EASI-90 and 5 patients (56%) a vIGA score of 0 or 1. Treatments have been well-tolerated to date and no new safety signals were identified. There have been no reports of conjunctivitis and no reports of injection site reactions. Topline unblinded data from the full dataset is expected at the end of 2024. “63% of dupilumab-treated patients fail to achieve clear or almost clear skin (IGA score of 0 or 1) after 16 weeks2, and around half of those patients that do achieve this response do not maintain it after the subsequent 36 weeks3, so there is a significant need for additional biologic therapies that could provide a safe and efficacious long-term treatment option for patients that do not achieve an adequate response to dupilumab. EASI-90 and vIGA are among the most stringent of endpoints in AD studies. Although this is based on a preliminary review of the blinded data, we are encouraged to observe a high percentage of patients in the TREK-DX study meeting these endpoints to date. Our market research found that most AD patients are only moderately satisfied with their current treatment. This, together with the translational data we have generated, supports the potential role of eblasakimab as a treatment for these patients, and the data we are generating in the TREK-DX study could demonstrate that, for many patients, eblasakimab could control their disease even where dupilumab has not,” saidDr Carl Firth, Chief Executive Officer, ASLAN Pharmaceuticals. Translational data demonstrates differentiated effects of targeting IL-13R versus IL-4R, suggesting eblasakimab has the potential to be effective even in instances where dupilumab is not Eblasakimab targets the IL-13 receptor (IL-13R) subunit of the Type 2 receptor, preventing signaling through both interleukin 4 (IL-4) and interleukin 13 (IL-13). Both are key drivers of inflammation in AD, however, recently published translational data highlighted the advantages of targeting IL-13R by eblasakimab over the IL-4 receptor (IL-4R), the target of dupilumab, in AD patient peripheral blood mononuclear cells4. IL-13R blockade resulted in more efficient reduction of cytokines implicated in Type 2-driven (allergic) inflammation compared to IL-4R blockade, as well as lower levels of Type 1 pro-inflammatory cytokines. Additional data from head-to-head studies between eblasakimab and dupilumab in skin biopsies from AD patients confirmed the differentiated effects of targeting IL-13R versus IL-4R5. In this study, eblasakimab reduced localized secretion of pro-inflammatory Type 2 cytokines by the skin tissue more efficiently than dupilumab, suggesting eblasakimab could have the potential to be effective in AD patients that do not achieve an adequate response to dupilumab. References Decision Resources Group (2023) Atopic Dermatitis Disease Landscape and Forecast Report Thaci et al (2019) J Dermatol Sci 94(2):266-275 Worm et al (2020) JAMA Derm 156(2):131-143 Cevikbas et al (2023) 1st International Society of Investigative Dermatology Meeting, May 10-14, 2023 Cevikbas et al (2023) 7th Annual Dermatology Drug Development Summit, October 31-November 2, 2023 About TREK-DX TREK-DX trial is a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of eblasakimab in patients with moderate-to-severe AD previously treated with dupilumab. The trial will enroll approximately 75 patients who have discontinued dupilumab treatment for any reason, including inadequate control of AD, loss of access or an adverse event. The trial consists of a 16-week treatment period and an 8-week safety follow-up period. The primary efficacy endpoint is percentage change in Eczema Area Severity Index (EASI) score from baseline to week 16. Key secondary efficacy endpoints include the proportion of patients achieving validated Investigator Global Assessment (vIGA) score of 0 (clear) or 1 (almost clear), proportion of patients with a 75% or greater reduction in EASI (EASI-75), proportion of patients achieving EASI-50 and EASI-90, and changes in peak pruritus. About eblasakimab Eblasakimab is a potential first-in-class monoclonal antibody targeting the IL-13 receptor subunit of the Type 2 receptor, a key pathway driving several allergic inflammatory diseases. Eblasakimab’s unique mechanism of action enables specific blockade of the Type 2 receptor and has the potential to improve upon current biologics used to treat allergic disease. By blocking the Type 2 receptor, eblasakimab prevents signaling through both interleukin 4 (IL-4) and interleukin 13 (IL-13) – the key drivers of inflammation in AD and Type 2 driven COPD. Positive results from the Phase 2b TREK-AD study in moderate-to-severe AD support eblasakimab’s potential to deliver a monthly dosing regimen from initiation in AD without compromising on efficacy and with an encouraging safety pro to date, with preparations for Phase 3 underway. ASLAN is also investigating eblasakimab in dupilumab experienced, moderate-to-severe AD patients in the Phase 2 TREK-DX study. About ASLAN Pharmaceuticals ASLAN Pharmaceuticals (Nasdaq: ASLN) is a clinical-stage, immunology-focused biopharmaceutical company developing innovative treatments to transform the lives of patients. ASLAN is developing eblasakimab, a potential first-in-class antibody targeting the IL-13 receptor in moderate-to-severe atopic dermatitis (AD) with the potential to improve upon current biologics used to treat allergic disease, and has reported positive topline data from a Phase 2b, dose-ranging study in moderate-to-severe AD patients. ASLAN is also investigating eblasakimab in dupilumab experienced, moderate-to-severe AD patients in the Phase 2 TREK-DX study with a topline data readout expected at the end of 2024. Farudodstat, a potent oral inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH), is being developed by ASLAN as a potential first-in-class treatment for alopecia areata (AA) in a Phase 2a, proof-of-concept trial with an interim readout expected in mid-2024. ASLAN has teams in San Mateo, California, and in Singapore. For additional information please visit ASLAN’s website or follow ASLAN on LinkedIn. Forward-looking statements This release contains forward-looking statements. These statements are based on the current beliefs and expectations of the management of ASLAN Pharmaceuticals Limited and/or its affiliates (the "Company"). These forward-looking statements may include, but are not limited to statements regarding the Company’s business strategy and clinical development plans; the Company’s plans to develop and commercialize eblasakimab; statements related to the safety and efficacy of eblasakimab, including preliminary blinded data; the Company’s plans and expected timing with respect to manufacturing activities, clinical trials, clinical trial enrolment and clinical trial results for eblasakimab; and the potential of eblasakimab as a first-in-class treatment for atopic dermatitis. The Company’s estimates, projections and other forward-looking statements are based on management's current assumptions and expectations of future events and trends, which affect or may affect the Company’s business, strategy, operations, or financial performance, and inherently involve significant known and unknown risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of many risks and uncertainties, which include, unexpected safety or efficacy data observed during preclinical or clinical studies; risks that future clinical trial results may not be consistent with interim, initial or preliminary results or results from prior preclinical studies or clinical trials; risks that trends or characteristics based on preliminary blinded data may not be consistent with unblinded data; clinical site activation rates or clinical trial enrolment rates that are lower than expected; the impact of geopolitical conflicts and bank failures on the Company’s business and the global economy; general market conditions; changes in the competitive landscape; and the Company’s ability to obtain sufficient financing to fund its strategic and clinical development plans. Other factors that may cause actual results to differ from those expressed or implied in such forward-looking statements are described in the Company’s US Securities and Exchange Commission filings and reports (Commission File No. 001- 38475), including the Company’s Annual Report on Form 20-F filed with the US Securities and Exchange Commission on March 24, 2023. All statements other than statements of historical fact are forward-looking statements. The words “believe,” “may,” “might,” “could,” “will,” “aim,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” “plan,” or the negative of those terms, and similar expressions that convey uncertainty of future events or outcomes are intended to identify estimates, projections, and other forward-looking statements. Estimates, projections, and other forward-looking statements speak only as of the date they were made, and, except to the extent required by law, the Company undertakes no obligation to update or review any estimate, projection, or forward-looking statement. ASLAN Media and IR contacts Emma Thompson Spurwing Communications Tel: +65 6206 7350 Email: ASLAN@spurwingcomms.com Ashley R. Robinson LifeSci Advisors, LLC Tel: +1 (617) 430-7577 Email: arr@lifesciadvisors.com